StemCell Therapy

Yang Guo,1 4 Bobin Ning,5 Qunhui Zhang,1 4 Jing Ma,4 Linlin Zhao,1 4 QiQin Lu,1 4 Dejun Zhang1,4

1Research Center for High Altitude Medicine, Medical College of Qinghai University, Xining, 810001, Peoples Republic of China; 2Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province, Medical College of Qinghai University, Xining, 810001, Peoples Republic of China; 3Qinghai-Utah Joint Research Key Lab for High Altitude Medicine, Medical College of Qinghai University, Xining, 810001, Peoples Republic of China; 4Department of Eco-Environmental Engineering, Qinghai University, Xining, 810016, Peoples Republic of China; 5Department of Medicine, The General Hospital of the Peoples Liberation Army, Beijing, 100038, Peoples Republic of China

Correspondence: Dejun ZhangDepartment of Eco-Environmental Engineering, Qinghai University, Qinghai, 810016, Peoples Republic of ChinaEmail [emailprotected]

Purpose: The objective of this study was to identify the potential regulatory mechanisms, diagnostic biomarkers, and therapeutic drugs for heart failure (HF).Methods: Differentially expressed genes (DEGs) between HF and non-failing donors were screened from the GSE57345, GSE5406, and GSE3586 datasets. Database for Annotation Visualization and Integrated Discovery and Metascape were used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses respectively. The GSE57345 dataset was used for weighted gene co-expression network analysis (WGCNA). The intersecting hub genes from the DEGs and WGCNA were identified and verified with the GSE5406 and GSE3586 datasets. The diagnostic value of the hub genes was calculated through receiver operating characteristic analysis and net reclassification index (NRI). Gene set enrichment analysis (GSEA) was used to filter out the signaling pathways associated with the hub genes. SYBYL 2.1 was used for molecular docking of hub targets and potential HF drugs obtained from the connection map.Results: Functional annotation of the DEGs showed enrichment of negative regulation of angiogenesis, endoplasmic reticulum stress response, and heart development. PTN, LUM, ISLR, and ASPN were identified as the hub genes of HF. GSEA showed that the key genes were related to the transforming growth factor- (TGF-) and Wnt signaling pathways. Sirolimus, LY-294002, and wortmannin have been confirmed as potential drugs for HF.Conclusion: We identified new hub genes and candidate therapeutic drugs for HF, which are potential diagnostic, therapeutic and prognostic targets and warrant further investigation.

Keywords: differentially expressed genes, weighted gene co-expression network analysis, diagnostic biomarkers, therapeutic drugs, heart failure

HF is a clinical syndrome characterized by congestion of the lungs and vena cava, leading to abnormal heart structure or function, which is the final stage of the development of heart disease.1 Approximately 40 million people worldwide suffer from HF, and the incidence rates are steadily rising.2 Despite significant progress in the HF management in recent decades, the treatment options are mainly palliative rather than curative.3 Given the complex pathogenesis of HF, it is essential to elucidate the underlying molecular mechanisms in order to identify potential therapeutic targets and prognostic markers.

Bioinformatics is a high-throughput technique that can screen multiple databases to identify the potential pathological biomarkers of various diseases.4 Weighted gene co-expression network analysis (WGCNA) is a systems biology application that mines the genetic interaction networks to construct highly coordinated gene modules.4 WGCNA has been widely used for detecting disease biomarkers, and elucidating biological mechanisms and drug interactions.57 Although biomarkers of HF have been identified, but due to heterogeneity of HF and its complicated pathophysiological manifestations, a single gene cannot accurately predict the characteristics of HF.8,9

In this study, the differentially expressed genes (DEGs) between HF patients and non-failing donors (NFD) were screened from multiple GEO datasets and functionally annotated. The hub genes were then screened through the degree of connectivity in the PPI network, and used to build a co-expression network with WGCNA. The intersecting hub genes between DEGs and WGCNA were identified and validated in other human HF datasets. Gene set enrichment analysis (GSEA) was used to discover the signaling pathways associated with these hub genes. Finally, the potential HF drugs were predicted through the Connectivity Map (cMap) database, and molecular docking between the drug candidates and hub genes was simulated using SYBYL 2.1 software.

We conducted a bioinformatics analysis using DEGS and WGCNA to further investigate the occurrence and development of HF and identify potential therapeutic drugs for biomarkers of HF.

The study design is outlined in Figure 1. We searched the GEO database and included data on human heart tissue samples in this study. The mRNA expression profiles from HF and NFD samples were downloaded from the GSE57345, GSE5406 and GSE3586 datasets of the GEO database (http://www.ncbi.nlm.nih.gov/geo/). The subjects included in our study suffered from heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Among them were 96 patients with ischemic heart disease, 84 patients with dilated cardiomyopathy (CMP), and 139 non-heart failure samples from GSE57345.10 The GSE5406 dataset included 16 samples without heart failure, 86 patients with dilated cardiomyopathy (CMP), and 108 patients with ischemic heart disease.11 The GSE3586 dataset included 13 patients with dilated cardiomyopathy and 15 patients without heart failure.12 The gene annotation files of GSE57345, GSE5406 and GSE3586 were GPL11532, GPL96, and GPL3050 respectively. GEO2R online tool was used for screening DEGs between HF and NFD with p < 0.05 (calculated by t-test) as the threshold.

The overlapping DEGs were uploaded to the Database for Annotation, Visualization, and Integrated Discovery (DAVID, https://david.ncifcrf.gov/) and Metascape (http://metascape.org/) databases for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses respectively. P<0.05 was considered statistically significant.

The protein-protein interaction (PPI) network was constructed using the STRING database, and visualized with the Cytoscape software (3.7.2). DEGs with connectivity 5 in the PPI network were considered to be the hub genes.

The R package WGCNA was used to construct the weight co-expression network of the GSE57345 dataset. The GSE57345 dataset was used in the WGCNA analysis because it contained the largest sample size. The weighing coefficient was first calculated based on R2> 0.9 of the scale-free real biological network. After determining the adjacency function parameter , a hierarchical clustering tree of different gene modules was constructed. The Pearson correlation coefficient was then used to transform the correlation matrix into an adjacency matrix and subsequently to a topological overlap matrix (TOM).

The correlation among the genes in the aforementioned modules was analyzed and a heatmap was constructed. The module most closely related to the HF state was considered the key module of HF. To verify specific modulus-character associations, the correlation between GS and MM was investigated. Genes with |MM| > 0.8 were subsequently screened out as hub genes in the key module. The intersecting hub genes between the key module and the DEGs were finally defined as the hub genes of HF.

We used the GSE57345, GSE5406, and GSE3586 datasets to confirm the identity of the hub genes that may be associated with HF. Then, we used the t-test to determine the significance of the correlation between the expression of hub genes and HF. Receiver operating characteristic (ROC) curves were drawn for the core genes in the three datasets, and the area under the curve (AUC) was calculated. Specificity, sensitivity, and net reclassification index (NRI) were calculated to evaluate the value of the genetic diagnosis.

GSEA was performed to clarify the biological functions of the hub genes using the KEGG gene set (c2.cp. kegg. v7.2.) as the default and p < 0.05, as the threshold. The HF samples of the GSE57345 data set were divided into high and low expression groups of each hub gene. The enrichment graph was plotted using the clusterProfiler package of the R language and GSEA function.

The CMap database includes 1309 compounds and expression data of > 7000 human genes. The DEGs intersecting GSE57345, GSE5406, and GSE3585 datasets were uploaded to CMap. The negatively correlated small molecules were screened out using p < 0.0001 and mean < 0.4 as the criteria. ChemBioDrawUltta 17.0 software (http://www.chemdraw.com.cn) was used to draw the 3D structural formulas of potential therapeutic drugs and save them in mol2 format as small molecule compounds. The 3D crystal structures of the core targets were downloaded from the UniProt database (https://www.uniprot.org/). The Surflex-Dock module of SYBYL2.1 software was used for molecular docking, with total score >4 as the threshold for binding ability. The docking results were visualized using the Pymol software.

A total of 583 DEGs were identified between the HF and NFD samples across three GEO datasets (Figure 2AD). The most significantly enriched GO terms pertaining to biological process (BP) were negative regulation of angiogenesis (p = 1.55E-04), response to endoplasmic reticulum stress (p = 6.63E-04), heart development (p = 0.002463), regulation of ventricular cardiac muscle cell action potential (p = 0.004523), MAPK cascade (p = 0.005025), and blood vessel development (p =0.007107) (Figure 3A and Table S1). The cellular components (CC) terms including extracellular exosome (p =2.72E-08), cytoplasm (p =9.57E-06), actin cytoskeleton p (p =4.94E-05), mitochondrion (p =8.84E-05), nucleoplasm (p =1.03E-04), Golgi apparatus (p =1.21E-04) and lysosome (p =6.84E-04) were significantly enriched (Figure 3B and Table S1). The top enriched molecular function (MF) terms were activating transcription factor binding (p = 0.003852), actin filament binding (p =0.006599), cadherin binding involved in cell-cell adhesion (p = 0.00701), transcription coactivator activity (p =0.018332) and collagen binding (p =0.034108) (Figure 3C and Table S1). In addition, KEGG analysis revealed that the Ras signaling pathway (p =5.15548E-07), Focal adhesion (p =1.11814E-05), Lysosome (p = 2.43906E-05), MAPK signaling pathway (p = 4.23641E-05), PI3K-Akt signaling (p = 4.85396E-05), Protein processing in endoplasmic reticulum (p = 5.21303E-05) and Hippo signaling pathway (p =7.03525E-05) were significantly enriched among the DEGs (Figure 3D and Table S1).

Figure 2 The DEGs between HF and NFD. The volcano plots of DEGs in (A) GSE57345, (B) GSE5406 and (C) GSE3586. (D) Venn diagrams of DEGs in three data sets.

Figure 3 GO and KEGG pathway enrichment analysis. Significantly enriched GO terms for (A) Biological processes, (B) Cellular component, (C) Molecular function. (D) KEGG pathway Molecular function p < 0.05 is considered statistically significant.

A total of 1589 genes were screened from the GSE57345 dataset for WGCNA (p < 0.05, |Log2FoldChange| > 0.5). Sample clustering showed no significant differences in the WGCNA (Figure 4A). At = 4, the scale-free network fitting index R2 was 0.9, and the average connectivity approached 0, indicating that this value could obtain a scale-free network that met all requirements. Thus, = 4 was selected to construct a scale-free network (Figure 4BC). A dynamic shearing algorithm was used to cluster the genes and module divisions.

Figure 4 Determination of soft-threshold power . (A) Clustering dendrogram of 319 samples. (B) Scale-free topology fit index as a function of the soft-threshold power. The red line indicates that R2 is equal to 0.9. (C) Mean connectivity as a function of the soft-threshold power.

Five gene co-expression modules were finally obtained by calculating the module feature vector of each and merging similar modules (Figure 5A). The genes were clustered in the black, blue, yellow and green-yellow modules, and those that could not be clustered into any module were specified to the gray module. The yellow module with 73 genes showed the strongest correlation with HF (r = 0.77, p = 1e-61) (Figure 5B), as well as with the clinical phenotype as per GS and MM analyses (cor = 0.96, p = 5.5e-41; Figure 5CG). The genes distributed in the upper right corner were closely related to HF pathogenesis, and are likely the key disease genes. Twenty-one genes in the yellow module were confirmed as hub genes.

Figure 5 Identification of key HF gene modules. (A) Clustering dendrograms of genes and module detecting. (B) Heat map of the correlation between HF modules. (CG) Correlation of GS and MM in the HF-related module. p < 0.05 is considered statistically significant.

From the 583 overlapping DEGs, 322 hub genes were selected for subsequent analysis (Figure 6A). The key intersecting genes between the 322 hub DEGs and 21 hub genes of the yellow module included PTN, LUM, ISLR and ASPN. The expression levels of these potentially key genes were analyzed in the HF and NFD samples of the GSE57345, GSE5406 and GSE3586 datasets. We further visualized their expression levels in the GSE57345 data set, and found that all four genes were overexpressed in HF samples compared to the NFD group (p < 0.05, Figure 6B). Afterwards, the genes were verified in GSE5406 and GSE3586, which verified higher expression levels in the HF group (p < 0.05, Figure 6C and D).

Figure 6 Analysis of key genes. (A) The Venn diagram of hub genes in the yellow module and hub genes in DEGs. Expression of PTN, LUM, ISLR and ASPN in the (B) GSE57345, (C) GSE5406 and (D) GSE3586 datasets. **p < 0.01 and ***p < 0.001 are considered statistically significant.

The potential diagnostic value of PTN, LUM, ISLR and ASPN was ascertained by plotting the ROC curve based on the expression data in GSE57345, GSE5406 and GSE3586. As shown in Figure 7AC, the AUC of all genes in all datasets exceeded 0.9, except for 0.785 calculated for ISLR in GSE3586. We uploaded AUC and Standard Error data into MedCalc software, and applied the Z test to compare the expression of PTN, LUM, ISLR and APSN between the datasets. The results showed that there was no statistical difference (p >0.05). We used the NRI to analyze differences in the expression levels of the four predicted HF hub genes in the GSE57345, GSE5406 and GSE3586 datasets. The PTN and ISLR of the GSE5406 dataset showed significant differences in predicting HF (NRI [95% CI]: 0.3228 [0.03610.6095], p: 0.027); the prediction effects of the PTN and ISLR genes were significantly different, NRI [95% CI]: 0.3905 [0.00730.7736], p: 0.045). The prediction effects of ISLR and LUM gene in the GSE5406 dataset were significantly different (NRI [95% CI]: 0.5077 [0.93610.0793], p: 0.020). Subsequently, ROC analysis was performed to determine the diagnostic value of the four key genes, and the results suggested that these four hub genes can diagnose HF with high sensitivity and specificity (Table 1).

Table 1 ROC Curve Analysis of Hub Genes

Figure 7 The ROC curve of hub genes (A) GSE57345. (B) GSE5406. (C) GSE3586. The x-axis shows specificity, and the y-axis shows sensitivity.

Abbreviations: ROC, receiver operating characteristic; AUC: area under the ROC curve.

GSEA of PTN, LUM, ISLR and ASPN revealed direct involvement in the pathogenesis of HF. As shown in Figure 8AD, all genes were enriched in arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy, ecm receptor interaction, focal adhesion, gap junction, hypertrophic cardiomyopathy (HCM), regulation of actin cytoskeleton and TGF- signaling pathway. In addition, PTN, LUM and ASPN were enriched in the WNT signal pathway, LUM in the calcium signaling pathway, and ASPN is likely involved in seleno-amino acid metabolism.

Figure 8 Results of GSEA. (A) PTN. (B) LUM. (C) ISLR. (D) ASPN.

There were 264 upregulated and 499 down-regulated genes intersecting across the three datasets. The genes were uploaded to the cMap database to filter out negatively related small molecule compounds (p < 0.0001 and mean < 0.4). Sirolimus, LY-294002, and wortmannin were identified as potential drugs of HF (Figure 9AC). Molecular docking showed that sirolimus had good affinity for PTN, ISLR, LUM, and ASPN, and wortmannin for PTN and LUM (Figure 9D). The molecular docking diagrams of potential compounds and hub targets are shown in Figure 9EJ.

Figure 9 The potential therapeutic drugs of HF. (AC) The 2D structure of Sirolimus, LY-294002 and Wortmannin. (D) Heat map of the docking score between potential drugs and hub targets. The intensity of red color indicates binding ability. (EJ) Molecular docking diagram of certain core compounds and hub targets.

In this study, we combined WGCNA and DEGs to screen for genes associated with HF and found that the expression levels of the PTN, ISLR, LUM, and ASPN genes were all upregulated in HF. Further analysis using the ROC curve showed that these four genes may be potential biomarkers of HF. At present, PTN and ISLR have not been reported to be associated with HF, but there is evidence that they may be potentially associated with HF. Single-gene GSEA showed that the hub genes of HF are related to arrhythmic right ventricular cardiomyopathy, dilated cardiomyopathy and hypertrophic cardiomyopathy, which is consistent with reports demonstrating that these cardiovascular disorders precede the final HF stage.1315 Single-gene GSEA showed that the hub genes of HF are related to arrhythmic right.

GO analysis of the DEGs showed that endoplasmic reticulum stress (ERS) is closely related to HF pathogenesis, which is consistent with previous reports.1618 The risk factors of HF can induce ERS in myocardial cells, which culminates in apoptosis and cardiovascular dysfunction. In addition, the DEGs were enriched in ferroptosis, MAPK signaling pathway, PI3K-Akt signaling pathway, and the Hippo signaling pathway, all of which are involved in HF. Liu et al19 detected a high level of ferroptosis in the cardiomyocytes of a rat model of pressure overload-induced HF. Exogenous expression of ferritin FTH1 and GPX4 and reduction in ROS levels through NOX4 knockdown inhibited ferroptosis in cardiomyocytes and improved cardiac function. Fang and Koleini et al20,21 found that doxorubicin induced the accumulation of oxidized phospholipids in undifferentiated cardiomyocytes and up-regulated heme oxygenase1 (HMOX1), resulting in heme degradation, free iron overload, and ferroptosis, which eventually leads to HF. The loss of myeloid differentiation protein 1 (MD1) activates ROS and exacerbates autophagy induced by the MAPK signaling pathway. Therefore, the MD1-ROS-MAPK axis is a novel therapeutic target for HF that can preserve the ejection fraction.22 Mao Liu et al23 showed that paeoniflorin reduced myocardial fibrosis and improved cardiac function in rats with chronic HF by regulating the p38/MAPK signaling pathway. Apelin-13 can slow down oxidative stress by inhibiting the PI3K/Akt signaling pathway in the rat HF model and ameliorate angiotensin IIinduced cardiac insufficiency, impaired cardiac hemodynamics, and fibroblast fibrosis.24 Hou and Li et al25,26 showed that YAP/TAZ can initiate the transcription of connective tissue growth factor by interacting with the TEAD domain family, increase the expression of extracellular matrix genes, promote cardiac remodeling and fibrosis, and thus delay the progression of HF. Leach et al27 found that knocking out the SALV gene increased the number of left ventricular myocardial cells in mice with myocardial infarction, which reduced ventricular fibrosis and increased the number of new capillaries around the injured myocardium, indicating that the Hippo signaling pathway can enhance heart function.

PTN is a highly conserved proto-oncogene closely related to tumor angiogenesis and metastasis.28 It is highly expressed in various malignant tumors, such as breast cancer, prostate cancer and rectal cancer,29,30 and promotes the proliferation, mitosis, differentiation, and migration of vascular endothelial cells.31 Overexpression of PTN gene can promote bone formation, whereas PTN gene knockout mice have dysfunctional bone growth and remodeling.32 LUM is a member of the SLRP family of leucine-rich proteins that are secreted by the extracellular matrix. It is widely distributed in various tissues, and shows aberrant expression levels in pancreatic cancer, colorectal cancer, breast cancer and cervical cancer.33 LUM has both oncogenic and tumor-suppressive functions depending on the cancer type. For instance, LUM facilitated the metastasis of colon cancer cells by reconstructing the actin cytoskeleton, but inhibited the adhesion of osteosarcoma cells via the TGF-2 signaling pathway.34,35 ISLR is a conserved immune-related protein that is mainly expressed in stromal cells.36 Xu et al37 showed that ISLR can inhibit Hippo signal transduction during intestinal regeneration and tumorigenesis and activate YAP factor in epithelial cells. Knocking out ISLR in mouse stromal cells significantly affected intestinal regeneration and inhibited colorectal tumorigenesis. Zhang and Hara et al38,39 further showed that the ISLR can promote muscle regeneration and improve myocardial tissue repair. However, little is known regarding the correlation between ISLR and HF. ASPN is an extracellular matrix protein and a member of the leucine-rich small proteoglycan family.40 Sasaki et al41 showed that ASPN protected gastric tumor cells against oxidative stress by up-regulating HIF1 and reducing the levels of mitochondrial ROS. It also increased the expression of CD44 to accelerate the migration and infiltration of gastric cancer cells. However, other reports indicate an anti-tumorigenic role of ASPN in breast cancer.42,43 Studies also show that ASPN is up-regulated during aortic stenosis or coronary artery ligation in ischemic cardiomyopathy patients and animal models.44 ASPN may also increase the apoptosis and fibrosis of H9C2 cardiomyocytes.45 However, the exact role of ASPN in HF pathogenesis needs further investigation.

Lu A et al46 found that Wnt3a binds to FZD and LRP5/6 receptors, thereby activating the classic Wnt-Dvl--catenin signaling pathway and promoting myocardial hypertrophy. Wnt signaling can inhibit Na+ channels by directly or indirectly inhibiting the expression of Scn5a. Thus, blocking these intracellular cascades is a rational therapeutic strategy against HF.46 He et al47 found that Wnt3a and Wnt5a ligand were up-regulated in a mouse model of cardiac hypertrophy, underscoring the role of the Wnt signaling pathway in HF pathogenesis. TGF- is an important factor regulating myocardial fibrosis, which gradually worsens during HF and alters cardiac function from the compensatory phase to the decompensated phase.48 Kakhi et al49 found that sirolimus, an mTOR inhibitor, reversed new HF after kidney transplantation in mammals. Gao et al50 also showed that rapamycin (sirolimus) can reduce cardiomyocyte apoptosis and promote autophagy by regulating mTOR and ERS, thus preventing myocardial damage caused by chronic HF. LY294002 and wortmannin are protein kinase inhibitors that block the PI3K signaling pathway. Melatonin alleviates cardiac hypertrophy by inhibiting the Akt/mTOR pathway and reducing Atg5-dependent autophagy, which can be reversed by LY294002.51 Studies show that apelin may reduce the myocardial damage caused by acute HF by regulating the APJ/Akt/ERS signaling pathway. However, wortmannin and LY294002 can reverse the cardioprotective effects of apelin.52 The PI3K-Akt signaling pathway was also enriched among the HF-related DEGs, indicating a vital mechanistic role in its pathological progression. Molecular docking showed that sirolimus and wortmannin had a high affinity to the hub targets, LY-294002 bound weakly and may therefore have other targets. Nevertheless, all three drugs could be potentially effective for treating HF.

There are several limitations in this study. First, the data used in this study was obtained from the GEO database, which lacks clinical, in vivo, and in vitro experimental research certifications for pivotal genes and HF-associated genes. Second, the datasets used in this study were relatively small, and a larger sample size is needed to verify our results. However, our findings provide new insights into the underlying molecular mechanisms of HF, along with potential diagnostic biomarkers and candidate therapeutic drugs, which will help provide new clues for HF research, diagnosis and treatment, and target selection.

PTN, LUM, ISLR, and ASPN are overexpressed in HF patients compared to NFD, and are mainly related to the TGF- and Wnt signaling pathways. Sirolimus, LY-294002, and wortmannin are potential drug candidates for HF treatment. The in silico data will need to be verified by functional and clinical studies.

All datasets generated and analyzed during the current study were uploaded with the manuscript as additional files.

The ethics committee of the Qinghai University has waived the need for ethical approval for the reasons that the present study used public database, so it did not involve ethics.

This research was supported by the Technology Department project of Qinghai Science (No. 2020-ZJ-922).

The authors report no conflicts of interest in this work.

