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. 2020 Mar;16(3):512-530. doi: 10.1080/15548627.2019.1630222. Epub 2019 Jun 24. Seonghee Jung 1 ,Seongwon Choe 1 ,Hanwoong Woo 1 ,Hyeonjeong Jeong 1 ,Hyun-Kyu An 1 ,Hyewon Moon 1 ,Hye Young Ryu 1 ,Bo Kyoung Yeo 1 ,Ye Won Lee 1 ,Hyosun Choi 2 ,Ji Young Mun 3 ,Woong Sun 4 ,Han Kyoung Choe 1 ,Eun-Kyoung Kim 1 5 ,Seong-Woon Yu 1 5
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Seonghee Junget al. Autophagy. 2020 Mar.
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Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders.Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA1: bafilomycin A1; BrdU: Bromodeoxyuridine/5-bromo-2'-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3'-diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor.
Keywords: Atg7 knockout; autophagic cell death; corticosterone; hippocampal neurogenesis; serum/glucocorticoid regulated kinase 3; stress.
Figure 1.
Chronic restraint stress (CRS)-induced reduction
Figure 1.
Chronic restraint stress (CRS)-induced reduction in the number of adult hippocampal NSCs is
Chronic restraint stress (CRS)-induced reduction in the number of adult hippocampal NSCs is prevented by Atg7 deletion. (A) Scheme of mouse breeding and experimental time line for generation of tamoxifen (TAM)-inducible NSC-specific Atg7-NSC cKO mice. (B) Gene dosedependence of ATG7 immunofluorescence intensities in the DG of the hippocampus. Scale bar: 50 m. Solid and dotted circles indcate granule neurons and NSCs, respectively. The graph shows quantification of SOX2+ and ATG7+ cells (n =6). (c) Timeline of the experiment. (D) Representative images of BrdU and SOX2 staining in the subgranular zone (SGZ) of the hippocampus. Scale bar: 20 m. The graph on the right shows quantification of BrdU+ and SOX2+ cells (n =68 per group). (E) Immunofluorescence of SOX2, NES and VIM in the SGZ of the DG of the hippocampus. Scale bar: 50 m. Arrows indicate NSCs positive for each marker. ***P <0.001 for the total SOX2+ cells. ###P <0.001 for BrdU+ SOX2+ cells. n.s., not significant.
Figure 2.
CRS induces autophagy in adult
Figure 2.
CRS induces autophagy in adult hippocampal NSCs. ( A ) Work flow of
CRS induces autophagy in adult hippocampal NSCs. (A) Work flow of correlative light electron microscopy (CLEM) imaging. (B) CLEM imaging of SOX2-positive cells at day-4 of CRS (n =13 cells per group). Representative images of autophagosomes (white arrows) in CRS group are shown at higher magnification. The number of autophagosomes was counted per 5m5m without counting the autophagosomes of whole cells using serial sections. Scale bars: 2 m. (C) Nes promoter-driven lentiviral expression of mRFP-EGFP-MAP1LC3B in vivo. Virus was injected 4days prior to CRS and analyzed at day 2 of CRS. Scale bar: 20 m. The graph on the right shows quantification of autophagosomes and autolysosomes (n =7 or 8 cells per group). (D and E) Cleaved CASP3 (c.CASP3) staining (D) and TUNEL assay (E) in the DG at day 7 of CRS. STS was injected 12h before analysis. Arrows indicate c.CASP3-positive cells. Scale bar: 100 m. ***P <0.001. n.s., not significant.
Figure 3.
Suppression of hippocampal neurogenesis, anxiety-like
Figure 3.
Suppression of hippocampal neurogenesis, anxiety-like and depressive behaviors, and spatial memory deficits induced
Suppression of hippocampal neurogenesis, anxiety-like and depressive behaviors, and spatial memory deficits induced by CRS are prevented in Atg7-NSC cKO mice. (A) Timeline for the measurement of the number of BrdU+ and RBFOX3+ double-positive NSCs. (B) Representative images of BrdU+ RBFOX3+ staining. Scale bar: 20 m. Arrow indicate RBFOX3+ BrdU+ double-positive cells. (C) Quantification of BrdU+ RBFOX3+-positive cells (n =6 or 7 per group). (D and E) Measurement of anxiety-like behaviors by the open field test (n =6 or 7 per group) (D) and elevated plus maze test (n =613 per group) (E). (F) Measurement of depressive behavior by the sucrose preference test (n =6). (G) Assessment of spatial working memory by the Y-maze test (n =68 per group). (H) Spatial learning and memory test using the acquisition phase (left graph) and probe test at day 6 (right graph) in MWM test (n =68 per group). TQ, target quadrant; AL, adjacent left; AR, adjacent right; OP, opposite. *P <0.05, **P <0.01, ***P <0.001.
Figure 4.
Atg7 deficiency prevents loss of
Figure 4.
Atg7 deficiency prevents loss of subtypes of NSCs in the adult DG and
Atg7 deficiency prevents loss of subtypes of NSCs in the adult DG and the activity of NSCs in neurosphere cultures. (A) Representative image of each subtype of NSCs in the SGZ of the DG. (band c) Quantification of GFAP+ SOX2+ (type 1), GFAP+ SOX2+ MKI67+ (active type 1), ASCL1+ SOX2+ (type 2a), DCX+ SOX2+ (type 2b), and DCX+ (type 3) NSCs 1 day (n =4 or 5 per group) (B) and 28days after CRS (n =5 or 6 per group) (C). (D) Representative image of neurospheres in culture for 7days. Scale bar: 40 m. (E) Quantification of neurospheres after 7days in cultures (n =35 per group). (F) Measurement of neurosphere size after 7days in cultures (n =35 per group). *P <0.05, **P <0.01, ***P <0.001.
Figure 5.
CORT-induced reduction of NSC number
Figure 5.
CORT-induced reduction of NSC number and hippocampal dysfuction is prevented in Atg7-NSC cKO
CORT-induced reduction of NSC number and hippocampal dysfuction is prevented in Atg7-NSC cKO mice. (A) Timeline of the CORT injection experiment. (B) Quantification of BrdU+ and SOX2+ cells (n =4 or 5 per group). **P <0.01 for the total SOX2+ cells ##P <0.01 for BrdU+ SOX2+ cells. (C) Nes promoter-driven lentiviral expression of mRFP-EGFP-MAPLC3B in SOX2+ cells in vivo. Scale bar: 20m. The graph on the right shows quantification of autophagosomes and autolysosomes (n =7 or 8 cells per group). (D) Timeline for the measurement of the number of BrdU+ RBFOX3+ doublepositive NSCs. (E) Quantification of BrdU+ RBFOX3+ double-positive cells (n =4 or 5 per group). (f) Elevated plus maze test (n =4 per group). (g) Y-maze test (n =4 per group). *P <0.05, **P <0.01, ***P <0.001.
Figure 6.
CORT treatment does not induce
Figure 6.
CORT treatment does not induce apoptosis or necroptosis in HCN cells. ( A
CORT treatment does not induce apoptosis or necroptosis in HCN cells. (A) Death rate of HCN cells after CORT treatment (n =4). Right, representative image of Hoechst and PI staining 48h after CORT treatment in HCN cells. (B) Nucleus condensation assay with Hoechst staining. (C) Immunostaining of cleaved CASP3 (c.CASP3). (D) Nuclear fragmentation assay by TUNEL staining. Scale bar: 40m for b-d. (E and F) Agarose gel electrophoresis of DNA fragmentation assay (E) and western blots of c.CASP3 (F) are representative of at least 3 experiments with similar results. All apoptotic markers were analyzed after CORT (200M for 48h, except western blotting analysis of c.CASP3 with 72h) or staurosporine (STS, 0.5M for 6h) treatment. (G) Effects of Z-VAD (25 M) or necrostatin-1 (NEC-1, 100 M) on HCN cell death after CORT treatment for 48h (n =3). (H) Western blotting analysis of the effects of Z-VAD (25 M) on autophagy flux after CORT treatment for 48h. The blots are representative of 3 experiments with similar results. *P <0.05, **P <0.01, ***P <0.001. n.s., not significant.
Figure 7.
CORT treatment induces ACD in
Figure 7.
CORT treatment induces ACD in HCN cells. ( A ) Representative EM images
CORT treatment induces ACD in HCN cells. (A) Representative EM images of HCN cells treated with CORT for 48h. Scale bar: 2 m. N, nucleus. The graph on the right shows quantification of autophagosomes (n =35 cells per group). (B) Western blotting analyses of MAP1LC3B and SQSTM1 levels after CORT treatment for 48h. The graphs on the right show quantification of MAP1LC3B-II (n =6) and SQSTM1 (n =4) after normalization to ACTB. (C) Analysis of autophagy flux using mRFP-EGFP-MAP1LC3B after CORT treatment for 48h. Scale bar: 10m. The graph on the right shows quantification of MAP1LC3B puncta (n =8). ***P <0.001 for the total MAP1LC3B puncta. #P <0.05, ##P <0.01 for yellow puncta. (D) Death rates of HCN cells after KO of Ulk1 (sgUlk1) or with stable knockdown of ATG7 (shAtg7), SQSTM1 (shSqstm1) or MAP1LC3B (shMap1lc3b) in comparison with control cells (sgCon or shCon) after CORT treatment for 48h (n =3). In all experiments, BafA1 (20nM) was added 1 h before cell harvest. *P <0.05, **P <0.01, ***P <0.001.
Figure 8.
SGK3 is critical for CORT-induced
Figure 8.
SGK3 is critical for CORT-induced cell death, but dispensable for apoptosis or necroptosis
SGK3 is critical for CORT-induced cell death, but dispensable for apoptosis or necroptosis in HCN cells. (A and B) Changes in the expression levels of SGK1, 2, and 3 following CORT treatment in HCN cells. mRNA levels after CORT treatment for 24h (n =3) (A). Western blotting analyses of protein levels (B). Blots are representative of 3 experiments with similar results. (C) KO of Sgk1 (sgSgk1) and Sgk2 (sgSgk2). (D) Death rates of sgSgk1 and sgSgk2 cells after CORT treatment for 48h (n =3). (E) KO of Sgk3 (sgSgk3). (F) Death rate of sgSgk3 cells (n =8). (G) Death rate of sgSgk3 cells after STS treatment (0.5 M) for 24h (n =3). (G) Death rate of sgSgk3 cells after H2O2 treatment (100M) for 6h (n =3). ***P <0.001. n.s., not significant.
