StemCell Therapy

TORONTO, Aug. 03, 2021 (GLOBE NEWSWIRE) -- Avicanna Inc. (the “Company” or “Avicanna”) (TSX: AVCN) announces that the Ontario Securities Commission ("OSC") has issued an order dated July 30, 2021 (the “Partial Revocation Order”) partially revoking the failure-to-file cease trade order issued against the Company on June 11, 2021 (the "FFCTO") for failing to file certain outstanding continuous disclosure documents (collectively, the “Documents”) within the timeframes prescribed by applicable securities laws.

Link:
Avicanna Announces Partial Revocation of Cease Trade Order and Proposed Financing

MELBOURNE, Australia, Aug. 03, 2021 (GLOBE NEWSWIRE) -- Telix Pharmaceuticals Limited (ASX: TLX, ‘Telix’, the ‘Company’) is pleased to announce that Ms. Helen Hovenga has joined the Telix executive team in the role of Chief People Officer (CPO).

Here is the original post:
Ms. Helen Hovenga Joins Telix as Chief People Officer

WARREN, N.J., Aug. 03, 2021 (GLOBE NEWSWIRE) -- Aquestive Therapeutics, Inc. (NASDAQ:AQST), a pharmaceutical company focused on developing and commercializing differentiated products that address patients’ unmet needs and solve therapeutic problems, today reported financial results for the second quarter ended June 30, 2021 and provided an update on recent developments in its business.

See the original post:
Aquestive Therapeutics Reports Second Quarter 2021 Financial Results, Provides Business Update and Raises Full Year Revenue Guidance

- A Combined Analysis of Pregnancy and Live Birth in more than 1800 IVF Patients Across Three Randomized, Placebo-Controlled Clinical Trials Published in the Journal of Human Reproduction-

Read more:
ObsEva Announces Two Cornerstone Publications Describing Clinical Trials of Nolasiban for Improving Pregnancy and Live Birth Outcomes Following IVF

August 4, 2021Breda, the Netherlands – argenx (Euronext & Nasdaq: ARGX), a global immunology company committed to improving the lives of people suffering from severe autoimmune diseases and cancer, today announced that members of management will participate in a fireside chat at the 2021 Wedbush PacGrow Virtual Healthcare Conference on Wednesday, August 11, 2021 at 11:30 a.m. ET.

See the original post:
argenx to Present at 2021 Wedbush PacGrow Virtual Healthcare Conference

On target to grow the broad product pipeline with at least 3 additional programmes before end 2021Significant expansion of commercial footprint of non-opioid pain treatment Maxigesic® IV

See more here:
Hyloris Reports 2021 Half-Year Results: Multiple Potential Value Inflection Points Ahead

ExtramuralBy Megan Avakian

An NIEHS-funded study in mice showed how chlorine exposure leads to Acute Chest Syndrome (ACS), a leading cause of death in patients with sickle cell disease (SCD). The results point to a potential lifesaving therapy for SCD patients exposed to chlorine. Chlorine is found in some household cleaning products and is commonly encountered in industrial accidents and chemical warfare.

SCD is a group of blood disorders in which the hemoglobin protein is defective, causing red blood cells (RBCs) to rupture. The researchers used genetically engineered mice that resembled SCD in humans (sickle mice) and compared them to healthy control mice with human hemoglobin. They exposed both groups to chlorine gas or normal air and assessed survival, lung injury, and hemolysis, or the rupture of RBCs which releases hemoglobin into the blood. They repeated this process but injected mice with hemopexin, which binds to hemoglobin.

Within six hours of chlorine exposure, 64 percent of sickle mice died while none of the controls died. Compared to controls, surviving sickle mice had hemolysis and lung injury. Hemolysis resulted in increased blood levels of heme, a component of hemoglobin known to cause lung injury. Hemopexin treatment following exposure significantly improved survival and reduced blood heme levels and lung injury. RBCs from chlorine-exposed sickle mice had high carbonylation, which increases cell rupture. Carbonylation was absent after hemopexin treatment.

According to the authors, results indicate that chlorine exposure induces ACS-like outcomes in sickle mice and that hemopexin treatment after exposure reduces death and lung injury.

Citation:Alishlash AS, Sapkota M, Ahmad I, Maclin K, Ahmed NA, Molyvdas A, Doran S, Albert CJ, Aggarwal S, Ford DA, Ambalavanan N, Jilling T, Matalon S. 2021. Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin. Redox Biol 44:102009.

Women exposed to higher temperatures had a lower ovarian reserve, found NIEHS-funded researchers. Ovarian reserve refers to the number and quality of a womans eggs. A diminished ovarian reserve reduces a womans ability to get pregnant.

The study included 631 women aged 18-45 years enrolled in a reproductive health study in Massachusetts. Using each womans home address, the researchers estimated daily ambient temperature exposures for three months, one month, and two weeks before the ovarian reserve examination. They used ultrasonography to measure antral follicle count (AFC), a measure of ovarian reserve.

Exposure to higher temperatures was associated with a lower AFC. Specifically, a 1-degree Celsius increase in average maximum temperature three months before ovarian reserve testing was associated with a 1.6 percent lower AFC. This relationship remained negative but weakened for one month and two weeks before AFC testing. The negative association between temperature and AFC was stronger in November through June compared to the summer months. According to the researchers, this suggests that women may be more susceptible to heat during certain times of the year, potentially because they adapt to heat in the summer.

Study findings raise concerns that the steady increase in global temperature due to climate change may result in accelerated reproductive aging in women, say the researchers.

Citation:Gaskins AJ, Minguez-Alarcon L, VoPham T, Hart JE, Chavarro JE, Schwartz J, Souter I, Laden F. 2021. Impact of ambient temperature on ovarian reserve. Fertil Steril; doi: 10.1016/j.fertnstert.2021.05.091. [Online 8 June 2021]

NIEHS grantees developed a gene expression atlas that captures the cellular makeup of the mammary gland across life stages, providing clues to how breast cancer originates. The female breast is made up of different cell types and undergoes reorganization during development, pregnancy, and menopause, increasing breast cancer risk.

To build the atlas, the researchers used single cell RNA sequencing data, which assesses gene and protein expression of an individual cell. They integrated data from 50,000 mouse mammary cells covering eight life stages and 24,000 adult human mammary cells.

The data formed three clusters. Using known genetic markers, they identified the clusters as three breast epithelial cell types. Connecting the clusters were embryonic mammary stem cells, which can give rise to each epithelial cell type. Advanced computational methods suggested the breast epithelium originated from embryonic mammary stem cells that differentiated into epithelial cells through postnatal progenitor cells.

The researchers compared genetic profiles for each epithelial cell type with known cancer-related genes to infer breast cancer cells of origin. This can help pinpoint tumor origin since cancer often starts from a single transformed cell. They also examined how reorganization during different life stages altered breast cellular makeup and breast cancer subtype risk. For example, during pregnancy the breast had increased basal epithelial cells, potentially increasing risk of the basal breast cancer subtype. According to the authors, the atlas provides insights into cellular makeup and development of breast cancer subtypes.

Citation:Saeki K, Chang G, Kanaya N, Wu X, Wang J, Bernal L, Ha D, Neuhausen SL, Chen S. 2021. Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis. Commun Biol 4(1):660.

The placenta may play a critical role in conveying the effects of particulate matter air pollution (PM2.5) exposure during pregnancy to the developing fetus, according to a new NIEHS-funded study. The researchers found that maternal PM2.5 exposure during certain periods of pregnancy leads to reduced fetal growth, especially in females.

The study included 840 women and their children enrolled in a birth cohort study in Rhode Island between 2009-2013. Using spatiotemporal models and the womens home addresses, the researchers estimated maternal weekly PM2.5 exposure from 12 weeks preconception until birth. They overlaid a previously developed placental gene network with PM2.5 exposure data to identify genes associated with air pollution exposure. They used gestational age and birth weight collected at birth to assess fetal growth.

The researchers identified a sensitive window spanning 12 weeks prior to and 13 weeks into pregnancy during which higher maternal PM2.5 exposure was associated with significantly lower infant birthweight and shorter gestational age across all timepoints. Female infants were particularly vulnerable to PM2.5-induced deficits in fetal growth. Disruption of placental genes important in amino acid transport and cellular respiration were correlated with maternal PM2.5 exposure and infant birthweight, suggesting that the placenta conveyed air pollution-related impacts to the developing fetus.

According to the authors, results suggest that maternal PM2.5 exposure may alter placental programming of fetal growth, with potential implications for downstream health effects.

Citation:Deyssenroth MA, Rosa MJ, Eliot MN, Kelsey KT, Kloog I, Schwartz JD, Wellenius GA, Peng S, Hao K, Marsit CJ, Chen J. 2021. Placental gene networks at the interface between maternal PM2.5 exposure early in gestation and reduced infant birthweight. Environ Res 199:111342.

(Megan Avakian is a research and communication specialist for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)

See more here:
Environmental Factor - August 2021: Extramural Papers of the Month - Environmental Factor Newsletter

Introduction

Traumatic brain injury is a leading global cause of mortality and morbidity and the main cause of death in young people living in industrialized countries.1,2 Traumatic brain injury is mainly caused by an external mechanical force causing brain trauma. Traumatic brain injury and the ensuing neuroinflammation, in addition to causing motor and cognitive deficits, may persist long after the initial injury.3 Furthermore, long-term neuroinflammation has been related to increased risk of neurodegenerative disorders and various other deficits.4 Traumatic brain injury as a risk factor for brain tumors has been a controversial topic in medicine for over a century.58 However, as statistical reports on brain tumors often exclude post-traumatic glioma, relevant information on the incidence of gliomas caused by traumatic brain injuries is rare. Although previous clinical studies and case reports are often vague and difficult to evaluate since most of them were published so many years ago,512 some are quite striking, such as the cohort study by Munch et al5 in which the reduced long-term risk of malignant astrocytic tumors after structural brain injury was evaluated. However, this study was conducted using a small population. Furthermore, it is to be noted that traumatic brain injury is only one type of structural brain injury in this study. Additionally, it is challenging to confirm the incidence of post-traumatic glioma owing to the frequently considerable time gap between traumatic brain injury and glioma. Thus, there is an urgent need to systematically evaluate the role and outcome of head trauma in the incidence and progression of glioma. In this review, our primary focus is to document the interrelationship between traumatic brain injury and glioma based on a comprehensive review of the existing literature, which is discussed in detail. First, we present an overview of previous cohort studies and various case reports regarding the relationship between traumatic brain injury and glioma. Next, we discuss the roles of microglial cells, macrophages, astrocytes, and stem cells in post-traumatic glioma formation and development. Moreover, we also briefly discuss the various carcinogenic factors during traumatic brain injury that could explain the interplay between these two parameters. We have also summarized the common inflammatory and oxidative stress-related signaling pathways related to traumatic brain injury and glioma. Lastly, we have elaborated on the strategy that could be considered in a clinical setting, and have concluded this review with directions for future research.

All previously published cohort studies and case-control studies are not directly comparable owing to differences in exposures and outcomes (Table 1). A population-based study by Inskip et al8 reveals an increased overall incidence of intracranial tumors of head trauma patients, whereas no significant association was found in the case of malignant astrocytic tumors. In a cohort study by Nygren et al7 no significant association between traumatic brain injuries and brain tumors was identified; moreover, specific risks for malignant astrocytic tumors were not reported. However more recently, a cohort study by Chen et al6 indicated an increased risk for not otherwise specified malignant brain tumors within 3 years after a traumatic brain injury. Besides, interestingly, a research group demonstrated a decreased risk 5 or more years after structural brain injury; however, they did not find convincing evidence for an association between structural brain injury and malignant astrocytic tumors within the first 5 years of follow-up.5 The authors speculated that the inflammatory response after traumatic injury could cause elevated immunological alertness for astrocytes undergoing neoplastic transformation, as well as a clearance of premalignant astrocytes or neural stem cells, which may otherwise have developed into glioma. Although their study demonstrated that structural brain injury may generally reduce the long-term risk of malignant astrocytic tumors, their data also supported that structural brain injury specifically caused by trauma (different from other types of exposures such as cerebral ischemic infarction and intracerebral hemorrhage) could increase the long-term risk of malignant astrocytic tumors. Thus, the relationship between traumatic brain injury and glioma is still not conclusive and warrants further studies.

Table 1 Overview of Published Epidemiological Studies Exploring the Causal Relationship Between Traumatic Brain Injury and Glioma

It is often a challenge to compare the results of previously published epidemiological studies,58 as it involves individuals of different ages who live in different environments. Importantly, most studies have also not been standardized regarding the type or the severity of brain damage. The low incidence of brain tumors also hinders the design of relevant research. There is currently an urgent need for more comprehensive and larger-scale epidemiological investigations, including cohort studies and case-control studies, to evaluate post-traumatic glioma. To date, very few case-control studies have specifically reported the risk for malignant astrocytoma/glioma after traumatic brain injury, and conclusively, the currently available findings are equivocal with null9,10 or positive associations.11,12 For the first time, Hochberg et al12 have done a case-control study of 160 persons with glioblastoma, and the results suggested that severe head trauma in adults is a significant risk factor for glioblastoma. After that, Zampieri et al12 did another case-control study to find potential risk factors for cerebral glioma in adults, however, their study yielded no meaningful association between head trauma and glioma. Besides, the case-control study done by Preston-Martin et al10 investigated the role of head trauma from injury in adult brain tumor risk. Although not significant association between head trauma and glioma has been found, their findings suggest that an association between head trauma and brain tumor risk cannot be ruled out and should therefore be further studied, and future studies of head trauma and brain tumor risk should consider potential initiators of carcinogenesis, such as nitrite from cured meats, as modifiers of the trauma effect on risk of brain tumor. Furthermore, Hu et al11 also exerted case-control study of risk factors for glioma in adults, interestingly positive associations between brain trauma and glioma has been found. Unfortunately, all case-control studies were conducted before the year 1998, and no newly published research worthy of reference could be found suitable for discussion in this review. The advantages of cohort studies have been highlighted in various studies; therefore, most researchers give more weightage to cohort studies than case-control studies when systematically evaluating evidence.13,14 Thus, additional more cohort investigations with correct and standardized study designs are much needed to gain a better understanding of post-traumatic glioma.