1. Bragazzi NL, Zhong W, Shu J, et al. Burden of heart failure and underlying causes in 195 countries and territories from 1990 to 2017. Eur J Prev Cardiol. 2021;28(15):16821690. doi:10.1093/eurjpc/zwaa147

2. Baman JR, Ahmad FS. Heart failure. JAMA. 2020;324(10):1015. doi:10.1001/jama.2020.13310

3. Brann A, Tran H, Greenberg B. Contemporary approach to treating heart failure. Trends Cardiovasc Med. 2020;30(8):507518. doi:10.1016/j.tcm.2019.11.011

4. Servant N, Romjon J, Gestraud P, et al. Bioinformatics for precision medicine in oncology: principles and application to the SHIVA clinical trial. Front Genet. 2014;5:152. doi:10.3389/fgene.2014.00152

5. Yin X, Wang P, Yang T, et al. Identification of key modules and genes associated with breast cancer prognosis using WGCNA and ceRNA network analysis. Aging. 2020;13(2):25192538. doi:10.18632/aging.202285

6. Bai KH, He SY, Shu LL, et al. Identification of cancer stem cell characteristics in liver hepatocellular carcinoma by WGCNA analysis of transcriptome stemness index. Cancer Med. 2020;9(12):42904298. doi:10.1002/cam4.3047

7. Nangraj AS, Selvaraj G, Kaliamurthi S, et al. Integrated PPI- and WGCNA-retrieval of hub gene signatures shared between Barretts esophagus and esophageal adenocarcinoma. Front Pharmacol. 2020;11:881. doi:10.3389/fphar.2020.00881

8. Zhang K, Qin X, Wen P, et al. Systematic analysis of molecular mechanisms of heart failure through the pathway and network-based approach. Life Sci. 2021;265:118830. doi:10.1016/j.lfs.2020.118830

9. Zhou J, Zhang W, Wei C, et al. Weighted correlation network bioinformatics uncovers a key molecular biosignature driving the left-sided heart failure. BMC Med Genomics. 2020;13(1):93. doi:10.1186/s12920-020-00750-9

10. Liu Y, Morley M, Brandimarto J, et al. RNA-seq identifies novel myocardial gene expression signatures of heart failure. Genomics. 2015;105(2):8389. doi:10.1016/j.ygeno.2014.12.002

11. Hannenhalli S, Putt ME, Gilmore JM, et al. Transcriptional genomics associates FOX transcription factors with human heart failure. Circulation. 2006;114(12):12691276. doi:10.1161/CIRCULATIONAHA.106.632430

12. Barth AS, Kuner R, Buness A, et al. Identification of a common gene expression signature in dilated cardiomyopathy across independent microarray studies. J Am Coll Cardiol. 2006;48(8):16101617. doi:10.1016/j.jacc.2006.07.026

13. Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res. 2017;121(7):749770. doi:10.1161/CIRCRESAHA.117.311059

14. Hnselmann A, Veltmann C, Bauersachs J, et al. Dilated cardiomyopathies and non-compaction cardiomyopathy. Herz. 2020;45(3):212220. doi:10.1007/s00059-020-04903-5

15. Zoppo F, Gagno G, Perazza L, et al. Electroanatomic voltage mapping and characterisation imaging for right ventricle arrhythmic syndromes beyond the arrhythmia definition: a comprehensive review. Int J Cardiovasc Imaging. 2021;37(8):23472357. doi:10.1007/s10554-021-02221-3

16. Goh KY, Qu J, Hong H, et al. Impaired mitochondrial network excitability in failing Guinea-pig cardiomyocytes. Cardiovasc Res. 2016;109(1):7989. doi:10.1093/cvr/cvv230

17. Bertero E, Maack C. Metabolic remodelling in heart failure. Nat Rev Cardiol. 2018;15(8):457470. doi:10.1038/s41569-018-0044-6

18. Gutirrez T, Parra V, Troncoso R, et al. Alteration in mitochondrial Ca(2+) uptake disrupts insulin signaling in hypertrophic cardiomyocytes. Cell Commun Signal. 2014;12:68. doi:10.1186/s12964-014-0068-4

19. Liu B, Zhao C, Li H, et al. Puerarin protects against heart failure induced by pressure overload through mitigation of ferroptosis. Biochem Biophys Res Commun. 2018;497(1):233240. doi:10.1016/j.bbrc.2018.02.061

20. Fang X, Wang H, Han D, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A. 2019;116(7):26722680. doi:10.1073/pnas.1821022116

21. Koleini N, Nickel BE, Edel AL, et al. Oxidized phospholipids in Doxorubicin-induced cardiotoxicity. Chem Biol Interact. 2019;303:3539. doi:10.1016/j.cbi.2019.01.032

22. Yang HJ, Kong B, Shuai W, et al. MD1 deletion exaggerates cardiomyocyte autophagy induced by heart failure with preserved ejection fraction through ROS/MAPK signalling pathway. J Cell Mol Med. 2020;24(16):93009312. doi:10.1111/jcmm.15579

23. Liu M, Feng J, Du Q, et al. Paeoniflorin attenuates myocardial fibrosis in Isoprenaline-induced chronic heart failure rats via inhibiting P38 MAPK pathway. Curr Med Sci. 2020;40(2):307312. doi:10.1007/s11596-020-2178-0

24. Zhong S, Guo H, Wang H, et al. Apelin-13 alleviated cardiac fibrosis via inhibiting the PI3K/Akt pathway to attenuate oxidative stress in rats with myocardial infarction-induced heart failure. Biosci Rep. 2020;40(4):4. doi:10.1042/BSR20200040

25. Hou N, Wen Y, Yuan X, et al. Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy. Exp Mol Pathol. 2017;103(3):267275. doi:10.1016/j.yexmp.2017.11.006

26. Li C, Wang J, Wang Q, et al. Qishen granules inhibit myocardial inflammation injury through regulating arachidonic acid metabolism. Sci Rep. 2016;6(1):36949. doi:10.1038/srep36949

27. Leach JP, Heallen T, Zhang M, et al. Hippo pathway deficiency reverses systolic heart failure after infarction. Nature. 2017;550(7675):260264. doi:10.1038/nature24045

28. Magnusson PU, Dimberg A, Mellberg S, et al. FGFR-1 regulates angiogenesis through cytokines interleukin-4 and pleiotrophin. Blood. 2007;110(13):42144222. doi:10.1182/blood-2007-01-067314

29. Perez-Pinera P, Chang Y, Deuel TF. Pleiotrophin, a multifunctional tumor promoter through induction of tumor angiogenesis, remodeling of the tumor microenvironment, and activation of stromal fibroblasts. Cell Cycle. 2007;6(23):28772883. doi:10.4161/cc.6.23.5090

30. Liu S, Shen M, Hsu EC, et al. Discovery of PTN as a serum-based biomarker of pro-metastatic prostate cancer. Br J Cancer. 2021;124(5):896900. doi:10.1038/s41416-020-01200-0

31. Hamma-Kourbali Y, Bermek O, Bernard-Pierrot I, et al. The synthetic peptide P111-136 derived from the C-terminal domain of heparin affin regulatory peptide inhibits tumour growth of prostate cancer PC-3 cells. BMC Cancer. 2011;11(1):212. doi:10.1186/1471-2407-11-212

32. Xi G, Demambro VE, DCosta S, et al. Estrogen stimulation of pleiotrophin enhances osteoblast differentiation and maintains bone mass in IGFBP-2 null mice. Endocrinology. 2020;161(4). doi:10.1210/endocr/bqz007

33. Nikitovic D, Berdiaki A, Zafiropoulos A, et al. Lumican expression is positively correlated with the differentiation and negatively with the growth of human osteosarcoma cells. FEBS J. 2008;275(2):350361. doi:10.1111/j.1742-4658.2007.06205.x

34. Radwanska A, Litwin M, Nowak D, et al. Overexpression of lumican affects the migration of human colon cancer cells through up-regulation of gelsolin and filamentous actin reorganization. Exp Cell Res. 2012;318(18):23122323. doi:10.1016/j.yexcr.2012.07.005

35. Nikitovic D, Chalkiadaki G, Berdiaki A, et al. Lumican regulates osteosarcoma cell adhesion by modulating TGF2 activity. Int J Biochem Cell Biol. 2011;43(6):928935. doi:10.1016/j.biocel.2011.03.008

36. Nagasawa A, Kubota R, Imamura Y, et al. Cloning of the cDNA for a new member of the immunoglobulin superfamily (ISLR) containing leucine-rich repeat (LRR). Genomics. 1997;44(3):273279. doi:10.1006/geno.1997.4889

37. Xu J, Tang Y, Sheng X, et al. Secreted stromal protein ISLR promotes intestinal regeneration by suppressing epithelial Hippo signaling. EMBO J. 2020;39(7):e103255. doi:10.15252/embj.2019103255

38. Zhang K, Zhang Y, Gu L, et al. Islr regulates canonical Wnt signaling-mediated skeletal muscle regeneration by stabilizing Dishevelled-2 and preventing autophagy. Nat Commun. 2018;9(1):5129. doi:10.1038/s41467-018-07638-4

39. Hara A, Kobayashi H, Asai N, et al. Roles of the mesenchymal stromal/stem cell marker meflin in cardiac tissue repair and the development of diastolic dysfunction. Circ Res. 2019;125(4):414430. doi:10.1161/CIRCRESAHA.119.314806

40. Polley A, Khanam R, Sengupta A, et al. Asporin reduces adult aortic valve interstitial cell mineralization induced by osteogenic media and wnt signaling manipulation in vitro. Int J Cell Biol. 2020;2020:2045969. doi:10.1155/2020/2045969

41. Sasaki Y, Takagane K, Konno T, et al. Expression of asporin reprograms cancer cells to acquire resistance to oxidative stress. Cancer Sci. 2021;112(3):12511261. doi:10.1111/cas.14794

42. Castellana B, Escuin D, Peir G, et al. ASPN and GJB2 are implicated in the mechanisms of invasion of ductal breast carcinomas. J Cancer. 2012;3:175183. doi:10.7150/jca.4120

43. Simkova D, Kharaishvili G, Korinkova G, et al. The dual role of asporin in breast cancer progression. Oncotarget. 2016;7(32):5204552060. doi:10.18632/oncotarget.10471

44. Wang HB, Huang R, Yang K, et al. Identification of differentially expressed genes and preliminary validations in cardiac pathological remodeling induced by transverse aortic constriction. Int J Mol Med. 2019;44(4):14471461. doi:10.3892/ijmm.2019.4291

45. Li XL, Yu F, Li BY, et al. The protective effects of grape seed procyanidin B2 against asporin mediates glycated low-density lipoprotein induced-cardiomyocyte apoptosis and fibrosis. Cell Biol Int. 2019. doi:10.1002/cbin.11229

46. Lu A, Kamkar M, Chu C, et al. Direct and indirect suppression of Scn5a gene expression mediates cardiac Na+ channel inhibition by Wnt signalling. Can J Cardiol. 2020;36(4):564576. doi:10.1016/j.cjca.2019.09.019

47. He J, Cai Y, Luo LM, et al. Expression of Wnt and NCX1 and its correlation with cardiomyocyte apoptosis in mouse with myocardial hypertrophy. Asian Pac J Trop Med. 2015;8(11):930936. doi:10.1016/j.apjtm.2015.10.002

48. Yatabe J, Sanada H, Yatabe MS, et al. Angiotensin II type 1 receptor blocker attenuates the activation of ERK and NADPH oxidase by mechanical strain in mesangial cells in the absence of angiotensin II. Am J Physiol Renal Physiol. 2009;296(5):F10521060. doi:10.1152/ajprenal.00580.2007

49. Kakhi S, Phanish MK, Anderson L. Dilated cardiomyopathy in an adult renal transplant recipient: recovery upon tacrolimus to sirolimus switch: a case report. Transplant Proc. 2020;52(9):27582761. doi:10.1016/j.transproceed.2020.06.011

50. Gao G, Chen W, Yan M, et al. Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling. Int J Mol Med. 2020;45(1):195209. doi:10.3892/ijmm.2019.4407

51. Xu CN, Kong LH, Ding P, et al. Melatonin ameliorates pressure overload-induced cardiac hypertrophy by attenuating Atg5-dependent autophagy and activating the Akt/mTOR pathway. Biochim Biophys Acta Mol Basis Dis. 2020;1866(10):165848. doi:10.1016/j.bbadis.2020.165848

52. Li Y, Lu H, Xu W, et al. Apelin ameliorated acute heart failure via inhibiting endoplasmic reticulum stress in rabbits. Amino Acids. 2021;53(3):417427. doi:10.1007/s00726-021-02955-3

Follow this link:
Biomarkers and Candidate Therapeutic Drugs in Heart Failure | IJGM - Dove Medical Press

BattleVision Storm Glasses sales skyrocket after major winter storms hit across the United States.

LOS ANGELES (PRWEB) December 31, 2021

BattleVision Storm glasses were created to help drivers stay safe at night, no matter what type of weather. The main purpose of BattleVision Storm glasses is to help drivers to see well while driving, even if you have 20/20 vision. It filters all light from daytime to even nighttime. The company saw an uptick in sales after storms overtake the Midwest during the winter months.

BattleVision Storm glasses are designed to give better sight overall in every scenario, even during a winter storm. Customers love how during a snowstorm these glasses deflect the glare from passing headlights, allowing clients to see even clearly through the snow.

The glasses also help customers at night, when it is hard to make out a sign in the darkness. These glasses allow people to have enhanced vision so everyone can read even when it is near pitch black outside.

Many BatteVision Storm reviews have deemed the new products as essential for driving at night or in rough conditions. One reviewer claims that the glasses are "helping your eyesight stay healthy".

BattleVision Storm Glasses helps people by:

A major selling point of the glasses is the affordability. Everyone is able to see clearly and safely while driving. BattleVision Storm glasses save everyone costs.

BattleVision sunglasses by Atomic Beam helped you battle through the glare from the sun. Now you can battle through the nighttime glare with BattleVision Night Vision Glasses by Atomic Beam. The yellow-tinted night driving glasses offer your eyes protection from debilitating headlight glare, as well as glare from street lights, and enhance your vision. Battle Vision Night Vision Glasses are also the perfect anti-glare glasses and polarized glasses for driving during the daytime in inclement weather like fog and rain. Part of the Atomic Beam family, Battle Vision Night Vision Glasses are built atomically tough.

For the original version on PRWeb visit: https://www.prweb.com/releases/battlevision_storm_glasses_sees_uptick_in_sales_as_winter_hits/prweb18413424.htm

See the article here:
BattleVision Storm Glasses Sees Uptick in Sales as Winter Hits - Benzinga - Benzinga

DUBLIN, Dec. 29, 2021 /PRNewswire/ -- The "Eye Care Surgical Market Research Report by Application, End-user, and Region - Global Forecast to 2026 - Cumulative Impact of COVID-19" report has been added to ResearchAndMarkets.com's offering.

The Global Eye Care Surgical Market size was estimated at USD 3,276.23 million in 2020, is expected to reach USD 3,547.10 million in 2021, and projected to grow at a CAGR of 8.60% reaching USD 5,376.45 million by 2026.

Market Statistics

The report provides market sizing and forecast across five major currencies - USD, EUR GBP, JPY, and AUD. It helps organization leaders make better decisions when currency exchange data is readily available. In this report, the years 2018 and 2019 are considered historical years, 2020 as the base year, 2021 as the estimated year, and years from 2022 to 2026 are considered the forecast period.

Competitive Strategic Window

The Competitive Strategic Window analyses the competitive landscape in terms of markets, applications, and geographies to help the vendor define an alignment or fit between their capabilities and opportunities for future growth prospects. It describes the optimal or favorable fit for the vendors to adopt successive merger and acquisition strategies, geography expansion, research & development, and new product introduction strategies to execute further business expansion and growth during a forecast period.

FPNV Positioning Matrix

The FPNV Positioning Matrix evaluates and categorizes the vendors in the Eye Care Surgical Market based on Business Strategy (Business Growth, Industry Coverage, Financial Viability, and Channel Support) and Product Satisfaction (Value for Money, Ease of Use, Product Features, and Customer Support) that aids businesses in better decision making and understanding the competitive landscape.

Market Share Analysis

The Market Share Analysis offers the analysis of vendors considering their contribution to the overall market. It provides the idea of its revenue generation into the overall market compared to other vendors in the space. It provides insights into how vendors are performing in terms of revenue generation and customer base compared to others. Knowing market share offers an idea of the size and competitiveness of the vendors for the base year. It reveals the market characteristics in terms of accumulation, fragmentation, dominance, and amalgamation traits.

Company Usability Profiles

The report profoundly explores the recent significant developments by the leading vendors and innovation profiles in the Global Eye Care Surgical Market, including A.R.C. Laser GmbH, Abbott Laboratories Inc, Alcon Vision LLC, Avedro, Inc., Bausch & Lomb Incorporated, Beaver-Visitec International, Inc., Carl Zeiss Meditec AG, Essilor International S.A., Glaukos Corp, Hoya Corporation, iSTAR Medical SA, Lumenis Ltd, NIDEK CO., LTD., Novartis AG, Ophthalmic Instruments Inc., Optotune GmbH, RetinAI Medical GmbH, SENSIMED SA, Sight Sciences, Inc., Topcon Corporation, TRIOPTICS GmbH, Valeant Pharmaceuticals International Inc., and Virtual Expo Group.

The report provides insights on the following pointers:1. Market Penetration: Provides comprehensive information on the market offered by the key players2. Market Development: Provides in-depth information about lucrative emerging markets and analyze penetration across mature segments of the markets3. Market Diversification: Provides detailed information about new product launches, untapped geographies, recent developments, and investments4. Competitive Assessment & Intelligence: Provides an exhaustive assessment of market shares, strategies, products, certification, regulatory approvals, patent landscape, and manufacturing capabilities of the leading players5. Product Development & Innovation: Provides intelligent insights on future technologies, R&D activities, and breakthrough product developments

The report answers questions such as:1. What is the market size and forecast of the Global Eye Care Surgical Market?2. What are the inhibiting factors and impact of COVID-19 shaping the Global Eye Care Surgical Market during the forecast period?3. Which are the products/segments/applications/areas to invest in over the forecast period in the Global Eye Care Surgical Market?4. What is the competitive strategic window for opportunities in the Global Eye Care Surgical Market?5. What are the technology trends and regulatory frameworks in the Global Eye Care Surgical Market?6. What is the market share of the leading vendors in the Global Eye Care Surgical Market?7. What modes and strategic moves are considered suitable for entering the Global Eye Care Surgical Market?

Key Topics Covered:

1. Preface

2. Research Methodology

3. Executive Summary

4. Market Overview4.1. Introduction4.2. Cumulative Impact of COVID-19

5. Market Dynamics5.1. Introduction5.2. Drivers5.2.1. Rising prevalence of eye diseases5.2.2. Technological advancements in eye surgical instruments5.2.3. Increasing government initiatives to control visual impairment5.3. Restraints5.3.1. High cost of surgical instruments and lack of skilled professional5.4. Opportunities5.4.1. Rising development in advanced products and technologies5.4.2. Increasing healthcare facilities in the emerging markets5.5. Challenges5.5.1. Lack of awareness and low accessibility to eye care in low-income economies

6. Eye Care Surgical Market, by Application6.1. Introduction6.2. Cataract Surgery6.3. Corneal Surgery6.4. Glaucoma Surgery6.5. Oculoplastic Surgery6.6. Refractive Surgery6.7. Vitreo-retinal Surgery

7. Eye Care Surgical Market, by End-user7.1. Introduction7.2. Ambulatory Surgical Centers7.3. Eye Research Institutes7.4. Hospitals7.5. Ophthalmology Clinics

8. Americas Eye Care Surgical Market8.1. Introduction8.2. Argentina8.3. Brazil8.4. Canada8.5. Mexico8.6. United States

9. Asia-Pacific Eye Care Surgical Market9.1. Introduction9.2. Australia9.3. China9.4. India9.5. Indonesia9.6. Japan9.7. Malaysia9.8. Philippines9.9. Singapore9.10. South Korea9.11. Taiwan9.12. Thailand

10. Europe, Middle East & Africa Eye Care Surgical Market10.1. Introduction10.2. France10.3. Germany10.4. Italy10.5. Netherlands10.6. Qatar10.7. Russia10.8. Saudi Arabia10.9. South Africa10.10. Spain10.11. United Arab Emirates10.12. United Kingdom

11. Competitive Landscape11.1. FPNV Positioning Matrix11.1.1. Quadrants11.1.2. Business Strategy11.1.3. Product Satisfaction11.2. Market Ranking Analysis11.3. Market Share Analysis, by Key Player11.4. Competitive Scenario11.4.1. Merger & Acquisition11.4.2. Agreement, Collaboration, & Partnership11.4.3. New Product Launch & Enhancement11.4.4. Investment & Funding11.4.5. Award, Recognition, & Expansion

12. Company Usability Profiles12.1. A.R.C. Laser GmbH12.2. Abbott Laboratories Inc.12.3. Alcon Vision LLC12.4. Avedro, Inc.12.5. Bausch & Lomb Incorporated12.6. Beaver-Visitec International, Inc.12.7. Carl Zeiss Meditec AG12.8. Essilor International S.A.12.9. Glaukos Corp12.10. Hoya Corporation12.11. iSTAR Medical SA12.12. Lumenis Ltd.12.13. NIDEK CO., LTD.12.14. Novartis AG12.15. Ophthalmic Instruments Inc.12.16. Optotune GmbH12.17. RetinAI Medical GmbH12.18. SENSIMED SA12.19. Sight Sciences, Inc.12.20. Topcon Corporation12.21. TRIOPTICS GmbH12.22. Valeant Pharmaceuticals International Inc.12.23. Virtual Expo Group

13. Appendix

For more information about this report visit https://www.researchandmarkets.com/r/u3sbq2

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900

U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716

SOURCE Research and Markets

http://www.researchandmarkets.com

More here:
Insights on the Eye Care Surgical Global Market to 2026 - Featuring Abbott Laboratories, Alcon Vision and Avedro Among Others - PRNewswire

Joe Rogan first popped up more squarely on my radar screen years ago because of a concerning video thats out there of him talking with Mel Gibson about stem cells.

At the time it was one of the most-watched videos on YouTube on stem cells.

I took apart thatstem cell video and its claims including related to a Panama stem cell clinic, which in my opinion were way out there. It seems to me that the video was likely encouraging everyday people to take risks for themselves and their families at the clinics.

I thought at the time that maybe that was that.

However, it turns out that Joe Rogan is still really into stem cells. There are many videos out there of him talking with celebrities about stem cells. In addition to Mel Gibson, he has also talked stem cells with former boxer Mike Tyson (see above), rapper Action Bronson, MMA fighter Henry Cejudo, and quite a few others. In some of the videos, Rogan is talking about his own experiences.

The clip promoting the clinic Bioxcellerator ends with Rogan saying, Yeah, its real shit man about the stem cells.

So whats the big deal?

One problem is that the stem cell content on his show encourages risk-taking by the public. The supposed stem cell treatments arent based on solid, consistent data and they focus largely on anecdotes.

As with the Mel Gibson video, in the other videos Joe also often seems to promote specific unproven clinics. Theres no balance in the interviews. I havent watched all the Rogan videos mentioning stem cells but much of the content feels like advertising to me. Like infomercials.

Searching for Joes name and stem cells on the web under videos on Google or on YouTube and youll easily see much of this content.

Strikingly, some of the clips were uploaded to YouTube by the unproven stem cell clinics mentioned in the videos.

If nothing else this tells us that the clinics view the videos as promotional material. Does Rogan get paid for some of this? Or maybe he gets a discount or free treatments for himself or his family?

Who knows, but these are important questions. He might just be extremely enthusiastic about stem cells without some compensation.

Has he ever had a physician doing legit stem cell-related clinical trials on his show too? If so, I havent seen that.About the closest thing is a 2020 interview with Aubrey De Grey, which Ive included above. Theres some sober discussion in there from Aubrey, but unfortunately, its mixed in with Rogan going on about stem cell clinic offerings. Aubrey has a somewhat more relaxed view about stem cell tourism than I do, but you can tell from this video and other talks that Ive seen him give that he still wants to see all the data.

Moving forward, Rogan could do some good by bringing attention to strong stem cell clinical trials and advocating for a data-focused approach. Thats not likely. In the bigger picture, there are some major concerns about Joe Rogans statements about COVID-19and other health issues as well.

Related Posts

View post:
Digging into extensive Joe Rogan stem cell clinic ...

A North Lanarkshire couple have tied the knot after the groom was given a devastating terminal cancer diagnosis just weeks ago.

Julie Neilson and Michael Duffy, who are parents to five girls, got engaged last Christmas Eve.

While couple had planned to get married in 2022, Michael was given shocking news that he had secondary cancer in his liver in December.

READ MORE: Get the latest news from Glasgow Live here.

Doctors told the 44-year-old machinist he had 'weeks to months' to live, the Daily Record reports.

Without wasting anymore time, the Airdrie couple got married yesterday with their children at Celtic Park as a tribute to Michael's favourite team.

One of those who will watch Julie walk down the aisle is eight-year-old daughter Ava, who has stage five cerebral palsy and a range of other medical conditions which are also sadly terminal.

Julie, 41, told the Record before the big day: "It feels amazing that after all this time it has finally happened.

"It still hasn't sunk in yet and I think it will take a while for both me and Michael to settle down and let it all sink in.

"It's all been non-stop with dresses and make-up artists today, Michael had to sneak out of the house at 9am to go to his pals so he wouldn't see my dress.

"I've been keeping it hidden from everyone - not even the bridal party got to see my dress until I went down the aisle."

The couple set about the task of organising their dream wedding in just over three weeks - so this Christmas period has been the busiest of all.

Julie said: "It's been a very busy couple of weeks.

"On December 5 we were given the news that Michael had secondary adenocarcinoma of the liver.

"It has an unknown origin. The doctors can't find the primary cancer because Michael's own immune system has actually managed to fight that off.

Have your say on this story in the comments section.

"But part of the cancer has broken away and attacked his liver.

"The doctors have said it is very aggressive and he just has weeks to months.

"Michael proposed to me last Christmas Eve and we've been together for four years but we have known each other most of our lives.

"He was my high school crush and it's just unbelievable this has all come together."

Julie and Michael have been supported by the Wedding Wish Makers charity and generous donations from loved ones and well-wishers to help create their dream big day.

But there was only one venue that would do for Celtic fan Michael.

Julie said: "Michael is a big Hoops fan, I don't know that much about football but I like to help out with his predictions.

"It has been hard to organise with all the hospital visits and Michael's diagnosis being so new.

"But I'm used to it because my daughter Ava is medically complex and terminally ill. She has level five cerebral palsy and is medically fragile, it means she requires 24/7 care.

"She can't swallow properly and has to be fed through a button in her stomach.

"So when Michael was given his news it was especially devastating- he has been my support and helped me get through it all."

With the pair now married, Julie says they are not giving up hope yet.

They managed to get stem cell treatment for Ava in Panama around five years ago that has improved her quality of life, and Julie hopes to find treatment for Michael.

She said: "We are looking at all sorts of different options and seeing if there is anything we can do to slow down his condition or somewhere we can get a better variety of treatments.

"We are not giving up yet. We are fighters."

Sign up to Glasgow Live newsletters for more headlines straight to your inbox

Read more here:
Couple marry at Celtic Park after groom told he has only weeks to live - Glasgow Live

Asia-Pacific now ranks in first for the total number of trials taking place, compared to its fourth-placed ranking in 2010. Credit: Shutterstock

The Asia-Pacific region has seen a 158% increase in the number of musculoskeletal disorders trials taking place over the past decade, the largest increase for any region worldwide.

The region now ranks in first for the total number of trials taking place, compared to its fourth-placed ranking in 2010.

These figures come from GlobalDatas extensive clinical trials database which seeks to track the number of clinical trials taking place in countries around the world, in numerous therapy areas.

The Asia-Pacific region saw the biggest increase in musculoskeletal disorders related trials.

Between 2010 and 2020, there was a 158% increase in the number of trials taking place.

In 2020, the largest proportion of trials in the region took place in China with 46.5% of all trials in the region taking place there.

India and South Korea had the next largest percentage of trials taking place in the region with 19.2% and 7.3%, respectively.

The Middle East saw a 142% increase in the number of musculoskeletal disorders trials taking place.

Iran saw the largest amount of trials taking place, in 2020, at 76.1%.

Trials in Saudi Arabia and Israel also made up a large proportion of the trials taking place with 13% and 6.5%, respectively.

Africa saw a 100% increase in the number trials taking place.

Egypt, South Africa and Zimbabwe made up the most trials in the region, with 75%, 10% and 5%, respectively.