Figure 9.
SGK3 mediates ACD in HCN
Figure 9.
SGK3 mediates ACD in HCN cells following CORT treatment. ( A ) Analysis
SGK3 mediates ACD in HCN cells following CORT treatment. (A) Analysis of autophagy flux by western blotting of MAP1LC3B. The graph shows quantification of MAP1LC3B-II after normalization to ACTB (n =5). (B) Analysis of autophagosome formation using mRFP-MAP1LC3B. Scale bar: 10m. The graph shows quantification of autophagosomes (n =4 or 5). (C) Time-course analysis of EGFP-ZFYVE1 puncta formation after CORT treatment using EGFP-ZFYVE1. Scale bar: 10m. The graph shows quantification of ZFYVE1 puncta (n =46). (D) Domain diagrams of SGK1, 2, and 3 showing the critical Arg90 residue in the Phox homology (PX) domain in SGK3. SGK1 has an incomplete PX domain [38]. (E) Effects of SGK3WT and SGK3R90A mutant on sgSgk3 cell death (n =4). EV, empty vector. (F) Analysis of autophagy flux by western blotting of MAP1LC3B in sgSgk3 cells transfected with SGK3WT or SGK3R90A mutant. The graph shows quantification of MAP1LC3B-II after normalization to ACTB (n =3). (G) Effects of the SGK3R90A mutation on the MAP1LC3B puncta formation and colocalization of SGK3 with MAP1LC3B. sgSgk3 cells were co-transfected with EGFP-tagged SGK3WT or SGK3R90A mutant with mRFP-MAP1LC3B. Scale bar: 10 m. In all experiments, BafA1 (20nM) was added 1 h before cell harvest. *P <0.05, ***P <0.001. n.s., not significant.
Figure 10.
SGK3 silencing attenuates NSC reduction
Figure 10.
SGK3 silencing attenuates NSC reduction in the DG after CRS. ( A )
SGK3 silencing attenuates NSC reduction in the DG after CRS. (A) Experimental design illustrating stereotaxic injection of AAV1/2-guide RNAs into DG of S-Cas9 KI mice. (B) Image of AAV1/2-sgSGK3-mCherry expression in the SGZ of DG. Scale bar, 100m. (C) KO of Sgk1 (AAV-sgSgk1) and Sgk3 (AAV-sgSgk3). (D) Timeline of the experiment. (E) Representative images of mCherry and SOX2 co-labeling in the SGZ of DG 3weeks after injection of AAV-sgSgk1 or AAV-sgSgk3 in S-Cas9 mice. Scale bar, 50m. (F) The graph shows quantification of SGK-mCherry and SOX2 double-positive cells. (n =5). ***P <0.001.
All figures (10)
An HK, Chung KM, Park H, Hong J, Gim JE, Choi H, Lee YW, Choi J, Mun JY, Yu SW. An HK, et al. Autophagy. 2020 Sep;16(9):1598-1617. doi: 10.1080/15548627.2019.1695398. Epub 2019 Dec 10. Autophagy. 2020. PMID: 31818185 Free PMC article.
Wang C, Haas M, Yeo SK, Sebti S, Fernndez F, Zou Z, Levine B, Guan JL. Wang C, et al. Autophagy. 2022 Feb;18(2):409-422. doi: 10.1080/15548627.2021.1936358. Epub 2021 Jun 8. Autophagy. 2022. PMID: 34101533 Free PMC article.
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This work was supported by the National Research Foundation of Korea (NRF) grants (2017R1A2B4004289, 2018M3C7A1056275), the KBRI basic research program (19-BR-01-08), and the DGIST Convergence Science Center Program (19-BD-04) of the Ministry of Science and ICT of Korea; National Research Foundation of Korea [2018M3C7A1056275]; National Research Foundation of Korea [2017R1A2B4004289]; Ministry of Science and ICT of Korea [19-BR-01-08]; Ministry of Science and ICT of Korea [19-BD-04].
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Autophagic death of neural stem cells mediates chronic stress-induced ...
Death of a cell mediated by intracellular program, often as part of development
Programmed cell death (PCD; sometimes referred to as cellular suicide[1]) is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy.[2][3] PCD is carried out in a biological process, which usually confers advantage during an organism's lifecycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development.
Apoptosis and autophagy are both forms of programmed cell death.[4] Necrosis is the death of a cell caused by external factors such as trauma or infection and occurs in several different forms. Necrosis was long seen as a non-physiological process that occurs as a result of infection or injury,[4] but in the 2000s, a form of programmed necrosis, called necroptosis,[5] was recognized as an alternative form of programmed cell death. It is hypothesized that necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations. Most recently, other types of regulated necrosis have been discovered as well, which share several signaling events with necroptosis and apoptosis.[6]
The concept of "programmed cell-death" was used by Lockshin & Williams[7] in 1964 in relation to insect tissue development, around eight years before "apoptosis" was coined. The term PCD has, however, been a source of confusion and Durand and Ramsey[8] have developed the concept by providing mechanistic and evolutionary definitions. PCD has become the general terms that refers to all the different types of cell death that have a genetic component.
The first insight into the mechanism came from studying BCL2, the product of a putative oncogene activated by chromosome translocations often found in follicular lymphoma. Unlike other cancer genes, which promote cancer by stimulating cell proliferation, BCL2 promoted cancer by stopping lymphoma cells from being able to kill themselves.[9]
PCD has been the subject of increasing attention and research efforts. This trend has been highlighted with the award of the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner (United Kingdom), H. Robert Horvitz (US) and John E. Sulston (UK).[10]
Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms.[12] Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. It is now thought that- in a developmental context- cells are induced to positively commit suicide whilst in a homeostatic context; the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors.[13]
Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles.
Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection and cancer.
A critical regulator of autophagy induction is the kinase mTOR, which when activated, suppresses autophagy and when not activated promotes it. Three related serine/threonine kinases, UNC-51-like kinase -1, -2, and -3 (ULK1, ULK2, UKL3), which play a similar role as the yeast Atg1, act downstream of the mTOR complex. ULK1 and ULK2 form a large complex with the mammalian homolog of an autophagy-related (Atg) gene product (mAtg13) and the scaffold protein FIP200. Class III PI3K complex, containing hVps34, Beclin-1, p150 and Atg14-like protein or ultraviolet irradiation resistance-associated gene (UVRAG), is required for the induction of autophagy.
The ATG genes control the autophagosome formation through ATG12-ATG5 and LC3-II (ATG8-II) complexes. ATG12 is conjugated to ATG5 in a ubiquitin-like reaction that requires ATG7 and ATG10. The Atg12Atg5 conjugate then interacts non-covalently with ATG16 to form a large complex. LC3/ATG8 is cleaved at its C terminus by ATG4 protease to generate the cytosolic LC3-I. LC3-I is conjugated to phosphatidylethanolamine (PE) also in a ubiquitin-like reaction that requires Atg7 and Atg3. The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane.
Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two. During nutrient deficiency, autophagy functions as a pro-survival mechanism, however, excessive autophagy may lead to cell death, a process morphologically distinct from apoptosis. Several pro-apoptotic signals, such as TNF, TRAIL, and FADD, also induce autophagy. Additionally, Bcl-2 inhibits Beclin-1-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator.
Besides the above two types of PCD, other pathways have been discovered.[14]Called "non-apoptotic programmed cell-death" (or "caspase-independent programmed cell-death" or "necroptosis"), these alternative routes to death are as efficient as apoptosis and can function as either backup mechanisms or the main type of PCD.
Other forms of programmed cell death include anoikis, almost identical to apoptosis except in its induction; cornification, a form of cell death exclusive to the eyes; excitotoxicity; ferroptosis, an iron-dependent form of cell death[15] and Wallerian degeneration.
Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. Nemosis is another programmed form of necrosis that takes place in fibroblasts.[16]
Eryptosis is a form of suicidal erythrocyte death.[17]
Aponecrosis is a hybrid of apoptosis and necrosis and refers to an incomplete apoptotic process that is completed by necrosis.[18]
NETosis is the process of cell-death generated by NETs.[19]
Paraptosis is another type of nonapoptotic cell death that is mediated by MAPK through the activation of IGF-1. It's characterized by the intracellular formation of vacuoles and swelling of mitochondria.[20]
Pyroptosis, an inflammatory type of cell death, is uniquely mediated by caspase 1, an enzyme not involved in apoptosis, in response to infection by certain microorganisms.[20]
Plant cells undergo particular processes of PCD similar to autophagic cell death. However, some common features of PCD are highly conserved in both plants and metazoa.