The results of the published epidemiological studies could not be compared uncritically, as the types of brain injuries differed, and patients belonged to different ethnic groups and different ages. Difficulties in conducting epidemiological studies can be attributed to the low incidence of brain tumors. More efforts should be directed toward investigating the causal relationship between traumatic brain injury and glioma, which is supported by several published case reports.1527 Although these reports from epidemiological observations have not conclusively confirmed the relationship between traumatic brain injury and glioma,58 some reports discuss the follow-up details of patients in great detail and are indicative of the possibility of such a relationship.1527 Anselmi et al15 reported two cases of brain glioma that developed in the scar of an old brain trauma, these two cases fulfill the established criteria for a traumatic origin of brain tumors and add further support to the relationship between cranial trauma and the onset of glioma. Di Trapani et al16 reported that several years after sustaining a commotive left parietal trauma, one patient developed a mixed glioma in the left temporo-parietal-occipital region in continuity with the scar resulting from the trauma. Magnavita et al17 reported the case of a patient who suffered a severe head injury to the right temporoparietal lobe, and the patient developed a glioblastoma multiforme at the precise site of the meningocerebral scar 4 years later. Moorthy et al18 reported a case of a 56-year-old man who had history of head injury 5 years prior with CT evidence of bilateral basifrontal contusions. Imaging showed a large left frontal intra-axial mass lesion and the histopathology was reported as glioblastoma multiforme. The authors formulated additional radiologic criteria for tumors that may present following trauma. Mrowka et al19 reported that a glioblastoma multiforme developed 30 years after a penetrating craniocerebral injury in the left parietal region caused by fragments of an artillery projectile. Sabel et al20 reported that a patient developed a left-sided frontal glioblastoma multiforme at the precise site of the meningocerebral scar and posttraumatic defect 37 years later. Witzmann et al21 reported a case of a 28-year-old male who suffered a frontal penetrating gunshot injury with subsequent bifrontal brain abscess and subdural empyema, and five years later developed a large bifrontal glioblastoma multiforme at the precise site of the meningo-cerebral scar and posttraumatic defect. Zhou et al22 also reported one case of glioblastoma multiforme that developed in the scar of an old brain trauma 10 years ago. Han et al23 presented the first case of pregnancy-related post-traumatic malignant glioma in a 29-year-old female, and suggested that pregnancy may promote the manifestation of the clinical symptoms. Tyagi et al24 used radiographic evidence from two patients to assess the possibility of a link between TBI and glioblastoma multiforme. Salvati et al25 presented 4 cases of post-traumatic glioma with radiological evidence of absence of tumor at the time of the injury. Henry et al26 reported a case of post-traumatic malignant glioma with radiological evidence of only a contusion prior to the development of the glioma. Simiska et al27 reported one case of post-traumatic glioma 2 years after head injury. Overall, some data from these studies might support the conclusion that the association is almost weak, while others not; but a causal relationship between traumatic brain injury and glioma is highly possible. This is because traumatic brain injury initiates inflammation, oxidative stress, repair, oncogene activation, and other pathophysiological changes, which are bound to lead to malignancy in at least some patients.28,29

Besides, to better identify reported cases addressing the relationship between traumatic brain injury and the incidence and development of glioma, an important aspect is to be able to recognize and differentiate between a tumor, traumatic brain injury-induced glioma, and post-traumatic glioma. We believe that only specific cases that fulfill certain conditions or criteria, could add to revealing the etiological association between head trauma and glioma. Thus, more efforts should be directed in establishing if there is a relationship between traumatic brain injury and gliomas, as well as diagnosing post-traumatic glioma. Since traumatic incidents are much more frequent than a possibly related tumor, James Ewing30 defined five criteria that could aid in the identification of post-traumatic glioma that could contribute to establishing the relationship between brain injury and the subsequent glioma. Subsequently, Zulch and Manuelidis31 revised Ewings criteria while adding their viewpoints. And Moorthy and Rajshekhar32 further added imaging-related screening criteria to this list. We believe that specific cases that fulfill these criteria, as well as possibly other cases with accurate retrospective data of traumatic brain injury and high risk of developing glioma, could add to the clarification of the etiological association between traumatic brain injury and glioma.

Neuroinflammation accompanying the activation of microglial cells and other effector cells has been suggested as an important mechanism of TBI.33 Active microglial cells can transform to the M1 phenotype, to secrete proinflammatory or cytotoxic mediators that mediate post-TBI cell death and neuronal dysfunction, or to the M2 phenotype, to participate in phagocytosis and secrete anti-inflammatory cytokines and neurotrophic factors that are important for neural protection and repair.34 Indeed, they can become polarized ranging from the classic M1 phenotype to an alternative M2 phenotype after TBI.35 The M1 response is presumed to be pro-inflammatory,36 whereas the M2 phenotype owns anti-inflammatory effects.37 Multiple molecular pathways, such as STAT, nuclear factor-B (NF-B), and interferon regulatory factor (IRF), are involved in the regulation of M1/M2 phenotypic transitions.3840 Preclinical evidence indicated that mixed phenotypes are present in the pathological processes of TBI, which offer opportunities for therapeutic interventions.41

Several mechanisms have been shown to be associated with the formation of post-traumatic glioma, specifically, inflammatory processes and oxidative stress, both of which are mainly involved in the removal of damaged components from the brain and are known to play irreplaceable roles in this process.24 In the brain, these mechanisms are mainly mediated by the microglia or other cells of the immune system.24,42 Microglia in the brain play a role in phagocytosis and antigen presentation, leading to the release of chemokines or cytokines.43 Interestingly, recent in vivo studies have shown that microglia could have different effects on the development of brain glioma, and also result in immunosuppressive conditions that promote glioma development.44,45 Although the growth-promoting effect of glioma by microglia after traumatic brain injury is controversial, its significant role in promoting an environment that can facilitate glioma development has been identified.43 Microglia can produce metalloproteinases in the tissues adjacent to glioma, which can facilitate tumor invasion.44 Besides, PGE2 can also contribute to the creation of an environment that facilitates glioma development.46 PGE2 is released by the microglia accompanying the developing glioma and can suppress T lymphocytes. The net effect is a decreased expression of major histocompatibility complex (MHC) class II molecules on antigen-presenting cells.46 Brain-repair processes mainly involve the microglia in normal conditions; however, during traumatic brain injury, various other cells from the immune system can also enter the brain parenchyma along with blood. These effects cannot be ignored.

Oxidative stress caused by ROS in the acute phase of TBI and cerebral infarction is thought to be detrimental, and macrophages have been recognized as the main cells that produce ROS.47 During traumatic brain injury, macrophages migrate to the site of the damaged blood-brain barrier and secrete interleukin 6 (IL-6). In normal conditions, the expression of IL-6 is very low, whereas, during traumatic brain injury, its production increases considerably.48 Brain injury elevates IL-6 production in both serum and CSF to high concentration. Notably, multiple TBI patients samples have also showed that the combination of elevated IL-6 concentrations is correlated with better outcomes in patients with TBI, suggesting IL-6 as a new therapeutic strategy as well as for prediction of disease outcome of patients with TBI.49 Importantly, high levels of IL-6 in the brain generally result in an adverse impact on microcirculation and lead to the destruction of the blood-brain barrier in an obviously wider area compared to the initial area of trauma.27 Thus, in traumatic brain injuries, it is crucial that the blood-brain barrier is not initially compromised, as IL-6 can subsequently promote the entry of macrophages to the site of injury and aggravate brain edema.24,42 Besides, Xu et al reported that IL-6 also impacts cell-cycle regulation42 and activates signal transducer and activator of transcription-3 (STAT3), which is important for cell proliferation, differentiation, and apoptosis. Previous studies show that STAT3 inhibition suppresses the growth of glioma cells and promotes apoptosis.43 These findings have also been confirmed in other in vivo studies.50,51 Besides, STAT3 activation can inhibit T lymphocytes and MHC II molecules on microglial and other antigen-presenting cells.43 Thus, STAT3 has an immunosuppressive effect and is likely a carcinogenic factor for glioma. Importantly, the increased concentrations of IL-6 and its receptors in the cerebrospinal fluid of patients who underwent traumatic brain injury are indicative of the involvement of IL-6 in glioma progression.42,43

The neuronal stem cells in the brain are mainly generated from the subgranular zone of the hippocampal dentate gyrus and the subependymal zones of the lateral ventricles.24 Traumatic brain injury leads to the migration of neuronal stem cells to the damaged sites to promote regeneration, thereby differentiating into astrocytes, neurons, and oligodendrocytes. Additionally, neuronal stem cells could release cytokines and neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF).24 Thus neuronal stem cells may be an effective treatment for neurological recovery after TBI.52 Interestingly, neuronal stem cells show a high expression of oncogenic genes and high sensitivity to chemical mutagenic factors.24 This is important because stem cells are involved in the production of ROS and various pro-inflammatory factors.24 Neuronal stem cells can be highly sensitive to mutagenic agents and could, thus, be easily mutated as a result of the action of certain agents. These characteristics may promote the formation of rapidly proliferating tumor cells and increase the progression of glioma in the brain.24,53 Migration of stem cells has already been identified in cases of traumatic brain injury, ischemia, and demyelination. However, there is a much higher risk of increased neoplastic transformation only during traumatic brain injury.24 Therefore, it is reasonable to accept the causal relationship between traumatic brain injury that induces brain stem cell activity and subsequent development of glioma.24 Stem cells have been generally recognized as potentially oncogenic in glioma54 and several studies have demonstrated their important role in the formation of gliomas.5557 The role of stem cells should be emphasized in the analysis of relevant mechanisms leading to glioma development induced by traumatic brain injury.

Multiple studies have suggested that astrocytes play a key role in the pathogenesis of TBI.58,59 Increased reactive astrocytes and astrocyte-derived factors are generally observed in both experimental animal models and TBI patients.60 Astrocytes have beneficial and detrimental effects on TBI, including acceleration and suppression of neuroinflammation, promotion and restriction of neurogenesis and synaptogenesis, and disruption and repair of the BBB through various bioactive factors.61 Additionally, astrocytic aquaporin-4 is also involved in the formation of cytotoxic edema. Thus, astrocytes are attractive targets for novel therapeutic drugs for TBI.

Based on case reports studying glioblastomas, neoplastic transformation of damaged astrocytes has been proposed as a possible mechanism occurring at the site of traumatic brain injuries.1527 Besides, it is generally accepted that astrocytes are essential components of the blood-brain barrier, and damage to the blood-brain barrier often occurs after the action of pro-inflammatory prostaglandins and leukotrienes, which triggers the effect of the relaxing of tight junctions.54 The pro-inflammatory factors lead to a relaxation of the capillary epithelium and the glial cells are exposed to potentially mutagenic agents.62 Traumatic brain injury accompanied by damage to the blood-brain barrier always causes a recovery reaction, which explains the recurrence of glioma in some cases.

To conclude, the summary of various carcinogenic factors that play a role during traumatic brain injury is presented in Figure 1. Traumatic brain injury can lead to the influx of macrophages to the site of brain injury, where they are activated and produce IL-6. Traumatic brain injury also induces enhanced IL-6 secretion by astrocytes and microglial cells. Increased IL-6 levels caused by traumatic brain injury can thus activate STAT3, thereby increasing cell proliferation at the site of injury and resulting in the inhibition of apoptosis. STAT3 can suppress T lymphocytes and decrease the activity of MHC class II molecules on cells of the immune system. Furthermore, the increased levels of IL-6 also impact the blood-brain barrier. Additionally, microglial cells secrete metalloproteinases in the tissues adjacent to the tumor, facilitating its migration and, consequently, facilitating its development. PGE2, which is synthesized by microglial cells during the development of the glioma, suppresses the T lymphocytes and decreases the expression of MHC II molecules. Besides, the generation of reactive oxygen species (ROS) might lead to certain mutations in stem cells that migrate to the injury site. At the site of injury, the risk of mutations and cell proliferation increases, and along with the inhibition of apoptosis, these factors may jointly contribute to carcinogenesis.

Figure 1 Schematic representation of various carcinogenic factors during traumatic brain injury. Traumatic brain injury could lead to the migration of macrophages to the site of injury, followed by increased IL-6 production. Traumatic brain injury also induces enhanced IL-6 secretion by astrocytes and microglial cells. The increased IL-6 could thus activate STAT3, which increases cell proliferation at the site of injury, as well as inhibition of apoptosis. STAT3 suppresses T lymphocytes and inhibits major histocompatibility complex (MHC) class II molecules on cells of the immune system. The increased IL-6 also damages the blood-brain barrier (BBB). In addition, microglia secretes metalloproteinases in the tissues adjacent to the tumor, facilitating its migration and development. PGE2 is also synthesized by microglia and suppress T lymphocytes, and also decrease the expression of MHC II molecules on antigen-presenting cells. Besides, reactive oxygen species (ROS) might lead to certain mutations in stem cells that migrate to the site of injury. At the site of injury, the risk of these mutations, and cell proliferation increase, as well as the apoptosis inhibition, may jointly contribute to carcinogenesis.

Inflammation at the site of traumatic brain injury and glioma has been well documented in the literature.63,64 Besides, ROS, the major contributor of oxidative stress, are metabolic byproducts originating from different sources in hypoxic65 conditions and exhibit condition-dependent functions.66,67 The activation of inflammation and oxidative stress are reported in both traumatic brain injury and glioma, and both conditions appear to share a common network of signaling for downstream functions (Figure 2). Interestingly, the activation of inflammation can also contribute to oncogenesis via the generation of ROS and the activation of oxidative stress,68 and conversely, oxidative stress also promotes inflammation.69 Specifically, in this situation, astrocytes, microglia, stem cells, and even neurons can be stimulated to increase ROS and RNS (NO, ONOO),7072 which participate in regulating inflammation and oxidative stress in traumatic brain injury and glioma.