North America saw a 15% increase in musculoskeletal disorders related trials taking place.

The United States saw the largest percentage of trials taking place in the region at 87.6%.

Canada and Mexico also made up a significant proportion of the trials taking place.

Europe saw a decrease in the number of musculoskeletal disorders trials.

The region saw a 40% decrease in the number of trials.

Russia made up 10.3% the largest proportion of trials taking place in the region.

Spain and the United Kingdom also made up a large amount of the trials taking place with 9.6% and 8.9%, respectively.

South and Central America saw the biggest decrease in musculoskeletal disorders trials.

The number of trials in the region fell by 50% between 2010 and 2020.

Brazil saw the largest percentage of trials taking place in the region with 50%.

Aseptic Process Solutions for the Pharmaceutical Industry

Aseptic Process Solutions for the Pharmaceutical Industry

28 Aug 2020

Original post:
A cloudy day in paradise for pharma tax havens in Cayman Islands & Bermuda? Impact of OECD tax deal on pharma in Cayman Islands and Bermuda tax...

TruStem Cell Therapy provides access to treatment that utilizes a patients stem cells isolated from their own bone marrow. There are multiple inherent benefits afforded by the utilization of bone marrow derived stem cells asBone marrow (BM) and bone marrow components function in various diverse, innate therapeutic capacities.

Hematopoietic stem cells (HSCs), found within BM, are the bodys source of most cells found in the peripheral or circulating blood. These include red blood cells and white blood cells (such as monocytes). Evidence suggests that BM-derived monocytes may act to improve certain chronic inflammatory auto-immune conditions conditions.

In addition to HSCs, mesenchymal stem cells (MSCs) are also contained within BM. Evidence suggests MSCs can enter the circulating blood during injury and have been shown to readily home to areas of injury or inflammation. Once at these damaged tissue sites, MSCs can exert both protective cellular and immunomodulatory effects believed to be critical in many auto-immune conditions.

Read the original:
Type 2 Diabetes Stem Cell Therapy - Top U.S. Stem Cell ...

This article was originally published here

Pediatr Blood Cancer. 2021 Dec 31:e29537. doi: 10.1002/pbc.29537. Online ahead of print.

ABSTRACT

BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in children. Those with high-risk disease are treated with multimodal therapy, including high-dose chemotherapy, stem cell transplant, radiation, and immunotherapy that have led to multiple long-term complications in survivors. In the late 1990s, consolidation therapy involved myeloablative conditioning including total body irradiation (TBI) with autologous stem cell rescue. Recognizing the significant long-term toxicities of exposure to TBI, more contemporary treatment protocols have removed this from conditioning regimens. This study examines an expanded cohort of 48 high-risk neuroblastoma patients to identify differences in the late effect profiles for those treated with TBI and those treated without TBI.

PROCEDURE: Data on the study cohort were collected from clinic charts, provider documentation in the electronic medical record of visits to survivorship clinic, including all subspecialists, and ancillary reports of laboratory and diagnostic tests done as part of risk-based screening at each visit.

RESULTS: All 48 survivors of BMT for high-risk neuroblastoma had numerous late effects of therapy, with 73% having between five and 10 late effects. TBI impacted some late effects significantly, including growth hormone deficiency (GHD), bone outcomes, and cataracts.

CONCLUSION: Although high-risk neuroblastoma survivors treated with TBI have significant late effects, those treated without TBI also continue to have significant morbidity related to high-dose chemotherapy and local radiation. A multidisciplinary care team assists in providing comprehensive care to those survivors who are at highest risk for significant late effects.

PMID:34971017 | DOI:10.1002/pbc.29537

Go here to read the rest:
Late effects in survivors of high-risk neuroblastoma following stem cell transplant with and without total body irradiation - DocWire News

From immunotherapy combinations to treatments for the complications that can arise from stem cell transplantation, the year 2021 brought countless Food and Drug Administration (FDA) approvals that are changing patients lives.

CURE made a roundup of some of the most-read FDA approvals throughout the year. They were:

1. FDA Approves Welireg for Several Cancers Associated With VHL Disease

In August, the FDA approved Welireg (belzutifan) for adults with von Hippel-Lindau (VHL)-related kidney cancer, central nervous system (CNS) hemangioblastomas or pancreatic neuroendocrine tumors (pNET) that do not require immediate surgery. The drug led to response rates in 49% of patients with kidney cancer, 63% of CNS hemangioblastoma and 83% of pNET.

2. FDA Approves Keytruda/Chemo for Triple-Negative Breast Cancer

Keytruda (pembrolizumab), an immunotherapy agent, plus chemotherapy was approved for patients with high-risk, early-stage triple-negative breast cancer (TNBC) an advancement that has the potential to change the treatment paradigm, according to Dr. Joyce OShaughnessy.

3. FDA Approves Yescarta for Third-Line Treatment of Relapsed or Refractory Follicular Lymphoma

This March, the FDA approved Yescarta (axicabtagene ciloleucel), for pretreated indolent (low-grade) follicular lymphoma the first CAR-T cell therapy to be approved in this patient population. The ZUMA-5 clinical trial led to the drugs approval and showed that 91% of patients with relapsed/refractory follicular lymphoma were in continued remission at 18 months post treatment.

4. FDA Approves Radiation Therapy for Outpatient Setting in Liver Cancer Subtype

TheraSphere Yttrium-90 (Y-90) Glass Microspheres was granted FDA approval for patients with hepatocellular carcinoma the most common type of liver cancer. The approval is notable because it allowed an option for this patient population to be treated without being hospitalized.

5. FDA Approves Rezurock for Chronic Graft-Versus-Host Disease After Two Prior Lines of Therapy

Individuals with chronic graft-versus-host disease (GVHD) that was previously treated with at least two other therapy now have a new treatment option Rezurock (belumosudil) thanks to the FDAs approval of the agent this summer. Rezurock has shown robust and durable responses across the spectrum of (chronic graft-versus-host disease) and is safe and well tolerated, allowing patients to stay on therapy and achieve meaningful benefit from treatment, said Dr. Corey Cutler.

6. FDA Approves First CAR-T Cell Therapy for Multiple Myeloma

In March, the FDA approved the first cell-based gene therapy Abecma (idecabtagene vicleucel) for the treatment of adults with multiple myeloma who did not respond to at least four lines of therapy or whose disease returned after the same number of therapies.

7. FDA Approves Cabometyx For Thyroid Cancer Subset

Cabometyx (cabozantinib) was given the greenlight by the FDA for the treatment of patients with previously treated radioactive iodine-refractory differentiated thyroid cancer.

8. FDA Approves First Targeted Therapy for Subset of Non-Small Cell Lung Cancer

The agency approved Lumakras (sotorasib), the first targeted therapy for patients with non-small cell lung cancer and a KRAS G12C mutation, whose disease progressed after one systemic therapy.

For more news on cancer updates, research and education, dont forget tosubscribe to CUREs newsletters here.

Read more from the original source:
Cancer Drug Approvals from 2021 That Patients May Have Missed - Curetoday.com

When he was just 10 years old, a giant facial tumor took over his face, completely disfigured it, and caused his mother will reject him and abandon him. Is about Kambou you, a young man from Ivory Coast, who is 18 today, and who had a very difficult life since childhood.

The aggressive mass began its journey on her cheek and then spread until her vision was difficult. I only had him support from his father, who accompanied him to undergo an operation abroad and obtained gratifying results, although he still has to undergo other surgeries to finish repairing the damage caused.

Read also: He is a painter, he lived anguished by the shape of his nose and a meeting at work brought him back his joy: God sent me an angel

In the beginning, Kambou, who likes to be called Prosper, was not treated and, as time went by, the tumor began to completely thicken his facial features. In addition to health problems, it also caused complications when interacting in the community: people used to ignore it or avoid it because no one knew anything about his condition and they thought it was contagious.

According to the definition of Macmillan, the British organization against cancer, this type of malformation is generated in the lymphatic system and develops when the body produces abnormal white blood cells.

It can have different manifestations, but the most extreme is the formation of tumors in areas such as the abdomen or face and it brings with it a lot of pain, bloating, nausea, and diarrhea. In the case of Kambou, it is added that the endemic species is found in Africa, so that your population is more exposed to contracting it.

Read also: Historic operation to build gender identity in Neuqun: they performed the first genital modification surgery

The serious illness led him from Bondoukou, his hometown in Ivory Coast, until Italy to start a treatment that would allow him to face the tumor and embark on a new course in his life.

Already installed in the European country, he visited the Hospital Pascale of Naples where they did various tests and found that it was a rare form of cancer that attacks the immune system called Burkitts lymphoma.

When I came here, I was often afraid. I think fear was the only thing I felt. My nose made it difficult for me to see and I had to cover it to be able to seeSaid Kambou, who underwent six months of chemotherapy, radiation therapy and stem cell replacement to shrink the tumor.

And he added: Three days after starting chemotherapy I realized that I no longer needed to cover my nose to see. Im very happy because when I go out I dont cry. Glad to meet people. I go out, I have fun, I play. I have no problems, I am very happy .

Once the cancer was removed, Prosper underwent three facial surgeries in which surgeons set about reconstructing her face. Having had a tumor of an extraordinary size, they had to repair the bone damage that the mass had caused.

According to what the specialist explained Doctor Fran Ionna, the results were amazing. However, there are still structures to improve on the young mans face: There is a defect in the development of the facial bones. There is an asymmetry. The right side of the face has an underdeveloped cheek bone and an eye socket that will have to be reconstructed , he explained.

In that sense, he assured that the young man will have to undergo several more surgeries because The cancer has affected the bone structure of his skull.

The young Ivorian stressed that, after treatment, he feels like a new man, Although he knows that there are still stages to achieve a definitive face and be able to return to his country. My face has changed. This is not over, but it has changed. I have also improved, I am not like before , he stressed.

Prosper is looking forward to returning to the Ivory Coast and starting a life from scratch. However, he valued have returned to school and have a girlfriend.

Disclaimer: This article is generated from the feed and not edited by our team.

Read the original:
The new life of a teenager with a strange tumor on his face after the operation - Market Research Telecast

Country

United States of AmericaUS Virgin IslandsUnited States Minor Outlying IslandsCanadaMexico, United Mexican StatesBahamas, Commonwealth of theCuba, Republic ofDominican RepublicHaiti, Republic ofJamaicaAfghanistanAlbania, People's Socialist Republic ofAlgeria, People's Democratic Republic ofAmerican SamoaAndorra, Principality ofAngola, Republic ofAnguillaAntarctica (the territory South of 60 deg S)Antigua and BarbudaArgentina, Argentine RepublicArmeniaArubaAustralia, Commonwealth ofAustria, Republic ofAzerbaijan, Republic ofBahrain, Kingdom ofBangladesh, People's Republic ofBarbadosBelarusBelgium, Kingdom ofBelizeBenin, People's Republic ofBermudaBhutan, Kingdom ofBolivia, Republic ofBosnia and HerzegovinaBotswana, Republic ofBouvet Island (Bouvetoya)Brazil, Federative Republic ofBritish Indian Ocean Territory (Chagos Archipelago)British Virgin IslandsBrunei DarussalamBulgaria, People's Republic ofBurkina FasoBurundi, Republic ofCambodia, Kingdom ofCameroon, United Republic ofCape Verde, Republic ofCayman IslandsCentral African RepublicChad, Republic ofChile, Republic ofChina, People's Republic ofChristmas IslandCocos (Keeling) IslandsColombia, Republic ofComoros, Union of theCongo, Democratic Republic ofCongo, People's Republic ofCook IslandsCosta Rica, Republic ofCote D'Ivoire, Ivory Coast, Republic of theCyprus, Republic ofCzech RepublicDenmark, Kingdom ofDjibouti, Republic ofDominica, Commonwealth ofEcuador, Republic ofEgypt, Arab Republic ofEl Salvador, Republic ofEquatorial Guinea, Republic ofEritreaEstoniaEthiopiaFaeroe IslandsFalkland Islands (Malvinas)Fiji, Republic of the Fiji IslandsFinland, Republic ofFrance, French RepublicFrench GuianaFrench PolynesiaFrench Southern TerritoriesGabon, Gabonese RepublicGambia, Republic of theGeorgiaGermanyGhana, Republic ofGibraltarGreece, Hellenic RepublicGreenlandGrenadaGuadaloupeGuamGuatemala, Republic ofGuinea, RevolutionaryPeople's Rep'c ofGuinea-Bissau, Republic ofGuyana, Republic ofHeard and McDonald IslandsHoly See (Vatican City State)Honduras, Republic ofHong Kong, Special Administrative Region of ChinaHrvatska (Croatia)Hungary, Hungarian People's RepublicIceland, Republic ofIndia, Republic ofIndonesia, Republic ofIran, Islamic Republic ofIraq, Republic ofIrelandIsrael, State ofItaly, Italian RepublicJapanJordan, Hashemite Kingdom ofKazakhstan, Republic ofKenya, Republic ofKiribati, Republic ofKorea, Democratic People's Republic ofKorea, Republic ofKuwait, State ofKyrgyz RepublicLao People's Democratic RepublicLatviaLebanon, Lebanese RepublicLesotho, Kingdom ofLiberia, Republic ofLibyan Arab JamahiriyaLiechtenstein, Principality ofLithuaniaLuxembourg, Grand Duchy ofMacao, Special Administrative Region of ChinaMacedonia, the former Yugoslav Republic ofMadagascar, Republic ofMalawi, Republic ofMalaysiaMaldives, Republic ofMali, Republic ofMalta, Republic ofMarshall IslandsMartiniqueMauritania, Islamic Republic ofMauritiusMayotteMicronesia, Federated States ofMoldova, Republic ofMonaco, Principality ofMongolia, Mongolian People's RepublicMontserratMorocco, Kingdom ofMozambique, People's Republic ofMyanmarNamibiaNauru, Republic ofNepal, Kingdom ofNetherlands AntillesNetherlands, Kingdom of theNew CaledoniaNew ZealandNicaragua, Republic ofNiger, Republic of theNigeria, Federal Republic ofNiue, Republic ofNorfolk IslandNorthern Mariana IslandsNorway, Kingdom ofOman, Sultanate ofPakistan, Islamic Republic ofPalauPalestinian Territory, OccupiedPanama, Republic ofPapua New GuineaParaguay, Republic ofPeru, Republic ofPhilippines, Republic of thePitcairn IslandPoland, Polish People's RepublicPortugal, Portuguese RepublicPuerto RicoQatar, State ofReunionRomania, Socialist Republic ofRussian FederationRwanda, Rwandese RepublicSamoa, Independent State ofSan Marino, Republic ofSao Tome and Principe, Democratic Republic ofSaudi Arabia, Kingdom ofSenegal, Republic ofSerbia and MontenegroSeychelles, Republic ofSierra Leone, Republic ofSingapore, Republic ofSlovakia (Slovak Republic)SloveniaSolomon IslandsSomalia, Somali RepublicSouth Africa, Republic ofSouth Georgia and the South Sandwich IslandsSpain, Spanish StateSri Lanka, Democratic Socialist Republic ofSt. HelenaSt. Kitts and NevisSt. LuciaSt. Pierre and MiquelonSt. Vincent and the GrenadinesSudan, Democratic Republic of theSuriname, Republic ofSvalbard & Jan Mayen IslandsSwaziland, Kingdom ofSweden, Kingdom ofSwitzerland, Swiss ConfederationSyrian Arab RepublicTaiwan, Province of ChinaTajikistanTanzania, United Republic ofThailand, Kingdom ofTimor-Leste, Democratic Republic ofTogo, Togolese RepublicTokelau (Tokelau Islands)Tonga, Kingdom ofTrinidad and Tobago, Republic ofTunisia, Republic ofTurkey, Republic ofTurkmenistanTurks and Caicos IslandsTuvaluUganda, Republic ofUkraineUnited Arab EmiratesUnited Kingdom of Great Britain & N. IrelandUruguay, Eastern Republic ofUzbekistanVanuatuVenezuela, Bolivarian Republic ofViet Nam, Socialist Republic ofWallis and Futuna IslandsWestern SaharaYemenZambia, Republic ofZimbabwe

Read the original post:
Best of what was new in diabetes health for 2021 - Dickson Post

A 13-year-old girl in California continues to be on a ventilator after being declared brain-dead by doctors. Although a brain-dead person is not legally alive, how much of the body will keep on working with the help of technology, and for how long?

Jahi McMath of Oakland, Calif., was declared brain-dead last month after experiencing an extremely rare complication from tonsil surgery. Jahi's family members have fought to keep their daughter on a ventilator, but a judge has ordered that the machine be turned off next week.

A person is considered brain-dead when he or she no longer has any neurological activity in the brain or brain stem meaning no electrical impulses are being sent between brain cells. Doctors perform a number of tests to determine whether someone is brain-dead, one of which checks whether the individual can initiate his or her own breath, a very primitive reflex carried out by the brain stem, said Dr. Diana Greene-Chandos, an assistant professor of neurological surgery and neurology at Ohio State University Wexner Medical Center. "It's the last thing to go," Greene-Chandos said. [10 Surprising Facts About the Brain]

In the United States and many other countries, a person is legally dead if he or she permanently loses all brain activity (brain death) or all breathing and circulatory functions. In Jahi's case, three doctors have concluded that she is brain-dead.

However, the heart's intrinsic electrical system can keep the organ beating for a short time after a person becomes brain-dead in fact, the heart can even beat outside the body, Greene-Chandos said. But without a ventilator to keep blood and oxygen moving, this beating would stop very quickly, usually in less than an hour, Greene-Chandos said.

With just a ventilator, some biological processes including kidney and gastric functions can continue for about a week, Greene-Chandos said.

Kenneth Goodman, director of the Bioethics Program at the University of Miami, stressed that such functions do not mean the person is alive. "If you're brain-dead, you're dead, but [with technology], we can make the body do some of the things it used to do when you were alive," Goodman said.

Without the brain, the body does not secrete important hormones needed to keep biological processes including gastric, kidney and immune functions running for periods longer than about a week. For example, thyroid hormone is important for regulating body metabolism, and vasopressin is needed for the kidneys to retain water.

Normal blood pressure, which is also critical for bodily functions, often cannot be maintained without blood-pressure medications in a brain-dead person, Greene-Chandos said.

A brain-dead person also cannot maintain his or her own body temperature, so the body is kept warm with blankets, a high room temperature and, sometimes, warm IV fluids, Greene-Chandos said.

The body of a brain-dead person is usually not supported for very long, Greene-Chandos said. Doctors sometimes provide support (in the form of a ventilator, hormones, fluids, etc.) for several days if the organs will be used for donation, or if the family needs more time to say good-bye, Greene-Chandos said.

If all of the criteria for brain death are met, "then it's pretty clear that there's nothing left, and we're supporting the body," Greene-Chandos said.

Greene-Chandos said Jahi's case is tragic, and as a mother, she is heartbroken for the family.

There is very little research on just how long the body of a brain-dead person can be maintained. The discussion of brain death dates back to the 1950s in France with six patients who were kept "alive" for between two and 26 days without blood flow to the brain. This generated the idea that "perhaps there's a second way to die, because these patients will eventually die," Greene-Chandos said. (Previously, a person was considered dead only when their heartbeat and breathing stopped.)

Today, with ventilators, blood-pressure augmentation and hormones, the body of a brain-dead person could, in theory, be kept functioning for a long time, perhaps indefinitely, Greene-Chandos said. But with time, Greene-Chandos added, the body of a brain-dead person becomes increasingly difficult to maintain, and the tissue is at high risk for infection.

Terri Schiavo's family, who fought to keep their brain-damaged daughter on life support for 15 years, has said they are trying to help move Jahi to another facility for long-term support. Unlike Jahi, Terri Schiavo was not brain dead, but in a vegetative state in which she had some brain activity.

Editor's note: The article has been updated to remove the incorrect statement that hair and nails grow after death.

Follow Rachael Rettner @RachaelRettner.FollowLiveScience@livescience,Facebook&Google+. Original article on LiveScience.

See original here:
Life After Brain Death: Is the Body Still 'Alive'? | Live ...

Treatment durability

Tumors commonly relapse regardless of strong initial therapeutic effects. Like most chemotherapies, stem cell therapy using a single agent generally cannot eliminate tumors. Therefore, an optimum drug combination should be rationally selected [6]. Many combination therapies have been tested to improve treatment durability. For example, IFN- immunotherapy combined with chemotherapy using a prodrug/suicide gene system has shown synergistic therapeutic effects against human colorectal cancer [69]. Irradiating tumor cells can induce production of factors that stimulate MSC invasion through integral basement membranes, increasing the number of MSCs in tumors [70]. Combining stem cell-based oncolytic virotherapy with chemoradiotherapy can minimize residual disease volumes and sensitize glioma cells to CRAd-S-pk7 (OV CRAd-Survivin-pk7) during radiotherapy [35]. Kim, et al. [71] found that TMZ sensitized glioma cells to TRAIL-induced apoptosis by modulating the apoptotic machinery, and enhanced MSC-TRAIL gene therapy antitumor effects. Epidermal growth factor receptor (EGFR), which is mutated and overexpressed in various tumors, is associated with poor prognosis and shortened survival [72]. TRAIL combined with stem cell-delivered immunoconjugates of EGFR-specific nanobodies enhanced treatment outcomes [73].

Normal stem cells share some characteristics with CSCs, including self-renewal, differentiation, and epithelial-to-mesenchymal transition capacities. Stem cell therapy may increase cancer risk, as evidence by tumor formation four years after fetal neural stem cell transplantation for ataxia-telangiectasia [74]. Thus, prevention of tumor formation by transplanted stem cells requires additional study [63]. However, whether stem cells promote the growth of certain tumors or form tumors themselves is uncertain. Karnoub, et al. demonstrated that bone-marrow-derived MSCs mixed with otherwise weakly metastatic human breast carcinoma cells increased the cancer cells metastatic potentials, allowing for tumor formation in subcutaneous xenografts [75]. The breast cancer cells promoted MSC secretion of chemokine CCL5, which acted in a paracrine fashion to increase cancer cell motility, invasion, and metastasis. Increased breast cancer cell metastatic capability was reversible and dependent on CCL5 signaling through the chemokine receptor, CCR5. Therefore, MSCs in the tumor microenvironment facilitated metastasis by reversibly changing cancer cell phenotypes.

Rosland, et al. [76] showed that spontaneous malignant transformation occurred in 45.8% (11/24) of bone marrow-derived MSC long-term (5106 weeks) cultures, indicating spontaneous malignant transformation. In vitro cell culture conditions may initiate stress-induced genomic instability, promoting the malignant phenotype. Mutation tendency has also been related to oxygen tension [77] and matrix elasticity [78]. Therefore, optimization of in vitro culture conditions is important for MSC expansion for clinical use. However, other groups present contradictory findings regarding MSC transformation tendencies. Bernardo, et al. reported that MSC remain stable and do not transform in long-term cultures [79]. Thus, stem cell fates may be largely dependent on culture environments, and implanted stem cells may contribute to the growth of certain tumors or produce tumors themselves.

Multipotent NSCs, MSCs, and HSCs appear safer for clinical use than ESCs and iPSCs. Most studies focus on pluripotent stem cells that may be highly tumorigenic. There are six strategies to eliminate any possibility of neoplastic transformation [80]. First, undifferentiated pluripotent stem cells, which are potentially tumorigenic, can be excluded from clinical preparations using antibodies that target specific surface-displayed biomarkers. Stem cell differentiation downregulates display of these biomarkers. Monoclonal antibodies may facilitate fluorescence activated cell sorting or magnetic activated cell sorting of undifferentiated, pluripotent stem cells modified with fluorochromes or superparamagnetic chelates, respectively. Second, directed differentiation of iPSCs includes monitoring the expression of differentiation lineage-specific genes. Successfully differentiated cells can be identified and sorted using recombinant reporter proteins. GFP and similar proteins work well as reporters of undifferentiated vs. differentiated cells. Undifferentiated pluripotent stem cells transformed to express GFP emit telltale fluorescence upon illumination with specific wavelengths as long as they remain undifferentiated. This facilitates their sorting out or eradication through laser ablation. Third, undifferentiated cells can be killed using toxic antibodies or antibody-guided toxins. For example, monoclonal antibodies against claudin-6, a biomarker for undifferentiated pluripotent ESCs and iPSCs, can guide toxins to these stem cells for selective, targeted killing [81]. Fourth, undifferentiated stem cells can be eradicated using cytotoxic agents, which can be applied to selectively kill pluripotent stem cells that could develop into tumors. PluriSIn#1 inhibits stearoyl-CoA desaturase-1, an enzyme involved in monounsaturated fatty acid metabolism, and induces apoptosis in treated cells [82]. PluriSIn#1 treatment selectively eliminates undifferentiated iPSCs and ESCs [83]. Fifth, potentially tumorigenic stem cells can be sensitized to prodrugs through transformation using suicide genes. The enzyme/prodrug cancer therapy strategy can also be adapted to kill undifferentiated stem cells. For example, hESCs engineered to express the HSV-TK gene were killed following GCV treatment, whereas non-transfected hESCs were unaffected [84]. Finally, differentiated refractive stem cells can be eliminated through self-induced transgenic expression of recombinant human DNases. To this end, and to improve treatment safeties and efficacies, a toxic reagent-independent feedback loop was developed to select for differentiated stem cells [85]. iPSCs were directed to differentiate into endothelial or myocardial lineages, and were then transfected with human recombinant DNASE1, DNASE1L3, DNASE2, and DFFB, guided by antiSSEA-4 and anti-TRA-1-60 synthetic antibodies. Transgenes were delivered only to pluripotent, differentiation-refractive stem cells. Thus, iPSCs that maintained their pluripotency and specific cell surface display profiles, and continued proliferating instead of differentiating, expressed the human recombinant DNases. Genomic DNA was degraded in these potentially tumorigenic stem cells, ultimately killing the cells. These six strategies could safeguard against tumor transformation in stem cell population.