An atrophic factor is a force that causes a cell to die. Only natural forces on the cell are considered to be atrophic factors, whereas, for example, agents of mechanical or chemical abuse or lysis of the cell are considered not to be atrophic factors.[by whom?] Common types of atrophic factors are:[21]
The initial expansion of the developing nervous system is counterbalanced by the removal of neurons and their processes.[22] During the development of the nervous system almost 50% of developing neurons are naturally removed by programmed cell death (PCD).[23] PCD in the nervous system was first recognized in 1896 by John Beard.[24] Since then several theories were proposed to understand its biological significance during neural development.[25]
PCD in the developing nervous system has been observed in proliferating as well as post-mitotic cells.[22] One theory suggests that PCD is an adaptive mechanism to regulate the number of progenitor cells. In humans, PCD in progenitor cells starts at gestational week 7 and remains until the first trimester.[26] This process of cell death has been identified in the germinal areas of the cerebral cortex, cerebellum, thalamus, brainstem, and spinal cord among other regions.[25] At gestational weeks 1923, PCD is observed in post-mitotic cells.[27] The prevailing theory explaining this observation is the neurotrophic theory which states that PCD is required to optimize the connection between neurons and their afferent inputs and efferent targets.[25] Another theory proposes that developmental PCD in the nervous system occurs in order to correct for errors in neurons that have migrated ectopically, innervated incorrect targets, or have axons that have gone awry during path finding.[28] It is possible that PCD during the development of the nervous system serves different functions determined by the developmental stage, cell type, and even species.[25]
The neurotrophic theory is the leading hypothesis used to explain the role of programmed cell death in the developing nervous system.[29] It postulates that in order to ensure optimal innervation of targets, a surplus of neurons is first produced which then compete for limited quantities of protective neurotrophic factors and only a fraction survive while others die by programmed cell death.[26] Furthermore, the theory states that predetermined factors regulate the amount of neurons that survive and the size of the innervating neuronal population directly correlates to the influence of their target field.[30]
The underlying idea that target cells secrete attractive or inducing factors and that their growth cones have a chemotactic sensitivity was first put forth by Santiago Ramon y Cajal in 1892.[31] Cajal presented the idea as an explanation for the "intelligent force" axons appear to take when finding their target but admitted that he had no empirical data.[31] The theory gained more attraction when experimental manipulation of axon targets yielded death of all innervating neurons. This developed the concept of target derived regulation which became the main tenet in the neurotrophic theory.[32][33] Experiments that further supported this theory led to the identification of the first neurotrophic factor, nerve growth factor (NGF).[34]
Different mechanisms regulate PCD in the peripheral nervous system (PNS) versus the central nervous system (CNS). In the PNS, innervation of the target is proportional to the amount of the target-released neurotrophic factors NGF and NT3.[35][36] Expression of neurotrophin receptors, TrkA and TrkC, is sufficient to induce apoptosis in the absence of their ligands.[23] Therefore, it is speculated that PCD in the PNS is dependent on the release of neurotrophic factors and thus follows the concept of the neurotrophic theory.
Programmed cell death in the CNS is not dependent on external growth factors but instead relies on intrinsically derived cues. In the neocortex, a 4:1 ratio of excitatory to inhibitory interneurons is maintained by apoptotic machinery that appears to be independent of the environment.[36] Supporting evidence came from an experiment where interneuron progenitors were either transplanted into the mouse neocortex or cultured in vitro.[37] Transplanted cells died at the age of two weeks, the same age at which endogenous interneurons undergo apoptosis. Regardless of the size of the transplant, the fraction of cells undergoing apoptosis remained constant. Furthermore, disruption of TrkB, a receptor for brain derived neurotrophic factor (Bdnf), did not affect cell death. It has also been shown that in mice null for the proapoptotic factor Bax (Bcl-2-associated X protein) a larger percentage of interneurons survived compared to wild type mice.[37] Together these findings indicate that programmed cell death in the CNS partly exploits Bax-mediated signaling and is independent of BDNF and the environment. Apoptotic mechanisms in the CNS are still not well understood, yet it is thought that apoptosis of interneurons is a self-autonomous process.
Programmed cell death can be reduced or eliminated in the developing nervous system by the targeted deletion of pro-apoptotic genes or by the overexpression of anti-apoptotic genes. The absence or reduction of PCD can cause serious anatomical malformations but can also result in minimal consequences depending on the gene targeted, neuronal population, and stage of development.[25] Excess progenitor cell proliferation that leads to gross brain abnormalities is often lethal, as seen in caspase-3 or caspase-9 knockout mice which develop exencephaly in the forebrain.[38][39] The brainstem, spinal cord, and peripheral ganglia of these mice develop normally, however, suggesting that the involvement of caspases in PCD during development depends on the brain region and cell type.[40] Knockout or inhibition of apoptotic protease activating factor 1 (APAF1), also results in malformations and increased embryonic lethality.[41][42][43] Manipulation of apoptosis regulator proteins Bcl-2 and Bax (overexpression of Bcl-2 or deletion of Bax) produces an increase in the number of neurons in certain regions of the nervous system such as the retina, trigeminal nucleus, cerebellum, and spinal cord.[44][45][46][47][48][49][50] However, PCD of neurons due to Bax deletion or Bcl-2 overexpression does not result in prominent morphological or behavioral abnormalities in mice. For example, mice overexpressing Bcl-2 have generally normal motor skills and vision and only show impairment in complex behaviors such as learning and anxiety.[51][52][53] The normal behavioral phenotypes of these mice suggest that an adaptive mechanism may be involved to compensate for the excess neurons.[25]
Learning about PCD in various species is essential in understanding the evolutionary basis and reason for apoptosis in development of the nervous system. During the development of the invertebrate nervous system, PCD plays different roles in different species.[54] The similarity of the asymmetric cell death mechanism in the nematode and the leech indicates that PCD may have an evolutionary significance in the development of the nervous system.[55] In the nematode, PCD occurs in the first hour of development leading to the elimination of 12% of non-gonadal cells including neuronal lineages.[56] Cell death in arthropods occurs first in the nervous system when ectoderm cells differentiate and one daughter cell becomes a neuroblast and the other undergoes apoptosis.[57] Furthermore, sex targeted cell death leads to different neuronal innervation of specific organs in males and females.[58] In Drosophila, PCD is essential in segmentation and specification during development.
In contrast to invertebrates, the mechanism of programmed cell death is found to be more conserved in vertebrates. Extensive studies performed on various vertebrates show that PCD of neurons and glia occurs in most parts of the nervous system during development. It has been observed before and during synaptogenesis in the central nervous system as well as the peripheral nervous system.[25] However, there are a few differences between vertebrate species. For example, mammals exhibit extensive arborization followed by PCD in the retina while birds do not.[59] Although synaptic refinement in vertebrate systems is largely dependent on PCD, other evolutionary mechanisms also play a role.[25]
Programmed cell death in plants has a number of molecular similarities to animal apoptosis, but it also has differences, the most obvious being the presence of a cell wall and the lack of an immune system that removes the pieces of the dead cell. Instead of an immune response, the dying cell synthesizes substances to break itself down and places them in a vacuole that ruptures as the cell dies.[60]
In "APL regulates vascular tissue identity in Arabidopsis",[61] Martin Bonke and his colleagues had stated that one of the two long-distance transport systems in vascular plants, xylem, consists of several cell-types "the differentiation of which involves deposition of elaborate cell-wall thickenings and programmed cell-death." The authors emphasize that the products of plant PCD play an important structural role.
Basic morphological and biochemical features of PCD have been conserved in both plant and animal kingdoms.[62] Specific types of plant cells carry out unique cell-death programs. These have common features with animal apoptosisfor instance, nuclear DNA degradationbut they also have their own peculiarities, such as nuclear degradation triggered by the collapse of the vacuole in tracheary elements of the xylem.[63]
Janneke Balk and Christopher J. Leaver, of the Department of Plant Sciences, University of Oxford, carried out research on mutations in the mitochondrial genome of sun-flower cells. Results of this research suggest that mitochondria play the same key role in vascular plant PCD as in other eukaryotic cells.[64]
During pollination, plants enforce self-incompatibility (SI) as an important means to prevent self-fertilization. Research on the corn poppy (Papaver rhoeas) has revealed that proteins in the pistil on which the pollen lands, interact with pollen and trigger PCD in incompatible (i.e., self) pollen. The researchers, Steven G. Thomas and Vernonica E. Franklin-Tong, also found that the response involves rapid inhibition of pollen-tube growth, followed by PCD.[65]
The social slime mold Dictyostelium discoideum has the peculiarity of either adopting a predatory amoeba-like behavior in its unicellular form or coalescing into a mobile slug-like form when dispersing the spores that will give birth to the next generation.[66]
The stalk is composed of dead cells that have undergone a type of PCD that shares many features of an autophagic cell-death: massive vacuoles forming inside cells, a degree of chromatin condensation, but no DNA fragmentation.[67] The structural role of the residues left by the dead cells is reminiscent of the products of PCD in plant tissue.
D. discoideum is a slime mold, part of a branch that might have emerged from eukaryotic ancestors about a billion years before the present. It seems that they emerged after the ancestors of green plants and the ancestors of fungi and animals had differentiated. But, in addition to their place in the evolutionary tree, the fact that PCD has been observed in the humble, simple, six-chromosome D. discoideum has additional significance: It permits the study of a developmental PCD path that does not depend on caspases characteristic of apoptosis.[68]
The occurrence of programmed cell death in protists is possible,[69][70] but it remains controversial. Some categorize death in those organisms as unregulated apoptosis-like cell death.[71][72]
Biologists had long suspected that mitochondria originated from bacteria that had been incorporated as endosymbionts ("living together inside") of larger eukaryotic cells. It was Lynn Margulis who from 1967 on championed this theory, which has since become widely accepted.[73] The most convincing evidence for this theory is the fact that mitochondria possess their own DNA and are equipped with genes and replication apparatus.
This evolutionary step would have been risky for the primitive eukaryotic cells, which began to engulf the energy-producing bacteria, as well as a perilous step for the ancestors of mitochondria, which began to invade their proto-eukaryotic hosts. This process is still evident today, between human white blood cells and bacteria. Most of the time, invading bacteria are destroyed by the white blood cells; however, it is not uncommon for the chemical warfare waged by prokaryotes to succeed, with the consequence known as infection by its resulting damage.
One of these rare evolutionary events, about two billion years before the present, made it possible for certain eukaryotes and energy-producing prokaryotes to coexist and mutually benefit from their symbiosis.[74]
Mitochondriate eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide.[75] It is not clear why apoptotic machinery is maintained in the extant unicellular organisms. This process has now been evolved to happen only when programmed.[76] to cells (such as feedback from neighbors, stress or DNA damage), mitochondria release caspase activators that trigger the cell-death-inducing biochemical cascade. As such, the cell suicide mechanism is now crucial to all of our lives.
The BCR-ABL oncogene has been found to be involved in the development of cancer in humans.[77]
c-Myc is involved in the regulation of apoptosis via its role in downregulating the Bcl-2 gene. Its role the disordered growth of tissue.[77]
A molecular characteristic of metastatic cells is their altered expression of several apoptotic genes.[77]
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Programmed cell death - Wikipedia
Hematopoietic Stem Cells: In living organisms, a specialized system that consist of blood and its progenitors are referred to as the hematopoietic system.
In particular, this system is made up of cells with specialized functions such as the red blood cells (for carrying oxygen to tissues), white blood cells (for immune defense against pathogens, and foreign agents), platelets (for blood clotting), macrophages and lymphocytes (also for immune defense).