Figure 2 Common inflammatory and oxidative stress-related signaling pathways for traumatic brain injury and glioma. Activation of inflammation and oxidative stress are reported in both traumatic brain injury and glioma, and both conditions share a common network of signaling for downstream functions. Specifically, in the cases of oxidative stress or inflammation in the brain, more ROS could thus be generated. Several cancer-specific external stimuli like the TNF-, could lead to a decrease in the mitochondrial membrane potential that activates ROS generation. Besides, the NADPH oxidase (NOXs) family proteins are one of the main producers of ROS in various cancers, as well as in traumatic brain injuries. And specific signals like TGF-, MAPK, AKT, ERK and various others, could lead to conformational changes in the NOX complex and increase ROS generation. Another important pathway that acts on glioma and traumatic brain injury in a similar manner is hypoxia-inducing factor 1 (HIF-1), which could be upregulated due to the inhibition of degradation via PHD inactivation. HIF-1 could increase the expression of glucose transporter 3 (GLUT3), erythropoietin (EPO), VEGF, as well as BNIP3. Besides, nuclear factor-B (NF-B) can increase the production of ROS, which can also be regulated by the Ras-Raf-MEK pathway via regulating GATA-6. Transcriptional enhancement of HSF1 by Ras could activate the SESN1 and SESN3 genes to promote the production of ROS. TGF also increases the production of ROS through activating GSK3 and mTOR signaling pathways in mitochondria, as well as inhibiting antioxidant enzymes, like the SOD and glutathione peroxidase (GPx).

After traumatic brain injury, there is sequential migration of the resident microglia and myeloid inflammatory cells to the site of injury.73 These inflammatory cells contribute to oncogenesis via promoting ROS generation, which has mutagenic properties, or via the secretion of cytokines and growth factors, in addition to maintaining an inflammatory response.68 During oxidative stress or inflammation in the brain, there is an increase in ROS could generation in the mitochondria.7476 Several cancer-specific external stimuli, including TNF-, lead to a decrease in the mitochondrial membrane potential and interfere with the components of the electron transport chain (ETC), thereby promoting ROS generation.77,78 Besides, the NADPH oxidase (NOXs) protein family is one of the main producers of ROS in various cancers and traumatic brain injuries.79 Moreover, specific markers, such as TGF-, MAPK, AKT, and ERK, among others,80,81 can lead to conformational changes in the NOX complex and increase ROS generation.82 Another indispensable pathway that has an impact on glioma and traumatic brain injury is hypoxia-inducing factor 1 (HIF-1), which can be upregulated owing to the inhibition of degradation via the inactivation of PHD.83,84 HIF-1 increases the expression of glucose transporter 3 (GLUT3), erythropoietin (EPO), VEGF, and BNIP3.8588 Several other signaling pathways are involved in the activation of inflammation and oxidative stress. Nuclear factor-B (NF-B) can increase ROS generation via a positive feedback loop of TNF regulation.89 Additionally, ROS can be regulated by the Ras-Raf-MEK pathway through the transcriptional regulation of GATA-6.90,91 It has been reported that transcriptional enhancement of HSF1 by Ras upregulates SESN1 and SESN3 genes to promote ROS production.92 Besides, TGF also increases the production of ROS by activating the GSK3 and mTOR signaling pathways in the mitochondria and inhibiting antioxidant enzymes, including SOD and glutathione peroxidase (GPx) (Figure 2).93,94

Following a traumatic brain injury, there is an increase in free radicals and the expression of several pro-inflammatory genes by various transcription factors such as NF-B.95,96 This knowledge could be used in anticancer drug discovery. ROS levels increased by oxidation therapy can trigger cell death via necrosis or apoptosis.97 Flavonoids, such as quercetin,98,99 catechins,100 and proanthocyanins,101,102 protect glial cells from inflammation and oxidative stress. These compounds exert protective effects in the brains of patients with cancer and help prevent traumatic brain injury. An anticancer agent, gallic acid, is not only toxic to glioma cells but also exerts beneficial effects in the recovery from traumatic brain injuries.103105 Cardamonin (a chalcone) is effective as an anti-inflammatory and anti-carcinogenic agent in glioma.106,107 Hyperbaric oxygen (HBO) therapy is a recently developed method108 that has been extensively used as an adjuvant in the treatment of various diseases predominantly related to hypoxic conditions. As traumatic brain injury and glioma are related to hypoxia, HBO therapy may be expected to be efficacious in the management of these diseases.109111 However, there could be significant differences in outcomes among patients, depending on the size of the lesion, tumor type, and malignancy.112114 Besides, several drugs, including glycyrrhizin,115 salidroside,116118 and astragaloside,119,120 may be used in both glioma and traumatic brain injury treatment due to the counteracting effect of common signaling pathways (Figure 3).

Figure 3 Selected common therapeutic approaches applied for both glioma and traumatic brain injury. An anticancer agent, gallic acid, could be of great toxic effects on glioma cells, and together exerts beneficial effects on recovery of traumatic brain injuries. Cardamonin (a chalcone) indicates effective anti-inflammatory and anti-carcinogenic activity in glioma. Hyperbaric oxygen (HBO) therapy is a recently developed method that has been extensively used as an adjunctive treatment for various diseases predominantly related to hypoxic conditions, and could be effective for treatment of both glioma and traumatic brain injury. Besides, several other kinds of drugs, like the glycyrrhizin, salidroside and astragaloside, could be used in both glioma and traumatic brain injury treatment due to the counteracting effect of common signaling pathways. Several flavonoids such as quercetin, catechins, and proanthocyanins also protect the glial cells from inflammation and oxidative stress, and could be potentially effective for treatment of these two diseases.

Currently, comprehensive research establishing the relationship between the mechanisms of traumatic brain injury and tumorigenesis is necessary. However, there could be some obstacles. First, the considerable time interval between brain injury and the onset of glioma poses a challenge to perform in vivo studies. Secondly, designing in vitro studies using primary cultures can also be difficult owing to a large number of different types of cells that constitute the brain tissue. The use of immortalized glial cell lines is also excluded owing to their physiological dissimilarity with normal brain cells. Therefore, more efforts should be directed toward establishing suitable in vivo and in vitro models to explore the causal relationship between traumatic brain injury and glioma.

The possible association between traumatic brain injury and glioma should be further examined by designing additional experimental and clinical research. Much more additional factors may be involved in the formation of the post-traumatic glioma. These factors might have been unintentionally omitted during the selection of study groups in various previous studies, leading to the result of the lack of connection between injury and glioma, which is why further explorations on the etiology of post-traumatic glioma are urgently needed. Besides, it may be more difficult to effectively treat patients who suffer from both glioma and traumatic brain injury compared to those with traumatic brain injury without glioma. The survival rate of patients with glioma is bound to increase with the development of anticancer drugs, including those suggested in this review. Treating traumatic brain injury in patients with glioma can be still challenging and requires specific treatment modalities. Thus, the development of effective strategies in the management of traumatic brain injury in patients with glioma is essential.

The authors warrant that the article and all figures included in this work are the authors original work and has not been published before.

The authors declare no competing financial interests and no conflicts of interest for this work.

1. Iaccarino C, Carretta A, Nicolosi F, Morselli C. Epidemiology of severe traumatic brain injury. J Neurosurg Sci. 2018;62:535541. doi:10.23736/S0390-5616.18.04532-0

2. Dewan MC, Rattani A, Gupta S, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2019;130:10801097. doi:10.3171/2017.10.JNS17352

3. Hay JR, Johnson VE, Young AM, Smith DH, Stewart W. Blood-Brain barrier disruption is an early event that may persist for many years after traumatic brain injury in humans. J Neuropathol Exp Neurol. 2015;74:11471157.

4. Gardner RC, Yaffe K. Epidemiology of mild traumatic brain injury and neurodegenerative disease. Mol Cell Neurosci. 2015;66:7580. doi:10.1016/j.mcn.2015.03.001

5. Munch TN, Grtz S, Wohlfahrt J, Melbye M. The long-term risk of malignant astrocytic tumors after structural brain injury-a nationwide cohort study. Neuro Oncol. 2015;17(5):718724. doi:10.1093/neuonc/nou312

6. Chen YH, Keller JJ, Kang JH, Lin HC. Association between traumatic brain injury and the subsequent risk of brain cancer. J Neurotrauma. 2012;29(7):13281333. doi:10.1089/neu.2011.2235

7. Nygren C, Adami J, Ye W, Bellocco R. Primary brain tumors following traumatic brain injury-a population-based cohort study in Sweden. Cancer Causes Control. 2001;12(8):733737. doi:10.1023/A:1011227617256

8. Inskip PD, Mellemkjaer L, Gridley G, Olsen JH. Incidence of intracranial tumors following hospitalization for head injuries (Denmark). Cancer Causes Control. 1998;9(1):109116. doi:10.1023/A:1008861722901

9. Zampieri P, Meneghini F, Grigoletto F, et al. Risk factors for cerebral glioma in adults: a case-control study in an Italian population. J Neurooncol. 1994;19(1):6167. doi:10.1007/BF01051049

10. Preston-Martin S, Pogoda JM, Schlehofer B, et al. An international case-control study of adult glioma and meningioma: the role of head trauma. Int J Epidemiol. 1998;27(4):579586. doi:10.1093/ije/27.4.579

11. Hu J, Johnson KC, Mao Y, et al. Risk factors for glioma in adults: a case-control study in northeast China. Cancer Detect Prev. 1998;22(2):100108. doi:10.1046/j.1525-1500.1998.CDOA22.x

12. Hochberg F, Toniolo P, Cole P. Head trauma and seizures as risk factors of glioblastoma. Neurology. 1984;34(11):15111514. doi:10.1212/WNL.34.11.1511

13. Johansen C. Mind as a risk factor for cancer-some comments. Psychooncology. 2012;21:922926. doi:10.1002/pon.3143

14. Mann CJ. Observational research methods. Research design II: cohort, cross sectional, and case-control studies. Emerg Med J. 2003;20:5460. doi:10.1136/emj.20.1.54

15. Anselmi E, Vallisa D, Bert R, Vanzo C, Cavanna L. Post-traumatic glioma: report of two cases. Tumori. 2006;92(2):175177. doi:10.1177/030089160609200215

16. Di Trapani G, Carnevale A, Scerrati M, Colosimo C, Vaccario ML, Mei D. Post-traumatic malignant glioma. Report of a case. Ital J Neurol Sci. 1996;17(4):283286. doi:10.1007/BF01997787

17. Magnavita N, Placentino RA, Mei D, Ferraro D, Di Trapani G. Occupational head injury and subsequent glioma. Neurol Sci. 2003;24(1):3133. doi:10.1007/s100720300018

18. Moorthy RK, Rajshekhar V. Development of glioblastoma multiforme following traumatic cerebral contusion: case report and review of literature. Surg Neurol. 2004;61(2):180184. doi:10.1016/S0090-3019(03)00423-3

19. Mrowka R, Bogunska C, Kulesza J, Bazowski P, Wencel T. Grave cranio-cerebral trauma 30 years ago as cause of the brain glioma at the locus of the trauma particulars of the case. Zentralbl Neurochir. 1978;39(1):5764.

20. Sabel M, Felsberg J, Messing-Junger M, Neuen-Jacob E, Piek J. Glioblastoma multiforme at the site of metal splinter injury: a coincidence? Case report. J Neurosurg. 1999;91(6):10411044. doi:10.3171/jns.1999.91.6.1041

21. Witzmann A, Jellinger K, Weiss R. Glioblastoma multiformedeveloping after a gunshot injury of the brain (authors transl). Neurochirurgia. 1981;24(6):202206.

22. Zhou B, Liu W. Post-traumatic glioma: report of one case and review of the literature. Int J Med Sci. 2010;7(5):248250. doi:10.7150/ijms.7.248

23. Han Z, Du Y, Qi H, Yin W. Post-traumatic malignant glioma in a pregnant woman: case report and review of the literature. Neurol Med Chir (Tokyo). 2013;53(9):630634. doi:10.2176/nmc.cr2013-0029

24. Tyagi V, Theobald J, Barger J, et al. Traumatic brain injury and subsequent glioblastoma development: review of the literature and case reports. Surg Neurol Int. 2016;26:7778.

25. Salvati M, Caroli E, Rocchi G, Frati A, Brogna C, Orlando ER. Post-traumatic glioma. Report of four cases and review of the literature. Tumori J. 2004;90:416419. doi:10.1177/030089160409000410

26. Henry PT, Rajshekhar V. Post-traumatic malignant glioma: case report and review of the literature. Br J Neurosurg. 2000;14:6467. doi:10.1080/02688690042979

27. Simiska D, Kojder K, Jeewski D, et al. The Pathophysiology of Post-Traumatic Glioma. Int J Mol Sci. 2018;19(8):2445. doi:10.3390/ijms19082445

28. Liao Y, Liu P, Guo F, Zhang ZY, Zhang Z. Oxidative burst of circulating neutrophils following traumatic brain injury in human. PLoS One. 2013;8:e68963. doi:10.1371/journal.pone.0068963

29. Woodcock T, Morganti-Kossmann MC. The role of markers of inflammation in traumatic brain injury. Front Neurol. 2013;4:15. doi:10.3389/fneur.2013.00018

30. Ewing J. The Bulkley Lecture. The modern attitude toward traumatic cancer. Bull New York Academy Med. 1935;11:281333.

31. Ohana N, Benharroch D, Sheinis D, Cohen A. Traumatic glioblastoma: commentary and suggested mechanism. J Int Med Res. 2018;46(6):21702176. doi:10.1177/0300060518771265

32. Moorthy RK, Rajshekhar V. Development of glioblastoma multiforme following traumatic cerebral contusion: case report and review of literature. Surg Neurol. 2001;61:180184.

33. Witcher KG, Bray CE, Dziabis JE, et al. Traumatic brain injury-induced neuronal damage in the somatosensory cortex causes formation of rod-shaped microglia that promote astrogliosis and persistent neuroinflammation. Glia. 2018;66(12):27192736. doi:10.1002/glia.23523

34. Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol. 2016;142:2344.

35. Simon DW, McGeachy MJ, Bayr H, Clark RS, Loane DJ, Kochanek PM. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol. 2017;13(3):171191.