Read more here:
Stem cells in cancer therapy: opportunities and challenges

1Regenerative Medicine Centre, Arabian Gulf University, Manama, Bahrain; 2Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain

Introduction: Stroke is a leading cause of death and disability worldwide. The disease is caused by reduced blood flow into the brain resulting in the sudden death of neurons. Limited spontaneous recovery might occur after stroke or brain injury, stem cell-based therapies have been used to promote these processes as there are no drugs currently on the market to promote brain recovery or neurogenesis. Adult stem cells (ASCs) have shown the ability of differentiation and regeneration and are well studied in literature. ASCs have also demonstrated safety in clinical application and, therefore, are currently being investigated as a promising alternative intervention for the treatment of stroke.Methods: Eleven studies have been systematically selected and reviewed to determine if autologous adult stem cells are effective in the treatment of stroke. Collectively, 368 patients were enrolled across the 11 trials, out of which 195 received stem cell transplantation and 173 served as control. Using data collected from the clinical outcomes, a broad comparison and a meta-analysis were conducted by comparing studies that followed a similar study design.Results: Improvement in patients clinical outcomes was observed. However, the overall results showed no clinical significance in patients transplanted with stem cells than the control population.Conclusion: Most of the trials were early phase studies that focused on safety rather than efficacy. Stem cells have demonstrated breakthrough results in the field of regenerative medicine. Therefore, study design could be improved in the future by enrolling a larger patient population and focusing more on localized delivery rather than intravenous transplantation. Trials should also introduce a more standardized method of analyzing and reporting clinical outcomes to achieve a better comparable outcome and possibly recognize the full potential that these cells have to offer.

Keywords: adult stem cells, autologous, neurogenesis, inflammation, clinical application, stroke, stroke recovery, systematic review, meta-analysis

Stroke is the second leading cause of death worldwide and one of the leading causes of disability.1 The blockade or the rupture of a blood vessel to the brain leads to either ischemic or hemorrhagic stroke, respectively.2,3 The extent and the location of the damaged brain tissue may be associated with irreversible cognitive impairment or decline in speech, comprehension, memory, and partial or total physical paralysis.4

Four chronological phases, namely hyperacute, acute, subacute, and chronic, describe the strokes cellular manifestations.5 The hyperacute phase is immediate and associated with glutamate-mediated excitotoxicity and a progressive neuronal death that can last a few hours.6 The glutamate, a potent excitatory neurotransmitter, is also an inducer of neurodegeneration following stroke.7 The acute phase, which could last over a week after the stroke, is associated with the delayed and progressive neuronal death and the infiltration of immune cells.5 The following subacute phase can extend up to three months after the stroke and is mainly associated with reduced inflammation and increased plasticity of neurons, astrocytes, microglia, and endothelial cells, allowing spontaneous recovery.8 In the chronic phase that follows, the plasticity of cells is reduced and only permits rehabilitation-induced recovery.5

The immediate treatments differ for ischemic and hemorrhagic strokes. Immediate intervention is required to restore the blood flow to the brain following an ischemic stroke. Thrombolytic agents, such as activase (Alteplase), a recombinant tissue plasminogen activator (tPA), are commonly given intravenously to dissolve the blood clots. Other more invasive approaches, such as a thrombectomy, use stents or catheters to remove the blood clot.9 Antiplatelet agents like Aspirin, anticoagulants, blood pressure medicines, or statins are generally given to reduce the risk of recurrence. Some ischemic strokes are caused by the narrowing of the carotid artery due to the accumulation of fatty plaques; a carotid endarterectomy is performed to correct the constriction.

The treatment of a hemorrhagic stroke requires a different approach. An emergency craniotomy is usually performed to remove the blood accumulating in the brain and repair the damaged blood vessels. Accumulation of cerebrospinal fluid in brain ventricles (hydrocephalus) is also a frequent complication following a hemorrhagic stroke, which requires surgery to drain the fluid. Medications to lower blood pressure are given before surgery and to prevent further seizures.10

These immediate treatments are critical to minimize the long-term consequence of the stroke but do not address the post-stroke symptoms caused by neurodegeneration. New therapeutic approaches adapted to the physiology of each phase of the stroke are currently developed. A promising therapy has been the use of stem cells.11 In this review, different clinical trials involving the use of various stem cells for the treatment of stroke are presented and compared using a meta-analysis of the published results.

To narrow down the relevant literature, a search strategy focused on original literature and reporting the clinical application of stem cells in stroke was established. An NCBI PubMed word search for stroke, stem cells, and adult stem cells yielded 146 clinical studies between 2010 and 2021. Finally, 11 studies, using autologous adult stem cells in the treatment of stroke, were considered. A PRISMA flow diagram detailing an overview of the study selection procedure and the inclusion and exclusion of papers is included in Appendix I. The inclusion criteria comprise the injection of autologous adult stem cells at any stroke stages (hyperacute, acute, sub-acute, chronic), and clinical trials whose results have been published in the last 11 years. The exclusion criteria include studies published more than 11 years ago, studies not published in English, all preclinical studies, other diseases related to stroke (ex. cardiovascular diseases), embryonic or induced pluripotent stem cells, allogeneic stem cells, and other cell therapies. Two independent researchers reviewed and filtered the 146 studies by reading the titles and abstracts. All three authors approved the final selected studies.

Stem cells are undifferentiated and unspecialized cells characterized by their ability to self-renew and their potential to differentiate into specialized cell types.12 Ischemic stroke causes severe damage to the brain cells by destroying the heterogeneous cell population and neuronal connections along with vascular systems. The regenerative potential of several types of stem cells like embryonic stem cells, neural stem cells, adult stem cells (mesenchymal stem cells), and induced pluripotent stem cells have been assessed for treating stroke.

Adult stem cells exhibit multipotency and the ability to self-renew and differentiate into specialized cell types. They have been widely used in clinical trials and a safe option thus far in treating various diseases.12,13,14 The plasticity of these cells allow their differentiation across tissue lineages when exposed to defined cell culture conditions.15 There are multiple easily accessible sources of adult stem cells, mainly the bone marrow, blood, and adipose tissue. In clinical settings, both autologous and HLA-matched allogeneic cells have been transplanted and are deemed to be safe.

Adult stem cells can secrete a variety of bioactive substances into the injured brain following a stroke in the form of paracrine signals.1618 The paracrine signals include growth factors, trophic factors, and extracellular vesicles, which may be associated with enhanced neurogenesis, angiogenesis, and synaptogenesis (Figure 1). Also, mesenchymal stem cells (MSCs) are thought to contribute to the resolution of the stroke by attenuating inflammation,19 reducing scar thickness, enhancing autophagy, normalizing microenvironmental and metabolic profiles and possibly replacing damaged cells.20

Figure 1 Schematic depicting the clinical application of different cells in stroke patients. The cells were delivered in one of three ways, intravenously, intra-arterially, or via stereotactic injections. Once administered, the cells play a role in providing paracrine signals and growth factors to facilitate angiogenesis and cell regeneration, immunomodulatory effects that serve to protect the neurons from further damage caused by inflammation, and finally, trans-differentiation of stem cells. Data from Dabrowska S, Andrzejewska A, Lukomska B, Janowski M.19 Created with BioRender.com.

A few routes of administration have been used to deliver the stem cells to the patients. The most common is through intravenous injection. Intra-arterial delivery is also performed; but this mode can be extremely painful to patients compared to an intravenous transfusion. The third approach is via stereotactic injections. This is an invasive surgery that involves injecting the cells directly into the site of affected in the brain.

Also known as mesenchymal stromal cells or medicinal signaling cells, MSCs can be derived from different sources including bone marrow, peripheral blood, lungs, heart, skeletal muscle, adipose tissue, dental pulp, dermis, umbilical cord, placenta, amniotic fluid membrane and many more.21 MSCs are characterized by positive cell surface markers, including Stro-1, CD19, CD44, CD90, CD105, CD106, CD146, and CD166. The cells are also CD14, CD34, and CD45 negative.22,23 The cells are thought to provide a niche to stem cells in normal tissue and releases paracrine factors that promote neurogenesis (Figure 2).19,20,24 During the acute and subacute stage of stroke, MSCs may inhibit inflammation, thus, reducing the incidence of debilitating damage and symptoms that may occur post-stroke.

Figure 2 Schematic describing the role of mesenchymal stem cells in stroke. The cells release different growth factors, signals, and cytokines that serve to facilitate various functions. Through the release of cytokines, they can modulate inflammation and block apoptosis. The growth factors aid in promoting angiogenesis and neurogenesis. Data from Maleki M, Ghanbarvand F, Behvarz MR, Ejtemaei M, Ghadirkhomi E.23 Created with BioRender.com.

Derived from the bone marrow, mononuclear cells contain several types of stem cells, including mesenchymal stem cells and hematopoietic progenitor cells that give rise to hematopoietic stem cells and various other differentiated cells. They can produce and secrete multiple growth factors and cytokines. They are also attracted to the lesion or damage site where they can accelerate angiogenesis and promote repair endogenously through the proliferation of the hosts neural stem cells. Mononuclear cells have also demonstrated the ability to decrease neurodegeneration, modulate inflammation, and prevent apoptosis in animal models.25,26

Blood stem cells are a small number of bone marrow stem cells that have been mobilized into the blood by hematopoietic growth factors, which regulate the differentiation and proliferation of cells. They are increasingly used in cell therapies, most recently for the regeneration of non-hematopoietic tissue, including neurons. Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used as a stimulator of hematopoiesis, which in turn amplifies the yield of peripheral blood stem cells.27

The literature review considered 11 clinical trials that satisfied the inclusion criteria. A total of 368 patients were enrolled including 179 patients treated with various types of adult stem cells. The clinical trial number 7 contained a historical control of 59 patients included in the data analysis (Figure 3). The analysis was done on the published clinical and functional outcomes of various tests such as mRS, and mBI. The analysis compared the patients clinical outcomes post stem cell therapy to the baseline clinical results. The variance in the patient population should be noted.

Figure 3 Schematic representing an overview of the total number of patients enrolled in all 11 clinical trials and the number of patients administered with each type of adult stem cell.

Abbreviations: MSC, mesenchymal stem cells; PBSC, peripheral blood stem cells; MNC, mononuclear stem cells; ADSVF, adipose derived stromal vascular fraction; ALD401, aldehyde dehydrogenase-bright stem cells.

Meta-analyses were conducted using modified Rankin scale (mRS) and Barthel Index (BI) scores. In the clinical trials, mRS and BI scores are commonly used scales to assess functional outcome in stroke patients. The BI score was developed to measures the patients performance in 10 activities of daily life from self-care to mobility. An mRS score follows a similar outcome but measures the patients independence in daily tasks rather than performance. OpenMeta[Analyst], an open-source meta-analysis software, was used to produce random-effects meta-analyses and create the forest plots. The number of patients, mean, and standard deviation (SD) of the scores were calculated to determine the study weights and create the forest plots.

All 11 clinical trials were compared based on their clinical and functional outcomes (Table 1; Figure 4). The data shows that stem cell therapy is relatively safe and viable in the treatment of stroke, indicating an improvement in patients overall health. However, when compared to the control, the improvement is not significant as patients in the control group also exhibited an improved clinical and functional outcome. Across trials that assigned a control group, the patients either received a placebo, or alternative form of treatment including physiotherapy. Variance in functional and clinical tests used to assess patients, and the number of patients enrolled in each trial results in a discrepancy in reporting. Most of the trials failed to report whether the patients suffered from an acute, subacute or chronic stroke which also affects the results of the treatments, with acute and subacute being the optimal periods to receive treatment due to cell plasticity and inhibiting unwarranted inflammation.39 The deaths in both the treatment and control population were attributed to the progression of the disease and are likely not the result of the treatment. Albeit, it has been noted down as they had occurred during the follow-up period.

Table 1 Overview of Selected Clinical Trials

Figure 4 Overview of clinical outcomes of the 11 clinical trials (N=368). (A) The chart shows the percentages of patients who have either improved, remained stable, deteriorated, or deceased. Some clinical trials are without a control arm. (B) The plot shows the overall percentage of patients that have improved after receiving either the stem cell treatment versus the standard of care. (C) The plot shows the overall percentage of patients that have remained stable and showed no clinical or functional improvement in the follow up period. (D) The plot shows the overall percentage of the patients whose condition has deteriorated in the follow up period.

A meta-analysis was conducted using modified Rankin scale (mRS) and Barthel Index (BI) scores. The results of the mRS scores were analyzed (Figure 5A; Table 2). In terms of study weights, CT6 is the highest (40.07%) as shown in Table 2. The combined results of the mRS functional test from CT1, CT5, CT6, and CT11 show a non-significant statistical heterogeneity in the studies (p-value 0.113). In conjunction, BI scores were analyzed and a meta-analysis was conducted using four comparable trials (Figure 5B; Table 3). In terms of study weights, CT3 is the highest (32.384%) as shown in Table 3. The combined results of BI scores from CT5, CT3, CT10, and CT11 show a statistical heterogeneity in the results of the studies (p-value 0.004) thus, precision of results is uncertain. More comparable studies are needed to have a better outcome. Therefore, standardized testing in trails should be considered in future trials.

Table 2 Clinical Outcomes of mRS Test

Table 3 Clinical Outcomes of BI Test

Figure 5 Meta-analysis conducted using three comparable trials. (A) Meta-analysis conducted using four comparable trials (CT1, CT5, CT6, CT11) for the mRS test. (B) Meta-analysis conducted using four comparable trials (CT3, CT5, CT10, and CT11) for the BI test.

Across all trials, patients injected with the MSCs, and other cell types did not trigger a degradation of the patient conditions demonstrating the safety of the procedures. However, the efficacy of the use of adult stem cells is less clear when compared to patients in the control group. This discrepancy could, however, exhibit improvement in patients receiving the treatment compared to the baseline clinical outcomes. However, when therapy results are compared to the patients in the control population that either received a placebo, physiotherapy, or prescribed medication, the efficacy of the use of adult stem cells is less clear.

Although multiple adult stem cell types have been used, mesenchymal stem cells have been widely used in many clinical trials. Albeit there is a consensus that the therapeutic and clinical outcomes of mesenchymal stem cell treatments are not yet significantly effective compared to the control treatment. Some trials have shown patient improvements, such as CT6 and CT8, where the investigators used PBSCs or BMMNSC, respectively. Although subjectively, the cells appear to be therapeutic, objectively, there are many limitations to the study designs included in this review. Not all the trials enrolled a control arm for a better comparison as some were only testing safety rather than efficacy. Therefore, we cannot conclude whether autologous adult stem cells are an effective therapeutic stroke treatment. Only autologous cells were included in this review as they are non-immunogenic.

Another factor to consider is the evident discrepancy in the number of patients enrolled in each trial. The trials included in this review are in Phase I and II trials, which primarily focus on safety rather than efficacy. Intravenous injection was the most used method of cell delivery due to its convenience and safety. However, it is commonly considered that this approach is not the most effective way of delivery, as the majority of the transplanted cells get absorbed by non-targeted organs, and the remaining cells find difficulty passing the blood-brain barrier. Due to this dilemma, the most obvious approach would be to inject the cells directly into the brain. However, a stereotactic procedure is invasive and will require general anesthesia, which may compromise patients health, especially ones suffering from acute ischemic stroke.40 Thus, an intra-arterial delivery seems feasible to accomplish the task as it is less invasive and might be more effective than an intravenous treatment such as the cases observed in CT3 and CT8. In CT11, the patients demonstrated a visible fmRI recovery as well as recovery of motor function in patients that have received a stem cell treatment. However, the analysis and test scores show no significance between the treatment group and the control group.

Only a few studies were comparable using a similar evaluation approach. Considering these factors, better study designs enrolling a higher number of patients in randomized clinical trial against the standard of care are needed. Moreover, a better grouping of the patients based on the type and stage of stroke may provide more relevant information for the safety and efficacy of adult stem cells for the recovery and prevention of recurrence of stroke patients.

ADSVF, Adipose-derived stromal vascular fraction; ASCs, Adult stem cells; ALD-401, Aldehyde dehydrogenase 401; BI, Barthel Index; BM-MNC, Bone marrow-derived mononuclear cells; FLAIR, Fluid attenuated inversion recovery; fMRI, Functional magnetic resonance imaging; G-CSF, Granulocyte colony-stimulating factor; MRI, Magnetic resonance imaging; MSCs, Mesenchymal stem cells; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; PBSC, Peripheral blood stem cells; SD, Standard deviation; tPA, tissue plasminogen activator.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

There is no funding to report.

We declare there is no conflict of interest.

1. Johnson W, Onuma O, Owolabi M, Sachdev S. Stroke: a global response is needed. Bull World Health Organ. 2016;94(9):634A635A. doi:10.2471/BLT.16.181636

2. Donnan G, Fisher M, Maclead M, Davis S. Stroke. Lancet. 2008;373(9674):1496. doi:10.1016/S0140-6736(09)60833-3

3. Umut Canbek YB, Imerci A, Akgn U, Yesil M, Aydin A. Characteristics of injuries caused by paragliding accidents: a cross-sectional study. World J Emerg Med. 2015;6(1):4447. doi:10.5847/wjem.j.1920

4. Roth EJ, Heinemann AW, Lovell LL, Harvey RL, McGuire JR, Diaz S. Impairment and disability: their relation during stroke rehabilitation. Arch Phys Med Rehabil. 1998;79(3):329335. doi:10.1016/S0003-9993(98)90015-6

5. Joy MT, Carmichael ST. Encouraging an excitable brain state: mechanisms of brain repair in stroke. Nat Rev Neurosci. 2021. doi:10.1038/s41583-020-00396-7

6. Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol. 2014;115:157188. doi:10.1016/j.pneurobio.2013.11.006

7. Fern R, Matute C. Glutamate receptors and white matter stroke. Neurosci Lett. 2019;694:8692. doi:10.1016/j.neulet.2018.11.031

8. Zhao L, Willing A. Progress in neurobiology enhancing endogenous capacity to repair a stroke-damaged brain: an evolving fi eld for stroke research. Prog Neurobiol. 2018;163164:526. doi:10.1016/j.pneurobio.2018.01.004

9. Hasan TF, Rabinstein AA, Middlebrooks EH, et al. Diagnosis and management of acute ischemic stroke. Mayo Clin Proc Themat Rev Neurosci. 2018;93(4):523538. doi:10.1016/j.mayocp.2018.02.013

10. Abraham MK, Chang WTW. Subarachnoid hemorrhage. Emerg Med Clin NA. 2016;34(4):901916. doi:10.1016/j.emc.2016.06.011

11. Wei L, Wei ZZ, Jiang MQ, Mohamad O, Yu SP. Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke. Prog Neurobiol. 2017. doi:10.1016/j.pneurobio.2017.03.003

12. Biehl JK, Russell B. Introduction to stem cell therapy. J Cardiovasc Nurs. 2009;24(2):98103. doi:10.1097/JCN.0b013e318197a6a5

13. Larijani B, Esfahani EN, Amini P, et al. Stem cell therapy in treatment of different diseases. Acta Med Iran. 2012;50(2):7996.

14. Lo B, Parham L. Ethical issues in stem cell research. Endocr Rev. 2009;30(3):204213. doi:10.1210/er.2008-0031

15. Wagers AJ, Weissman IL. Plasticity of adult stem cells. Cell. 2004;116(5):639648. doi:10.1016/S0092-8674(04)00208-9

16. Fernndez-Susavila H, Bugallo-Casal A, Castillo J, Campos F. Adult stem cells and induced pluripotent stem cells for stroke treatment. Front Neurol. 2019;10. doi:10.3389/fneur.2019.00908

17. Bang OY. Current status of cell therapies in stroke. Int J Stem Cells. 2009;2(1):3544. doi:10.15283/ijsc.2009.2.1.35

18. Einstein O, Ben-Hur T. The changing face of neural stem cell therapy in neurologic diseases. Arch Neurol. 2008;65(4):452456. doi:10.1001/archneur.65.4.452

19. Dabrowska S, Andrzejewska A, Lukomska B, Janowski M. Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. J Neuroinflammation. 2019;16(1):117. doi:10.1186/s12974-019-1571-8

20. Wagenaar N, Nijboer CHA, Van Bel F. Repair of neonatal brain injury: bringing stem cell-based therapy into clinical practice. Dev Med Child Neurol. 2017;59(10):9971003. doi:10.1111/dmcn.13528

21. Secunda R, Vennila R, Mohanashankar AM, Rajasundari M, Jeswanth S, Surendran R. Isolation, expansion and characterisation of mesenchymal stem cells from human bone marrow, adipose tissue, umbilical cord blood and matrix: a comparative study. Cytotechnology. 2015;67(5):793807. doi:10.1007/s10616-014-9718-z

22. Lin CS, Xin ZC, Dai J, Lue TF. Commonly used mesenchymal stem cell markers and tracking labels: limitations and challenges. Histol Histopathol. 2013;28(9):11091116. doi:10.14670/HH-28.1109

23. Maleki M, Ghanbarvand F, Behvarz MR, Ejtemaei M, Ghadirkhomi E. Comparison of mesenchymal stem cell markers in multiple human adult stem cells. Int J Stem Cells. 2014;7(2):118126. doi:10.15283/ijsc.2014.7.2.118

24. Bhartiya D. Clinical translation of stem cells for regenerative medicine: a comprehensive analysis. Circ Res. 2019;124(6):840842. doi:10.1161/CIRCRESAHA.118.313823

25. Lv W, Li WY, Xu XY, Jiang H, Bang OY. Bone marrow mesenchymal stem cells transplantation promotes the release of endogenous erythropoietin after ischemic stroke. Neural Regen Res. 2015;10(8):12651270. doi:10.4103/1673-5374.162759

26. Muir T. Peripheral blood mononuclear cells: a brief review origin of peripheral blood mononuclear cells; 2020:17.

27. Wang Z, Schuch G, Williams JK, Soker S. Peripheral blood stem cells. Handb Stem Cells. 2013;2:573586. doi:10.1016/B978-0-12-385942-6.00050-0

28. Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke.. Stem Cells. 2010;28(6):10991106. doi:10.1002/stem.430

29. Honmou O, Houkin K, Matsunaga T, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 2011;134(6):17901807. doi:10.1093/brain/awr063

30. Banerjee S. T ISSUE -S PECIFIC P ROGENITOR AND S TEM C ELLS intra-arterial immunoselected CD34 + stem cells for acute ischemic stroke; 2014.