However, many of the said blood cells are temporary and need to be replaced with new ones continuously. But fret not because a single cell can solve the problem!
Every day, almost billions of new blood cells are synthesized within the body with each coming from a specific progenitor cell called the hematopoietic stem cell.
How to pronounce Hematopoietic Stem Cells?
What is Hematopoiesis?
The formation of all kinds of blood cells including creation, development, and differentiation of blood cells is commonly known as Hematopoiesis or Haemopoiesis.
All types of blood cells are generated from primitive cells (stem cells) that are pluripotent (they have the potential to develop into all types of blood cells).
Also referred to as hemocytoblasts, hematopoietic cells are the stem cells that give rise to blood cells in hematopoiesis.
Where Does Hematopoiesis Occur?
In a healthy adult, hematopoiesis occurs in the bone marrow and lymphatic tissues, where 1000+ new blood cells (all types) are generated from the hematopoietic stem cells to main the steady-state levels.
Where Are Hematopoietic Stem Cells Found?
They can also be found in the umbilical cord and in the blood from the placenta.
Who Discovered Hematopoietic Stem Cells?
It was long believed that the majority of hematopoiesis occurs during ontogeny (origination and development of organism) and that the mammalian hematopoietic system originated from the yolk sac per se.
Functions of Hematopoietic Cells
As alluded to earlier, blood cells and blood cell components are formed in a process called hematopoiesis.
Coming from the Greek words hemato and poiesis which mean blood and to make respectively, hematopoiesis occurs in the bone marrow and is responsible not only for the synthesis but also the multiplication, and differentiation of blood cells.
Shown below is a diagrammatic illustration of the different blood cell types that hematopoietic cells can give rise to:
Clinical uses of Hematopoietic Stem Cells
The mammalian blood system showcases the equilibrium between the functions of hematopoietic stem cells. Intensive studies have already shown the structures and molecules that control these stem cells, but the exact picture of the underlying molecular mechanisms is still unclear.
Above everything else, it is important to note that such issues are not just of academic interest but can also be relevant in devising future novel methods of diagnosing and treating various diseases associated with cells.
Key References
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Hematopoietic Stem Cells | Hematopoiesis | Properties & Functions
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Canadian Blood Services Stem Cells for Life
A litle girl who thought she was winning a long battle against an aggressive form of cancer has died, leaving her family devastated. Libby Jones, 11, had neuroblastoma and it was throughout her body from her jaw to her knees.
She bravely underwent months of surgery, radiotherapy, chemotherapy and even a stem cell transplant that - doctors thought - was working to beat the cancer. The treatment included a seven-hour operation to remove the main tumour from her ribs, CoventryLive reported.
In June this year, the Nuneaton family received the news they had prayed and waited for with medics suggesting she would be clear of cancer by Christmas. But their joy was short lived and turned to devastation when, just weeks later on August 11, Libby became unwell and was taken back into hospital.
READ MORE: Violence flares during India v Pakistan cricket street celebrations in Belgrave, Leicester
Her family received the heartbreaking news that the cancer was back. It had moved to her brain and was even more aggressive than before.
Days later they were told the cancer was incurable and no further treatments were available. Libby returned home on August 18 and passed away on August 24.
A GoFundMe page has been set up to give the former Milby Primary School pupil the 'send off she deserves'. On the page, entitled 'Please help Libby have the send off she deserves', it says: "We desperately want to give Libby the send-off she deserves and Mara, Megan and Logan deserve this.
"If you can find it within your heart to be able to donate even 1 it really would make a difference."
So far, almost 2,500 has been raised in memory of Libby. Arrangements have been made for her funeral and it will take place on Monday, September 5, at 9.30am at the Heart of England Crematorium in Eastboro Way, Nuneaton.
The funeral procession will pass Higham Lane School at around 9.10am and then Milby Primary School at 9.20am. Tributes have been paid to Libby online. One person wrote: "Sad news - heaven has a beautiful angel."
Another wrote: "Such sad news - fly high angel." To donate to the GoFundMe page click here.
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Devastation over death of schoolgirl, 11, who hoped she was beating cancer - Leicestershire Live
City of Hope recently shared significant news at the 24th Annual AIDS Conference about a patient treated in 2019 whose HIV has been in remission. The man had been living with HIV for 31 years before coming to City of Hope with another grave diagnosisacute myeloid leukemia.One of the best hopes for long-term remission of acute myeloid leukemia (AML) is a stem cell transplant, and City of Hope has one of the nations leading transplant programs, having performed more than 17,000 transplants since 1976. In addition, the institution is at the forefront of using transplants to treat older adults with blood cancers, including increasing efficacy and safety in those over 60 and those with comorbidities, like the then 63-year-old City of Hope patient with HIV. The research was presented by Jana K. Dickter, M.D., City of Hope associate clinical professor in the Division of Infectious Diseases.
City of Hope hematologist Ahmed Aribi, M.D., assistant professor in the Division of Leukemia, prepared the patient for an allogeneic blood stem cell transplant with a chemotherapy-based, reduced-intensity regimen developed for treatment of older patients with blood cancers. Reduced-intensity chemotherapy makes the transplant more tolerable for older patients and reduces the potential for transplant-related complications from the procedure.
Aribi and his team worked with City of Hopes Unrelated Donor BMT Program directed by Monzr M. Al Malki, M.D. to find a donor who was a perfect match for the patient and had the rare genetic mutation, homozygous CCR5 Delta 32, which is found in just 1 to 2% of the general population.
People who have this mutation have a resistance to acquiring HIV. CCR5 is a receptor on CD4+ immune cells, and most strains of HIV use that receptor to enter and attack the immune system. But the CCR5 mutation blocks that pathway, which stops HIV from replicating.
After this successful transplant for both AML and HIV, the patient has been in remission for HIV since stopping ART in March 2021. While this outcome has happened in three other patients, the City of Hope patient was both the oldest to undergo a transplant with HIV and leukemia and go into remission for both. He had also lived with HIV the longest 31 years.
The City of Hope patient is another major advancement. It demonstrates that research and clinical care developed and led at City of Hope are changing the meaning of an HIV diagnosis for patients across the United States and the world, said John Zaia, M.D., director of City of Hopes Center for Gene Therapy, Aaron D. Miller and Edith Miller Chair for Gene Therapy and a leader in HIV research. City of Hope remains at the forefront of clinical research that changes peoples lives for the better.
When I was diagnosed with HIV in 1988, like many others, I thought it was a death sentence. I never thought I would live to see the day that I no longer have HIV. City of Hope made that possible, and I am beyond grateful. The City of Hope patient
The story above is one significant example of several important advances being made at City of Hope in the care of people with HIV. When many centers still treated patients with low-intensity, noncurative treatment approaches for HIV-related lymphoma, City of Hope challenged that paradigm by demonstrating that autologous transplantation could be used to cure patients who would otherwise die.
More recently, City of Hope is leveraging its leadership in CAR T cell therapya groundbreaking treatment currently used to rally the bodys natural defenses against cancer and exploring its potential in tandem with another advance, City of Hopes vaccine for cytomegalovirus (CMV).
In a proof-of-concept study, funded by theCalifornia Institute for Regenerative Medicine, lab models demonstrated that the combination therapy could recognize and eliminate HIV without serious toxicity to cells in the virus host. In cultured human cells, the CAR T cells killed cells tagged with the gp120 protein, and kept killing them, without significant signs of risking damage to healthy cells. In a mouse model for HIV/AIDS, high doses of the dual-action CAR T cells followed by the CMV vaccine were successful in controlling HIV, and even nestled into the bone marrow, indicating potential for treatment to keep working over the long term.
In addition to achieving breakthrough outcomes in cancer and HIV, City of Hope has been recognized as the seventh "Best Hospital" for cancer in the nation according to U.S. News & World Report's 2022-23 Best Hospitals: Specialty Ranking. This marks the first time the cancer treatment center has cracked the top 10 of the U.S. News & World Report annual rankings and the 16th consecutive year it has been distinguished as one of the nation's elite cancer hospitals. It was also rated as high performing in four cancer surgery specialties: lung, colon, prostate and ovarian cancers.
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From optimized stem cell transplants to CAR T cell therapy: Advancing options for cancer, HIV and more - City of Hope
Humans fear death so much that some of us would willingly trade our immortal souls if such a thing exists and become vampires for a chance to keep wandering the world a little longer. You can quench your thirst for vampire lore with the upcoming Vampire Academy series (streaming on Peacock Sept. 15), but in the meantime jellyfish might be teaching us how to live forever without needing to drink the blood of unsuspecting mortals.
Weve known for some time that Turritopsis dohrnii, otherwise known as the immortal jellyfish, was out there living its best life over and over again by intermittently switching between its adult and larval stages. When the stresses of being an adult become too much for it to bear, it simply turns back the clock to become a juvenile and starts the whole process over again. While disease or predation can and does end the life of individual jellies, they dont succumb to the same biological ticking clock as the rest of us.
While weve been able to observe this behavior in immortal jellyfish, so far it has been unclear what biological mechanisms contribute to their everlasting life. Now, scientists from the Department of Biochemistry and Molecular Biology at the University of Oviedo have identified the genes responsible, opening the door to future research. Their findings were published in the Proceedings of the National Academy of Sciences.
Zeroing in on what makes the immortal jellyfish special required a comparison of their genome with that of a close relative. Scientists compared their DNA with that of Turritopsis rubra, a jellyfish which is similar to the immortal jelly but, importantly, cannot regenerate. By comparing the genomes, they were able to identify specific sequences which the immortal jelly uses to revert from its adult medusa stage back to its larval stage, a process known as transdifferentiation.
The comparison revealed genes involved in DNA replication and repair, telomere maintenance, stem cell production, communication between cells, and reduction of the oxidative cellular environment, according to a press release from the University of Oviedo. All of those processes are associated with the healthy, or unhealthy, aging of humans.
The findings suggest there isnt one thing which allows immortal jellyfish to avoid the reaper. Instead, aging is akin to a series of locked doors, each of which needs a specific genetic key. Only by having the whole set of keys can you travel backward along the aging corridor. While most animals are strapped to a biological tram which only moves in one direction, their cells becoming what they are destined to be and then remaining that way, immortal jellyfish can coax their cells into becoming whatever they need to be no matter what stage of life they are in.