36. Loane DJ, Kumar A. Microglia in the TBI brain: the good, the bad, and the dysregulated. Exp Neurol. 2016;275(3):316327. doi:10.1016/j.expneurol.2015.08.018

37. Cherry JD, Olschowka JA, OBanion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014;11:98. doi:10.1186/1742-2094-11-98

38. Kobayashi K, Imagama S, Ohgomori T, et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 2013;4:e525. doi:10.1038/cddis.2013.54

39. Qin H, Yeh WI, De Sarno P, et al. Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc Natl Acad Sci U S A. 2012;109:50045009. doi:10.1073/pnas.1117218109

40. Tanaka T, Murakami K, Bando Y, Yoshida S. Interferon regulatory factor 7 participates in the M1-like microglial polarization switch. Glia. 2015;63:595610. doi:10.1002/glia.22770

41. Xu H, Wang Z, Li J, et al. The polarization states of microglia in TBI: a new paradigm for pharmacological intervention. Neural Plast. 2017;2017:5405104. doi:10.1155/2017/5405104

42. Xu B, Yu DM, Liu FS. Effect of siRNA induced inhibition of IL 6 expression in rat cerebral gliocytes on cerebral edema following traumatic brain injury. Mol Med Rep. 2014;10:18631868. doi:10.3892/mmr.2014.2462

43. Li W, Graeber MB. The molecular profile of microglia under the influence of glioma. Neuro Oncol. 2012;14:958978.

44. Markovic DS, Vinnakota K, Chirasani S, et al. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci USA. 2009;106:1253012535. doi:10.1073/pnas.0804273106

45. Zhai H, Heppner FL, Tsirka SE. Microglia/macrophages promote glioma progression. Glia. 2011;59:472485. doi:10.1002/glia.21117

46. Sawamura Y, Diserens AC, de Tribolet N. In vitro prostaglandin E2 production by glioblastoma cells and ist effect on IL2 activation of oncolytic lymphocytes. J Neuroncol. 1990;9:125130. doi:10.1007/BF02427832

47. Ma MW, Wang J, Dhandapani KM, Wang R, Brann DW. NADPH oxidases in traumatic brain injury-Promising therapeutic targets? Redox Biol. 2018;16:285293. doi:10.1016/j.redox.2018.03.005

48. Li Z, Xiao J, Xu X, et al. M-CSF, IL-6, and TGF-beta promote generation of a new subset of tissue repair macrophage for traumatic brain injury recovery. Sci Adv. 2021;7(11):eabb6260. doi:10.1126/sciadv.abb6260

49. Li Z, Xiao J, Xu X, et al. M-CSF, IL-6, and TGF-beta promote generation of a new subset of tissue repair macrophage for traumatic brain injury recovery. Sci Adv. 2021;7(11):eabb6260.

50. Chen F, Xu Y, Luo Y, et al. Down-regulation of Stat3 decreases invasion activity and induces apoptosis of human glioma cells. J Mol Neurosci. 2010;40:353359. doi:10.1007/s12031-009-9323-3

51. Iwamaru A, Szymanski S, Iwado E, et al. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene. 2007;26:24352444. doi:10.1038/sj.onc.1210031

52. Haus DL, Lpez-Velzquez L, Gold EM, et al. Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury. Exp Neurol. 2016;281:116. doi:10.1016/j.expneurol.2016.04.008

53. Korbecki J, Gutowska I, Kojder I, et al. New extracellular factors in glioblastoma multiforme development: neurotensin, growth differentiation factor-15, sphingosine-1-phosphate and cytomegalovirus infection. Oncotarget. 2018;9:72197270. doi:10.18632/oncotarget.24102

54. Bohman LE, Swanson KR, Moore JL, et al. Magnetic Resonance imaging characteristics of glioblastoma multiforme: implications for understanding gliomna ontogeny. Neurosurgery. 2010;67:13191328. doi:10.1227/NEU.0b013e3181f556ab

55. Gil-Perotin S, Marin-Husstege M, Li J, et al. Loss of p53 induces changes in the behavior of subventricular zone cells: implication for the genesis of glial tumors. J Neurosci. 2006;26:11071116. doi:10.1523/JNEUROSCI.3970-05.2006

56. Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, et al. PDGFR alphapositive B cells are neural stem cells in the adults SVZ that form glioma like growths in response to increased PDGF signaling. Neuron. 2006;51:187199. doi:10.1016/j.neuron.2006.06.012

57. Assanah M, Lochhead R, Ogden A, Bruce J, Goldman J, Canoll P. Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Naurosci. 2006;26:67816790. doi:10.1523/JNEUROSCI.0514-06.2006

58. Burda JE, Bernstein AM, Sofroniew MV. Astrocyte roles in traumatic brain injury. Exp Neurol. 2016;275(Pt 3):305315. doi:10.1016/j.expneurol.2015.03.020

59. Xu H, Fang T, Omran RP, Whiteway M, Jiang L. RNA sequencing reveals an additional Crz1-binding motif in promoters of its target genes in the human fungal pathogen Candida albicans. Cell Commun Signal. 2020;18:1. doi:10.1186/s12964-019-0473-9

60. Castejn OJ. Morphological astrocytic changes in complicated human brain trauma. A light and electron microscopic study. Brain Inj. 1998;12(5):409427. doi:10.1080/026990598122539

61. Michinaga S, Pathophysiological Responses KY. Roles of astrocytes in traumatic brain injury. Int J Mol Sci. 2021;22(12):6418. doi:10.3390/ijms22126418

62. Patel JP, Frey BN. Disruption in the blood-brain barrier: the missing link between brain and body inflammation in bipolar disorder? Neural Plast. 2015;2:708306.

63. Murray KN, ParryJones AR, Allan SM. Interleukin1 and acute brain injury. Front Cell Neurosci. 2015;9:18. doi:10.3389/fncel.2015.00018

64. Ross JL, Chen Z, Herting CJ, et al. Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma. Brain. 2020;54:awaa382.

65. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24:981990. doi:10.1016/j.cellsig.2012.01.008

66. Rajaraman P, Melin BS, Wang Z, et al. Genome-wide association study of glioma and metaanalysis. Hum Genet. 2012;131:18771888. doi:10.1007/s00439-012-1212-0

67. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med. 2005;353:811822. doi:10.1056/NEJMra043666

68. Liao Y, Liu P, Guo F, Zhang ZY, Zhang Z. Oxidative burst of circulating neutrophils following traumatic brain injury in human. PLoS One. 2013;8:e68963.

69. Kawabori M, Yenari MA. Inflammatory responses in brain ischemia. Curr Med Chem. 2015;22:12581277. doi:10.2174/0929867322666150209154036

70. Schwartzbaum J, Ahlbom A, Malmer B, et al. Polymorphisms associated with asthma are inversely related to glioblastoma multiforme. Cancer Res. 2005;65:64596465. doi:10.1158/0008-5472.CAN-04-3728

71. Shete S, Hosking FJ, Robertson LB, et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet. 2009;41:899904. doi:10.1038/ng.407

72. Simon M, Hosking FJ, Marie Y, et al. Genetic risk profiles identify different molecular etiologies for glioma. Clin Cancer Res. 2010;16:52525259. doi:10.1158/1078-0432.CCR-10-1502

73. Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain. 2013;136(Pt 1):2842. doi:10.1093/brain/aws322

74. Handy DE, Loscalzo J. Redox regulation of mitochondrial function. Antioxid Redox Signal. 2012;16:13231367. doi:10.1089/ars.2011.4123

75. Yang JL, Mukda S, Chen SD. Diverse roles of mitochondria in ischemic stroke. Redox Biol. 2018;16:263275. doi:10.1016/j.redox.2018.03.002

76. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94:909950. doi:10.1152/physrev.00026.2013

More here:
Role of traumatic brain injury in the development of glioma | JIR - Dove Medical Press

Targeted Therapeutics Market: Introduction

According to the report, the global targeted therapeutics market was valued over US$ 67.8 Bn in 2020 and is projected to expand at a moderate CAGR during the forecast period. Targeted therapies are drugs or other substances that block the growth of unwanted cells and pathogens by interfering with specific molecules ("molecular targets") involved in the growth, progression, and spread of disease. Targeted therapies are sometimes called molecularly targeted drugs, molecularly targeted therapies, precision medicines, etc. The emerging field of target therapeutics offers varied potential treatments. Targeted therapies offer the possibility of finding a cure for diseases with significant unmet needs, including orphan diseases and diseases having a high burden globally. Targeted therapy is widely used in the treatment of different forms of cancer such as renal, breast, lung, colorectal, and leukemia, and other diseases such as multiple sclerosis and wet age-related macular degeneration. The global targeted therapeutics market is driven by rise in prevalence of cancer across the globe, increase in global geriatric population, and surge in product approvals.

North America dominated the global targeted therapeutics market in 2020, followed by Europe, and the trend is anticipated to continue during the forecast period. North Americas dominance can be ascribed to high prevalence and increase in incidence rates of cancer, well-established healthcare industry, and rise in adoption of targeted therapeutics monoclonal antibodies in the region.

Request Brochure of Report - https://www.transparencymarketresearch.com/sample/sample.php?flag=B&rep_id=51390

Increase in Incidence of Cancer to Drive Global Market

The increase in incidence of cancers such as breast, lung, and leukemia has fueled the demand for targeted therapeutics. Cancer is a leading cause of death across the globe. It is more prevalent in developed and emerging markets. According to the International Agency for Research on Cancer, one in five persons develops cancer during his or her lifetime, and one in eight men, and one in 11 women succumbs to the disease. Tobacco smoking, pollution, changing lifestyle, and transmission of carcinogens and carcinogenic infections such as HPV, H. Pylori, and HCV have increased the incidence rate of cancer across the globe.

According to the International Agency for Research on Cancer (IARC), an estimated 19.3 million new cancer cases were recorded in 2020 and nearly 10 million individuals died from cancer-related causes. The global burden is expected to increase to 27.5 million new cancer cases and 16.3 million cancer deaths by 2040, primarily due to increase and aging of the population. Targeted therapy has proven to offer promising therapeutic outcomes across a broad range of cancers and is increasingly used in healthcare facilities. Hence, high prevalence and increase in incidence rate of cancer across the globe is a major factor projected to boost the growth of the global targeted therapeutics market during the forecast period.

Request for Custom Research - https://www.transparencymarketresearch.com/sample/sample.php?flag=CR&rep_id=51390

Targeted Therapeutics Market: Prominent Regions

In terms of region, the global targeted therapeutics market has been segmented into North America, Europe, Asia Pacific, Latin America, and Middle East & Africa. North America dominated the global targeted therapeutics market in 2020, followed by Europe. The U.S. dominated the targeted therapeutics market in North America in 2020, due to the presence of key players, adoption of targeted therapeutics monoclonal antibodies, and adequate reimbursement policies. This, in turn, is expected to boost the market in the region. The targeted therapeutics market in Asia Pacific is likely to expand at a high CAGR from 2021 to 2031. The growth of the market in the region can be attributed to the adoption of new targeted therapeutic drugs, increase in awareness about various oncological disorders, rise in healthcare expenditure, and high penetration of research activities across the region.

Strategic Acquisition and Collaborations by Key Players to Fuel Global Market

The global targeted therapeutics market is consolidated in terms of number of players. The market is dominated by key players with strong geographic presence. Key players operating in the global targeted therapeutics market include Amgen, Inc., F. Hoffmann-La Roche Ltd., AstraZeneca, Bristol-Myers Squibb Company, Bayer AG, Merck & Co., Inc., Novartis AG, and Pfizer, Inc. In March 2021, Amgen and Five Prime Therapeutics, a clinical-stage biotechnology company focused on developing immuno-oncology and targeted cancer therapies, announced an agreement under which Amgen will acquire Five Prime Therapeutics for US$ 38.00 per share in cash, representing an equity value of approximately US$ 1.9 Bn. This acquisition adds Five Prime's innovative pipeline to Amgen's leading oncology portfolio.

Pre Book Targeted Therapeutics Market Report at https://www.transparencymarketresearch.com/checkout.php?rep_id=51390&ltype=S

In October 2020, Bristol-Myers Squibb and MyoKardia, Inc. announced a definitive merger agreement, under which Bristol-Myers Squibb will acquire MyoKardia for US$ 13.1 Bn, or US$ 225.00 per share in cash. The transaction was unanimously approved by the Boards of Directors of Bristol-Myers Squibb and MyoKardia and is anticipated to close during the fourth quarter of 2020. MyoKardia is a clinical-stage biopharmaceutical company discovering and developing targeted therapies for the treatment of serious cardiovascular diseases.

Browse More Trending Reports by Transparency Market Research:

Stem Cell Gun Devices Market: https://www.transparencymarketresearch.com/stem-cell-gun-devices-market.html

Revascularization Devices Market: https://www.transparencymarketresearch.com/revascularization-devices-market.html

Anesthesia Disposables Market: https://www.transparencymarketresearch.com/anesthesia-disposables-market.html

About Us

Transparency Market Research is a next-generation market intelligence provider, offering fact-based solutions to business leaders, consultants, and strategy professionals.

Our reports are single-point solutions for businesses to grow, evolve, and mature. Our real-time data collection methods along with ability to track more than one million high growth niche products are aligned with your aims. The detailed and proprietary statistical models used by our analysts offer insights for making right decision in the shortest span of time. For organizations that require specific but comprehensive information we offer customized solutions through ad hoc reports. These requests are delivered with the perfect combination of right sense of fact-oriented problem solving methodologies and leveraging existing data repositories.

TMR believes that unison of solutions for clients-specific problems with right methodology of research is the key to help enterprises reach right decision.