31. Bhasin A, Padma Srivastava MV, Mohanty S, Bhatia R, Kumaran SS, Bose S. Stem cell therapy: a clinical trial of stroke. Clin Neurol Neurosurg. 2013;115(7):10031008. doi:10.1016/j.clineuro.2012.10.015

32. Prasad K, Sharma A, Garg A, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. 2014;45(12):36183624. doi:10.1161/STROKEAHA.114.007028

33. Chen DC, Lin S-Z, Fan J-R, et al. Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized Phase II study. Cell Transplantation. 2014;23(12):15991612. doi:10.3727/096368914X678562

34. Taguchi A, Sakai C, Soma T, et al. Intravenous autologous bone marrow mononuclear cell transplantation for stroke: phase1/2a clinical trial in a homogeneous group of stroke patients. Stem Cells Dev. 2015;24(19):22072218. doi:10.1089/scd.2015.0160

35. Bhatia V, Gupta V, Khurana D, Sharma RR, Khandelwal N. Randomized assessment of the safety and efficacy of intra-arterial infusion of autologous stem cells in subacute ischemic stroke. Am J Neuroradiol. 2018;39(5):899904. doi:10.3174/ajnr.A5586

36. Duma C, Kopyov O, Kopyov A, et al. Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year Phase 1 study of 113 injections in 31 patients. Mol Biol Rep. 2019;46(5):52575272. doi:10.1007/s11033-019-04983-5

37. Savitz SI, Yavagal D, Rappard G, et al. A phase 2 randomized, sham-controlled trial of internal carotid artery infusion of autologous bone marrow-derived ALD-401 cells in patients with recent stable ischemic stroke (RECOVER-stroke). Circulation. 2019;139(2):192205. doi:10.1161/CIRCULATIONAHA.117.030659

38. Jaillard A, Hommel M, Moisan A, et al. Autologous mesenchymal stem cells improve motor recovery in subacute ischemic stroke: a randomized clinical trial. Transl Stroke Res. 2020;11(5):910923. doi:10.1007/s12975-020-00787-z

39. Kwak K-A, Kwon H-B, Lee JW, Park Y-S. Current perspectives regarding stem cell-based therapy for ischemic stroke. Curr Pharm Des. 2018;24(28):33323340. doi:10.2174/1381612824666180604111806

40. Anastasian ZH. Anaesthetic management of the patient with acute ischaemic stroke. Br J Anaesth. 2014;113:ii9ii16. doi:10.1093/bja/aeu372

Read the original post:
Autologous Adult Stem Cells in the Treatment of Stroke | SCCAA - Dove Medical Press

Introduction

Given the multi-lineage differentiation abilities of mesenchymal stem cells (MSCs) isolated from different tissues and organs, MSCs have been widely used in various medical fields, particularly regenerative medicine.13 The representative sources of MSCs are bone marrow, adipose, periodontal, muscle, and umbilical cord blood.410 Interestingly, slight differences have been reported in the characteristics of MSCs depending on the different sources, including their population in source tissues, immunosuppressive activities, proliferation, and resistance to cellular aging.11 Bone marrow-derived MSCs (BM-MSCs) are the most intensively studied and show clinically promising results for cartilage and bone regeneration.11 However, the isolation procedures for BM-MSCs are complicated because bone marrow contains a relatively small fraction of MSCs (0.0010.01% of the cells in bone marrow).12 Furthermore, bone marrow aspiration to harvest MSCs in human bones is a painful procedure and the slower proliferation rate of BM-MSCs is a clinical limitation.13 In comparison with BM-MSCs, adipose-derived MSCs (AD-MSCs) are relatively easy to collect and can produce up to 500 times the cell population of BM-MSCs.14 AD-MSCs showed a greater ability to regenerate damaged cartilage and bone tissues with increased immunosuppressive ability.14,15 Umbilical cord blood-derived MSCs (UC-MSCs) proliferate faster than BM-MSCs and are resistant to significant cellular aging.11

MSCs have been investigated and gained worldwide attention as potential therapeutic candidates for incurable diseases such as arthritis, spinal cord injury, and cardiac disease.3,1623 In particular, the inherent tropism of MSCs to inflammatory sites has been thoroughly studied.24 This inherent tropism, also known as homing ability, originates from the recognition of various chemokine sources in inflamed tissues, where profiled chemokines are continuously secreted and the MSCs migrate to the chemokines in a concentration-dependent manner.24 Rheumatoid arthritis (RA) is a representative inflammatory disease that primarily causes inflammation in the joints, and this long-term autoimmune disorder causes worsening pain and stiffness following rest. RA affects approximately 24.5 million people as of 2015, but only symptomatic treatments such as pain medications, steroids, and nonsteroidal anti-inflammatory drugs (NSAIDs), or slow-acting drugs that inhibit the rapid progression of RA, such as disease-modifying antirheumatic drugs (DMARDs) are currently available. However, RA drugs have adverse side effects, including hepatitis, osteoporosis, skeletal fracture, steroid-induced arthroplasty, Cushings syndrome, gastrointestinal (GI) intolerance, and bleeding.2527 Thus, MSCs are rapidly emerging as the next generation of arthritis treatment because they not only recognize and migrate toward chemokines secreted in the inflamed joints but also regulate inflammatory progress and repair damaged cells.28

However, MSCs are associated with many challenges that need to be overcome before they can be used in clinical settings.2931 One of the main challenges is the selective accumulation of systemically administered MSCs in the lungs and liver when they are administered intravenously, leading to insufficient concentrations of MSCs in the target tissues.32,33 In addition, most of the administered MSCs are typically initially captured by macrophages in the lungs, liver, and spleen.3234 Importantly, the viability and migration ability of MSCs injected in vivo differed from results previously reported as favorable therapeutic effects and migration efficiency in vitro.35

To improve the delivery of MSCs, researchers have focused on chemokines, which are responsible for MSCs ability to move.36 The chemokine receptors are the key proteins on MSCs that recognize chemokines, and genetic engineering of MSCs to overexpress the chemokine receptor can improve the homing ability, thus enhancing their therapeutic efficacy.37 Genetic engineering is a convenient tool for modifying native or non-native genes, and several technologies for genetic engineering exist, including genome editing, gene knockdown, and replacement with various vectors.38,39 However, safety issues that prevent clinical use persist, for example, genome integration, off-target effects, and induction of immune response.40 In this regard, MSC mimicking nanoencapsulations can be an alternative strategy for maintaining the homing ability of MSCs and overcoming the current safety issues.4143 Nanoencapsulation involves entrapping the core nanoparticles of solids or liquids within nanometer-sized capsules of secondary materials.44

MSC mimicking nanoencapsulation uses the MSC membrane fraction as the capsule and targeting molecules, that is chemokine receptors, with several types of nanoparticles, as the core.45,46 MSC mimicking nanoencapsulation consists of MSC membrane-coated nanoparticles, MSC-derived artificial ectosomes, and MSC membrane-fused liposomes. Nano drug delivery is an emerging field that has attracted significant interest due to its unique characteristics and paved the way for several unique applications that might solve many problems in medicine. In particular, the nanoscale size of nanoparticles (NPs) enhances cellular uptake and can optimize intracellular pathways due to their intrinsic physicochemical properties, and can therefore increase drug delivery to target tissues.47,48 However, the inherent targeting ability resulting from the physicochemical properties of NPs is not enough to target specific tissues or damaged tissues, and additional studies on additional ligands that can bind to surface receptors on target cells or tissues have been performed to improve the targeting ability of NPs.49 Likewise, nanoencapsulation with cell membranes with targeting molecules and encapsulation of the core NPs with cell membranes confer the targeting ability of the source cell to the NPs.50,51 Thus, MSC mimicking nanoencapsulation can mimic the superior targeting ability of MSCs and confer the advantages of each core NP. In addition, MSC mimicking nanoencapsulations have improved circulation time and camouflaging from phagocytes.52

This review discusses the mechanism of MSC migration to inflammatory sites, addresses the potential strategy for improving the tropism of MSCs using genetic engineering, and discusses the promising therapeutic agent, MSC mimicking nanoencapsulations.

The MSC migration mechanism can be exploited for diverse clinical applications.53 The MSC migration mechanism can be divided into five stages: rolling by selectin, activation of MSCs by chemokines, stopping cell rolling by integrin, transcellular migration, and migration to the damaged site (Figure 1).54,55 Chemokines are secreted naturally by various cells such as tumor cells, stromal cells, and inflammatory cells, maintaining high chemokine concentrations in target cells at the target tissue and inducing signal cascades.5658 Likewise, MSCs express a variety of chemokine receptors, allowing them to migrate and be used as new targeting vectors.5961 MSC migration accelerates depending on the concentration of chemokines, which are the most important factors in the stem cell homing mechanism.62,63 Chemokines consist of various cytokine subfamilies that are closely associated with the migration of immune cells. Chemokines are divided into four classes based on the locations of the two cysteine (C) residues: CC-chemokines, CXC-chemokine, C-chemokine, and CX3 Chemokine.64,65 Each chemokine binds to various MSC receptors and the binding induces a chemokine signaling cascade (Table 1).56,66

Table 1 Chemokine and Chemokine Receptors for Different Chemokine Families

Figure 1 Representation of stem cell homing mechanism.

The mechanisms underlying MSC and leukocyte migration are similar in terms of their migratory dynamics.55 P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin ligand-1 (ESL-1) are major proteins involved in leukocyte migration that interact with P-selectin and E-selectin present in vascular endothelial cells. However, these promoters are not present in MSCs (Figure 2).53,67

Figure 2 Differences in adhesion protein molecules between leukocytes and mesenchymal stem cells during rolling stages and rolling arrest stage of MSC. (A) The rolling stage of leukocytes starts with adhesion to endothelium with ESL-1 and PSGL-1 on leukocytes. (B) The rolling stage of MSC starts with the adhesion to endothelium with Galectin-1 and CD24 on MSC, and the rolling arrest stage was caused by chemokines that were encountered in the rolling stage and VLA-4 with a high affinity for VACM present in endothelial cells.

Abbreviations: ESL-1, E-selectin ligand-1; PSGL-1, P-selectin glycoprotein ligand-1 VLA-4, very late antigen-4; VCAM, vascular cell adhesion molecule-1.

The initial rolling is facilitated by selectins expressed on the surface of endothelial cells. Various glycoproteins on the surface of MSCs can bind to the selectins and continue the rolling process.68 However, the mechanism of binding of the glycoprotein on MSCs to the selectins is still unclear.69,70 P-selectins and E-selectins, major cell-cell adhesion molecules expressed by endothelial cells, adhere to migrated cells adjacent to endothelial cells and can trigger the rolling process.71 For leukocyte migration, P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin ligand-1 (ESL-1) expressed on the membranes of leukocytes interact with P-selectins and E-selectins on the endothelial cells, initiating the process.72,73 As already mentioned, MSCs express neither PSGL-1 nor ESL-1. Instead, they express galectin-1 and CD24 on their surfaces, and these bind to E-selectin or P-selectin (Figure 2).7476

In the migratory activation step, MSC receptors are activated in response to inflammatory cytokines, including CXCL12, CXCL8, CXCL4, CCL2, and CCL7.77 The corresponding activation of chemokine receptors of MSCs in response to inflammatory cytokines results in an accumulation of MSCs.58,78 For example, inflamed tissues release inflammatory cytokines,79 and specifically, fibroblasts release CXCL12, which further induces the accumulation of MSCs through ligandreceptor interaction after exposure to hypoxia and cytokine-rich environments in the rat model of inflammation.7982 Previous studies have reported that overexpressing CXCR4, which is a receptor to recognize CXCL12, in MSCs improves the homing ability of MSCs toward inflamed sites.83,84 In short, cytokines are significantly involved in the homing mechanism of MSCs.53

The rolling arrest stage is facilitated by integrin 41 (VLA-4) on MSC.85 VLA-4 is expressed by MSCs which are first activated by CXCL-12 and TNF- chemokines, and activated VLA-4 binds to VCAM-1 expressed on endothelial cells to stop the rotational movement (Figure 2).86,87

Karp et al categorized the migration of MSCs as either systemic homing or non-systemic homing. Systemic homing refers to the process of migration through blood vessels and then across the vascular endothelium near the inflamed site.67,88 The process of migration after passing through the vessels or local injection is called non-systemic homing. In non-systemic migration, stem cells migrate through a chemokine concentration gradient (Figure 3).89 MSCs secrete matrix metalloproteinases (MMPs) during migration. The mechanism underlying MSC migration is currently undefined but MSC migration can be advanced by remodeling the matrix through the secretion of various enzymes.9093 The migration of MSCs to the damaged area is induced by chemokines released from the injured site, such as IL-8, TNF-, insulin-like growth factor (IGF-1), and platelet-derived growth factors (PDGF).9496 MSCs migrate toward the damaged area following a chemokine concentration gradient.87

Figure 3 Differences between systemic and non-systemic homing mechanisms. Both systemic and non-systemic homing to the extracellular matrix and stem cells to their destination, MSCs secrete MMPs and remodel the extracellular matrix.

Abbreviation: MMP, matrix metalloproteinase.

RA is a chronic inflammatory autoimmune disease characterized by distinct painful stiff joints and movement disorders.97 RA affects approximately 1% of the worlds population.98 RA is primarily induced by macrophages, which are involved in the innate immune response and are also involved in adaptive immune responses, together with B cells and T cells.99 Inflammatory diseases are caused by high levels of inflammatory cytokines and a hypoxic low-pH environment in the joints.100,101 Fibroblast-like synoviocytes (FLSs) and accumulated macrophages and neutrophils in the synovium of inflamed joints also express various chemokines.102,103 Chemokines from inflammatory reactions can induce migration of white blood cells and stem cells, which are involved in angiogenesis around joints.101,104,105 More than 50 chemokines are present in the rheumatoid synovial membrane (Table 2). Of the chemokines in the synovium, CXCL12, MIP1-a, CXCL8, and PDGF are the main ones that attract MSCs.106 In the RA environment, CXCL12, a ligand for CXCR4 on MSCs, had 10.71 times higher levels of chemokines than in the normal synovial cell environment. MIP-1a, a chemokine that gathers inflammatory cells, is a ligand for CCR1, which is normally expressed on MSC.107,108 CXCL8 is a ligand for CXCR1 and CXCR2 on MSCs and induces the migration of neutrophils and macrophages, leading to ROS in synovial cells.59 PDGF is a regulatory peptide that is upregulated in the synovial tissue of RA patients.109 PDGF induces greater MSC migration than CXCL12.110 Importantly, stem cells not only have the homing ability to inflamed joints but also have potential as cell therapy with the anti-apoptotic, anti-catabolic, and anti-fibrotic effect of MSC.111 In preclinical trials, MSC treatment has been extensively investigated in collagen-induced arthritis (CIA), a common autoimmune animal model used to study RA. In the RA model, MSCs downregulated inflammatory cytokines such as IFN-, TNF-, IL-4, IL-12, and IL1, and antibodies against collagen, while anti-inflammatory cytokines, such as tumor necrosis factor-inducible gene 6 protein (TSG-6), prostaglandin E2 (PGE2), transforming growth factor-beta (TGF-), IL-10, and IL-6, were upregulated.112116

Table 2 Rheumatoid Arthritis (RA) Chemokines Present in the Pathological Environment and Chemokine Receptors Present in Mesenchymal Stem Cells

Genetic engineering can improve the therapeutic potential of MSCs, including long-term survival, angiogenesis, differentiation into specific lineages, anti- and pro-inflammatory activity, and migratory properties (Figure 4).117,118 Although MSCs already have an intrinsic homing ability, the targeting ability of MSCs and their derivatives, such as membrane vesicles, which are utilized to produce MSC mimicking nanoencapsulation, can be enhanced.118 The therapeutic potential of MSCs can be magnified by reprogramming MSCs via upregulation or downregulation of their native genes, resulting in controlled production of the target protein, or by introducing foreign genes that enable MSCs to express native or non-native products, for example, non-native soluble tumor necrosis factor (TNF) receptor 2 can inhibit TNF-alpha signaling in RA therapies.28

Figure 4 Genetic engineering of mesenchymal stem cells to enhance therapeutic efficacy.

Abbreviations: Sfrp2, secreted frizzled-related protein 2; IGF1, insulin-like growth factor 1; IL-2, interleukin-2; IL-12, interleukin-12; IFN-, interferon-beta; CX3CL1, C-X3-C motif chemokine ligand 1; VEGF, vascular endothelial growth factor; HGF, human growth factor; FGF, fibroblast growth factor; IL-10, interleukin-10; IL-4, interleukin-4; IL18BP, interleukin-18-binding protein; IFN-, interferon-alpha; SDF1, stromal cell-derived factor 1; CXCR4, C-X-C motif chemokine receptor 4; CCR1, C-C motif chemokine receptor 1; BMP2, bone morphogenetic protein 2; mHCN2, mouse hyperpolarization-activated cyclic nucleotide-gated.

MSCs can be genetically engineered using different techniques, including by introducing particular genes into the nucleus of MSCs or editing the genome of MSCs (Figure 5).119 Foreign genes can be transferred into MSCs using liposomes (chemical method), electroporation (physical method), or viral delivery (biological method). Cationic liposomes, also known as lipoplexes, can stably compact negatively charged nucleic acids, leading to the formation of nanomeric vesicular structure.120 Cationic liposomes are commonly produced with a combination of a cationic lipid such as DOTAP, DOTMA, DOGS, DOSPA, and neutral lipids, such as DOPE and cholesterol.121 These liposomes are stable enough to protect their bound nucleic acids from degradation and are competent to enter cells via endocytosis.120 Electroporation briefly creates holes in the cell membrane using an electric field of 1020 kV/cm, and the holes are then rapidly closed by the cells membrane repair mechanism.122 Even though the electric shock induces irreversible cell damage and non-specific transport into the cytoplasm leads to cell death, electroporation ensures successful gene delivery regardless of the target cell or organism. Viral vectors, which are derived from adenovirus, adeno-associated virus (AAV), or lentivirus (LV), have been used to introduce specific genes into MSCs. Recombinant lentiviral vectors are the most widely used systems due to their high tropism to dividing and non-dividing cells, transduction efficiency, and stable expression of transgenes in MSCs, but the random genome integration of transgenes can be an obstacle in clinical applications.123 Adenovirus and AAV systems are appropriate alternative strategies because currently available strains do not have broad genome integration and a strong immune response, unlike LV, thus increasing success and safety in clinical trials.124 As a representative, the Oxford-AstraZeneca COVID-19 vaccine, which has been authorized in 71 countries as a vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spread globally and led to the current pandemic, transfers the spike protein gene using an adenovirus-based viral vector.125 Furthermore, there are two AAV-based gene therapies: Luxturna for rare inherited retinal dystrophy and Zolgensma for spinal muscular atrophy.126

Figure 5 Genetic engineering techniques used in the production of bioengineered mesenchymal stem cells.

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 were recently used for genome editing and modification because of their simpler design and higher efficiency for genome editing, however, there are safety issues such as off-target effects that induce mutations at sites other than the intended target site.127 The foreign gene is then commonly transferred into non-integrating forms such as plasmid DNA and messenger RNA (mRNA).128

The gene expression machinery can also be manipulated at the cytoplasmic level through RNA interference (RNAi) technology, inhibition of gene expression, or translation using neutralizing targeted mRNA molecules with sequence-specific small RNA molecules such as small interfering RNA (siRNA) or microRNA (miRNA).129 These small RNAs can form enzyme complexes that degrade mRNA molecules and thus decrease their activity by inhibiting translation. Moreover, the pre-transcriptional silencing mechanism of RNAi can induce DNA methylation at genomic positions complementary to siRNA or miRNA with enzyme complexes.

CXC chemokine receptor 4 (CXCR4) is one of the most potent chemokine receptors that is genetically engineered to enhance the migratory properties of MSCs.130 CXCR4 is a chemokine receptor specific for stromal-derived factor-1 (SDF-1), also known as CXC motif chemokine 12 (CXCL12), which is produced by damaged tissues, such as the area of inflammatory bone destruction.131 Several studies on engineering MSCs to increase the expression of the CXCR4 gene have reported a higher density of the CXCR4 receptor on their outer cell membrane and effectively increased the migration of MSCs toward SDF-1.83,132,133 CXC chemokine receptor 7 (CXCR7) also had a high affinity for SDF-1, thus the SDF-1/CXCR7 signaling axis was used to engineer the MSCs.134 CXCR7-overexpressing MSCs in a cerebral ischemia-reperfusion rat hippocampus model promoted migration based on an SDF-1 gradient, cooperating with the SDF-1/CXCR4 signaling axis (Figure 6).37

Figure 6 Engineered mesenchymal stem cells with enhanced migratory abilities.

Abbreviations: CXCR4, C-X-C motif chemokine receptor 4; CXCR7, C-X-C motif chemokine receptor 7; SDF1, stromal cell-derived factor 1; CXCR1, C-X-C motif chemokine receptor 1; IL-8, interleukin-8; Aqp1, aquaporin 1; FAK, focal adhesion kinase.

CXC chemokine receptor 1 (CXCR1) enhances MSC migratory properties.59 CXCR1 is a receptor for IL-8, which is the primary cytokine involved in the recruitment of neutrophils to the site of damage or infection.135 In particular, the IL-8/CXCR1 axis is a key factor for the migration of MSCs toward human glioma cell lines, such as U-87 MG, LN18, U138, and U251, and CXCR1-overexpressing MSCs showed a superior capacity to migrate toward glioma cells and tumors in mice bearing intracranial human gliomas.136

The migratory properties of MSCs were also controlled via aquaporin-1 (Aqp1), which is a water channel molecule that transports water across the cell membrane and regulates endothelial cell migration.137 Aqp1-overexpressing MSCs showed enhanced migration to fracture gap of a rat fracture model with upregulated focal adhesion kinase (FAK) and -catenin, which are important regulators of cell migration.138

Nur77, also known as nerve growth factor IB or NR4A1, and nuclear receptor-related 1 (Nurr1), can play a role in improving the migratory capabilities of MSCs.139,140 The migrating MSCs expressed higher levels of Nur77 and Nurr1 than the non-migrating MSCs, and overexpression of these two nuclear receptors functioning as transcription factors enhanced the migration of MSCs toward SDF-1. The migration of cells is closely related to the cell cycle, and normally, cells in the late S or G2/M phase do not migrate.141 The overexpression of Nur77 and Nurr1 increased the proportion of MSCs in the G0/G1-phase similar to the results of migrating MSCs had more cells in the G1-phase.

MSC mimicking nanoencapsulations are nanoparticles combined with MSC membrane vesicles and these NPs have the greatest advantages as drug delivery systems due to the sustained homing ability of MSCs as well as the advantages of NPs. Particles sized 10150 nm have great advantages in drug delivery systems because they can pass more freely through the cell membrane by the interaction with biomolecules, such as clathrin and caveolin, to facilitate uptake across the cell membrane compared with micron-sized materials.142,143 Various materials have been used to formulate NPs, including silica, polymers, metals, and lipids.144,145 NPs have an inherent ability, called passive targeting, to accumulate at specific sites based on their physicochemical properties such as size, surface charge, surface hydrophilicity, and geometry.146148 However, physicochemical properties are not enough to target specific tissues or damaged tissues, and thus active targeting is a clinically approved strategy involving the addition of ligands that can bind to surface receptors on target cells or tissues.149,150 MSC mimicking nanoencapsulation uses natural or genetically engineered MSC membranes to coat synthetic NPs, producing artificial ectosomes and fusing them with liposomes to increase their targeting ability (Figure 7).151 Especially, MSCs have been studied for targeting inflammation and regenerative drugs, and the mechanism and efficacy of migration toward inflamed tissues have been actively investigated.152 MSC mimicking nanoencapsulation can mimic the well-known migration ability of MSCs and can be equally utilized without safety issues from the direct application of using MSCs. Furthermore, cell membrane encapsulations have a wide range of functions, including prolonged blood circulation time and increased active targeting efficacy from the source cells.153,154 MSC mimicking encapsulations enter recipient cells using multiple pathways.155 MSC mimicking encapsulations can fuse directly with the plasma membrane and can also be taken up through phagocytosis, micropinocytosis, and endocytosis mediated by caveolin or clathrin.156 MSC mimicking encapsulations can be internalized in a highly cell type-specific manner that depends on the recognition of membrane surface molecules by the cell or tissue.157 For example, endothelial colony-forming cell (ECFC)-derived exosomes were shown CXCR4/SDF-1 interaction and enhanced delivery toward the ischemic kidney, and Tspan8-alpha4 complex on lymph node stroma derived extracellular vesicles induced selective uptake by endothelial cells or pancreatic cells with CD54, serving as a major ligand.158,159 Therefore, different source cells may contain protein signals that serve as ligands for other cells, and these receptorligand interactions maximized targeted delivery of NPs.160 This natural mechanism inspired the application of MSC membranes to confer active targeting to NPs.

Figure 7 Mesenchymal stem cell mimicking nanoencapsulation.

Cell membrane-coated NPs (CMCNPs) are biomimetic strategies developed to mimic the properties of cell membranes derived from natural cells such as erythrocytes, white blood cells, cancer cells, stem cells, platelets, or bacterial cells with an NP core.161 Core NPs made of polymer, silica, and metal have been evaluated in attempts to overcome the limitations of conventional drug delivery systems but there are also issues of toxicity and reduced biocompatibility associated with the surface properties of NPs.162,163 Therefore, only a small number of NPs have been approved for medical application by the FDA.164 Coating with cell membrane can enhance the biocompatibility of NPs by improving immune evasion, enhancing circulation time, reducing RES clearance, preventing serum protein adsorption by mimicking cell glycocalyx, which are chemical determinants of self at the surfaces of cells.151,165 Furthermore, the migratory properties of MSCs can also be transferred to NPs by coating them with the cell membrane.45 Coating NPs with MSC membranes not only enhances biocompatibility but also maximizes the therapeutic effect of NPs by mimicking the targeting ability of MSCs.166 Cell membrane-coated NPs are prepared in three steps: extraction of cell membrane vesicles from the source cells, synthesis of the core NPs, and fusion of the membrane vesicles and core NPs to produce cell membrane-coated NPs (Figure 8).167 Cell membrane vesicles, including extracellular vesicles (EVs), can be harvested through cell lysis, mechanical disruption, and centrifugation to isolate, purify the cell membrane vesicles, and remove intracellular components.168 All the processes must be conducted under cold conditions, with protease inhibitors to minimize the denaturation of integral membrane proteins. Cell lysis, which is classically performed using mechanical lysis, including homogenization, sonication, or extrusion followed by differential velocity centrifugation, is necessary to remove intracellular components. Cytochalasin B (CB), a drug that affects cytoskeletonmembrane interactions, induces secretion of membrane vesicles from source cells and has been used to extract the cell membrane.169 The membrane functions of the source cells are preserved in CB-induced vesicles, forming biologically active surface receptors and ion pumps.170 Furthermore, CB-induced vesicles can encapsulate drugs and NPs successfully, and the vesicles can be harvested by centrifugation without a purification step to remove nuclei and cytoplasm.171 Clinically translatable membrane vesicles require scalable production of high volumes of homogeneous vesicles within a short period. Although mechanical methods (eg, shear stress, ultrasonication, or extrusion) are utilized, CB-induced vesicles have shown potential for generating membrane encapsulation for nano-vectors.168 The advantages of CB-induced vesicles versus other methods are compared in Table 3.

Table 3 Comparison of Membrane Vesicle Production Methods

Figure 8 MSC membrane-coated nanoparticles.

Abbreviations: EVs, extracellular vesicles; NPs, nanoparticles.

After extracting cell membrane vesicles, synthesized core NPs are coated with cell membranes, including surface proteins.172 Polymer NPs and inorganic NPs are adopted as materials for the core NPs of CMCNPs, and generally, polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), chitosan, and gelatin are used. PLGA has been approved by FDA is the most common polymer of NPs.173 Biodegradable polymer NPs have gained considerable attention in nanomedicine due to their biocompatibility, nontoxic properties, and the ability to modify their surface as a drug carrier.174 Inorganic NPs are composed of gold, iron, copper, and silicon, which have hydrophilic, biocompatible, and highly stable properties compared with organic materials.175 Furthermore, some photosensitive inorganic NPs have the potential for use in photothermal therapy (PTT) and photodynamic therapy (PDT).176 The fusion of cell membrane vesicles and core NPs is primarily achieved via extrusion or sonication.165 Cell membrane coating of NPs using mechanical extrusion is based on a different-sized porous membrane where core NPs and vesicles are forced to generate vesicle-particle fusion.177 Ultrasonic waves are applied to induce the fusion of vesicles and NPs. However, ultrasonic frequencies need to be optimized to improve fusion efficiency and minimize drug loss and protein degradation.178

CMCNPs have extensively employed to target and treat cancer using the membranes obtained from red blood cell (RBC), platelet and cancer cell.165 In addition, membrane from MSC also utilized to target tumor and ischemia with various types of core NPs, such as MSC membrane coated PLGA NPs targeting liver tumors, MSC membrane coated gelatin nanogels targeting HeLa cell, MSC membrane coated silica NPs targeting HeLa cell, MSC membrane coated PLGA NPs targeting hindlimb ischemia, and MSC membrane coated iron oxide NPs for targeting the ischemic brain.179183 However, there are few studies on CMCNPs using stem cells for the treatment of arthritis. Increased targeting ability to arthritis was introduced using MSC-derived EVs and NPs.184,185 MSC membrane-coated NPs are proming strategy for clearing raised concerns from direct use of MSC (with or without NPs) in terms of toxicity, reduced biocompatibility, and poor targeting ability of NPs for the treatment of arthritis.