Researchers were careful to note that there are no immediate applications pertaining to human aging. Dont expect to visit your local department store and find immortal jellyfish face cream or dehydrated polyp powder promising to make you young. However, they did note that a better understanding of how immortal jellyfish control their cellular states could provide an avenue for tackling aging-related diseases.
What we have learned about the immortal jellyfish could lead to extended lifespan and, importantly, higher quality of life in old age, but its unlikely well be able to revert to our prepubescent stages like they do. When you stop to think about it, would you really want to even if you could? Immortality sounds nice, but at what cost?
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Scientists unlock the key to immortality in jellyfish - Syfy
COLUMBUS, Ohio--(BUSINESS WIRE)--Forge Biologics, a gene therapy-focused contract development and manufacturing organization, today announced that Maria Escolar, M.D., Chief Medical Officer, will present preliminary clinical data on the treatment of its first patient in the RESKUE Phase 1/2 clinical trial for FBX-101, the Companys novel gene therapy for the treatment of patients with Krabbe disease. The data will be presented on August 31, 2022, at the annual symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM) in Freiburg, Germany.
RESKUE is the first-in-human clinical trial where subjects are administered FBX-101, an Adeno-Associated Virus (AAV) systemic gene replacement strategy, after full myeloablation and umbilical cord blood transplantation. Clinical data support preclinical observations that this approach may lessen many of the immune challenges previously observed with systemic AAV gene delivery and can create a novel approach for extending the delivery of gene replacement strategies to target metabolic diseases amenable to UCBT. The first patients data from the RESKUE clinical trial demonstrate that intravenous FBX-101 following UCBT has been safe and well tolerated through Day 180. Notably, the data demonstrate an absence of humoral immune response against the vector and significantly increased GALC enzyme activity. Through Day 180, the patient exhibited improved motor activity and normal brain development compared to previously reported transplanted patients with Krabbe disease.
Krabbe disease is a rapidly fatal neurodegenerative disorder. While early transplant can help patients, they inevitably develop motor disease. FBX-101, a systemic AAV therapy administered after hematopoietic stem cell transplantation, was well tolerated in the first patient and the initial clinical data support normal brain development during this period of rapid myelination, and normal gross motor function," stated Dr. Escolar. "The increased GALC levels and ablated immune response achieved in this transplant environment may represent a paradigm shift in the treatment of patients with Krabbe disease and for the field of gene therapy. We are excited by results thus far and we look forward to continuing this trial.
We are thrilled with Forges commitment to get this much-needed therapy into a clinical trial, said Stacy Pike-Langenfeld, Co-Founder and President of KrabbeConnect.
We're deeply grateful for this progress toward better treatments for patients suffering from Krabbe disease thanks to the dedication of the team at Forge, said Anna Grantham, Leukodystrophy Care Network Director of Hunters Hope Foundation.
Dr. Escolars poster, Intravenous FBX-101 (AAVrh10.hGALC) following hematopoietic stem cell transplantation increases GALC activity, improves gross motor function, and maintains brain development in Krabbe patients in the RESKUE Phase 1/2 Clinical Trial, will be available virtually for all symposium attendees and displayed in the main poster hall throughout the course of the conference. The poster walk will take place on Wednesday, August 31, 2022, from 18:45-20:15 CET. For more details on the symposium, please visit: https://www.ssiem.org/
About Krabbe Disease
Krabbe disease is a rare, neurodegenerative disease affecting about 1-2.5 in 100,000 people in the U.S. and is inherited in an autosomal recessive manner. Krabbe disease is caused by loss-of-function mutations in the galactocerebrosidase (GALC) gene, a lysosomal enzyme responsible for the breakdown of certain types of lipids such as psychosine. Without functional GALC, psychosine accumulates to toxic levels in cells. The psychosine toxicity is most severe in the myelin cells surrounding the nerves in the brain and in the peripheral nervous system, eventually leading to the death of these cells and loss of motor function. The disease initially manifests as physical delays in development, muscle weakness and irritability and advances rapidly to difficulty swallowing, breathing and cognitive problems, and vision and hearing loss. Early onset or Infantile Krabbe disease cases usually results in death of patients by the age of two years, while later onset or Late Infantile patients usually die by the age of six. Although bone marrow transplant is the current standard of care for treating the central nervous system in patients with Krabbe disease, patients continue to develop peripheral nervous system disease that eventually results in death. Currently, 10 states in the USA are approved to try and identify babies with Krabbe disease as part of newborn screening programs.
About FBX-101
Forge developed FBX-101 to treat patients with Infantile Krabbe disease. FBX-101 is an adeno-associated viral serotype rh10 (AAVrh10) gene therapy that is typically delivered after a hematopoietic stem cell transplant. FBX-101 delivers a functional copy of the GALC gene to cells in both the central and peripheral nervous system. FBX-101 has been shown to functionally correct the central and peripheral neuropathy and correct the behavioral impairments associated with Krabbe disease, as well as to drastically improve lifespan in animal models of the disease. This approach has the potential to overcome some of the immunological safety challenges observed in traditional AAV gene therapies and extend the duration of gene transfer.
About Forge Biologics
Forge Biologics is a hybrid gene therapy contract manufacturing and clinical-stage therapeutics development company. Forges mission is to enable access to life changing gene therapies and help bring them from idea to reality. Forges 200,000 square foot facility utilizes 20 cGMP suites in Columbus, Ohio, the Hearth, to serve as its headquarters. The Hearth is a custom-designed cGMP facility focused on AAV manufacturing and can host end-to-end manufacturing services to accelerate gene therapy programs from preclinical through clinical and commercial stage manufacturing. By taking a patients-first approach, Forge aims to accelerate the timelines of these transformative medicines for those who need them the most. To learn more, visit http://www.forgebiologics.com.
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Forge Biologics Reports Positive Clinical Data on Brain Development and Motor Function from the RESKUE Novel Phase 1/2 Gene Therapy Trial in Patients...
The acute myeloid leukemia (AML) treatment landscape has a novel class of agents coming down the pipeline. Menin inhibitors that targetNMP1mutations andKMT2A and KMT2Arrearrangements have been showing early promise in terms of efficacy and safety in multiple clinical trials.
Success with menin inhibition was first shown in preclinical models.NMP1andKMT2A/KMT2Aralterations cause the complex and upregulation of transcription factors that are essential for leukemogenesis to activate, and menin inhibitors can block this activation.
We think when those processes are active. Myeloid cells become stuck in a dedifferentiated state, and that promotes leukemia growth. In preclinical studies, use of these menin inhibitors against acute leukemia cells with NMP1 mutations, as well as those characterized byKMT2Arearrangements, leading to apoptosis and cell death via induction of what we thought was similar to a clinical differentiation syndrome, said Eunice S. Wang, MD, in an interview with Targeted Oncology.
Early findings have now been reported from first-in-human studies of menin inhibitors in patients with AML, showing encouraging efficacy and safety. First, in the COMET-001 study (NCT04067336), KO-539 showed early biologic activity in patients with relapsed AML. The agent also demonstrated unique pharmacokinetic characteristics that could lead to clinical benefit. Notably, some patients in the study hadKMT2Armutations.1
In the AUGMENT-101 (NCT04065399) study, SNDX-5613 achieved promising antileukemia activity in patients with heavily-pretreated KMT2A and NMP1-mutated acute leukemia, along with acceptable safety.2
In the interview, Wang, chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center, discussed the growing use of menin inhibitors in AML and clinical trial research further supporting the treatment strategy.
TARGETED ONCOLOGY: Can you talk aboutNPM1mutations, KMT2A/KMT2Ar rearrangements in AML?
Wang: In acute myeloid leukemia, NMP1-mutated disease comprises about one-third of all newly diagnosed cases, particularly in patients under the age of 60. Patients who have rearrangements in the MLL gene, now known as the KMT2Ar gene have a prevalence of about 5% to 10%. Those patients are associated with an intermediate adverse prognosis and have translocation of 2 genes;1 that is located on the 11th chromosome, and 1that's located on a different chromosome. These rearrangements can occur with about 80 different chromosome partners and can occur not only in patients with AML, but in a small percentage of patients that have pediatric acute leukemias as well as acute lymphocytic leukemia.
Before the in-human trials that are happening, what was shown preclinically with the use of menin inhibitors in AML?
Menin inhibitors are targeted agents that block the binding of the protein menin to a complex epigenetic entity, which is based on the MLL or KMT2A gene. The interaction between menin and this KMT2A complex leads to activation of the complex and upregulation of transcription factors that are essential for leukemogenesis. Blocking that activation with a targeted protein inhibitor of menin allows that complex to be inactive, thereby downregulating some of the transcriptional processes that lead to the underlying leukemia.
We think when those processes are active, myeloid cells become stuck in a dedifferentiated state, and that promotes leukemia growth. In preclinical studies, use of these menin inhibitors against acute leukemia cells with NMP1 mutations as well as those characterized by KMT2A rearrangements lead to apoptosis and cell death via induction of what we thought was similar to a clinical differentiation syndrome.
Can you discuss the AUGMENT-101 study?
The AUGMENT study was the first-in-human evaluation of a menin inhibitor in patients with relapsed and refractory acute leukemias characterized by NMP1 mutations and KMT2A gene rearrangements.This study enrolled dozens of patients with very refractory disease that had failed multiple lines of therapy including allogeneic stem cell transplantation.
The menin inhibitor SNDX-5613 was given twice a day at both escalating dose characterizations and then also at fixed doses based on the initial dose-finding cohort results of the AUGMENT-101 study. Findings presented at the American Society of Hematology Annual Meeting 2021 demonstrated in the 50 evaluable patients with an NMP1 mutation or KMT2A rearrangement, an overall response rate of approximately 50%. The complete remission and incomplete account recovery rate was about 24%,and in patients who did achieve a response of which they were 9, the duration of response in those patients lasted over a year.
The major side effects of the AUGMENT-101 study and the dose-limiting toxicity of the drug were found to be QTC prolongation, which occurred in about 10% or 12% of individuals. Few individuals had evidence of serious differentiation syndrome. This first-in-human study of the first-in-class menin inhibitor demonstrated impressive efficacy as monotherapy in the select biological subgroups of patients, particularly in patients who had failed multiple lines of prior therapy.