ContactMr. Rohit BhiseyTransparency Market ResearchState Tower,90 State Street,Suite 700,Albany NY - 12207United StatesUSA - Canada Toll Free: 866-552-3453Email: sales@transparencymarketresearch.comWebsite: https://www.transparencymarketresearch.com/

Originally posted here:
Targeted Therapeutics Market: Increase in Incidence of Cancer to Drive Global Market - BioSpace

Introduction

Significant attention has been given to regulatory T cells (Tregs) expressing the transcription factor fork head box protein P3 (Foxp3).1 Tregs have a fundamental role in sustaining immunological tolerance and controlling autoimmunity.2 They act by controlling the activation and differentiation of CD4+ Th cells and CD8+ cytotoxic T cells in response to environmental, autogenous, or tumor associated antigens. Studies have confirmed that Tregs have opposing actions in cancer immunity leading to immune evasion of cancer cells and implying a functional impact on tumor progression and metastasis.35

Interestingly, the clinical relevance of tumor-infiltrating Tregs has been found ambiguous. For instance, a high Tregs density in hepatocellular carcinoma is predictive of poor prognosis, in line with the hypothesis that Tregs enhance tumor progression through tumor-specific T cell suppression. On the other hand, improved clinical outcome in other tumors as colorectal carcinoma is associated with a high Tregs density. These contrasting results indicate that the role of Tregs in tumor development may vary substantially according to the affected site.6

Similarly, Tregs were suggested to be correlated with good outcome of breast cancer in one study,7 while other studies revealed that Tregs were associated with poor outcome of breast cancer.8,9

Triple negative breast cancer (TNBC) is a type of breast tumors that do not express estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) on the surface.10 Patients with this TNBC have enhanced risk of metastasis and relapse, and cannot utilize targeted therapy.11

Increased tumor-infiltrating-lymphocytes (TILs) in TNBC support the high immunogenic nature of this subtype of breast cancer.1214

It is not evident whether the Tregs found intra-tumoral are comparable to those in normal tissues or in the peripheral blood. The tumor microenvironment might imprint distinctive transcriptional and functional characteristics upon Tregs.15,16 Recently, peripheral blood Tregs represented the main source of intra-tumoral Tregs in human breast cancers and that their response to cytokine signaling indicates intra-tumoral immunosuppressive possibility and predicts clinical outcome.17

So far, the prognostic value of Tregs in breast cancer is still controversial, and further studies are needed to fully understand its significance.1822 The present study was conducted to evaluate the number of Tregs in TNBC, in normal breast parenchyma and in the peripheral blood of these patients and controls, in addition to their correlations with the clinico-pathologic features and the outcomes of TNBC.

Thirty adult treatment-nave women undergoing surgical treatment of non-metastatic TNBC in the South Egypt Cancer Institute and Clinical Oncology Department, Assiut University Hospital were enrolled. The clinical and histopathological characteristics of the patients are shown in Table 1. In addition, 20 age matched healthy females participated as a control group.

Table 1 Clinical and Histopathological Characteristics of the TNBC Patients Group

The Committee of Medical Ethics of faculty of medicine, Assiut University reviewed and accepted the research proposal (IRB no. 17300416) and the study was done in compliance with the ethical guidelines of the Declaration of Helsinki 1975. Informed consent was obtained from all research participants before sharing in the study.

After confirmation of breast cancer by needle biopsy, patients were offered preoperative assessment by multisclice cut scans of chest and abdomen, bone scan, and tumor markers including CA15-3, and CEA in order to exclude metastatic cases, and then patients underwent either modified radical mastectomy (MRM), or breast conservative surgery (BCS).

After surgery, pathologic assessment of tumor type, size, grade, lymph node (LN) status was done, followed by immunophenotyping to ensure negativity of estrogen and progesterone receptors, and HER2neu. All patients received adjuvant chemotherapy according to standardized guidelines, patients with BCS, > T2 lesions, positive LN, positive surgical margins, and perineural invasion were treated with 3 DCRT with doses ranging from 40 to 66 Gy over 1533 fractions.

TNBC women in our study were followed up monthly by clinical examinations for the first 2 years, then every 36 months for additional 3 years, then yearly later on, MSCT chest and abdomen and tumor marker were done every 3 months in the first 2 years, then every 6 months in the next 3 years, and then yearly later on, bone scan was done when indicated (bone pain, rising ALP, rising serum calcium, etc.), these follows ups continued until disease recurrence or death of patients to determine their disease free survival (DFS).

Peripheral blood samples were collected from all participants in tubes containing heparin. Fresh tumor tissues were also obtained from all patients undergoing surgery for primary breast cancer immediately after surgery. In addition, 30 apparently normal breast tissue samples were obtained from the same patients from areas adjacent to the safety margins (20 tissue samples were areas devoid of any abnormalities; whether inflammatory or benign lesions and subsequently included for comparison, while the other remaining 10 sample tissues were found to have abnormalities subsequently, were excluded). The tumor tissues were mechanically fragmented to prepare single-cell suspension. The cell suspensions were filtered through cell strainers (100 M). The contaminating red blood cells were removed by incubation with lysing solution for 5 minutes at 4C, and the resultant suspension was washed twice with phosphate buffered saline (PBS).

Fluoroisothiocyanate (FITC)-conjugated-Foxp3 (clone PCH101, eBioscience, Invitrogen, Thermofisher, US), phycoerythrin (PE) conjugated-CD25 (clone 2A3, Becton Dickinson (BD) Bioscience, CA, USA) and peridinium-chlorophyll-protein (Per-CP)-conjugated-CD4 (clone SK3, BD Bioscience, CA, USA) were used to detect Tregs. For assessment of Tregs, 1106 cells of the breast tissue sample in 100 L of PBS in one tube and 50 L of blood sample in another tube were incubated with 5 L of CD4, CD25 for 15 minutes at 4C in the dark. Following incubation, red blood cells lysis, washing with PBS then addition of fixation solution to fix the cells and incubation for 10 minutes were done. After that, the cells were washed with PBS, and permeabilization solution (IntraSureTM kit, BD CA, USA) and 5 L of Foxp3 were added and incubated for 20 minutes. The cells were then resuspended in PBS and analyzed by FACSCalibur flow cytometry with Cell Quest software (Becton Dickinson Biosciences, USA). An isotype-matched IgG negative control was used for each sample. Forward and side scatter histogram was used to define the lymphocytes population. Then CD4+cells were gated. Total CD4+CD25+low, CD4+CD25+High and CD4+CD25+HighFoxp3+ T cells were evaluated as percentages of CD4+ cells in both blood and tumor tissue as shown in Figures 1 and 2, respectively.

Figure 1 Gating strategy to identify regulatory T cells in peripheral blood. (A) The lymphocyte population was identified based on the forward and side scatter characteristics and was selected by R1. (B, C) CD4+ cells among the gated lymphocytes were selected by (R2) for further analysis on the basis of the level of CD25 expression. (R3), (R4) and (R5) were drawn to identify CD4+cells with no, low and high CD25 expression, respectively. (D) Dot plot representing FoxP3 expression among the CD4+CD25+high cells to detect Tregs (CD4+CD25+high FoxP3+).

Figure 2 Gating strategy to identify regulatory T cells in tumor tissue. (A) The lymphocyte population was selected by R1. (B, C) CD4+ cells among the gated lymphocytes were selected by (R2) then (R3), (R4) and (R5) were drawn to identify CD4+cells with no, low and high CD25 expression, respectively. (D) Dot plot representing FoxP3 expression among the CD4+CD25+high cells to detect Tregs (CD4+CD25+high FoxP3+). (E, F) Representative dot plots of isotype control.

Numerical data was expressed as mean, median and standard deviation or standard error mean. Qualitative data were presented as number and percentage. The independent sample t-test and One-way ANOVA were used to assess the statistical differences between groups. Paired-t-test was applied to compare the percentages of cells between tumor tissue and peripheral blood. Pearson correlation was used to evaluate the strength of linear association between variables. The disease-free survival (DFS) was calculated using KaplanMeier curve and the receiver operating characteristic (ROC) curve was employed to estimate the accuracy of tumor-infiltrating Tregs in prediction of DFS (3 years). All analysis was performed by SPSS 20.0 software (SPSS, Inc., Chicago, IL, USA).

The patients ages ranged from 28 to 77 years with a mean of 50.410.4. The tumor size in most of the patients was T2 (63.3%). Most of the patients were either N0 (46.7%) or N1 (46.7%). Pathologic examination of breast cancer tissue showed that the majority was infiltrating ductal carcinoma (IDC) (98.3%) of G2 (83.3%). Modified radical mastectomy (MRM) was done in 73.3% of patients, whereas breast conservative surgery (BCS) in 26.7%. Local recurrence was observed in 16.7% of them. The median DFSSE was 322.1 months (95% CI= 2836.1) (Table 1).

As shown in Table 2, while the level of total CD4+ T cells in the peripheral blood was significantly lower in patients than healthy controls, their level in the malignant breast cancer tissue was higher than that in the normal tissue. The mean percentages of CD4+CD25+highT cells and Tregs were higher in TNBC than healthy controls and in malignant tissue than normal tissue. Moreover, the frequencies of tumor-infiltrating CD4+T cells and Tregs were exceeding those in the peripheral blood of cancer patients (p <0.0001).

Table 2 Tregs Levels in Peripheral Blood and Breast Cancer Tissue of Patients with TNBC in Comparison with the Control Group

CD4+CD25+subsets and Tregs have shown no significant associations with most of the tested clinicopathologic characteristics in both breast tissue and peripheral blood. Only tumor-infiltrating Tregs have shown increasing levels with the increase in the tumor size (p<0.0001) and were significantly higher in patients with local recurrences than those without recurrence (p =0.001), (Tables 3 and 4, Figure 3).

Table 3 Relations Between Tumor-Infiltrating Tregs and the Clinicopathologic Characteristics of Patients with TNBC

Table 4 Relations Between Peripheral Blood Tregs and the Clinicopathologic Characteristics of Patients with TNBC

Figure 3 Tumor-infiltrating Tregs showing increasing levels with the increase in the tumor size (A) and in patients with local recurrences (B).

Among all tested tumor-infiltrating CD4+CD25+subsets, only Tregs showed significant inverse relation with DFS (r=0.6, p<0.0001) and direct relation with the level of the peripheral Tregs (r= 0.4, p= 0.046). The predictive accuracy of the levels of tumor-infiltrating Tregs in assessing the DFS period (3 years) was estimated using the ROC curve. Tumor-infiltrating Tregs showed good predictive accuracy [Area under the curve (AUC) =0.90.06, 95% confidence interval (CI): 0.791.00, p=0.001) at the cutoff point 6.91% with a sensitivity of 86% and a specificity of 87%. The mean DFS for TNCB patients with tumor-infiltrating Tregs <6.91% was 47.84 months (95% CI=40.1555.43), while for those with Tregs >6.91% was 27.13 months (95% CI=21.832.4), log rank=17.36, (p<0.001) (Figure 4). Of the 30 TNBC patients, 19 had tumor-infiltrating Tregs level <6.91%, only one of them displayed local recurrence (5%), and 11 had Tregs level >6.91%, six of them showed local recurrences (55%) (p= 0.004).

Figure 4 Tumor-infiltrating Tregs (A) correlation with DFS, (B) correlation with peripheral Tregs, (C) accuracy of prediction of DFS period (3 years) using ROC curve and (D) differences in DFS according to the cutoff value of Tregs.

TNBC is an aggressive type of breast cancer characterized by poor prognosis and lack of targeted therapy.23 TNBC has higher immunogenicity and tends to have higher Tregs infiltration than other subtypes.22,24,25

Inconsistent findings on the influence and prognostic value of Tregs in TNBC has been reported in previous reports.1822

In this study, the mean percentages of Tregs were higher in the peripheral blood of TNBC patients than healthy controls and in tumor tissue than normal breast parenchyma. Consistent with our findings, Wang and Huang reported significantly increased serum levels of CD4+CD25+Foxp3+ Tregs in patients with breast cancer compared with healthy individuals.26 In addition, Plitas et al.16 found increased Tregs in breast cancer tissue as compared to normal breast parenchyma and peripheral blood. Furthermore, breast tumor cells utilize immune regulatory cells such as Treg and different immunosuppressive pathways involving CD39, PD-1 and CTLA-4 molecules in creating disturbed immune environment for them to survive.27

The increased tumor-infiltrating Tregs could be explained by expression of homing of receptors on Tregs that directs the migration of distinct populations to certain tissues28 and regional extension of pre-existing tissue resident Tregs.16 In addition, powerful stimulation of T cell receptors is needed for Treg cell activation, proliferation and inhibitory function.29 Additionally, chemokine signaling, and cell migration were found to be the main single group of genes enriched in tumor-infiltrating Tregs.16

The tumor-infiltrating Tregs showed significant direct relation with the level of Tregs in the peripheral blood. Similarly, Cai et al.30 reported that the level of CD25+Foxp3+ Tregs in circulating CD4+T cells was positively correlated with the level ofCD25+Foxp3+Tregs in CD4+tumor-infiltrating lymphocytes in TNBC.

In contrast to tissue infiltrating Tregs, peripheral blood CD 4+CD 25+Foxp3+ Tregs had no association with any of the clinico-pathological features of TNBC. These findings support the notion that tumor resident Tregs have distinct features that differ from Tregs in peripheral blood.16 On the other hand, the proportions of circulating Tregs were found to be associated with an increased occurrence of breast cancer.26

The association between the Tregs and the clinico-pathological features of TNBC suggested that increasing tumor-infiltrating Tregs was associated with increased tumor size and local recurrence as well as decreased disease-free survival.

Increased frequency of tumor-infiltrating Tregs was observed in the more aggressive BC subset; TNBC and was associated with higher-grade lesions among all studied breast cancer subsets.16 Liu et al.31 observed increased CD4+CD25+Foxp3+ Tregs infiltration in breast cancer tissues and that was associated with high histologic grade, negative estrogen and progesterone receptors status, and overexpression of human epidermal growth factor receptor type 2, along with diminished overall as well as progression-free survivals. On the other hand, Yeong et al.21 reported that high number of tumor-infiltrating CD4+CD25+Foxp3+ Tregs in TNBC patients was linked to a higher tumor grade, lymph node status and better prognosis. Increasing the numbers of tumor-infiltrating Tregs may augment local immunosuppressive abilities, suppressing the anti-tumor immunity, thus enhancing tumor growth and invasion,32 in addition; early breast cancer has an inflammatory milieu characterized by mDC, Treg, and cancer stem cells (CSC) infiltration. The frequencies of Treg, CSC and CD8/Treg ratio were associated with disease progression including lymph node metastasis.33

Moreover, a previous review34 proposed that Tregs have cytotoxic capability that may directly kill effector T cell, which may explain the association between Foxp3+ Tregs infiltration and poor recurrence free survival of breast cancer patients.35

The study findings support the notion that Tregs can directly contribute to tumor progression rather than they accumulate in the tumor tissue as a consequences of other immunologic mechanisms controlling tumor progression.