Exosomes are natural NPs that range in size from 40 nm to 120 nm and are derived from the multivesicular body (MVB), which is an endosome defined by intraluminal vesicles (ILVs) that bud inward into the endosomal lumen, fuse with the cell surface, and are then released as exosomes.186 Because of their ability to express receptors on their surfaces, MSC-derived exosomes are also considered potential candidates for targeting.187 Exosomes are commonly referred to as intracellular communication molecules that transfer various compounds through physiological mechanisms such as immune response, neural communication, and antigen presentation in diseases such as cancer, cardiovascular disease, diabetes, and inflammation.188

However, there are several limitations to the application of exosomes as targeted therapeutic carriers. First, the limited reproducibility of exosomes is a major challenge. In this field, the standardized techniques for isolation and purification of exosomes are lacking, and conventional methods containing multi-step ultracentrifugation often lead to contamination of other types of EVs. Furthermore, exosomes extracted from cell cultures can vary and display inconsistent properties even when the same type of donor cells were used.189 Second, precise characterization studies of exosomes are needed. Unknown properties of exosomes can hinder therapeutic efficiencies, for example, when using exosomes as cancer therapeutics, the use of cancer cell-derived exosomes should be avoided because cancer cell-derived exosomes may contain oncogenic factors that may contribute to cancer progression.190 Finally, cost-effective methods for the large-scale production of exosomes are needed for clinical application. The yield of exosomes is much lower than EVs. Depending on the exosome secretion capacity of donor cells, the yield of exosomes is restricted, and large-scale cell culture technology for the production of exosomes is high difficulty and costly and isolation of exosomes is the time-consuming and low-efficient method.156

Ectosome is an EV generated by outward budding from the plasma membrane followed by pinching off and release to the extracellular parts. Recently, artificially produced ectosome utilized as an alternative to exosomes in targeted therapeutics due to stable productivity regardless of cell type compared with conventional exosome. Artificial ectosomes, containing modified cargo and targeting molecules have recently been introduced for specific purposes (Figure 9).191,192 Artificial ectosomes are typically prepared by breaking bigger cells or cell membrane fractions into smaller ectosomes, similar size to natural exosomes, containing modified cargo such as RNA molecules, which control specific genes, and chemical drugs such as anticancer drugs.193 Naturally secreted exosomes in conditioned media from modified source cells can be harvested by differential ultracentrifugation, density gradients, precipitation, filtration, and size exclusion chromatography for exosome separation.194 Even though there are several commercial kits for isolating exosomes simply and easily, challenges in compliant scalable production on a large scale, including purity, homogeneity, and reproducibility, have made it difficult to use naturally secreted exosomes in clinical settings.195 Therefore, artificially produced ectosomes are appropriate for use in clinical applications, with novel production methods that can meet clinical production criteria. Production of artificially produced ectosomes begins by breaking the cell membrane fraction of cultured cells and then using them to produce cell membrane vesicles to form ectosomes. As mentioned above, cell membrane vesicles are extracted from source cells in several ways, and cell membrane vesicles are extracted through polycarbonate membrane filters to reduce the mean size to a size similar to that of natural exosomes.196 Furthermore, specific microfluidic devices mounted on microblades (fabricated in silicon nitride) enable direct slicing of living cells as they flow through the hydrophilic microchannels of the device.197 The sliced cell fraction reassembles and forms ectosomes. There are several strategies for loading exogenous therapeutic cargos such as drugs, DNA, RNA, lipids, metabolites, and proteins, into exosomes or artificial ectosomes in vitro: electroporation, incubation for passive loading of cargo or active loading with membrane permeabilizer, freeze and thaw cycles, sonication, and extrusion.198 In addition, protein or RNA molecules can be loaded by co-expressing them in source cells via bio-engineering, and proteins designed to interact with the protein inside the cell membrane can be loaded actively into exosomes or artificial ectosomes.157 Targeting molecules at the surface of exosomes or artificial ectosomes can also be engineered in a manner similar to the genetic engineering of MSCs.

Figure 9 Mesenchymal stem cell-derived exosomes and artificial ectosomes. (A) Wound healing effect of MSC-derived exosomes and artificial ectosomes,231 (B) treatment of organ injuries by MSC-derived exosomes and artificial ectosomes,42,232234 (C) anti-cancer activity of MSC-derived exosomes and artificial ectosomes.200,202,235

Most of the exosomes derived from MSCs for drug delivery have employed miRNAs or siRNAs, inhibiting translation of specific mRNA, with anticancer activity, for example, miR-146b, miR-122, and miR-379, which are used for cancer targeting by membrane surface molecules on MSC-derived exosomes.199201 Drugs such as doxorubicin, paclitaxel, and curcumin were also loaded into MSC-derived exosomes to target cancer.202204 However, artificial ectosomes derived from MSCs as arthritis therapeutics remains largely unexplored area, while EVs, mixtures of natural ectosomes and exosomes, derived from MSCs have studied in the treatment of arthritis.184 Artificial ectosomes with intrinsic tropism from MSCs plus additional targeting ability with engineering increase the chances of ectosomes reaching target tissues with ligandreceptor interactions before being taken up by macrophages.205 Eventually, this will decrease off-target binding and side effects, leading to lower therapeutic dosages while maintaining therapeutic efficacy.206,207

Liposomes are spherical vesicles that are artificially synthesized through the hydration of dry phospholipids.208 The clinically available liposome is a lipid bilayer surrounding a hollow core with a diameter of 50150 nm. Therapeutic molecules, such as anticancer drugs (doxorubicin and daunorubicin citrate) or nucleic acids, can be loaded into this hollow core for delivery.209 Due to their amphipathic nature, liposomes can load both hydrophilic (polar) molecules in an aqueous interior and hydrophobic (nonpolar) molecules in the lipid membrane. They are well-established biomedical applications and are the most common nanostructures used in advanced drug delivery.210 Furthermore, liposomes have several advantages, including versatile structure, biocompatibility, low toxicity, non-immunogenicity, biodegradability, and synergy with drugs: targeted drug delivery, reduction of the toxic effect of drugs, protection against drug degradation, and enhanced circulation half-life.211 Moreover, surfaces can be modified by either coating them with a functionalized polymer or PEG chains to improve targeted delivery and increase their circulation time in biological systems.212 Liposomes have been investigated for use in a wide variety of therapeutic applications, including cancer diagnostics and therapy, vaccines, brain-targeted drug delivery, and anti-microbial therapy. A new approach was recently proposed for providing targeting features to liposomes by fusing them with cell membrane vesicles, generating molecules called membrane-fused liposomes (Figure 10).213 Cell membrane vesicles retain the surface membrane molecules from source cells, which are responsible for efficient tissue targeting and cellular uptake by target cells.214 However, the immunogenicity of cell membrane vesicles leads to their rapid clearance by macrophages in the body and their low drug loading efficiencies present challenges for their use as drug delivery systems.156 However, membrane-fused liposomes have advantages of stability, long half-life in circulation, and low immunogenicity due to the liposome, and the targeting feature of cell membrane vesicles is completely transferred to the liposome.215 Furthermore, the encapsulation efficiencies of doxorubicin were similar when liposomes and membrane-fused liposomes were used, indicating that the relatively high drug encapsulation capacity of liposomes was maintained during the fusion process.216 Combining membrane-fused liposomes with macrophage-derived membrane vesicles showed differential targeting and cytotoxicity against normal and cancerous cells.217 Although only a few studies have been conducted, these results corroborate that membrane-fused liposomes are a potentially promising future drug delivery system with increased targeting ability. MSCs show intrinsic tropism toward arthritis, and further engineering and modification to enhance their targeting ability make them attractive candidates for the development of drug delivery systems. Fusing MSC exosomes with liposomes, taking advantage of both membrane vesicles and liposomes, is a promising technique for future drug delivery systems.

Figure 10 Mesenchymal stem cell membrane-fused liposomes.

MSCs have great potential as targeted therapies due to their greater ability to home to targeted pathophysiological sites. The intrinsic ability to home to wounds or to the tumor microenvironment secreting inflammatory mediators make MSCs and their derivatives targeting strategies for cancer and inflammatory disease.218,219 Contrary to the well-known homing mechanisms of various blood cells, it is still not clear how homing occurs in MSCs. So far, the mechanism of MSC tethering, which connects long, thin cell membrane cylinders called tethers to the adherent area for migration, has not been clarified. Recent studies have shown that galectin-1, VCAM-1, and ICAM are associated with MSC tethering,53,220 but more research is needed to accurately elucidate the tethering mechanism of MSCs. MSC chemotaxis is well defined and there is strong evidence relating it to the homing ability of MSCs.53 Chemotaxis involves recognizing chemokines through chemokine receptors on MSCs and migrating to chemokines in a gradient-dependent manner.221 RA, a representative inflammatory disease, is associated with well-profiled chemokines such as CXCR1, CXCR4, and CXCR7, which are recognized by chemokine receptors on MSCs. In addition, damaged joints in RA continuously secrete cytokines until they are treated, giving MSCs an advantage as future therapeutic agents for RA.222 However, there are several obstacles to utilizing MSCs as RA therapeutics. In clinical settings, the functional capability of MSCs is significantly affected by the health status of the donor patient.223 MSC yield is significantly reduced in patients undergoing steroid-based treatment and the quality of MSCs is dependent on the donors age and environment.35 In addition, when MSCs are used clinically, cryopreservation and defrosting are necessary, but these procedures shorten the life span of MSCs.224 Therefore, NPs mimicking MSCs are an alternative strategy for overcoming the limitations of MSCs. Additionally, further engineering and modification of MSCs can enhance the therapeutic effect by changing the targeting molecules and loaded drugs. In particular, upregulation of receptors associated with chemotaxis through genetic engineering can confer the additional ability of MSCs to home to specific sites, while the increase in engraftment maximizes the therapeutic effect of MSCs.36,225

Furthermore, there are several methods that can be used to exploit the targeting ability of MSCs as drug delivery systems. MSCs mimicking nanoencapsulation, which consists of MSC membrane-coated NPs, MSC-derived artificial ectosomes, and MSC membrane-fused liposomes, can mimic the targeting ability of MSCs while retaining the advantages of NPs. MSC-membrane-coated NPs are synthesized using inorganic or polymer NPs and membranes from MSCs to coat inner nanosized structures. Because they mimic the biological characteristics of MSC membranes, MSC-membrane-coated NPs can not only escape from immune surveillance but also effectively improve targeting ability, with combined functions of the unique properties of core NPs and MSC membranes.226 Exosomes are also an appropriate candidate for use in MSC membranes, utilizing these targeting abilities. However, natural exosomes lack reproducibility and stable productivity, thus artificial ectosomes with targeting ability produced via synthetic routes can increase the local concentration of ectosomes at the targeted site, thereby reducing toxicity and side effects and maximizing therapeutic efficacy.156 MSC membrane-fused liposomes, a novel system, can also transfer the targeting molecules on the surface of MSCs to liposomes; thus, the advantages of liposomes are retained, but with targeting ability. With advancements in nanotechnology of drug delivery systems, the research in cell-mimicking nanoencapsulation will be very useful. Efficient drug delivery systems fundamentally improve the quality of life of patients with a low dose of medication, low side effects, and subsequent treatment of diseases.227 However, research on cell-mimicking nanoencapsulation is at an early stage, and several problems need to be addressed. To predict the nanotoxicity of artificially synthesized MSC mimicking nanoencapsulations, interactions between lipids and drugs, drug release mechanisms near the targeted site, in vivo compatibility, and immunological physiological studies must be conducted before clinical application.

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2019M3A9H1103690), by the Gachon University Gil Medical Center (FRD2021-03), and by the Gachon University research fund of 2020 (GGU-202008430004).

The authors report no conflicts of interest in this work.

1. Chapel A, Bertho JM, Bensidhoum M, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med. 2003;5(12):10281038. doi:10.1002/jgm.452

2. Park JS, Suryaprakash S, Lao YH, Leong KW. Engineering mesenchymal stem cells for regenerative medicine and drug delivery. Methods. 2015;84:316. doi:10.1016/j.ymeth.2015.03.002

3. Ringe J, Burmester GR, Sittinger M. Regenerative medicine in rheumatic disease-progress in tissue engineering. Nat Rev Rheumatol. 2012;8(8):493498. doi:10.1038/nrrheum.2012.98

4. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230247. doi:10.1097/00007890-196803000-00009

5. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):42794295. doi:10.1091/mbc.e02-02-0105

6. Crisan M, Yap S, Casteilla L, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301313. doi:10.1016/j.stem.2008.07.003

7. Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000;97(25):1362513630. doi:10.1073/pnas.240309797

8. Young HE, Steele TA, Bray RA, et al. Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. Anat Rec. 2001;264(1):5162. doi:10.1002/ar.1128

9. Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood. 2001;98(8):23962402. doi:10.1182/blood.V98.8.2396

10. Wang HS, Hung SC, Peng ST, et al. Mesenchymal stem cells in the Whartons jelly of the human umbilical cord. Stem Cells. 2004;22(7):13301337. doi:10.1634/stemcells.2004-0013

11. Heo JS, Choi Y, Kim HS, Kim HO. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. Int J Mol Med. 2016;37(1):115125. doi:10.3892/ijmm.2015.2413

12. Drela K, Stanaszek L, Snioch K, et al. Bone marrow-derived from the human femoral shaft as a new source of mesenchymal stem/stromal cells: an alternative cell material for banking and clinical transplantation. Stem Cell Res Ther. 2020;11(1):262. doi:10.1186/s13287-020-01697-5

13. Li J, Wong WH, Chan S, et al. Factors affecting mesenchymal stromal cells yield from bone marrow aspiration. Chin J Cancer Res. 2011;23(1):4348. doi:10.1007/s11670-011-0043-1

14. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2013;2(6):455463. doi:10.5966/sctm.2012-0184

15. Trivanovic D, Jaukovic A, Popovic B, et al. Mesenchymal stem cells of different origin: comparative evaluation of proliferative capacity, telomere length and pluripotency marker expression. Life Sci. 2015;141:6173. doi:10.1016/j.lfs.2015.09.019

16. Lefevre S, Knedla A, Tennie C, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med. 2009;15(12):14141420. doi:10.1038/nm.2050

17. Cyranoski D. Japans approval of stem-cell treatment for spinal-cord injury concerns scientists. Nature. 2019;565(7741):544545. doi:10.1038/d41586-019-00178-x

18. Cofano F, Boido M, Monticelli M, et al. Mesenchymal stem cells for spinal cord injury: current options, limitations, and future of cell therapy. Int J Mol Sci. 2019;20(11):2698. doi:10.3390/ijms20112698

19. Liau LL, Looi QH, Chia WC, Subramaniam T, Ng MH, Law JX. Treatment of spinal cord injury with mesenchymal stem cells. Cell Biosci. 2020;10:112. doi:10.1186/s13578-020-00475-3

20. Williams AR, Hare JM, Dimmeler S, Losordo D. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109(8):923940. doi:10.1161/CIRCRESAHA.111.243147

21. Karantalis V, Hare JM. Use of mesenchymal stem cells for therapy of cardiac disease. Circ Res. 2015;116(8):14131430. doi:10.1161/CIRCRESAHA.116.303614

22. Bernstein HS, Srivastava D. Stem cell therapy for cardiac disease. Pediatr Res. 2012;71(4 Pt 2):491499. doi:10.1038/pr.2011.61

23. Guo Y, Yu Y, Hu S, Chen Y, Shen Z. The therapeutic potential of mesenchymal stem cells for cardiovascular diseases. Cell Death Dis. 2020;11(5):349. doi:10.1038/s41419-020-2542-9

24. Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther. 2008;15(10):730738. doi:10.1038/gt.2008.39

25. Vos T, Allen C, Arora M, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 19902015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):15451602.

26. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;(2):CD008794. doi:10.1002/14651858.CD008794.pub2

27. Majithia V, Geraci SA. Rheumatoid arthritis: diagnosis and management. Am J Med. 2007;120(11):936939. doi:10.1016/j.amjmed.2007.04.005

28. Park N, Rim YA, Jung H, et al. Etanercept-synthesising mesenchymal stem cells efficiently ameliorate collagen-induced arthritis. Sci Rep. 2017;7:39593. doi:10.1038/srep39593

29. Herberts CA, Kwa MS, Hermsen HP. Risk factors in the development of stem cell therapy. J Transl Med. 2011;9:29. doi:10.1186/1479-5876-9-29

30. Rodriguez-Fuentes DE, Fernandez-Garza LE, Samia-Meza JA, Barrera-Barrera SA, Caplan AI, Barrera-Saldana HA. Mesenchymal stem cells current clinical applications: a systematic review. Arch Med Res. 2021;52(1):93101. doi:10.1016/j.arcmed.2020.08.006

31. Kabat M, Bobkov I, Kumar S, Grumet M. Trends in mesenchymal stem cell clinical trials 20042018: is efficacy optimal in a narrow dose range? Stem Cells Transl Med. 2020;9(1):1727. doi:10.1002/sctm.19-0202

32. Leibacher J, Henschler R. Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther. 2016;7:7. doi:10.1186/s13287-015-0271-2

33. Zheng B, von See MP, Yu E, et al. Quantitative magnetic particle imaging monitors the transplantation, biodistribution, and clearance of stem cells in vivo. Theranostics. 2016;6(3):291301. doi:10.7150/thno.13728

34. Gholamrezanezhad A, Mirpour S, Bagheri M, et al. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl Med Biol. 2011;38(7):961967. doi:10.1016/j.nucmedbio.2011.03.008

35. Pittenger MF, Discher DE, Peault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. 2019;4:22. doi:10.1038/s41536-019-0083-6

36. Marquez-Curtis LA, Janowska-Wieczorek A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis. Biomed Res Int. 2013;2013:561098. doi:10.1155/2013/561098

37. Liu L, Chen JX, Zhang XW, et al. Chemokine receptor 7 overexpression promotes mesenchymal stem cell migration and proliferation via secreting Chemokine ligand 12. Sci Rep. 2018;8(1):204. doi:10.1038/s41598-017-18509-1

38. Rittiner JE, Moncalvo M, Chiba-Falek O, Kantor B. Gene-editing technologies paired with viral vectors for translational research into neurodegenerative diseases. Front Mol Neurosci. 2020;13:148. doi:10.3389/fnmol.2020.00148

39. Srifa W, Kosaric N, Amorin A, et al. Cas9-AAV6-engineered human mesenchymal stromal cells improved cutaneous wound healing in diabetic mice. Nat Commun. 2020;11(1):2470. doi:10.1038/s41467-020-16065-3

40. van Haasteren J, Li J, Scheideler OJ, Murthy N, Schaffer DV. The delivery challenge: fulfilling the promise of therapeutic genome editing. Nat Biotechnol. 2020;38(7):845855. doi:10.1038/s41587-020-0565-5

41. Gowen A, Shahjin F, Chand S, Odegaard KE, Yelamanchili SV. Mesenchymal stem cell-derived extracellular vesicles: challenges in clinical applications. Front Cell Dev Biol. 2020;8:149. doi:10.3389/fcell.2020.00149

42. Lou G, Chen Z, Zheng M, Liu Y. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med. 2017;49(6):e346. doi:10.1038/emm.2017.63

43. Phinney DG, Di Giuseppe M, Njah J, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472. doi:10.1038/ncomms9472

44. Villemin E, Ong YC, Thomas CM, Gasser G. Polymer encapsulation of ruthenium complexes for biological and medicinal applications. Nat Rev Chem. 2019;3(4):261282. doi:10.1038/s41570-019-0088-0

45. Su YQ, Zhang TY, Huang T, Gao JQ. Current advances and challenges of mesenchymal stem cells-based drug delivery system and their improvements. Int J Pharma. 2021;600:120477.

46. Kwon S, Kim SH, Khang D, Lee JY. Potential therapeutic usage of nanomedicine for glaucoma treatment. Int J Nanomed. 2020;15:57455765. doi:10.2147/IJN.S254792

47. Sanna V, Sechi M. Therapeutic potential of targeted nanoparticles and perspective on nanotherapies. ACS Med Chem Lett. 2020;11(6):10691073. doi:10.1021/acsmedchemlett.0c00075

View post:
Stem Cell Mimicking Nanoencapsulation for Targeting Arthrit | IJN - Dove Medical Press

Innovative approaches in multiple myeloma that focus on cellular therapies offer hope to patients with multiple myeloma.

Current approaches for multiple myeloma are stratified by patient fitness and age. For patients who can tolerate them, 3- or 4-drug combinations, with or without an autologous stem cell transplant (ASCT), can result in a complete remission, ideally with no residual disease. For patients who are elderly or fragile, 2-drug or 3-drug regimens are the standard.

For the standard-risk patient, a regimen of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) plus a CD38 monoclonal antibody such as daratumumab (Darzalex) or isatuximab (Sarclisa) is the norm. As a whole, these combinatorial approaches are needed because multiple myeloma is a heterogenous disease whose optimal treatment takes advantage of multiple mechanisms of action. These regimens can result in first remissions that range from 4 to 5 years.

Although these outcomes are promising, there is still an unmet need for patients with relapsed or refractory disease. Innovative approaches in multiple myeloma that focus on cellular therapies offer hope to these patients.

In a presentation during the 39th Annual CFS Innovative Cancer Therapy for Tomorrow, Shambavi Richard, MD, an assistant professor in medicine, hematology, and medical oncology at The Mount Sinai Hospital in New York, New York, addressed the emerging therapeutic frontiers in multiple myeloma with a focus on chimeric antigen receptor (CAR) approaches and bispecific antibodies.1 Richard explored updated results from the KarMMa trial (NCT03361748), which enrolled 149 patients with relapsed/refractory multiple myeloma (RRMM) and who were previously exposed to immunomodulatory agents, proteasome inhibitors (PIs), and CD38 antibodies (mAbs) and reported poor outcomes. Evaluable patients received idecabtagene vicleucel (ide-cel; n = 128).2,3

At a median follow-up of 15.4 months, the objective response rate (ORR) was 73% and median progression-free survival (PFS) was 8.8 months for all treated patients (TABLE3 ). Investigators reported that at the highest targeted dose of 450 106 CAR T cells, the overall response rate (ORR) was 81%, the complete response (CR) rate was 39%, and the median PFS increased by 12.2 months with longer follow-up. In a subgroup analysis of difficult-to-treat patients, the ORR for patients with extramedullary disease was 70%; patients with high-tumor burden, 71%; and patients with R-ISS stage III disease, 48%.

Regarding safety, 97% of patients had cytopenia and 89% had grade 3/4 neutropenia; 52% experienced thrombocytopenia and 60% developed anemia. Cytokine release syndrome (CRS) had a median onset of 1 day, with a median duration of 5 days. CRS was seen in 84% of patients but grade 3/4 was observed in only 6% of patients. Neurologic toxicity was observed in 18% of patients and 4% were grade 3/4.

Updated results from the CARTITUDE-1 trial (NCT03548207)4 showed that ciltacabtagene autoleucel (cilta-cel) yielded early, deep, and durable responses in heavily pretreated patients with multiple myeloma, with a manageable safety profile at the recommended phase 2 dose.

In the study, 97 patients with a median of 6 prior lines received cilta-cel. The overall response rate per independent review committee (primary end point) was 97% (95% CI, 91%-99%), with 67% of patients achieving stringent CR (sCR). The median time to first response was 1 month (range, 1-9), and median time to CR or better was 2 months (range, 1-15). Responses deepened over time, and the median duration of response was not reached. Of 57 patients evaluable for minimal residual disease (MRD) assessment, 93% were MRD-negative at 10-5. The 12-month PFS and overall survival (OS) rates (95% CI) were 77% (66%-84%) and 89% (80%-94%), respectively; the median PFS was not reached.

In terms of adverse events, neutropenia was 94.8% grade 3/4, and 60.8% of patients had grade 3/4 anemia, said Richard. CRS was almost universal, with any-grade CRS seen in 94.8% of patients. This was a little different compared with ido-cel in terms of time of onset, which was 7 days with this product vs 1 day with the ido-cell product, she said. In both of these trials, early death within the first 2 to 3 months was 2% or less.

When comparing ide-cel to conventional treatment, according to findings presented by Shah et al,5 the investigators observed that ide-cel was associated with a significantly higher ORR compared with conventional treatment (OR, 5.11; 95% CI, 2.92-8.94; P < .001). Similarly, ide-cel significantly extended PFS (HR, 0.55; 95% CI, 0.42-0.73; P < .001) and OS (HR, 0.36; 95% CI, 0.24-0.54; P < .001) vs conventional treatment. Richard said this analysis aimed to compare efficacy outcomes observed with ide-cel treatment in KarMMa and conventional treatment in the Monoclonal Antibodies in Multiple Myeloma: Outcomes After Therapy Failure (MAMMOTH) study.6 Investigators analyzed outcomes of 275 patients with multiple myeloma with disease refractory to CD38 monoclonal antibodies at 14 academic centers.

Turning to the challenge of resistance to therapies in multiple myeloma, Richard noted that there are 3 main strategies in play: multiple myelomacell directed, T-cell directed; and CAR construct.

Possible strategies employed that use multiple myeloma celldirected treatments involve pooling CAR T products with different antigens; using dual CAR products that are constructed using 2 antigen specifi cities, such as B-cell maturation antigen (BCMA)/CD19; or taking a tandem CAR approach. Investigators also can focus on alternate antigens including SLAMF7, CD138, or integrin beta7.

Strategies that are T-cell directed can focus on those that are enriched for central or stem cell memory T cells or use combination approaches with checkpoint inhibitors or immunomodulatory imide drugs and cereblon E3 ligase modulators (CelMoD).

Efforts that tweak the CAR construct are also undergoing evaluation. These include FasTCAR, in which manufacturing takes 24 to 36 hours; next-generation CARs, which are armored CAR T cells that prevent T-cell exhaustion; CARs that use a safety switch to mitigate adverse effects; and allogeneic CARS.

Richard highlighted results from a study evaluating teclistamab, a bispecific antibody that binds to BCMA and CD3 to redirect T cells to attack multiple myeloma cells.