The COMET-001 study of a novel menin inhibitor is ongoing in relapsed or refractory AML. Can you discuss this study?
The COMET-001 study is a first-in-human study of a different menin inhibitor, KO-539. This agent was initially evaluated in a dose escalation phase and then an expansion phase. The expansion phase has evolved 2 doses of the drug and is evaluating the agent specifically in patients who hadNMP1mutation, as well asKMT2Arearrangements.
To date, the early data on that trial presented in 2020 at the ASH meeting demonstrated tolerability and efficacy in patients both withKMT2Amutation orNMP1rearrangement. There have been incidences of differentiation syndrome which have been observed, and further results of this agent will be updated in the ASH 2022 meeting, for which we're eagerly awaiting the outcomes.
The fact that these 2 menin inhibitors have demonstrated evidence of clinical activity to date has spurred active interest in vetted inhibitors as a class of agents. There currently are at least 3 or 4 other menin inhibitors that have shown promising efficacy in preclinical models, which are now moving forward in the early-phase testing in patients with these 2 biological alterations.
What are some other agents that are coming down the pipeline in AML?
I think that the menin inhibitors as a class have the promise to be the next class of targeted therapies for acute myeloid leukemia. We've seen since 2017, the advent of multiple mutations specific agents for this disease, including FLT3 inhibitors and IDH1/IDH2 inhibitors. We're now moving towards more mutational-directed therapy with agents that are showing efficacy, not only in NMP1- and KMT2A-altered patients, but also potentially in patients that have the dreadedp53mutation.
We're looking forward to having agents that are already established in the field and for novel combinations of targeted therapy with chemotherapy backbones, whether they be intensive, 7 + 3, or non-intensive venetoclax-based/hypomethylating regimens. Looking into the future, we see combined therapy moving into the upfront setting for some of these mutational subsets. We also see the advent of additional targeted therapy moving forward for additional subsets of this disease. More and more, we are moving towards better drugs, better targeting, and improved personalization or individualization of therapy for both the patient as well as the patient's disease.
REFERENCES:
1. Wang ES, Altman JK, Pettit K, et al. Preliminary data on a phase 1/2A first in human study of the menin-KMT2A (MLL) Inhibitor KO-539 in patients with relapsed or refractory acute myeloid leukemia.Blood. 2020;136(suppl 1:7-8. doi:10.1182/blood-2020-134942
2. Stein EM, Aldoos I, DiPersio JF, et al. Safety and efficacy of menin inhibition in patients (pts) with MLL-rearranged and NPM1 mutant acute leukemia: A phase (Ph) 1, first-in-human study of SNDX-5613 (AUGMENT 101).Blood. 2021;138(suppl 1):699. doi:10.1182/blood-2021-146944
News
128 new homes in Ancoats have been approved by Manchesters planning committee in the first of a new council housing development project.
Manchester City Council explains that the green light given to the first phase of the new This City development will include 118 apartments across two buildings, alongside 10 townhouses which will have either three or four bedrooms.
The apartments will be a mix of 27 one-bedroom and 91 two-bedroom homes.
30% of the homes will be made available at the Manchester Living Rent, which is capped at theGovernmentsLocal Housing Allowance rate and is therefore affordable to residents on housing benefit, according to the Council.
This will increase the number of homes available to people on lower incomes in the citycentre, while the remainder will be available at market rent.
The development bringsback into use a Brownfield site bound byRodney Street, Jersey Street,WadefordClose, and Butler Street on the border ofAncoatsand Miles Platting.
As well as the homes sitting in a highlysustainable location close to the citycentre, which give residents the option of walking, cycling, and using public transportto access local servicesand employment, the town houses will also eachincludea parking spacewith electricvehiclecharging points, andprivategardens to the rear.
Therell also be plenty of space for bicycle parking, and the addition of The Mobility Hub a new concept thatthe Council says will centraliseand reduce the need for onsite car parking, as well as limiting traffic in the widerneighbourhood.
Read more: Manchester pledges to build 36,000 homes before 2032 in new housing strategy
32 million will be invested in the widerpublicrealm, and a greening scheme will also see Ancoatsbecome alow-carbon sustainableneighbourhood with a focus on active travel, walking, and cycling routes.
1,500 homes are expected to be deliveredinthis area in the coming years as the final phase of the regeneration ofAncoats, the Council confirms.
Its great tosee the first This City siteoutof theblocks and delivering the homes that we know Manchester people need, said Cllr Bev Craig Leader of Manchester City Council.
Our intention is to scale up development to at least 500 homes per year and at least 20percent of these will be made available at the Manchester Living Rent delivering high quality, affordable housing for families on lower incomes.
This is a really exciting time forAncoatsand the beginning of thecompletionofa regenerationjourneyspanning two decades.
Featured Image Manchester City Council
Preclinical evaluation of FasT CAR-T cellsFasT CAR-T (F-CAR-T) proliferation in vitro
To characterize the in vitro proliferative capacity of F-CAR-T cells, F-CAR-T and C-CAR-T cells were manufactured in parallel (Supplementary Methods, and Fig. S1) using T-cells from 6 B-ALL patients. To investigate the ex vivo proliferation of F-CAR-T, frozen CD19 F-CAR-T and C-CAR-T cells from each patient were thawed and stimulated with irradiated CD19-expressing K562 cells. The number of CD19-targeting CAR-T cells was then determined during the course of cell expansion in vitro. As shown in Fig. 1A, upon CD19 antigen stimulation, F-CAR-T proliferation was much more robust compared to C-CAR-T proliferation. On day 17 post co-culture, F-CAR-T expanded 1205.61226.3 fold (MeanSD), while C-CAR-T expanded only 116.437.2 fold (MeanSD), (p=0.001). To characterize the mechanism underlying the superior proliferative ability of F-CAR-T, we purified CD19+ CAR-T cells from both F-CAR-T and C-CAR-T. The expression of genes involved in cell proliferation, cell cycle, and apoptosis was analyzed using Nanostring (detailed gene sets are in Table S2). Gene expression profiles showed higher F-CAR-T expression scores for genes associated with cell cycle regulation (F-CAR-T vs. C-CAR-T, p<0.01) and lower expression scores for apoptosis-related genes (F-CAR-T vs. C-CAR-T, p<0.05) in F-CAR-T cells (Fig. S2A).
A Ex vivo cell proliferation of F-CAR-T and C-CAR-T derived from B-ALL patients (n=6) (***P=0.001, F-CAR-T vs. C-CAR-T, d17, unpaired student two-tailed t-test). B Tscm, Tcm, and Tem were characterized by surface staining of CD45RO and CD62L and analyzed with flow cytometry (***P<0.001 comparing F-CAR-T and C-CAR-T). C T-cell exhaustion was characterized by PD-1, LAG3, and TIM-3 staining; Statistical analyses of the percentage of PD1+ LAG3+ Tim3+ (***P<0.001, comparing F-CAR-T and C-CAR-T), unpaired student two-tailed t-test). D RTCA assay was used to examine the specific killing of HeLa-CD19 cells. Growth of target HeLa-CD19 or HeLa cells were monitored dynamically. E CD19+ target Nalm6-Luc cells or F Raji-Luc cells were co-cultured with either F-CAR-T or C-CAR-T for 6h. Target cell killing efficacy was calculated by luciferase activity. NS, P>0.05 F-CAR-T vs. C-CAR-T (unpaired student t-test, two-tailed). F-CAR-T FasT CAR-T, C-CAR-T conventional CAR-T, Tcm (CD45RO+CD62L+) T central memory cells, Tem (CD45RO+CD62L) T effector memory cells, Tscm (CD45ROCD62L+) T stem cell memory, PD1 programmed cell death protein 1, TIM-3 T cell immunoglobulin and mucin domain containing-3, LAG3 lymphocyte-activation gene 3, RTCA real-time cell analyzer, E:T effector cells: target cells, NT normal T-cell.
Phenotypes of unstimulated F-CAR-T from three healthy donors were analyzed by flow cytometry. The CD45ROCD62L+ population was 45.7%2.2% which was comparable to the un-transduced T-cells (data not shown). Upon stimulation with CD19+ tumor cells for 9 days, C-CAR-T central memory cells (Tcm, CD45RO+CD62L+ and effector memory cells (Tem, CD45RO+CD62L) were 56.62%11.97% and 40.48%9.70%, respectively, among the C-CAR-T cells (Fig. 1B and Figs. S2B and S2). In contrast, Tcm cells (87.92%4.36%) was predominant in F-CAR-T, with only a small fraction of Tem (7.84%3.79%). In addition, F-CAR-T cells demonstrated more abundant T stem cell memory (Tscm) (3.841.22% vs 2.342.48%, p<0.05) than C-CAR-T cells. We also examined the exhaustion status of the stimulated CAR-T cells. A higher percentage of PD-1+LAG3+Tim3+T-cells were detected in the C-CAR-T (11.19%2.54%) compared to F-CAR-T (3.59%2.51%, p<0.001) (Fig. 1C). Together these data indicated that the F-CAR-T exhibited a younger phenotype and was less exhausted compared to C-CAR-T.
We used a real-time cell analyzer (RTCA) assay to measure the cytotoxicity of F-CAR-T and C-CAR-T against CD19+ cells in vitro. F-CAR-T and C-CAR-T killing of Hela-CD19 target cells were comparable using this assay (Fig. 1D). Similar levels of IFN- and IL-2 production were also observed (Fig. S2D). In a luciferase-based cytotoxicity assay, CD19+ B leukemia cell lines, Raji and Nalm6, were both effectively killed to similar or better levels at different E:T ratios (Fig. 1E, F).