The current study had a number of limitations, the small number of patients was a crucial limitation that was responsible for absence of several statistical relations, and heterogeneity of patients as the study recruited early and locally advanced diseases.

The findings of the current study support the possibility that TNBC microenvironment conveys specific characteristics on Tregs distinguishing them from those in normal breast tissue or Tregs in peripheral blood, improving the capabilities of tumor-infiltrating Tregs to enhance tumor growth, local recurrence and reduce the DFS. They also suggest the therapeutic value of targeting the function of tumor-infiltrating Tregs in TNBC.

All analyzed data are included within the article.

There is no funding to report.

All authors reported no conflicts of interest for this work.

1. Tang J, Yang Z, Wang Z, et al. Foxp3 is correlated with VEGF-C expression and lymphangiogenesis in cervical cancer. World J Surg Oncol. 2017;15:173.

2. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531564.

3. Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta analysis. Sci Rep. 2015;5:15179.

4. Joshi NS, Akama-Garren EH, Lu Y, et al. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity. 2015;43:579590.

5. Pastille E, Bardini K, Fleissner D, et al. Transient ablation of regulatory T cells improves antitumor immunity in colitis-associated colon cancer. Cancer Res. 2014;74:42584269.

6. Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother. 2011;60:909918.

7. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557560.

8. Demir L, Yigit S, Ellidokuz H, et al. Predictive and prognostic factors in locally advanced breast cancer: effect of intratumoral FOXP3+ tregs. Clin Exp Metastasis. 2013;30(8):10471062.

9. Takenaka M, Seki N, Toh U, et al. FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis. Mol Clin Oncol. 2013;1(4):625632.

10. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype. Cancer. 2007;109(9):17211728. doi:10.1002/cncr.22618

11. Newman LA, Reis-Filho JS, Morrow M, Carey LA, King TA. The 2014 Society of Surgical Oncology Susan G. Komen for the cure symposium: triple-negative breast cancer. Ann Surg Oncol. 2015;22(3):874882.

12. Disis ML, Stanton SE. Triple-negative breast cancer: immune modulation as the new treatment paradigm. Am Soc Clin Oncol Educ Book. 2015;35:2530.

13. Kwa MJ, Adams S. Checkpoint inhibitors in triple-negative breast cancer (TNBC): where to go from here. Cancer. 2018;124:20862103.

14. Denkert C, Liedtke C, Tutt A, Minckwitz GV. Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet. 2017;389:24302442.

15. Kim S, Lee A, Lim W, et al. Zonal difference and prognostic significance of foxp3 regulatory T cell infiltration in breast cancer. J Breast Cancer. 2014;17:817.

16. Plitas G, Konopacki C, Wu K, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity. 2016;45(5):11221134. doi:10.1016/j.immuni.2016.10.032

17. Wang L, Simons DL, Lu X, et al. Connecting blood and intratumoral Treg cell activity in predicting future relapse in breast cancer. Nat Immunol. 2019;20:12201230.

18. Mahmoud SM, Paish EC, Powe DG, et al. An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res Treat. 2011;127:99108.

19. Lee S, Cho EY, Park YH, Ahn JS, Y-h IM. Prognostic impact of FOXP3 expression in triple negative breast cancer. Acta Oncol. 2013;52:7381.

20. West NR, Kost SE, Martin SD, et al. Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in estrogen receptor-negative breast cancer. Br J Cancer. 2013;108:155162.

21. Yeong J, Thike AA, Lim JCT, et al. Higher densities of Foxp3+ regulatory T cells are associated with better prognosis in triple-negative breast cancer. Breast Cancer Res Treat. 2017;163:2135.

22. Zhang L, Wang XI, Ding J, et al. The predictive and prognostic value of Foxp3+/CD25+ regulatory T cells and PD-L1 expression in triple negative breast cancer. Ann Diagn Pathol. 2019;40:143151.

23. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:19381948.

24. Denkert C, Von Minckwitz G, Darb-Esfahani S, et al. Tumor-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19:4050.

25. Kim ST, Jeong H, Woo OH, et al. Tumor-infiltrating lymphocytes, tumor characteristics, and recurrence in patients with early breast cancer. Am J Clin Oncol. 2013;36:224231.

26. Wang R, Huang K. CCL11 increases the proportion of CD4+CD25+Foxp3+ Tregs and the production of IL-2 and TGF- by CD4+ T cells via the STAT5 signaling pathway. Mol Med Rep. 2020;21.6:25222532.

27. Syed Khaja AS, Toor SM, El Salhat H, et al. Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment. Oncotarget. 2017;8:3315933171.

28. Huehn J, Siegmund K, Lehmann JC, et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J Exp Med. 2004;199:303313.

29. Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nat Immunol. 2014;15:10701078.

30. Cai B, Ma P, Ding P, Sun D-W, Bu Q, Zhang J. Composition and plasticity of triple-negative breast carcinoma-infiltrating regulatory T cells. APMIS. 2020;128:260269.

31. Liu F, Lang R, Zhao J, et al. CD 8+ cytotoxic T cell and FOXP3+ regulatoryT cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat. 2011;130:645655.

32. Xue D, Xia T, Wang J, Chong M, Wang S, Zhang C. Role of regulatory T cells and CD8+ T lymphocytes in the dissemination of circulating tumor cells in primary invasive breast cancer. Oncol Lett. 2018;16(3):30453053. doi:10.3892/ol.2018.8993

33. Solis-Castillo LA, Garcia-Romo GS, Diaz-Rodriguez A, et al. Tumor-infiltrating regulatory T cells, CD8/Treg ratio, and cancer stem cells are correlated with lymph node metastasis in patients with early breast cancer. Breast Cancer. 2020;27(5):837849.

34. Lu L, Barbi J, Pan F. The regulation of immune tolerance by FOXP3. Nat Rev Immunol. 2017;17(11):703717. doi:10.1038/nri.2017.75

35. Zhou Y, Shao N, Aierken N, et al. Prognostic value of tumor-infiltrating Foxp3+ regulatory T cells in patients with breast cancer: a meta-analysis. J Cancer. 2017;8(19):40984105. doi:10.7150/jca.21030

Read the original here:
Accumulation of Regulatory T Cells in Triple Negative Breast Cancer Ca | CMAR - Dove Medical Press

It's "an arithmetic inevitability" that some people vaccinated against the coronavirus will contract so-called "breakthrough" infectionsbut a vaccinated person's immune system responds to the virus in distinctive ways that dramatically reduce the risk of serious disease, Katherine J. Wu writes for The Atlantic.

Your top resources on the Covid-19 vaccines

According to the Washington Post, it's difficult to track the absolute rate of breakthrough infections, both because many such infections are asymptomatic and because surveillance testing has declined in areas where vaccines are readily available.

It's clear, however, that breakthrough infections are uncommon and very rarely cause serious disease. According to CDC director Rochelle Walensky, 97% of all Covid-19 hospitalizations and 99.5% of all Covid-19 deaths are currently among the unvaccinated.

So why are breakthrough infections so much milder? It's because a vaccinated person's immune response looks very different than an unvaccinated person's, Wu writes.

When an unvaccinated person is exposed to the coronavirus, Wu writes, their only protection comes from the body's innate defenders, which are "short-lived and woefully imprecise."

"They'll sink their teeth into anything they don't recognize, and are easily duped by stealthier invaders," Wu writes, making them "a pretty flimsy first line of defense."

If left to its own devices, an unvaccinated person's so-called "adaptive" immune system will eventually develop a more powerful, customized response to the coronavirusbut it can take weeks to do so.

By then, Wu writes, "the virus may have run roughshod over everything it can." It may be too late for the immune system to prevent serious long-term damage or even death.

By contrast, a vaccinated person's immune system has already been trained to mount that more powerful, adaptive response. Vaccine shots "act as confidential informants, who pass around intel on the pathogen" before an infection occurs, Wu writes.

In particular, vaccination prepares the body's adaptive B cells to more quickly produce antibodies when they encounter the coronavirus, and T cells can more quickly target and kill off infected cells. This enables a vaccinated person to mount a powerful immune response much more quickly.

"In the best-case scenario, the virus might even be instantly sniped at by immune cells and antibodies," Wu writes. But even if the virus overwhelms the body's initial defenses, the vaccine has prepared the body to mount a fuller response.

"A breakthrough, despite what it might seem, does not cause our defenses to crumble or even break," Wu writes. "[I]t does not erase the protection that's already been built."

Rather, according to Deepta Bhattacharya, an immunologist at the University of Arizona, the virus must overcome "backup layer after backup layer" of defenses. So even if a virus continues to spread through a person's body, "[e]ach stage it has to get past takes a bigger chunk" out of it, Bhattacharya said.

That's why people who have been vaccinated tend to experience fewer and milder symptoms and recover more quickly, Wu writes.

"People tend to think of this as yes or noif I got vaccinated, I should not get any symptoms; I should be completely protected," Laura Su, an immunologist at the University of Pennsylvania, said. "But there's way more nuance than that."

"The vaccines were developed to keep us out of those terrible institutions we call hospitals," William Schaffner, an infectious disease expert at Vanderbilt University, said. "We have to keep coming back to that." (Gale, Washington Post, 7/25; AP/Modern Healthcare, 7/21; Cohen, Forbes, 7/22; Wu, The Atlantic, 7/26)

Read more here:
Your immune system responds very differently to a 'breakthrough' Covid-19 infection - The Daily Briefing

Get ready to have a cold. Thats the message from doctors, immunologists, virologists and architects as England emerges from lockdown.

An amalgamation of 16 months cooped up inside, a culture of showing up to work despite sickness, and woefully outdated building infrastructure in the UK is set to become a pressure cooker for viruses. The country at large is about to experience the rush of a kind of post-lockdown Freshers Flu.

Never before in modern human history have we had global distancing, social distancing, mask wearing, quarantining and isolating, says Gregory Poland, head of the Vaccine Research Group at the Mayo Clinic in the US. Its going to be an interesting experiment of nature to see what happens when you stop the circulation of those viruses for a season.

Like Covid, colds are spread through inhaling droplets from the air, and also by touch. Under normal circumstances, the average adult has between two and four colds a year, while children have between six and eight. These move easily between people and can be contagious for up to two weeks after symptoms appear.

Pre-pandemic, our bodies were often exposed to viral respiratory pathogens. Sometimes these made us sick, and other times they boosted our immune responses. But lockdowns, increased hand washing, and masks may have dulled this risk and left a hole in our natural defences.

The hygiene hypothesis posits that early exposure to a variety of germs builds better immunity for life. As such, evidence suggests children who are exposed to lots of different microbes are less likely to develop allergies and autoimmune disorders. Bodies remember responses to viruses and bacteria, and are able to mobilise and protect us against them. Our immune systems may struggle with new, cold-causing viruses in circulation, though, meaning we will still get sick, but the immune response will still know how to fight it even after lockdowns.

There are, however, other variables to consider. Whether you are getting enough vitamin D, are stressed, or have been particularly lonely could also factor into your anti-viral response. An analysis of studies monitoring more than 300,000 people found that people who are more socially connected are 50 per cent less likely to die over a given period. Research has also shown that people with lots of social ties are even less susceptible to the common cold. Stress, which produces cortisol, also harms immune function.

Rates of colds in the UK are difficult to track; they rarely cause hospitalisations, and people are encouraged to ride them out rather than visiting their GP. However, scientists can make a good guess at what is set to hit the northern hemisphere due to patterns happening in the south. Australia has already seen a resurgence of respiratory illnesses other than Covid, as have parts of the US.

In the US, numbers of cases of respiratory syncytial virus (RSV) a type of virus that infects the lungs and commonly causes hospitalisations in children have headed upwards in recent weeks, with around 1,600 confirmed cases nationally in the week of July 17, and 2,000 the week before. In the week of 25 July a year ago there were only 11 RSV cases recorded by the Centers for Disease Control (CDC).

Similarly in Australia, a surge in RSV cases was seen in spring in states such as New South Wales and Western Australia, followed by rising rates in Queensland and Victoria. They were at an all-time low throughout the Australian winter.

The Royal Australian College of General Practitioners warned that, as in Australia, relaxing of Covid restrictions may provide an opportunity for rapid spread of RSV. Our experience should serve as a warning for paediatric hospitals in the Northern Hemisphere to ensure adequate staffing and available resources to meet the possible increased need, it wrote.

Add in pressure to attend the office even when people are feeling unwell, and youve got a recipe for transmission. A report from the ADP Research Institute showed that, during the pandemic, more than half (54 per cent) of employees globally have felt pressure from their employer to come into work at some point, even though the official line has been to stay home.

Meanwhile, the government has repeatedly encouraged a return to offices for non-essential workers in-between lockdowns, trading off trying to reignite the economy and get people back into Pret a Mangers with the risk of breathing new life into Covid caseloads.

Read the original here:
Your immune system is not ready for the office - Wired.co.uk

Antibodies are crucial for vaccination to work, but scientists don't yet know what level they must reach. The new delta variant poses another problem.

After a coronavirus infection or a vaccination, the body produces antibodies against the virus's spike protein, which SARS-CoV-2 uses to dock onto the cells and penetrate them. This spike protein allows antibodies to recognize the virus and bind to it, making it visible to immune cells.

Scientists previously assumed that people vaccinated with mRNA vaccines such as the one produced by BioNTech-Pfizer had more than 90 per cent protection against the virus - but that does not apply to the new delta variant. This variant is much more contagious than the ancestral virus and is spreading all over the world.