Findings from MajesTEC-1 (NCT03145181) demonstrated that the ORR in response-evaluable patients treated at the recommended phase 2 dose (n = 40) was 65% (95% CI, 48%-79%); 58% achieved a very good partial response or better.7 At the recommended phase 2 dose, the median duration of response was not reached. After 7.1 months median follow-up, 22 (85%) of 26 responders were alive and continuing treatment. During the 2021 American Society of Clinical Oncology Annual Meeting, Krishnan et al presented updated findings showing 58% of evaluable patients had achieved a very good partial response or better and 30% had achieved a CR or better; the median time to first confirmed response was 1.0 month (range, 0.2-3.1).8

Another bispecific antibody, talquetamab, has continued to show promising clinical activity in patients with RRMM. Updated findings from a phase 1 trial (NCT03399799)9 showed the ORR at the recommended phase 2 dose (RP2D) in response-evaluable patients (n = 24) was 63%, with 50% reaching very good partial response or better; 9/17 (53%) evaluable patients with triple-class refractory disease and 3/3 (100%) patients who were penta-refractory had a response. Median time to first confirmed response at the RP2D was 1.0 month (range, 0.2-3.8). Overall, responses were durable and deepened over time (median follow-up, 6.2 months [range, 2.7-9.7+] for responders at the RP2D).

When comparing CAR T-cell therapy to bispecific antibodies, Richard noted that patients undergo CAR T-cell therapy once with no further therapy indicated. Additionally, patients can enjoy a long chemotherapy holiday, whereas bispecific antibodies require more frequent doses. Toxicities are similar for the 2 approaches, although Richard said that CRS can be slightly more profound and at a somewhat higher grade with the CAR T-cell approach compared with that of bispecific antibodies.

In conclusion, Richard also noted that the costs associated with both these approaches will have an impact, especially in high up-front costs. Bispecific c antibodies, however, due to their chronic recurrent administration, may also come with a long-term financial burden.

REFERENCES:

1. Richard S. New therapeutic frontiers for RRMM: CAR T and bispecifi c antibodies. Presented at: 39th Annual CFS. Chemotherapy Foundation Symposium. Innovative Cancer Therapy for Tomorrow. November 3-5, 2021; New York, NY.

2. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850

3. Anderson LD, Munshi NC, Shah N, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in relapsed and refractory multiple myeloma: Updated KarMMa results. J Clin Oncol. 2021;39(suppl 15):8016-8016. doi: 10.1200/JCO.2021.39.15_suppl.8016

4. Usmani SZ, Berdeja JG, Madduri D, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy, in relapsed/refractory multiple myeloma: updated results from CARTITUDE-1. J Clin Oncol. 2021;39(suppl 15; abstr 8005). doi: 10.1200/JCO.2021.39.15_suppl.8005

5. Shah N, Ayers D, Davies FE, et al. A matching-adjusted indirect comparison of efficacy outcomes for idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy versus conventional care in triple-class-exposed relapsed and refractory multiple myeloma. Presented at: 62nd American Society of Hematology Meeting and Exposition, December 5-8, 2020. Abstract 1653. https://bit.ly/3nQb458

6. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275. doi:10.1038/ s41375-019-0435-7

7. Usmani SZ, Garfall AL, van de Donk NWCJ, et al. Teclistamab, a B-cell maturation antigen CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021;398(10301):665- 674. doi:10.1016/S0140-6736(21)01338-6

8. Krishnan AY, Garfall Al, Mateos M-V, et al. J Clinical Oncol. 2021;39(suppl 15):8007-8007. doi: 10.1200/JCO.2021.39.15_suppl.8007

9. Berdeja JG, Krishnan AY, Oriol A, et al. Updated results of a phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). J Clin Oncol. 2021;39(suppl 15):8008. doi: 10.1200/JCO.2021.39.15_suppl.8008

Read the original here:
Cellular Therapies Fill Unmet Needs in R/R Multiple Myeloma - Targeted Oncology

Introduction

Pancreatic cancer (PC) with high aggressiveness and malignancy has become an enormously common cancer of the digestive system during 10 years. Globally, the 5year overall survival (OS) rate of patients with PC is less than 9%, and the mortality rate is predicted to peak by 2030.1 Due to insidious symptoms, only less than 10% of PC is initially diagnosed with a local stage, and the prognosis of PC is extremely poor.2 Therefore, further investigation into novel cancer-related genes is required and meaningful for the improvement of prognosis.

SWI/SNF complexes are evolutionarily conserved multi-subunit molecular machines that mediate transcriptional regulation3 and are linked to a poor prognosis across several cancer types.46 Among them, Actin-like 6A (ACTL6A), encoded by Actl6a, acts as a chromatin-remodeling factor and regulates the function of progenitor and stem cell transcriptionally.7,8 In addition, ACTL6A expression is associated with prognosis in many types of cancer, such as hepatocellular carcinoma,9 colon cancer,10 and esophageal squamous cell carcinoma.11 Recently, research revealed that epithelial-to-mesenchymal transition (EMT) was also regulated by ACTL6A.9,12 In addition, the study showed that ACTL6A overexpression could lead to increased repair of cisplatin-DNA adducts and cisplatin resistance.13 However, the role of ACTL6A in tumorigenicity and clinical prognosis of PC remains unclear so far.

In this connection, we analyzed the differences of ACTL6A expression in PC tissues and normal tissues, and we investigated the prognostic effect of ACTL6A on PC based on cases in public databases and confirmed it in our center.

Differential expression of Actl6a mRNA between pancreatic tumor and normal tissues was analyzed using the Gene Expression Profiling Interactive Analysis website (GEPIA; http://gepia.cancerpku.cn/). Data for 179 patients with PC and 171 normal tissue samples analyzed on the GEPIA website were obtained from TCGA and normal tissue samples from Genotype-Tissue Expression (GTEx).1416 The gene expression, determined as transcripts per million (TPM), was calculated by log2 (TPM + 1) for comparison. Based on the expression levels of Actl6a mRNA, the overall survival (OS) of patients was also analyzed.

A total of 60 patients with PC confirmed by histopathology from January 2013 to June 2020 at Zhongda Hospital, Medical School of Southeast University were selected for the study. Sixty paired pancreatic tumor and normal tissues from patients who did not receive chemotherapy or radiotherapy were obtained to detect ACTL6A expression. Any patients with incomplete epidemiological and clinical information or lack of follow-up information were excluded. The results of serum tumor markers were collected from 60 healthy individuals who were admitted to the hospital for physical examination at the same time. All patients provided informed consent. Patients were followed up by telephone or at office visits every 3 months from the end date of surgery. The latest follow-up ended in July 2021. According to the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, pathological stages were validated. The study was conducted with approval from the ethics committee of Zhongda Hospital, Southeast University. The study protocol protected the private information of enrolled patients in accordance with the provisions of the Helsinki Declaration.

The paraffin-embedded pathological specimens were cut into 4-m-thick sections. After being dewaxed in xylene and rehydrated in grade alcohol, the paraffin sections were submerged in a pH 6.0 citric acid solution and heated at 95C for approximately 15 minutes for antigen retrieval. Next, the sections were incubated with rabbit ACTL6A antibody (Abcam Corp, USA, diluted 1:200) overnight at 4C and washed 3 times with phosphate buffer saline (PBS). The sections were then incubated with horseradish peroxidase-conjugated secondary antibody for 30 minutes at room temperature in the dark. After stained with freshly prepared 3,3-diaminobenzidine (DAB), they were counterstained with hematoxylin and differentiated with 1% hydrochloric acid. PBS was used to substitute the primary antibody as negative control. Finally, the sections were dehydrated with alcohol and sealed with neutral gum, and pictures were taken by microscope for positive cell calculation. Immunohistochemical staining analysis was performed independently by two pathologists according to the staining intensity and the percentage of positive cells. The staining intensities were 0 (negative), 1 (positive 1+), 2 (positive 2+), and 3 (positive 3+), respectively. The percentages of cells were 0 (negative), 1 (125%), 2 (2650%), 3 (5175%), and 4 (76100%), respectively.17,18 Total scores were calculated by multiplying the scores of staining intensity and percentage.

Statistical analyses and mapping were performed using SPSS software (version 18.0, IBM Corporation, Armonk, NY, USA), GraphPad Prism (Version 8.4.3, GraphPad Software, La Jolla, CA, USA), and R (version 3.4.1, http://www.r-project.org/) in the present study. Wilcoxon test was used to evaluate significant differences between pancreatic cancer and normal tissues, and the 2 test and continuity correction were used to explore the relationship between ACTL6A expression and clinicopathological features. The diagnostic efficiency of ACTL6A expression was analyzed through receiver operating characteristic (ROC) curves for PC. The sensitivity and specificity were evaluated at an optimal cutoff. The expression of ACTL6A was classified as high expression and low expression according to the cutoff. Survival analysis was analyzed using KaplanMeier curve, and difference among groups was assessed using Log rank test. Both univariable and multivariable analyses were used in survival analysis, respectively. The clinicopathological factors with significant associations (p < 0.1) in the aforementioned univariable analysis were subjected to multivariate analysis. p < 0.05 was considered to be statistically significant.

To explore the potential role of ACTL6A in PC, the expression of Actl6a mRNA was analyzed with the publicly available GEPIA database. In clinical PC specimens (n = 178) and normal tissues (n = 171), Actl6a mRNA had significant differential expression between the two groups. What is more, Actl6a mRNA was upregulated in PC than normal tissues (p < 0.05, Figure 1A). Then, the protein expression of ACTL6A was validated and compared in PC samples (n = 60) and normal tissues (n = 60) with immunohistochemistry staining in our center. The typical immunohistochemical results of normal tissues and PC tissues are shown in Figure 1B, which demonstrated that ACTL6A was mainly observed in the nucleus of cells. By multiplying the staining intensity and percentage, the protein expression of ACTL6A was also overexpressed in pancreatic cancer (p < 0.001, Figure 1C). Table 1 shows the number of patients with different scores based on immunohistochemistry staining. The results above indicated that ACTL6A was upregulated in PC.

Table 1 The Number of Patients in Different Scores Based on Immunohistochemistry Staining

Figure 1 Expression of ACTL6A in PC and normal tissues. (A) Differential expression of Actl6a mRNA between pancreatic tumor and normal tissues. (B) Immunohistochemical results of typical normal tissues and PC tissues with different staining intensities. (C) Differential expression of ACTL6A between pancreatic tumor and normal tissues. (D) ACTL6A represented a moderate diagnostic value. The ROC of pancreatic cancer samples and normal tissues. (E) ROC for the diagnostic efficiency of ACTL6A, serum CEA, and serum CA199. *p<0.05.

Abbreviations: ACTL6A, actin like 6A; PC, pancreatic cancer; ROC, receiver operating characteristic curves; CA199, carbohydrate antigen 199; CEA, carcinoembryonic antigen.

To investigate the diagnostic value of ACTL6A expression for PC, we performed ROC analysis on total scores of pancreatic cancer and normal pancreatic tissue, as shown in Figure 1D and E, and the AUC value was 0.724, which was higher than that of carbohydrate antigen 199 (CA199) and carcinoembryonic antigen (CEA). These results represented a moderate diagnostic value for PC. The specificity and sensitivity of ACTL6A expression for PC diagnosis were 0.867 and 0.567, respectively. The cut-off value established for ACTL6A expression for the diagnosis of PC was 5.

To further understand the role of ACTL6A in PC, we analyzed the relationship between ACTL6A expression and the clinicopathological characteristics. Patients with PC were divided into ACTL6A low-expression group (score 05; n = 34) and ACTL6A high-expression group (score 612; n = 26) with the cut-off value of score 5. The relationship between ACTL6A expression and clinicopathological factors of pancreatic cancer is summarized in Table 2. Lymphovascular space invasion (LVSI) of PC was significantly associated with ACTL6A expression, which was more likely to occur in the ACTL6A high group. LVSI was present in 55.9% (19/34) of patients in the ACTL6A high group and 26.9% (7/26) in ACTL6A low group.

Table 2 Relationships Between the Expression Level of ACTL6A and the Clinicopathological Characteristics of PC Patients

The survival data of 178 PC patients was obtained from TCGA dataset. Patients are split into two groups according to the median value of Actl6a mRNA expression. One-half (89 patients) was defined as high Actl6a mRNA expression, and the other was defined as low Actl6a mRNA expression. Obviously, high Actl6a mRNA was associated with poor overall survival in patients with PC (p < 0.001, Figure 2A). Furthermore, based on data from our center, the KaplanMeier method was used to investigate the relationship between the expression of ACTL6A protein and OS of patients. The median OS in PC patients for the high and low expression of ACTL6A was 8.0 0.4 months and 13.0 1.6 months, respectively. Obviously, patients with low ACTL6A expression had significantly longer survival time than those with high ACTL6A expression (p < 0.001, Figure 2B).

Figure 2 (A) KaplanMeier curves of overall survival in PC patients with high and low Actl6a mRNA expression. (B) KaplanMeier curves of overall survival in PC patients with high and low ACTL6A expression.

Abbreviations: ACTL6A, actin like 6A; PC, pancreatic cancer.

Univariate and multivariate Cox analyses were performed to identify the prognostic factors on OS of patients with PC. The results demonstrated that ACTL6A overexpression (p = 0.032) and grade (p = 0.008) were risk factors for survival in patients with PC through univariate Cox analysis. Further multivariate Cox analysis showed that ACTL6A expression (p = 0.046) was an independent risk factor for poor prognosis of PC (Table 3). As shown in Figure 3A and B, the forest plot visualizes the specific HR of risk factors.

Table 3 Univariate and Multivariate Analysis of Clinicopathological Characteristics Affecting Prognosis of Patients with PC

Figure 3 Forest plot of univariate (A) and multivariate (B) cox regression.

Abbreviations: ACTL6A, actin like 6A; PC, pancreatic cancer; LVSI, lymphovascular space invasion.

Worldwide, PC has become a malignancy with a dismal prognosis and high mortality, which has a 5-year survival rate of less than 10%.19 There are two clinical features that are involved with the poor prognosis of PC. First, initial symptoms of PC are insidious, which leads to many challenges for early diagnosis. Second, PC has a significant potential for invasion and metastasis.20 In detail, the distant spread may occur in the early stages of PC, and more than 50% of patients with PC have no possibility to be treated with surgical resection.21 Scientific problems covering early diagnosis, the mechanisms of metastasis, and the risk factors of prognosis are necessary to be solved to improve survival of PC. In this study, we clarified that ACTL6A is highly expressed in PC, and it is a reliable marker for predicting the prognosis of PC patients.

ACTL6A is involved in a variety of cellular processes, including vesicle transport, spindle orientation, nuclear migration, and chromatin remodeling.7,22 Increasing evidence has suggested its involvement with tumorigenesis and development of cancer.7 ACTL6A has been reported to be overexpressed in a variety of malignancies, including hepatocellular carcinoma,9 ovarian cancer,18 cervical cancer,23 and esophageal squamous cell carcinoma,11 which is correlated with the prognosis of patients with malignancies. This evidence suggests that ACTL6A is a potential oncogene, and it is observed that ACTL6A expression is also upregulated in PC in our study, which is consistent with previous studies. Researchers have been constantly exploring diagnostic markers for PC. Jelski et al reported that the activity of alcohol dehydrogenase (ADH) class III isoenzyme in pancreatic cancer was significantly higher than that in normal tissues.24 And the total activity of ADH and class III isoenzyme was increased in the serum of patients with PC, which can be due to the release of this isoenzyme from PC cells.25 Nevertheless, it was not observed that other types of ADH isoenzymes (I, II, IV) had a significant change in either pancreatic tissue or serum. Further exploration revealed that ADH III had the diagnostic value for PC.26 Also, our evidence demonstrated a potential role for ACTL6A as a marker of PC.

ACTL6A plays a vital role in the invasion and metastasis of tumors by promoting EMT, leading to poor prognosis. ACTL6A expression is higher in fibroblasts and progenitor cells and inhibits the epithelial properties of epidermal tissues.27,28 Moreover, the functions of ACTL6A are similar to features of stem cells, including the inhibition of cell differentiation and the ability of self-renewal, which is closely related to the biological functions of EMT.28 In hepatocellular carcinoma, ACTL6A activated Notch1 signaling via SOX2, which regulated EMT to affect the biological function and clinical prognosis of hepatocellular carcinoma. Other studies also revealed ACTL6A as an EMT activator to promote metastasis in osteosarcoma29 and colon cancer,10 respectively. Some studies mentioned the potential role of ACTL6A involvement with tumors. Zhang et al found that ACTL6A was a glycolytic regulator by phosphoglycerate kinase 1(PGK1) in ovarian cancer and participated in FSH-induced tumorigenesis of ovarian cancer.18 And in triple negative breast cancer, ACTL6A promoted tumor cell proliferation by enhancing the stability of MYC oncogene.30 Additional evidence suggested that ACTL6A promoted the progression of cervical cancer and laryngeal squamous cell carcinoma through activation of yes-associated protein (YAP) signaling.23,31 Besides, ACTL6A could stabilize transcriptional regulators YAP and transcriptional coactivator with PDZ-binding motif (TAZ) to regulate the proliferation, migration, and invasion of glioma.32 Further studies revealed that the knockdown of ACTL6A gene resulted in the inhibition of protein kinase B (AKT) signaling pathway to suppress cell migration and increased sensitivity of glioma cells to temozolomide.33 Moreover, in vivo and in vitro, Shrestha et al revealed that p21Cip1, a tumor suppressor, was suppressed by ACTL6A in epidermal squamous cell carcinoma, leading to epidermal squamous cell carcinoma progression.34 More importantly, overexpressed ACTL6A was related to cisplatin-induced DNA damage and led to resistance to cisplatin.13 These studies have further confirmed the contribution of ACTL6A in the invasion, metastasis, and clinical prognosis of tumors.

In this research, we reveal a correlation between the expression of ACTL6A and the invasion and prognosis of PC. It was found that LVSI was more likely to occur in PC patients with high ACTL6A expression, which might be related to the high aggressiveness caused by ACTL6A. Univariate and multivariate Cox analysis suggested that ACTL6A expression and grade were independent risk factors for poor prognosis of PC. This study also confirmed ACTL6A as a valid prognostic biomarker and potential therapeutic target in PC. Given a follow-up and survival analysis of survival data of PC patients, patients with high ACTL6A expression had significantly poorer prognosis. It was suggested that ACTL6A expression in PC was a risk factor, which was consistent with the existing studies. And ACTL6A overexpression was associated with tumor progression. However, whether ACTL6A could induce PC cell proliferation, invasion, and metastasis in vitro, as well as the specific regulatory mechanisms, deserved further investigation.

In conclusion, it was found that levels of ACTL6A expression were elevated in PC tissues, which was associated with LVSI. Moreover, it was demonstrated that ACTL6A was an independent risk prognostic indicator for PC. ACTL6A could be used as a valuable biomarker to predict the prognosis of PC, assisting clinicians to develop preventative measures and better treatment strategies to improve mortality in patients with PC.

The authors are grateful to all the patients, researchers and institutions that participated in the TCGA and GTEx database.

The authors report no conflicts of interest in this work.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209249.

2. Zhang L, Sanagapalli S, Stoita A. Challenges in diagnosis of pancreatic cancer. World J Gastroenterol. 2018;24(19):20472060.

3. Mittal P, Roberts CWM. The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol. 2020;17(7):435448.

4. Naito T, Udagawa H, Umemura S, et al. Non-small cell lung cancer with loss of expression of the SWI/SNF complex is associated with aggressive clinicopathological features, PD-L1-positive status, and high tumor mutation burden. Lung Cancer. 2019;138:3542.

5. Cyrta J, Augspach A, De Filippo MR, et al. Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity. Nat Commun. 2020;11(1):5549.

6. Fukumoto T, Magno E, Zhang R. SWI/SNF complexes in ovarian cancer: mechanistic insights and therapeutic implications. Mol Cancer Res. 2018;16(12):18191825.

7. Krasteva V, Buscarlet M, Diaz-Tellez A, Bernard MA, Crabtree GR, Lessard JA. The BAF53a subunit of SWI/SNF-like BAF complexes is essential for hemopoietic stem cell function. Blood. 2012;120(24):47204732.

8. Panwalkar P, Pratt D, Chung C, et al. SWI/SNF complex heterogeneity is related to polyphenotypic differentiation, prognosis, and immune response in rhabdoid tumors. Neuro Oncol. 2020;22(6):785796.

9. Xiao S, Chang RM, Yang MY, et al. Actin-like 6A predicts poor prognosis of hepatocellular carcinoma and promotes metastasis and epithelial-mesenchymal transition. Hepatology. 2016;63(4):12561271.

10. Zeng Z, Yang H, Xiao S. ACTL6A expression promotes invasion, metastasis and epithelial mesenchymal transition of colon cancer. BMC Cancer. 2018;18(1):1020.

11. Li RZ, Li YY, Qin H, Li SS. ACTL6A promotes the proliferation of esophageal squamous cell carcinoma cells and correlates with poor clinical outcomes. Onco Targets Ther. 2021;14:199211.

12. Nieto MA, Huang RY, Jackson RA, Thiery JP. Emt: 2016. Cell. 2016;166(1):2145.

13. Xiao Y, Lin FT, Lin WC. ACTL6A promotes repair of cisplatin-induced DNA damage, a new mechanism of platinum resistance in cancer. Proc Natl Acad Sci U S A. 2021;118(3):e2015808118.

14. Cancer Genome Atlas Research N; Weinstein JN, Collisson EA, et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013;45(10):11131120.

15. Consortium GT. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348(6235):648660.

16. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98W102.

17. Rao X, Wang J, Song HM, Deng B, Li JG. KRT15 overexpression predicts poor prognosis in colorectal cancer. Neoplasma. 2020;67(2):410414.

18. Zhang J, Zhang J, Wei Y, Li Q, Wang Q. ACTL6A regulates follicle-stimulating hormone-driven glycolysis in ovarian cancer cells via PGK1. Cell Death Dis. 2019;10(11):811.

19. Zhu H, Li T, Du Y, Li M. Pancreatic cancer: challenges and opportunities. BMC Med. 2018;16(1):214.

20. Ansari D, Tingstedt B, Andersson B, et al. Pancreatic cancer: yesterday, today and tomorrow. Future Oncol. 2016;12(16):19291946.

21. Lamb YN, Scott LJ. Liposomal irinotecan: a review in metastatic pancreatic adenocarcinoma. Drugs. 2017;77(7):785792.

22. Zhao K, Wang W, Rando OJ, et al. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell. 1998;95(5):625636.

23. Zhao J, Li L, Yang T. MiR-216a-3p suppresses the proliferation and invasion of cervical cancer through downregulation of ACTL6A-mediated YAP signaling. J Cell Physiol. 2020;235(12):97189728.

24. Jelski W, Chrostek L, Szmitkowski M. The activity of class I, II, III, and IV of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in pancreatic cancer. Pancreas. 2007;35(2):142146.

25. Jelski W, Zalewski B, Szmitkowski M. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with pancreatic cancer. Dig Dis Sci. 2008;53(8):22762280.

26. Jelski W, Kutylowska E, Laniewska-Dunaj M, Szmitkowski M. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as candidates for tumor markers in patients with pancreatic cancer. J Gastrointestin Liver Dis. 2011;20(3):255259.

27. Bao X, Tang J, Lopez-Pajares V, et al. ACTL6a enforces the epidermal progenitor state by suppressing SWI/SNF-dependent induction of KLF4. Cell Stem Cell. 2013;12(2):193203.

28. Lu W, Fang L, Ouyang B, et al. Actl6a protects embryonic stem cells from differentiating into primitive endoderm. Stem Cells. 2015;33(6):17821793.

29. Sun W, Wang W, Lei J, Li H, Wu Y. Actin-like protein 6A is a novel prognostic indicator promoting invasion and metastasis in osteosarcoma. Oncol Rep. 2017;37(4):24052417.

30. Jian Y, Huang X, Fang L, et al. Actin-like protein 6A/MYC/CDK2 axis confers high proliferative activity in triple-negative breast cancer. J Exp Clin Cancer Res. 2021;40(1):56.

31. Dang Y, Zhang L, Wang X. Actin-like 6A enhances the proliferative and invasive capacities of laryngeal squamous cell carcinoma by potentiating the activation of YAP signaling. J Bioenerg Biomembr. 2020;52(6):453463.

32. Ji J, Xu R, Zhang X, et al. Actin like-6A promotes glioma progression through stabilization of transcriptional regulators YAP/TAZ. Cell Death Dis. 2018;9(5):517.

33. Chen X, Xiang Z, Li D, Zhu X, Peng X. ACTL6A knockdown inhibits cell migration by suppressing the AKT signaling pathway and enhances the sensitivity of glioma cells to temozolomide. Exp Ther Med. 2021;21(2):175.

34. Shrestha S, Adhikary G, Xu W, Kandasamy S, Eckert RL. ACTL6A suppresses p21(Cip1) expression to enhance the epidermal squamous cell carcinoma phenotype. Oncogene. 2020;39(36):58555866.

View post:
Upregulated expression of actin-like 6A is a risk factor | CMAR - Dove Medical Press

As the COVID-19 pandemic continues to evolve, five studies presented during the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition shed light on the persisting burden that COVID-19 has had on people with underlying blood disorders.

We take care of the patients at the highest risk for COVID-19 illness and those who are among the least likely to respond to the vaccine; these and other studies underscore the dual vulnerability facing many of our patients, said press briefing moderator,Laura Michaelis, MD, of the Medical College of Wisconsin. Hematologists have continued to play a unique role in contributing to the emerging science of COVID-19, especially given our expertise in clotting, and ASH has continued to provide leadership in an uncertain time with vetted resources and timely guidance for how best to manage our patients amid the pandemic.

Two studies analyze data from theASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology, which started in the early days of the pandemic to provide real-time observational data summaries to clinicians on the front lines of the fight against COVID-19, as well as researchers and providers around the world.