To compare the in vivo cytotoxicity of F-CAR-T and C-CAR-T, severe immunodeficient NOG mice were engrafted with Raji-luciferase cells. One week after the tumor grafts were established, F-CAR-T and C-CAR-T were intravenously injected at various doses. The engrafted tumors progressed aggressively in control groups with either vehicle alone or control T-cells (Fig. 2A). In contrast, F-CAR-T or C-CAR-T treatment greatly suppressed tumor growth in a dose-dependent manner (Fig. 2A). In the high dose group (2106/mice), both F-CAR-T and C-CAR-T eliminated the tumor rapidly. However, in the low dose group (5105/mice), F-CAR-T showed more effective tumor-killing compared to C-CAR-T. On day 20, mice in the low dose F-CAR-T group became tumor-free, while C-CAR-T treated mice exhibited tumor relapse (Fig. 2A). We examined the CAR-T cell expansion in vivo after infusion. As shown in Fig. 2B, both F-CAR-T and C-CAR-T began to expand in the peripheral blood 7 days after infusion. C-CAR-T cell numbers reached their peak on day 14 and receded on day 21. In contrast, the F-CAR-T cell number peaked on day 21 and declined to a baseline level on day 28. F-CAR-T not only persisted longer but also underwent 26 folds greater expansion than C-CAR-T (Fig. 2B).
A Raji-Luc cell engraftment NOG mice were given high dose (2106/mice, n=3) and low dose (5105/mice, n=3) F-CAR-T/C-CAR-T along with control groups. Tumor growth was monitored with IVIS scan once every 3 days; B CAR-T expansion in peripheral blood of mice was analyzed by flow cytometry (n=6). ***P<0.001 for F-CAR-T HD vs. C-CAR-T HD; F-CAR-T LD vs. C-CAR-T LD; F-CAR-T HD vs. F-CAR-T LD; C-CAR-T HD vs. C-CAR-T LD (two-way ANOVA statistical analysis); C Schematic of the Nalm6 (1106) xenograft model, CAR-T (2106) infused 1 day after cyclophosphamide (20mg/kg) treatment. Bone marrow infiltration of F-CAR-T was analyzed 10 days after CAR-T infusion (n=3); D CD45+CD2 F-CAR-T vs. C-CAR-T in peripheral blood of mice were analyzed by flow cytometry; *P<0.05 (unpaired student two-tailed t-test). IVIS in vivo imaging system, PB peripheral blood, i.v. intravenous, HD high dose, LD low dose, Cy cyclophosphamide; *p<0.05; #: number.
We examined the BM infiltration of F-CAR-T cells after infusion into Nalm6-bearing mice (Fig. 2C). A larger population of CAR-T cells was observed 10 days after infusion in BM in F-CAR-T infused group than that in the C-CAR-T group (p<0.05) (Fig. 2D), suggesting F-CAR-T cells possessed a better BM homing capability than C-CAR-T.
The chemokine receptor CXCR4 is known to be critical for BM homing of T-cells [25, 26]. Indeed, a higher percentage of CXCR4+ T cells were detected in F-CAR-T than in the C-CAR-T. Interestingly, this phenotype was more pronounced for CD4+ T cells than CD8+ T cells (Fig. S3A). In a two-chamber system, more F-CAR-T cells could be detected in the lower chamber than their C-CAR-T counterparts (Fig. S3B).
Between Jan. 2019 and Oct. 2019, 25 pediatric and adult patients with CD19+R/R B-ALL were enrolled onto our phase 1 trial, including two patients who had relapsed following a prior allo-HSCT. Patient characteristics are detailed in Table 1. The median age of patients was 20 (range: 344) years old. Twenty patients were >14 years old, and five were 14 years old. The median percentage of pre-treatment BM blasts was 9.05% (range: 0.1982.9%). As our pre-clinical studies demonstrated that F-CAR-T cells had a superior expansion capability as compared to C-CAR-T, we infused a relatively low doses of F-CAR-T cells, ranging from 104105 cells/kg: 3.0104 cells/kg (n=2), 6.5 (5.867.43)104 cells/kg (n=9), 1.01 (1.01.16)105 cells/kg (n=12), 1.52(1.471.56)105 cells/kg (n=2), (Fig. S4). The median time from apheresis to the infusion of CD19+F-CAR-T cells was 14 days (range: 1220). Although the manufacturing time of F-CAR-T was next day, the quality control time and detailed final product releases including sterility testing require a minimum of 710 days to complete. In addition, transportation of cell products requires approximately two days. Of the 25 patients who received CD19 F-CAR-T infusion, 22 (88%) received bridging chemotherapy between apheresis and lymphodepleting chemotherapy to control rapid disease progression (Table S3).
F-CAR-T cells were manufactured successfully for all patients. The mean transduction efficiency of F-CAR-T was 35.4% (range: 13.170.3%) (Fig. S5A). Both CD4+/CAR+ (mean, 49.6%; range: 13.673.2%) and CD8+/CAR+ (mean, 41.5%; range: 20.677.7%) subsets were present in the CD3+CAR+ T cell subsets of all products. The mean proportion of Tscm, Tem, and Tcm cells in the CD3+CAR+ T cell subsets of all products was 23.3% (range: 3.5545.3%), 33.2% (range: 17.267.9%), and 36.1% (range: 20.758.1%), respectively (Fig. S5B). F-CAR-T products exerted significant IFN- release and cytotoxic effects against the CD19+ cell line HELA-CD19 (Fig. S5, C, D).
All 25 infused patients experienced adverse events (AEs) of any grade, with 25 (100%) experiencing grade 3 or higher adverse events. No grade 5 events related to F-CAR-T treatment were observed (Table 2).
CRS occurred in 24 (96%) patients with 18 (72%) grade 12 CRS,6 (24%) of grade 3, and no grade 4 or higher CRS (Fig. S6). In the >14 years old group, 16/20 (80%) patients developed mild CRS, and only 2/20 (10%) developed grade 3 CRS. For 14 years old patients, 2/5 (40%) had mild CRS, yet 3/5 (60%) experienced grade 3 CRS (Table S4). ICANS was observed in 7 (28%) patients, with 2 (8%) grade 3 ICANS occurring in patients >14 years old and 5 (20%) grade 4 ICANS all occurring in patients 14 years old. No grade 5 ICANS was developed (Fig. S7 and Table S4). The most frequent presentation of CRS was fever, particularly a high fever of >39C. The first onset of CRS symptoms occurred between day 3 and 8 post-CAR-T infusion with a median onset at day 4 (range: 110 days). The most common symptoms of ICANS were seizure (5/7) and depressed consciousness (5/7). The median time to ICANS onset from CAR-T cell infusion was 7 days (range: 58), and the median time to resolution was 2 days (Fig. S7). All CRS and ICANS events were managed including early intervention when fever of 39C persisted for 24h. Sixteen (64%) patients received tocilizumab with a median total dose of 160mg (range: 160320mg). Twenty-one (84%) patients received corticosteroids including dexamethasone (median total dose, 43mg; range: 4127mg) and or methylprednisolone (median total dose, 190mg; range: 401070mg). The vast majority of these patients discontinued corticosteroids within 2 weeks. The change in IL-6, IFN-, IL-10, and GM-CSF levels after infusion are selectively shown in Fig. S8. The peak levels of these four cytokines were observed between day 710. Among all 21 cytokines examined, only post-infusion IL-6 levels were associated with moderate to severe CRS and/or ICANS (Figs. S9 and S10).
Superior in vivo proliferation and persistence of F-CAR-T compared to C-CAR-T cells were observed regardless of dose levels. The median peak level was reached on day 10 (range: 714 days) with 1.9105 transgene copies/g of genomic DNA (range: 0.225.2105 transgene copies/g of genomic DNA) by qPCR and 83 F-CAR-T cells per l blood (range: 42102 F-CAR-T cells per l blood) by FCM (Fig. 3A, B). No significant differences were observed among the different dose groups in the mean F-CAR-T copies peak (Fig. 3C). Importantly, there was no significant difference in the mean F-CAR-T copies peak between patients who received corticosteroids compared to those who did not (Fig. 3D).
A F-CAR-T cells in peripheral blood by qPCR. Purple, dose level 1; black, dose level 2; blue, dose level 3; red, dose level 4; B F-CAR-T cells in peripheral blood by flow cytometry. Purple, dose level 1; black, dose level 2; blue, dose level 3; red, dose level 4; C Comparison of the mean peak copy number of F-CAR-T cells in peripheral blood at each dose level. Statistical significance was determined by the MannWhitney test. D Comparison of the mean peak copy number of F-CAR-T cells in peripheral blood with or without steroids. Statistical significance was determined by the MannWhitney test.
Fourteen days after F-CAR-T cell infusion, all patients achieved morphologic CR including 2/25 with CR and 23/25 CR with incomplete hematologic recovery (CRi), which further improved to 11/25 CR and 14/25 CRi 28 days post F-CAR-T (Table 1 and Fig. 4). More importantly, 23/25 (92%) had the minimal residual disease (MRD)-negative remission on day 14 and day 28 after F-CAR-T treatment. Patients achieving remission through CAR-T were given the option to proceed to allo-HSCT. With a median time of 54 days (range: 4581 days) post F-CAR-T infusion, 20 of 23 patients with MRD-negative status decided to pursue consolidative allo-HSCT including one patient who received a 2nd transplant. As of 18 October 2021, with a median follow-up duration of 693 days (range: 84973 days) among the 20 patients who had received allo-HSCT, one patient relapsed on day 172 and died 3 months after relapse, and four patients died from transplant-related mortality (TRM) including infection (n=3) and chronic GVHD (n=1) on day 84, day 215, day 220, and day 312, respectively. The other 15 patients remained in MRD-negative CR with a median remission duration of 734 days (range: 208973) except for one who became MRD-positive on day 294 with CD19+ disease. Among the other three patients (F05, F06, F16), one remained in MRD-negative CR on day 304, one remained in MRD-negative CR until day 303, received allo-HSCT but died from an infection on day 505, and one was lost to follow-up after day 114. Two patients who had MRD-positive CR after infusion withdrew from the study on day 42 and day 44, respectively, to seek other studies.