ALSO READ: Pfizer, AstraZeneca vaccine antibody levels may wane after 2-3 months: Study

Carsten Watzl, an immunologist at the Leibniz Institute of the Dortmund Technical University, estimates that the effectiveness of BioNTech-Pfizer mRNA vaccines has reduced from 90 per cent, in the case of the original virus, to 88 per cent with delta. The AstraZeneca vector vaccine's effectiveness has gone from 66 per cent to 60 per cent.

Data from Israel indicates that protection against infection with the dangerous variant is only about 64 per cent when the BioNTech-Pfizer vaccine is used. But the vaccine still offers 93 per cent protection against a severe case of Covid-19. The Israeli Health Ministry is now considering offering people a third dose of the vaccine.

Measurement difficulties

After two shots, the majority of the people are immune to the virus variants known so far - but Carsten Watzl cautions that this does not necessarily apply to everyone who is double-vaccinated.

"Vaccination alone is no guarantee for being immune," he says, adding that what matters is whether the body has built up sufficient immune protection. "But we can't measure that at the moment," he says.

This is different from a tetanus vaccination, where tests can determine whether or not a body is sufficiently protected. A lab checks the blood for the level of antibody titers. If the number of antibodies is above a certain threshold, the person is immune to the tetanus virus. If the titer is too low, the patient needs a booster shot.

With the coronavirus, researchers have not yet reached that stage, Watzl says. "We don't know yet exactly what we need to measure to really determine whether someone is immune or not. Presumably, the neutralizing antibodies play a key role - they bind the virus in such a way that it cannot infect any more cells."

But it is unclear how high the number of these antibodies has to be, he adds.

What do the T cells do?

Only antibodies are not essential in the fight against infection. Once the virus has entered the cell, the antibodies can no longer reach it, because they cannot go into the cell. So, the virus will replicate.

"To fight that, our immune system has T cells; they are able to kill such virus-infected cells - in other words, we would rather sacrifice a few cells in our body, namely the infected ones, than give the virus the opportunity to multiply," Watzl says.

Both these processes can be measured. In practice, however, it is more difficult to determine the number of T cells than that of antibodies. The T cell test is relatively time-consuming but quite useful.

"The antibodies alone don't necessarily tell you anything about how well you are protected," says Watzl: He says that a person might have hardly any antibodies and so could still become infected with the virus. "But the response of the T cells is so strong that the person doesn't get seriously ill," he says.

People with a high level of antibodies are probably well protected against the coronavirus, the immunologist added. But the reverse conclusion - that few antibodies mean no protection - is probably not true, according to him.

A matter of levels

Coronavirus antibody tests employ various measurement methods. Normally, laboratory tests use a clear standard stipulating a minimum to a maximum value. This allows a doctor to see whether levels are within the normal range. The levels have not yet been defined for the coronavirus, however.

So, doctors approximate, with measured levels ranging from less than a hundred to several thousand antibodies. "If I am in the upper third or in the upper half, I probably have good immune protection. But I can't give you the exact threshold values yet," Watzl says.

It is not clear how quickly antibody levels drop, only that they do drop over time.

"It moves in two waves - if you look at the levels right after vaccination, you have the highest antibody level. In the first few months after vaccination, that level decreases relatively quickly. At some point, the whole thing settles at a certain value, and only drops very slowly from there," Watzl says, adding that scientists are familiar with this phenomenon from other vaccinations. "It appears to be true for the coronavirus vaccine, too; science just hasn't proven that yet," he says.

More is better

Some people who have been vaccinated twice have hardly any antibodies against the virus, so they are probably not properly protected, warns Watzl. Low antibody levels can be due to age or a suppressed immune system. Often patients need a third vaccination for the body to form antibodies at all.

Observations range from people who have many antibodies and are well protected to people who have too few antibodies and are poorly protected to people with few antibodies who are still protected.

The conclusion so far is that no one knows for sure. But Watzl is optimistic, emphasizing that "more is better."

"We don't know yet what the threshold levels are, and what level it takes to be protected," he says. "But we will get there someday."

Follow more stories on Facebook and Twitter

The rest is here:
How many antibodies does it take to be immune to the coronavirus? - Hindustan Times

An evolutionary arms race churns away under your skin sometimes quietly and unnoticed, other times with the ferocity of an embattled immune system repelling the invader.

Both sides in this war harmful parasites, viruses and bacteria on one hand, and your immune system on the other are looking to access a critical resource and keep it out of the others possession. That resource is iron, which every cell in your body needs to power its metabolism, as do the infectious agents that seek to exploit it. When one side evolves a battle strategy, the other evolves a way to defeat it something we are seeing in real time with the emergence of coronavirus variants.

Evolutionary medicine, a field within biological anthropology that first emerged in the 1990s, takes a large-scale view of the mechanisms behind human disease and health. By studying the evolution of humanity how early humans lived and the environments they lived in we begin to understand the factors that contribute to disease, which can lead to treatments or prevention today, explained Associate Professor of Anthropology Katherine Wander.

Thats where my interests in human biology and biology and my interest in public health come together, she said.

Wanders research touches on a wide array of topics: iron deficiency and infectious disease risk in Tanzania and Nigeria, the social determinants of disease in Bangladesh and among the matriarchal Mosuo people in China, human adaptations to living at high altitudes and the impact on chronic disease risk, the effect of adoption and fosterage on child health in the island nation of Vanuatu.

The sheer diversity can make it difficult to explain her research in two sentences, she admits.

Thats one of the best things about biomedical anthropology: you can research the things youre interested in. You dont have to stay in one lane, she said. You have to do your background research to be able to contribute to knowledge in a new area, but it doesnt hurt my career to be doing a lot of different things.

Evolutionary approaches to health are common in pop science articles, but these types of publications frequently rely on speculation and the latest trends. Even with a topic such as nutrition, the science is complex and nuanced, including such factors as the evolution of the human gut and innovations such as cooking, which increased our ability to extract nutrients.

Associate Professor of Anthropology Katherine Wander in her lab. Image Credit: Jonathan Cohen.We make a lot of assumptions about what ancient humans did and what we should do as a result. But we dont really know; we need to systematically study that, Wander said.

Ancient humans didnt live in utopia; they frequently met early deaths, Wander pointed out. Natural and healthy also arent equivalent; human beings, for example, evolved in tandem with diseases such tuberculosis that continue to kill people today although to a much lesser extent, due to the invention of modern medicines and vaccines.

In fact, humans today do many things right; our children often survive to adulthood, for example, which wasnt always the case. And there arent many species and no other primates that can occupy as many different environments as humans, from deserts to tundra.

While Wanders interests are wide-ranging, basic questions lie at the heart of her research: Why do children get sick? And what could we do to prevent that, from an evolutionary perspective?

These basic questions often lead to others. In her iron deficiency-related projects in sub-Saharan Africa, she is exploring what constitutes an optimal iron level, especially for a child in an environment with exposure to many infectious diseases.

On one end of the spectrum is anemia, in which low iron levels compromise the production of hemoglobin; on the other end, the individual might be iron replete, with plenty of iron available for their own cells and for those of infectious agents. Where on that spectrum is the lowest risk of infectious disease? Where is the potential for optimal brain development and growth?

A topic as elemental as iron and its role in disease also can lead to entirely new avenues. Wander recently received funding from the National Science Foundation to look at how iron levels affect coronavirus risk in healthcare workers, for example; researchers are still collecting data for that project.

Prospective students in the biomedical anthropology program need to be willing to ask questions both to explore their interests and find training opportunities. Whether youre interested in the skeletal remains of ancient human populations, public health in a specific area, cultural perspectives on health or health culture, or the genetic mechanisms of disease, you can find the path that works for you.

As a result, program graduates can look incredibly different from one another: Some might find their calling in a coroners office, others in public health, research or more.

For graduate students interested in the discipline, Wander is a ready guide. They have joined her in Tanzania to conduct research, and analyze samples connected with projects from around the world in her Binghamton lab. Students are also encouraged to pursue internships in the field and to start building the connections that will enliven their future careers.

Humans, after all, have evolved to be a cooperative species. In an interdisciplinary field such as evolutionary medicine, collaborating with colleagues and mentors can spark new ideas, leading to exciting and unexpected new directions.

Sitting by yourself, making all of the decisions on a project isnt nearly as fun as collaborating with a big group of people who have a lot of different ideas about what data you should collect and why, Wander said.

More here:
An evolving discipline: Evolutionary medicine brings together biological anthropology and public health | Binghamton News - Binghamton University

So what goes into it? According to Bock, there are a lot of different layers, with the first being your basic genetic predispositions, which we can't control.

On top of that, there are the factors that we can control, like stress, diet, environmental toxins, and more. "I think stress is very important," he says. "The value of the immune kettle is that, yes, frequently stress may be the largest component of the immune count."

Then you add in factors like allergies, sensitivities, hormone imbalances, and of course, big infections. "These are things that can really add layers to the immune kettle. And the key is that these layers can be different sizes," he explains. "So if they're small, they're low. The lower you reside in the immune kettle."

Importantly, Bock notes that, depending on how well you handle stress, it could be the very factor that puts you over the edge, to your kettle's boiling point. An overload of stress, he says, is what increases many people's susceptibility to illness.

View original post here:
I'm A Functional MD: Here's Why You Should Focus On Your "Immune Kettle" - mindbodygreen.com

Although studies show people who had COVID-19 and survived have some level of immunity, public health agencies still recommend they get vaccinated.

COVID-19 cases, hospitalizations and deaths are again rising across the United States, with the highest spread coming in areas with low vaccination rates, according to the Centers for Disease Control and Prevention. The increase in cases has come with the continued spread of the more contagious delta variant.

As a result, the CDC and Democratic and Republican leaders are urging more people to get vaccinated. But what about people who already had COVID-19? A VERIFY viewer asked if they are immune and wondered if they should get vaccinated.

THE QUESTION

Maria C. asked: Are people who recovered from COVID-19 completely immune?

THE SOURCES

THE ANSWER

No, people who recovered from COVID-19 are not completely immune to the virus and health officials recommend they get vaccinated.

WHAT WE FOUND

The World Health Organization says: Take whatever vaccine is made available to you first, even if you have already had COVID-19. It is important to be vaccinated as soon as possible once its your turn and not wait. Approved COVID-19 vaccines provide a high degree of protection against getting seriously ill and dying from the disease, although no vaccine is 100% protective.

The CDC alsorecommends people who already had COVID-19 get vaccinated. People who were treated with monoclonal antibodies or convalescent plasma should wait 90 days before getting vaccinated, the CDC says. But after that, the agency recommends those people get the vaccine as well.

Dr. Bill Moss, a professor and executive director of the International Vaccine Access Center at Johns Hopkins University, said immunity means a persons immune system has previously responded to a bacteria or virus that causes infection.

However, its more of a spectrum than an absolute, as there are different levels of immunity,he said.

People who were infected with COVID-19 and survived have some level of natural immunity, although the CDC says its unclear how long that protection lasts. The CDC saysreported cases of reinfection are rare.

One study, partially funded by the National Institutes of Health, concluded immunity may last as long as eight months after infection.Dr. Abinash Virk with the Mayo Clinic said recent studies show natural immunity may last for at least a year. But she said the COVID-19 vaccines boost immunity for people who already had COVID-19 and provide protection against variants of concern.

"Additionally, vaccinated persons have demonstrated longer immunity and lower rates of infection than those who were infected, suggesting the vaccines generate a more sustained immunity than natural infection alone, Virk said.

The CDC says studies suggest the currently authorized vaccines, developed by Pfizer, Moderna and Johnson & Johnson,work against the variants, including the widespread delta variant, which is estimated to make up more than80% of new COVID-19 cases across the U.S.

As of Aug. 2,nearly 50% of the U.S. population was fully vaccinated against COVID-19. More than 611,000 COVID-19 deaths have been reported in the U.S. during the pandemic.

The VERIFY team works to separate fact from fiction so that you can understand what is true and false. Please consider subscribing to our daily newsletter, text alerts and our YouTube channel. You can also follow us on Snapchat, Twitter, Instagram, Facebook and TikTok. Learn More

Text: 202-410-8808

Here is the original post:
No, people who recovered from COVID-19 are not completely immune to the virus - Local 5 - weareiowa.com

Over a year into the pandemic, questions around immune responses after Covid continue to confound.

One question many people are asking is whether the immunity you get from contracting Covid and recovering is enough to protect you in the future.

The answer is no, its not.

Heres why.

Immune responses are innate or acquired. Innate, or short-term immunity, occurs when immune cells that are the bodys first line of defence are activated against a pathogen like a virus or bacteria.

If the pathogen is able to cross the first line of defence, T-cells and B-cells are triggered into action. B-cells fight through secreted proteins called antibodies, specific to each pathogen. T-cells can be categorised into helper T-cells and killer T-cells. Helper T-cells help B-cells in making antibodies. Killer T-cells directly kill infected cells.

Once the battle is over, B-cells and T-cells develop memory and can recognise the invading pathogen next time. This is known as acquired or adaptive immunity, which triggers long-term protection.

What happens when you get reinfected? Memory B-cells dont just produce identical antibodies, they also produce antibody variants. These diverse set of antibodies form an elaborate security ring to fight SARS-CoV-2 variants.

Getting Covid and recovering (known as natural infection) doesnt appear to generate protection as robust as that generated after vaccination.

And the immune response generated post-infection and vaccination, known as hybrid immunity, is more potent than either natural infection or vaccination alone.

People who have had Covid and recovered and then been vaccinated against Covid have more diverse and high-quality memory B-cell responses than people whove just been vaccinated.

Studies indicate mRNA vaccines generate a more potent immune response with previous infection, at least against some variants including Alpha and Beta.

And studies have shown that antibody levels were higher among those whod recovered from Covid and were subsequently vaccinated than those whod only had the infection.

Memory B-cells against the coronavirus have been reported to be five to ten times higher in people vaccinated post-infection than natural infection or vaccination alone.

Some reports have suggested people whove had Covid need only one dose of the vaccine. Clinical trials of approved vaccines didnt generate relevant data because people whod already had Covid were excluded from phase 3 trials.