In September 2021, the Centers for Disease Control and Prevention (CDC) awarded the ASH RC funding to identify the overall burden of COVID-19, the effects of health disparities and outcomes, and the areas where future resources should be focused for treatment for people living with hematologic malignancies. Specifically, CDC funding, in part, supports additional data submissions to the ASH RC COVID-19 Registry, real-time public data summaries, and research activities. As the Registry dataset has grown, researchers have identified potential drivers of severe illness, hospitalization, and mortality. The data also suggest that aggressive supportive treatment of COVID-19 can improve outcomes for many patients and should be offered.

A third study conducted among individuals living with sickle cell disease suggests COVID-19 infection can cause occlusive events, resulting in pain episodes, but these patients seem to respond to COVID-19 treatments and also were quick to adopt precautions and shift to virtual appointments as needed.

The final two studies look at antibody response following vaccination among people with various hematologic malignancies, helping give clues into which groups of patients may still be at high risk of COVID-19 after getting the vaccines.

A number of studies have shown that people with blood cancers have less than optimal responses to vaccination, and there is a need to continue to push for mitigation strategies, said Dr. Michaelis.

Abstract 3040: Risks for Hospitalization and Death Among Patients with Blood Disorders from the ASH RC COVID-19 Registry for Hematology

Patients with blood cancers, particularly those with more advanced disease, are especially vulnerable to serious COVID-19 outcomes, including an elevated chance of severe illness and death from COVID-19, according to an analysis of more than 1,000 patients in the ASH RC COVID-19 Registry for Hematology. Based on the report, 17% of patients with blood cancers who developed COVID-19 died from COVID-related illness, a strikingly higher mortality rate than what was seen in the general population, according to researchers. Older age, male sex, poor cancer prognosis, and electing to defer intensive care when it was recommended were all independently associated with a heightened chance of dying.

In our analysis, having a poor prognosis for underlying disease prior to COVID-19 and deciding to forgo ICU-level care for that disease were the most powerful predictors of mortality among patients with blood cancer and COVID-19and the two may very well be related, saidLisa K. Hicks, MD, MSc, of St. Michaels Hospital in Toronto, Canada. If someone is sick enough to require ICU-level care and their preference is not to receive this type of care, we would expect that decision to have a major impact on their survival.

According to the data, patients whose physician had estimated that they had less than six months to live due to their cancer before getting COVID-19 had six-fold higher odds of dying and these odds nearly doubled among people who decided to forgo more intensive care due to COVID-19. However, these groups represented a small proportion of the overall sample with only 7% estimated to have a pre-COVID-19 prognosis of under six months, and 9% deferring ICU care.

Of particular interest to the field was whether blood cancer treatment would affect COVID-19 mortality. Most patients included in the dataset (71%) received cancer treatment during the previous year; others were either in remission or had not yet needed treatment. In addition, receiving cancer treatment in the year prior to COVID-19 infection did not significantly increase the risk of death as some had feared; however, it was linked to an increased risk of hospitalization if infected by COVID-19. Older age, being male, having active cancer, and having other health conditions were also associated with an increased risk of hospitalization from COVID-19 among patients with blood cancers.

In the early days of the pandemic, there was a lot of uncertainty about whether we should withhold or modify blood cancer treatments in regions with high levels of COVID-19, said Dr. Hicks. The data are somewhat reassuring in that, while recent cancer treatment was linked to a higher risk of hospitalization among those with blood cancer and COVID-19, it wasnt independently associated with a statistically greater likelihood of dying. The type of blood cancer was also not associated with a higher risk of COVID-19 mortality. These findings suggest that patients who need treatment for their hematologic malignancy should likely proceed with that treatment.

Data were collected between April 1, 2020, and July 2, 2021, as part of the ASH RCs COVID-19 Registry for Hematology, which is a public-facing, volunteer registry reporting outcomes of COVID-19 infection in patients with underlying blood disorders. A total of 1,029 patients from around the globe were included in this analysis. Of these, 41% were female. The median age was 50 to 59 years of age, and patients ranged from five to more than 90 years of age; 27% had at least one co-existing condition such as heart disease, hypertension, respiratory disease, or diabetes. Researchers sought to identify factors associated with a higher likelihood of hospitalization and death from COVID-19.

Of people included in the analysis, 354 (34%) had acute leukemia or myelodysplastic syndromes (MDS), 255 (25%) had lymphoma, 206 (20%) had plasma cell dyscrasia (myeloma/amyloid/POEMS), 116 (11%) had chronic lymphocytic leukemia (CLL), and 98 (10%) had myeloproliferative neoplasm (MPN).

Patients with MPN and plasma cell dyscrasia had less severe COVID-19 illness overall compared to patients with CLL, leukemia, MDS, or lymphoma, which Dr. Hicks said is not surprising as patients with MPN typically live with their disease for many years, are generally in better health, and may not require immunosuppressive treatment.

The data from the ASH RC COVID-19 Registry has limitations and findings should generally be regarded as hypothesis generating, Dr. Hicks said. Nonetheless, the data do suggest that patients with blood cancers are at substantial risk from COVID-19; this finding has implications for our patients, how we manage our clinics amid COVID-19 and the changing variants, and how vaccines, boosters, and antibody treatments are distributed.

In this analysis, 17% of those with blood cancers died of COVID-19; the mortality rate among those infected with SARS-CoV-2 in the general U.S. population has been reported to be between 1.6% and 6.2% at various times during the pandemic, Dr. Hicks added.

The ASH RC Registry is a public voluntary registry that continues to accrue cases and provide the information on a public dashboard to help keep the hematology community apprised on changing trends. Dr. Hicks said the team will also be looking at how the risks of hospitalization and death changed as vaccines and COVID-19 treatments became more widely available.

Abstract 2800: Clinical Predictors of Outcome in Adult Patients with Acute Leukemias and Myelodysplastic Syndrome and COVID-19 Infection: Report from the American Society of Hematology Research Collaborative (ASH RC) Data Hub

In separate analyses of 257 patients with acute leukemia or MDS who developed COVID-19 and are part of the ASH RC COVID-19 Registry for Hematology, both neutropenia (a type of low white blood cell count) and having active MDS or leukemia (versus being in remission) were found to strongly and independently predict severe COVID-19 illness.Once hospitalized, active disease by itself whether someone was newly diagnosed or had relapsed was not tied to a greater odds of dying from COVID-19, nor was receiving ongoing cancer treatment.

For this retrospective analysis, which included data from 135 patients with acute myeloid leukemia (AML), 82 with acute lymphocytic leukemia (ALL) and 40 with MDS who were diagnosed with COVID-19 from 2019 to present, researchers sought to identify characteristics that put patients at higher risk of severe illness or death from COVID-19. At the time of COVID-19 diagnosis, 46% were in remission and 44% had active disease.

COVID-19 severity was defined as mild (no hospitalization required), moderate (hospitalization required), or severe (ICU admission required). After adjusting for several risk factors, active disease and neutropenia at the time of COVID-19 diagnosis were also associated with severe COVID-19 illness that necessitated ICU-level care.

Overall, one out of five (21%) patients died from COVID-19, which was higher than the mortality rate reported for the registry as a whole (17%) or what was seen in the general public during the same period of time, researchers reported. Mortality among hospitalized patients with COVID-related illness was 34%, and mortality among patients once admitted in the ICU was 68%. The two factors most strongly associated with a higher likelihood of dying among these patients were: 1) how long someone was perceived to live from the underlying MDS or leukemia before getting COVID-19, as defined as a physicians estimated prognosis of less than six months survival, and 2) whether or not they decided to go to the ICU if it was recommended. Older age, male sex, and neutropenia at diagnosis were also associated with COVID-19 mortality though less strongly.

This is a particularly vulnerable population and we suspected they may do worse because they are immunocompromised and, as it is, the average survival for acute blood cancers if untreated is three to six months, so if COVID-19 comes together with that diagnosis, its very concerning, saidPinkal Desai, MD, MPH, of Weill Cornell Medical College, New York. Our data suggest these patients can survive COVID-19 and their underlying disease itself was not associated with worse mortality, which means that if these patients are given appropriate and aggressive treatment, we can help them recover. But if there are decisions that are made after they get to the hospital (for example, whether to go to the ICU) that clearly plays a role.

In fact, patients for whom ICU-level care was recommended and declined had five times higher odds of dying compared with patients who opted to go to the ICU.

Patients who went to the ICU did better regardless of disease status, said Dr. Desai. Just having acute leukemia or MDS puts these patients at high risk of severe COVID-19, and they need to be hospitalized and receive treatments, but decisions about the ICU should be individualized, a patients prognosis should be discussed, and if a patient wants aggressive care for COVID-19 that should be offered.

Patients were more likely to forgo ICU care if they were older, male, smokers, or if they had active disease or an estimated pre-COVID-19 survival of less than six months. Forgoing ICU care was associated with a higher COVID-19 mortality in all patients.

Our data show that these patients do survive COVID-19 after receiving care in the ICU and underscore that cancer treatments should not be withheld as inferior treatment would quickly put many of these patients into the category of a prognosis of less than six months, said Dr. Desai. COVID-19 vaccination is also critically important.

The data are limited in that they were collected before COVID-19 vaccines were widely available; future data should inform about mortality rates among vaccinated patients.

Patient Vigilance and Virtual Visits Credited for Reducing Exposure, Illness, and Death Due to COVID-19 in Cohort With Sickle Cell Disease

Abstract 3105: COVID-19 Infection and Outcomes at a Comprehensive Sickle Cell Center

The Georgia Comprehensive Sickle Cell Center at Grady Hospital in Atlanta the nations largest treatment center for adults living with sickle cell disease (SCD) quickly switched to offering virtual visits for routine follow-up care of its more than 1,300 patients as the COVID-19 pandemic emerged. People living with SCD, an inherited disorder characterized by crescent- or sickle-shaped red blood cells, are immunocompromised and thus at high risk for COVID-19. The center established a database to track all COVID-19 cases among its patients.

The first report from that database the largest single-center study to date on COVID-19 in people with SCD now shows that between March 2020 and March 2021, just 55 (4%) of the centers 1,343 patients contracted COVID-19, of whom 16 (29%) were hospitalized and two ultimately died from complications of infection with the virus. Eleven patients (20%) required neither hospitalization nor emergency-room treatment for complications of either COVID-19 or SCD during the one-year follow-up period.

Our findings show that when supported by virtual visits, most of our patients successfully reduced their exposure to and complications from COVID-19, said study authorFuad El Rassi, MD, of Emory University and director of research at the Grady Comprehensive Sickle Cell Center. They understood the risks and followed recommendations to stay at home and avoid interacting with other people.

The 55 patients who contracted COVID-19 were aged 28 on average and 51% were female. Of those who visited an emergency room or were hospitalized during the year of follow-up, 27 (49%) sought care for a painful episode of SCD and 15 (27%) for complications of COVID-19. Among those who sought care for COVID-19 symptoms, 32 (58%) had pain as their primary symptom, followed by cough and fever (40%) and shortness of breath (31%); 25% had chest X-ray evidence of pneumonia. Sixteen patients received treatment, with nine receiving the antibody treatment remdesivir, eight receiving the steroid drug dexamethasone, and seven receiving red-blood-cell products to treat pain.

Twenty cases of COVID-19 were diagnosed between March and September of 2020. The two patient deaths from COVID-19 occurred in June and July of 2020. Among the 35 cases diagnosed between October 2020 and March 2021, no patients died and the number of hospitalizations decreased as better treatments for COVID-19 became available.

One of the patient deaths was due to a blood clot in the lungs, Dr. El Rassi said. This unfortunately occurred before it became the standard of care to treat hospitalized COVID-19 patients with blood thinners, he said.

Despite the second peak in COVID-19 cases in the winter of 2021, there were no reported deaths among our patients who developed the disease, Dr. El Rassi added. This suggests that the patients vigilance in staying home may have been crucial to reducing illness and death, and having the option for virtual visits was also key. Patients who needed blood tests or to obtain medication refills were sent to satellite centers.

Patient adherence to COVID-19 precautions was measured based on their responses to physician questions at intake and during virtual follow-up visits.

Dr. El Rassi and his colleagues plan to conduct further studies to evaluate the impact of the delta variant on diagnosis, illness, and death from COVID-19 among the sickle cell centers patients.

Some People With Blood Disorders May Continue to Face High Risk of COVID-19 After Vaccination

Abstract 218: Antibody Response to Vaccination with BNT162b2, mRNA-1273, and ChADOx1 in Patients with Myeloid and Lymphoid Neoplasms

According to a new study, about 15% of people with blood cancers and other blood disorders had no vaccination-related antibodies after receiving a COVID-19 vaccine. While researchers say it is encouraging that 85% of study participants did show an antibody response, the findings suggest that additional precautions may be warranted to prevent COVID-19 infection among people with blood disorders.

The study examined antibody levels after COVID-19 vaccination in people with blood cancers such as lymphoid and myeloid neoplasms, autoimmune disorders, and non-cancerous disorders of blood or immune cells. The results suggest that patients with lymphoma and those currently receiving treatment are the least likely to build antibodies in response to a COVID-19 vaccine.

Some patients with hematologic diseases do not have an adequate antibody response and might, therefore, not have sufficient protection from vaccination, saidSusanne Saussele, MD, of III. Medizinische Klinik, Medizinische Fakultt Mannheim, Universitt Heidelberg, Germany. This study can help guide vaccination strategies for these patients. In addition, our study suggests that when it is possible to delay beginning treatment for their underlying disorder, it may be best to wait so that a patient can receive a vaccine or booster first.

People with blood disorders face a high risk of hospitalization and death if they become infected with COVID-19, especially if they are older or have received therapies that reduce B-cells, a type of immune cell. Since the majority of participants in the study did respond to COVID-19 vaccines, the results underscore the role of vaccination as an important strategy for preventing severe disease, researchers said. However, the findings also suggest vaccination should be complemented with other precautions. We should recommend ongoing protective measures such as masks, social distancing, and screenings, as well as prioritizing vaccination for family members and caregivers to protect the patients, Dr. Saussele said.

For the study, the researchers recruited 373 patients treated for blood disorders at University hospital Mannheim in Germany and measured vaccine-related antibodies in their blood a median of 12 weeks after final vaccination. More than 90% of participants had blood cancer, while 9% had either autoimmune disease or a non-malignant blood disorder. Most patients had received the Pfizer-BioNTech [BNT162b2]vaccine; 10% received the Moderna vaccine [mRNA-1273], 7% received the AstraZeneca vaccine [ChADOx1], and 6% received one dose from each of the two vaccine types.

Overall, 85% of participants tested positive for vaccine-related antibodies and 15% tested negative. The rate of negative antibody results was highest among those with lymphoid neoplasms, a group of diseases that include lymphoma, myeloma, and lymphoid leukemia. Among these patients, 36% tested negative for vaccine-related antibodies. Patients with indolent non-Hodgkin lymphoma, a slow-growing type of lymphoma, had the weakest response to vaccination overall.

Being on active therapy was associated with a reduced antibody response. Overall, 61% of study participants were on active therapy. Of those who tested negative for vaccine-related antibodies, most (71%) were on active therapy. Therapies correlated with a negative response were rituximab, ibrutinib/acalabrutinib, and ruxolitinib.

Our study suggests that most people with blood malignancies not only those who are currently under treatment should monitor their antibody levels and work closely with their care team to determine how to continue to protect themselves from COVID-19, Dr. Saussele said. Antibody measurements offer a hint of who has responded to the vaccine and can perhaps ease up on precautions a bit.

Dr. Saussele noted that the results are limited in that the study did not examine participants T-cell response to vaccination, meaning that some patients level of protection may have been underestimated. The researchers plan to continue to measure antibody levels for at least a year and to assess participants rates of breakthrough infections and response to vaccine boosters.

Strong Antibody Response Seen in Patients With AML and MDS After Second Dose of mRNA COVID-19 Vaccine

Abstract 217: Responses to SARS-Cov-2 Vaccines in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

In one of the largest studies to date of the antibody response to vaccination against COVID-19 in people who had been treated for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), patients responded well to two doses of the Moderna mRNA vaccine and saw a particularly dramatic increase in levels of antibodies against the virus after receiving their second vaccine dose.

We observed a strong antibody response to the vaccine in a group of patients at high risk for severe COVID-19, including among patients who were on active treatment for AML or MDS, said Jeffrey Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Florida. The fact that antibody levels increased so dramatically after the second vaccine dose suggests potential utility in additional dosing, even for patients who initially respond poorly to the vaccine.

Previous studies had shown that patients with other types of blood cancer specifically, B-cell lymphomas or chronic lymphocytic leukemia often have a poor antibody response to vaccination with one of the COVID-19 mRNA vaccines. Treatment of these cancers suppresses the ability of the immune system to produce white blood cells such as B cells and T cells to fight off infection.

The treatment of myeloid cancers such as AML and MDS, including allogeneic transplantation, also suppresses white blood cells and leaves patients vulnerable to infection, said Dr. Lancet. We conducted this study to find out whether patients with these cancers would also have a suppressed or absent immune response to COVID-19 vaccination.

The study involved 46 patients who either had previously or were currently undergoing treatment for AML or MDS. The patients median age was 68 years; 59% were male and 96% were white. On average, they were about two years out from the diagnosis of their cancer. Fifteen patients (33%) were receiving treatment for their cancer at the time they were vaccinated. Thirty-two patients (70%) had undergone a transplant of blood-forming stem cells from a healthy donor as part of their cancer treatment. Forty patients (87%) were in remission when they were vaccinated. (Note that some patients are counted twice e.g., if they had undergone a stem cell transplant and were in remission, they would be counted in both categories. For this reason, the percentages add up to more than 100%.)

All patients received a first dose of the Moderna mRNA vaccine (this vaccine type was being given at the clinic) in late January 2021 and a second dose four weeks later. The investigators collected blood specimens from each patient before each vaccine dose was administered and again at four weeks after the second dose. The primary aims of the study were to describe the immune response and assess the safety profile of the vaccine in a cohort of patients with AML or MDS.

Blood test results at 29 days after the first vaccine dose showed that 70% of patients had an antibody response; at 57 days following the second dose 97% had an antibody response. Antibody levels were significantly higher after the second dose compared with after the first dose. Patients antibody response was not significantly affected by age, gender, race, disease status (i.e., active or in remission), time from disease diagnosis to vaccination, number of treatments patients had undergone for their cancer, whether patients had received a stem cell transplant, or whether they were on active treatment at the time of vaccination.

The most common adverse events following vaccination were the typical ones reported after vaccination with a COVID-19 mRNA vaccine, such as fatigue, headache, arm swelling, and mild pain at the injection site.

The study results should be confirmed in a larger group of patients, Dr. Lancet said. However, based on these data, we feel comfortable advising patients with AML or MDS that they should get vaccinated against COVID-19. Due to their vulnerability to COVID-19, they stand to benefit from the vaccine more than most.

This is an observational study without an identified control, or comparator, group, Dr. Lancet cautioned. Another limitation is that because the participants were overwhelmingly white, it is not known whether patients of other races or ethnicities would show a similar antibody response. In addition, the actual protective effect of the vaccine and the T-cell responses to it in this patient population are not yet known; the researchers are currently gathering these data.

The investigators are now following the same cohort of patients to determine whether a third dose of the vaccine can achieve even higher antibody levels than were seen after the second dose.

This press release was published by the American Society of Hematology on December 11, 2022.

Go here to read the rest:
COVID-19 Takes a Toll on People with Blood Cancers and Disorders - Cancer Health Treatment News

Posted on Jan 01, 2022 | Author Dr. Tasaduk Hussain Itoo

Mental health forms a crucial part of one's overall health, comprising emotional, psychological, and social well-being of a person. Broadly, it involves how we think, feel and act. Any negative alteration in such aspects can interfere with one's ability of thinking, behaviour, mood, emotions and feelings, thereby amounting to mental health disorders.

Mental health disorders pose a strong risk to development of heart disease, the effects can arise both, directly through biological pathways, and indirectly through risky health behaviours including substance abuse.

Scientific research has revealed that people experiencing mental health issues like depression, anxiety, stress and even PTSD over a long period of time may experience certain physiologic effects on their body, such as increased cardiac reactivity (e.g., increased heart rate and blood pressure), reduced blood flow to the heart, and heightened levels of cortisol. Over the course of time, these physiologic effects can lead to calcium build-up in the arteries, metabolic disease and heart disease.

Conversely, it has been evidenced that mental health disorders like depression, anxiety, and PTSD can develop after major cardiac events like heart failure, stroke, and heart attack more so after an acute heart disease event from factors like pain, fear of death or disability including financial problems associated with the event.

Furthermore,it has been revealed thatthe impact of medicines used to treat mental health disorders pose a strong risk towards development of cardio-metabolic disease risk use of some antipsychotic medications has been associated with obesity, insulin resistance, diabetes, heart attacks, atrial fibrillation, stroke including death.

Moreover, mental health disorders such as anxiety and depression may increase the chance of adopting unhealthy behaviours such as smoking, alcoholism, sedentary lifestyle or development of resistance to taking prescribed medications. This is because people experiencing a mental health disorder may have fewer healthy coping strategies for stressful situations thus making it difficult for them to make healthy lifestyle choices to reduce their risk of heart disease.

Defining the preventive interventions

The first framework focuses on when in the course of a disease the preventive intervention is required. Primary prevention occurs before any evidence of disease and aims to reduce or eliminate causal risk factors, prevent onset and thus reduce incidence of the disease. Examples include vaccinations to prevent infectious diseases and encouraging healthy eating habits and physical activity to prevent obesity, diabetes, hypertension, and other chronic diseases and conditions.

Secondary prevention occurs at a latent stage of disease: after a disease has begun but before the person has become symptomatic. The goals that ultimately reduce the prevalence of the disease are early identification through screening as well as providing interventions to prevent the disease from becoming manifest. Screening tools and tests are examples of secondary prevention.

Finally, tertiary prevention is an intervention implemented after a disease is established, with the goal of preventing disability, further morbidity, and mortality. Medical treatments delivered during the course of diseases can be considered tertiary prevention. Relapse prevention is another form of tertiary prevention. For example, while talking about mental health disorders, primary, secondary, and tertiary prevention are exemplified respectively by eliminating certain forms of dementia that stem from vitamin deficiencies, screening for problematic drinking that precedes alcohol use disorder, and providing psychosocial treatments to reduce disability among individuals with serious mental illnesses.

The second approach of prevention, largely focuses on who receives an intervention, also has three levels of prevention: universal, selective, and indicated. Universal preventive interventions are given to the entire group (e.g., a school, an entire community, or the whole population), regardless of individuals' level of risk for the disease. Examples include fortification or enrichment of foods, school-based curricula about substance abuse, and informational campaigns, such as public announcements about wearing seat belts or not texting while driving.

Selective preventive interventions are those delivered to a subgroup at increased risk for a disease outcome. Examples include use of hypolipidaemic drugs among those with hyperlipidaemia (to prevent later cardiovascular disease) and pneumococcal vaccination in older adults.

Indicated preventive interventions are those given to an even more select group that is at particularly high risk or is already exhibiting subclinical symptoms. Examples include lifestyle modifications for pre-diabetes or pre-hypertension. While talking about mental health disorders universal, selective, and indicated preventive interventions are exemplified respectively by social and emotional development curricula provided in elementary schools, group-based psychotherapy for children of parents with depressive disorders, and efforts to identify and treat adolescents and young adults who appear to be at clinical high risk.

Prevention of heart diseases

Controlling high blood pressure: This is one of the most important things one can do to reduce their heart disease risk. Exercising, managing stress, maintaining a healthy weight and limiting the amount of sodium in your diet and avoiding alcohol can all help to keep high blood pressure in check. In addition to recommending lifestyle changes, one may need to take medications to treat high blood pressure.

Controlling diabetes: One can manage diabetes with diet, exercise, weight control and medications.

Lowering the amount of cholesterol and saturated fat in one's diet: Eating less cholesterol and fat, especially saturated fat and trans fats may reduce plaque formation in arteries. Besides dietary changes, one may need to take cholesterol-lowering medications.

Exercising regularly: Exercise reduces risk of heart disease in many ways. It can lower blood pressure, increase the level of high-density lipoprotein cholesterol, and improve the overall health of blood vessels and heart. It also helps in losing weight, controlling diabetes and reducing stress.

Eating a diet rich in fruits and vegetables: A diet containing five or more daily servings of fruits or vegetables may reduce risk of heart disease. Following a diet which emphasizes olive oil, fruit, nuts, vegetables and whole grains may be helpful.

Quitting tobacco use: Smoking raises the risk of heart disease for smokers and non-smokers exposed to second-hand smoke. So, quitting tobacco use reduces risk of heart disease.

Avoiding alcohol: It can be a risk factor for heart disease. Heavy alcohol consumption increases risk of high blood pressure, ischemic heart disease and heart attack.

Avoiding drug abuse: Certain drugs, such as cocaine and methamphetamines, are established risk factors for ischemic heart disease.

Anti-platelet drugs are commonly used as preventive medications. Platelets are cells in one's blood that form clots. Anti-platelet drugs make these cells less sticky and less likely to clot. The most commonly used anti-platelet medication is aspirin.

Anticoagulants: The drugs, which include heparin and warfarin reduce blood clotting. Heparin is fast acting and may be used over a short period of time in the hospital. Slower acting warfarin may be used over a longer term.

Link:
Mental health disorders and heart diseases - Rising Kashmir

LEIDEN, Netherlands & CAMBRIDGE, Mass., Dec. 30, 2021 (GLOBE NEWSWIRE) -- ProQR Therapeutics N.V. (Nasdaq:PRQR) (“ProQR”), a company dedicated to changing lives through the creation of transformative RNA therapies for genetic eye diseases, today announced that it has amended its convertible debt financing agreement entered into in 2020 with Kreos Capital (“Kreos”) and Pontifax Medison Debt Financing (“Pontifax”).

Continue reading here:
ProQR Announces Amendment to Convertible Debt Financing Agreement with Pontifax Ventures and Kreos Capital