One study from June showed people with previous exposure to SARS-CoV-2 tended to mount powerful immune responses to a single mRNA shot. They didnt gain much benefit from a second jab.

A single dose of an mRNA vaccine after infection achieves similar levels of antibodies against the spike proteins receptor binding domain (which allows the virus to attach to our cells) compared to double doses of vaccination in people never exposed to SARS-CoV-2.

We need more studies to fully understand how long memory B-cell and T-cell responses will last in both groups.

Also, a single dose strategy has only been studied for mRNA-based vaccines. More data is required to understand whether one jab post-infection would be effective for all the vaccines.

At this stage, its still good to have both doses of a Covid vaccine after recovering from Covid.

The development of new vaccines must keep pace with the evolution of the coronavirus.

At least one variant seems to have evolved enough to overtake others, Delta, which is about 60% more transmissible than the Alpha variant. Delta is moderately resistant to vaccines, meaning it can reduce how well the vaccines work, particularly in people whove only had one dose.

Theres no data available yet about how effective a single jab is for people who were previously infected with Delta and recovered.

The most important thing you can do to protect yourself from Delta is to get fully vaccinated.

According to a Public Health England report, one dose of Pfizer offered only about 33% protection against symptomatic disease with Delta, but two doses was 88% effective.

Two doses was also 96% effective against hospitalisation from Delta. The AstraZeneca vaccine was 92% effective against hospitalisation from Delta after two doses.

A few vaccine manufacturers, including Pfizer, are now planning to use a potential third dose as a booster to combat the Delta variant.

Sunit K. Singh, Professor of Molecular Immunology and Virology, Institute of Medical Sciences, Banaras Hindu University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

See the rest here:
If Ive already had Covid, do I need a jab? How does the immune system respond? An expert explains - News24

Scientists from Johns Hopkins Medicine, in collaboration with national and international researchers, have identified a genetic mutation in a small number of children with a rare type of inflammatory bowel disease. They say that this discovery could help to define the cause of more common bowel diseases and lead to more targeted treatments for gut conditions.

The study has been published in Human Genetics.

Anthony Guerreiro Jr., M.D, Ph.D., M.S., Director of the Very Early Onset Inflammatory Bowel Disease Clinic and Assistant Professor of Pediatrics at the Johns Hopkins University School of Medicine, said: We aimed to see if children have a greater genetic susceptibility for this type of inflammatory bowel disease because they develop it so young,

Unlike other inflammatory bowel diseases, very early onset inflammatory bowel disease is diagnosed in patients before the age of six, occurring in four out of every 100,000 births worldwide. In such young patients, the disease does not typically respond to anti-inflammatory medications, and surgery is sometimes required to remove all or parts of the colon.

Inflammatory bowel diseases are chronic, inflammatory conditions including Crohns disease and ulcerative colitis that occur when immune cells in the intestines are overactivated, causing sustained inflammation in the gut. These diseases are thought to be caused by multiple genetic mutations and environmental factors, such as diet and pollution, as well as disruptions to the makeup of gut bacteria. Common treatments include prescription drugs that curb inflammation.

Since the most common characteristic of bowel diseases is inflammation, scientists have long suspected genetic links between the immune system and bowel conditions.

In the study, scientists collected tissue samples from 24 patients with very early onset inflammatory bowel disease seen at The Johns Hopkins Hospital and Johns Hopkins Childrens Center and performed whole exome sequencing a method that looks at the protein-producing areas of a gene to identify mutations.

Of the 24 patients, mutations were found in four patients in parts of a gene called IFIH1, which produces a protein involved in the virus-fighting branch of the immune system. Other genetic sequencing studies have also linked the IFIH1 gene to inflammatory bowel diseases, and the current research backs up the genes involvement in very early onset inflammatory bowel disease.

As the number of patients in the first round of sequencing was small, the researchers turned to a Johns Hopkins-developed online database called GeneMatcher, which contains genetic variations from people worldwide. Guerrerio and GeneMatcher co-founder Nara Sobreira, M.D, Ph.D, Assistant Professor of Genetics and Pediatrics at the Johns Hopkins University of Medicine, found an additional 18 patients with very early onset inflammatory bowel disease being studied at both the NIH and in Padova, Italy.

The combined research teams found IFIH1 mutations in four of the 18 new patients, bringing the total of IFIH1 mutations found to eight out of the 42 patients. Among the IFIH1 mutations, the researchers discovered nine mutations which resulted in abnormal production of a protein called MDA5. In the eight patients with the mutations, MDA5 function was much lower than normal.

When functioning properly, MDA5 is a part of the inborn immune system that helps fight off viruses in the gut. Using protein assays that mimicked the activity of normal and abnormal MDA5, the researchers found that, in each patient with the IFIH1 mutation, the MDA5 proteins only partially worked, but not enough to do their job of battling viruses. The researchers suspect this loss of function in the protein causes the improper activation of the immune system, triggering the inflammation that leads to very early onset inflammatory bowel disease.

The researchers also believe that the partially functioning MDA5 proteins protect patients from more severe and rare immune diseases, such as Singleton-Merton syndrome and Aicardi-Goutires syndrome, that are associated with no MDA5 production.

Sobreira said: When you look at the physical changes associated with IFIH1 mutations, there are a wide range and they are really very different.

Its crucial to know that these different variations in the same gene can cause these different characteristics.

The researchers hope that their findings will help to improve understanding of the genetic cause of diseases and inform treatment options. They also believe the research provides additional evidence of the link between inflammatory bowel diseases and the virus-fighting part of the bodys immune response.

Recommended Related Articles

See the original post:
Genetic mutation linked to rare inflammatory bowel disease bowel-disease - Health Europa

Its a scientific riddle tangled up in a complex web. How do you turn an immune cold cancer into one that responds to immunotherapy?

Researchers led by the University of Michigan Rogel Cancer Center started with a simple thread: an inhibitor that showed promise against metastatic castration-resistant prostate cancer cells. This is the most challenging type of prostate cancer advanced disease that has become resistant to hormone-based treatment.

MORE FROM THE LAB: Subscribe to our weekly newsletter

From there, they continued to untangle the web to discover multiple levels of cellular processes that were preventing the immune system from mounting a response. Break past them with this inhibitor and suddenly whats considered an immune cold tumor turns red hot.

Immunotherapy has dramatically improved outcomes for some types of cancer. But prostate cancers are typically immune cold, which means these patients have benefited little from immunotherapies. Finding a way to rev up the immune response would create tremendous opportunity to improve patient outcomes, said Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine. Chinnaiyan is senior author of the paper published in Nature Cancer.

Researchers started by screening a library of 167 inhibitors against prostate cancer cells. They found one, ESK981, had the most impact.

ESK981 is a class of drugs called multi-tyrosine kinase inhibitors, which are designed to hit multiple targets. This means it functions like a combination therapy, able to block cancer on more than one front. It was originally developed to check blood vessel growth and has already been tested in phase 1 clinical trials, which found it to be safe and well-tolerated.

In cell lines and mice with metastatic castration-resistant prostate cancer, researchers found ESK981 inhibited tumor growth.

SEE ALSO: New Connections Reveal How Cancer Evades the Immune System

The response was intriguing, but we wanted to understand the mechanism at play with ESK981 in prostate cancer cells, Chinnaiyan said.

They discovered several cellular processes were occurring. First was the role of a type of cell death called autophagy. The authors surprisingly found that ESK981 was a potent inhibitor of autophagy in tumor cells. This caused the cancer cells to produce a protein called CXCL10, which led to recruitment of immune T cells to the tumor.

But there was one more layer to go. Ultimately, they traced it back to PIKfyve, a type of protein called a lipid kinase. The authors discovered that ESK981 directly targets PIKfyve, affecting these multiple processes involved in metabolism and cell death.

The researchers confirmed this by knocking down PIKfyve in cell lines and mice. They saw the same processes occur: tumors stopped growing, autophagy was controlled and more T cells were recruited to the tumor. When they added an immune checkpoint inhibitor to the PIKfyve knockdown, the impact was even greater, significantly reducing tumors.

Overcoming resistance to immunotherapy is an urgent need in prostate cancer. PIKfyve is a promising target, especially combined with an immune checkpoint inhibitor. This combination has potential to extend the benefit of immunotherapy to patients whose tumors have previously not responded, Chinnaiyan said.

Based on these findings, researchers have begun phase 2 clinical trials using ESK981 alone or in combination with the immunotherapy nivolumab for metastatic castration-resistant prostate cancer.

Like Podcasts? Add the Michigan Medicine News Break oniTunes, Google Podcasts or anywhere you listen to podcasts.

Additional authors includeYuanyuan Qiao, Jae Eun Choi, Jean C. Tien, Stephanie A. Simko, Thekkelnaycke Rajendiran, Josh N. Vo, Andrew D. Delekta, Lisha Wang, Lanbo Xiao, Nathan B. Hodge, Parth Desai, Sergio Mendoza, Kristin Juckette, Alice Xu, Tanu Soni, Fengyun Su, Rui Wang, Xuhong Cao, Jiali Yu, Ilona Kryczek, Xiao-Ming Wang, Xiaoju Wang, Javed Siddiqui, Zhen Wang, Amelie Bernard, Ester Fernandez-Salas, Nora M. Navone, Stephanie J. Ellison, Ke Ding, Eeva-Liisa Eskelinen, Elisabeth I. Heath, Daniel J. Klionsky, Weiping Zou

Funding for this work comes from the Prostate Cancer Foundation Challenge Award, National Cancer Institute Prostate SPORE Grant P50CA186786, Department of Defense grant PC130151P1, National Institutes of Health grant GM131919. In addition, individual researchers are supported by NCI grant R35CA231996, Howard Hughes Medical Institute, A. Alfred Taubman Institute, American Cancer Society, PCF Young Investigator Awards, DoD Postdoctoral Award W81XWH-16-1-0195, and the Academy of Finland.

Disclosure: The University of Michigan has filed a disclosure on the findings based on this study. Chinnaiyan and Qiao are named as co-inventors. Esanik Therapeutics Inc. licensed ESK981 from Teva Pharmaceuticals. Chinnaiyan is a co-founder and serves on the scientific advisory board of Esanik Therapeutics Inc. Esanik Therapeutics or Teva Pharmaceuticals were not involved in the design or approval of this study, nor was this study funded by them.

Paper cited: Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer, Nature Cancer. DOI: 10.1038/s43018-021-00237-1

Continue reading here:
Researchers uncover way to harness the power of immunotherapy for advanced prostate cancer - Michigan Medicine

The U.S. is reporting more than 100,000 new COVID-19 cases a day numbers not seen since February when most people couldnt get vaccinated. As a result, on Monday, seven Bay Area counties reimposed indoor masking requirements, joining LA, Sacramento and Yolo counties. And employers are reevaluating whether back-to-the-office-after-Labor Day plans are realistic anymore.

The spread of the Delta variant is even more nerve-wracking for people with weakened immune systems, who were left out of initial vaccine trials. Because of that, its unclear how well the vaccine protects immunocompromised patients.

One of those immunocompromised patients is Trevor Achilles, a 27-year-old resident of Charlottesville, Virginia. After undergoing a kidney transplant 12 years ago, hes had to take immunosuppressive drugs to ensure his body doesnt reject the kidney.

He says the last 17 months have felt like hell. He was laid off during the early days of the pandemic and often found himself stuck.

I couldn't really see friends, I couldn't really go to the gym, or do anything else that I used to do before the pandemic. And so it was very taxing on me mentally and physically. I gained a lot of weight. And I was just sitting around, and getting depressed, watching all the horrible news. It was not fun.

Earlier this year, Achilles was vaccinated. When he was tested for antibodies, it turned out he didnt have any. Achilles says thats due to the nature of immunosuppressive drugs they protect his kidneys but fight off anything else that enters his body.

I got the flu before the pandemic began, and I was knocked out flat practically. And when I get sick, I tend to get sicker than most. And so I'm particularly vulnerable to getting something like COVID. And unfortunately, that pertains to the [COVID vaccine] shots as well, because my body just won't accept any kind of foreign interference.

Achilles lack of antibodies doesnt surprise Ghady Haidar, M.D from the University of Pittsburgh Medical Center. He looks at how infectious diseases can affect transplant patients. Most recently, Haidar has focused on how people with cancer, organ transplants, and autoimmune diseases respond to the COVID vaccines.

Vaccines work by triggering your immune system to respond to something. When you're taking medicines that work by suppressing the immune system, it just makes sense that vaccines aren't going to work as well, Haidar tells KCRW. This isn't unique to just COVID-19. This is true for every single vaccine that's out there.

Haidar recently led a study examining antibody responses in immunocompromised patients. It found that about 37% of organ transplant recipients produced antibodies. Thats compared to 94% of patients with well-treated HIV and about 80% of patients with blood cancer and autoimmune diseases.

He says the wide-ranging results are indicative of how certain conditions and their treatments can impact the body.

For example: A person getting chemotherapy for cancer, their immune system is not the same as someone getting, let's say, a TNF [tumor necrosis factor] inhibitor for their Crohns disease. And it's not the same as someone who just had a lung transplant a month ago. And that's not the same as someone who had a liver transplant 20 years ago.

At the recommendation of his doctor, Achilles received a third COVID vaccine in hopes that it would help him develop antibodies.

[My doctors] first goal is to keep me alive and healthy and safe. And she knows all about COVID and how it's impacting those of us who are immunocompromised, and she was really worried about me. And she figured that it'd be better to try to get some protection as opposed to having no protection at all, Achilles says. I just felt like it was the right thing to do, the natural thing to do. And I'm just hoping and praying this third shot will give me the antibodies that I need.

Haidar says other countries, including France and Germany, have started to distribute booster shots. In the U.S. however, vaccine regulators are waiting for more clinical trials and data in order to make a decision.

In the meantime, Achilles says hes laying low to protect himself from the new Delta variant.

He adds, I may have to start hibernating again, so to speak. I'm just really concerned about the Delta variants because it's much more contagious. I'm willing to do anything and everything to protect myself and my family.

Read more here:
'I may have to start hibernating again': Immunocompromised 27-year-old on Delta variant and booster shots - KCRW