Clinical outcomes and consolidative allo-HSCT for the 25 patients who were treated with F-CAR-T therapy are shown. On day 28, 23/25 patients achieved MRD-negative CR/CRi. With a median time of 54 days (range: 4581) post F-CAR-T infusion, 20 of 23 patients with MRD-negative status received consolidative allo-HSCT. Among the 20 patients, 1 patient (F23) relapsed on day 172 and died 3 months after relapse. Four patients (F04, F09, F11, F12) died from transplant-related mortality (TRM) including infection (n=3) and chronic GVHD (n=1) on day 84, day 215, day 220, and day 312, respectively. The remaining 15 patients were in MRD-negative CR except for one (F18) who became MRD-positive on day 294. Among the other 3 patients (F05, F06, F16), 1 remained MRD-negative CR on day 304, 1 remained in MRD-negative CR until day 303, received allo-HSCT, and subsequently died from an infection on day 505. One patient was lost to follow-up after day 114. MRD minimal residual disease, CR complete remission, Allo-HSCT allogeneic hematopoietic stem cell transplantation.
F-CAR-T/T ratio in cerebrospinal fluid (CSF) was evaluated by FCM in 13/25 patients with available samples (Table S5). Between days 10 and 32, 9 patients were found to have considerable F-CAR-T penetration in their CSF, ranging from 40.65 to 79.2%, including 4 who developed severe ICANS. Among the other 4 patients, F-CAR-T cell abundance in the CSF ranged from 1.29% to 3.57%, and none experienced severe ICANS. Patients with higher levels of CAR-T in PB on day 10 consistently had higher levels of CAR-T in CSF with the exception of patient F15. Notably, CAR-T cells were still detectable in the CSF on day 101 with a 2.36% CAR-T/T ratio in patient F06, who also had undetectable circulating CAR-T cells at the same time.
In addition, concentrations of seven cytokines (IL-1b, IL-6, IL-10, IFN-, TNF-, MCP-1, and GM-CSF) in CSF samples from the above 10 of 13 patients were measured. Specifically, IL-1b was not detected in any of the 10 patients, and only one patient had detectable GM-CSF. For the other five cytokines, patients with severe ICANS had higher IL-6 levels in contrast to patients without severe ICANS, and the difference between the median level of IL-6 among these two groups of patients was statistically significant (Fig. S11). We did not observe significant differences among the other 4 cytokines between the two groups of patients. No clear relation between the CSF cytokine levels and the F-CAR-T/T % was observed.
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Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study | Blood Cancer Journal...
Could a brain ever exist on its own, divorced from or independent of a body? For a long time, philosophers have pondered such "brain-in-a-vat" scenarios, asking whether isolated brains could maintain consciousness when separated from their bodies and senses.
Typically, a person's experiences are characterized by a web of interactions between the human brain, body and environment.
But recent developments in neuroscience mean this conversation has moved from the realm of hypothetical speculation and science fiction, to isolated examples where consciousness could be sealed off from the rest of the world.
In a 2020 study, detailed in the journal Trends in Neuroscience (opens in new tab), philosopher Tim Bayne, of Monash University in Melbourne, and neuroscientists Anil Seth, of the University of Sussex in England, and Marcello Massimini, of the University of Milan in Italy, describe contexts in which such "islands of awareness" could exist.
Related: What happens in our brains when we 'hear' our own thoughts?
In one possible situation, a brain that has been removed from its host is able to sustain consciousness using the oxygen and nutrients necessary for function delivered via some kind of apparatus. This is called the ex cranio brain.
In a study that sounds like something out of a horror movie (opens in new tab), researchers were able to successfully restore blood flow to brain cells, cellular functions of neurons, and spontaneous synaptic activity in pigs' brains that were removed after death and connected to a system called BrainEx. The system, which is designed to slow the degeneration of brain tissue after death, can be connected to the base of a postmortem brain, delivering warm artificial oxygenated blood.
In people who suffer from severe refractory epilepsy, one treatment called a hemispherotomy (opens in new tab) involves completely disconnecting the damaged half of the brain from the other hemisphere, brainstem and thalamus. In these cases, the damaged half remains inside the skull, and connected to the vascular system. While the disconnected hemisphere continues to receive the nutrients and oxygen needed for function, some have wondered whether this isolated hemisphere supports an adjacent consciousness to the opposing, connected hemisphere.
And scientists have created lab-based mini-brains, 3D structures developed from stem cells that display various features of the developing human brain. Some of these brains-in-a-dish have brainwaves similar to those seen in preterm babies.
But do any of these "brains" actually possess consciousness?
Scientists can't deduce consciousness from behavior in these cases, nor can they ask these brains if they are experiencing consciousness. This conundrum has led neuroscientists to devise a potential "objective" measure of consciousness.
For instance, scientists could use the so-called perturbational complexity index (PCI), which is based on the level of interactions between neurons within these "brains." Using this index, scientists would electrically stimulate a part of the brain and then measure the resulting patterns of neural activity to gauge the complexity of brain-cell interactions. If the resulting measurement of these interactions carries lots of information, then the system can be said to be more conscious.
It's kind of like tossing a rock into a pond and measuring the resulting ripples. If the ripples interact with other objects in the pond, setting off more ripples, then the more conscious the system.
In states where people have not been fully conscious, PCI has been a reliable indicator of their level of consciousness. For instance, being in a coma, or sleeping, would be considered a "lower" level of consciousness or awareness.
"PCI has proven effective in detecting disconnected awareness during dreaming, ketamine anesthesia (opens in new tab), and has also been fruitfully applied to patients who are non-responsive following severe brain injury (opens in new tab)," Bayne told Live Science.
It could be the case that consciousness is tightly coupled to dynamics of the brain that are relatively easy to measure, such as the case with the PCI.
But even if consciousness doesn't turn out to be reducible to any neural signal in the brain, Bayne believes the task of developing an "objective" measure of consciousness is still a valid one.
While these techniques might not be able to definitively answer the question of whether consciousness is present in these contexts, they will provide answers to some fundamental questions, such as whether islands of awareness have the same levels of neural complexity as the brains of conscious subjects. Or do these brains slowly go offline once disconnected from the external world?
Understanding what the contents of consciousness could look like in such cases offers an even trickier problem.
Originally published on Live Science.
Originally posted here:
Can minds persist when they are cut off from the world? - Livescience.com
Black adolescent young adult patients with acute myeloid leukemia appeared to have inferior outcomes compared with White patients.
Adolescent and young adult patients who are Black with acute myeloid leukemia (AML) between 18 and 29 years old reportedly have worse survival than White patients receiving similar therapy, according to a study published in Blood Advances.
A higher rate of early death was observed in Black patients between the ages of 18 to 29 (16%) vs 3% the White population (3%; P = .002). Moreover, Black patients had a lower complete remission (CR) rate at 66% vs 83% (P = .01) in White patients, as well as a lower 5-year overall survival (OS) rate at 22% vs 51% (P <.001), respectively. Disparities were also observed across different cytogenetic subgroups, including worse 5-year OS rates among Black patients with non-core binding factor AML (12% vs 44%; P <.001) and cytogenetically normal AML (13% vs 50%; P = .003) compared with White patients.
Patients who were Black compared with White had a higher rates of early death at 11% vs 2% (P <.001), lower CR rates at 73% vs 82% (P = .06), and shorter 5-year OS rates at 32% vs 46% (P = .002). However, the 5-year disease-free survival (DFS) rate was in 32% in Black patients vs 40% in White patients (P = .25).
Patient characteristics were almost the same in regard to age and sex, while there were no differences in clinical features were apparent at diagnosis. A total of 327 samples were collected from 50 Black patients and 277 White patients. At diagnosis, 40% of White patients were cytogenetically normal vs 19% of Black patients (P <.001), and 22% vs 37% of patients, respectively, had abnormal karyotypes with chromosome rearrangement that were associated with core-binding factor AML (P = .005).
Mutations of t(8;21)(q22;q22)/RUNX1::RUNX1T1 were observed in 22% of patients who were Black vs 10% of those who were White (P = .002), while there were similar rates of inv(16)(p13.1q22)/CBFB::MYH11 or t(16;16)(p13.1;q22)/CBFB::MYH11 mutationsincluding 15% in Black patients vs 12% in White patients (P = .49).
Gene variants including ASXL1 (12% vs 1%; P <.001), KRAS (16% vs 5%; P = .01), ZRSR2 (6% vs 0.4%; P = .01), BCOR (8% vs 2%; P = .05), and CALR (8% vs 2%; P = .05) were more prevalent in Black patients vs White patients. However, more White patients had gene alterations in NPM1 (29% vs 4%; P <.001) and bi-allelic CEBPA (17% vs 3%; P = .02) compared with Black patients.
Overall patients who were Black had higher early death rates in 16% vs 3% (P = .002). The median OS for patients who were Black and between the ages of 18 to 29 years was 1.3 years vs 10.2 years for patients who were White (P <.001). Investigators did not find any significant differences in survival between patients who were Black or White between the ages of 30 to 39.
A total of 15% of patients who were White and 4.5% of those who were Black received allogeneic hematopoietic stem cell transplantation (HSCT) during first CR. Of those who underwent allogeneic HSCT, a longer DFS was observed among White patients vs Black patients and did not undergo the treatment. There were no significant differences in OS between treatment groups (P = .21).
Patients who were Black and had core-binding factor AML had higher rates of early death at 12% vs 3% of patients who were White (P = .06), lower CR rates at 85% vs 95% (P = .06), and shorter 5-year OS rates in 54% vs 70% (P = .05), respectively. No differences in DFS and OS were observed between patient subgroups with non-core binding factor AML with t(8;21) alterations. However, OS but not DFS was shorter for patients who were Black between 18 to 29 years of age with inv(16)/t(16;16) vs 18 to 29 and 30 to 39 year-olds who were White.
Larkin K, Nicolet D, Kelly BJ, et al. High early death rates, treatment resistance, and short survival of Black adolescents and young adults with AML.Blood Adv. Published Online July 5, 2022. doi:10.1182/bloodadvances.2022007544
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Black Adolescent Young Adults With AML Have Worse Outcomes Vs White Population - Cancer Network
Akari Therapeutics Plc
NEW YORK and LONDON, July 07, 2022 (GLOBE NEWSWIRE) -- Akari Therapeutics, Plc (Nasdaq: AKTX), a late-stage biotechnology company focused on developing advanced therapies for autoimmune and inflammatory diseases, today announced that a patient has completed the course of investigational nomacopan treatmentin the open-label, multi-center Phase IIIPart Aclinical trial in pediatric hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA). Nomacopan is a bispecific recombinant inhibitor of complement C5 and leukotriene B4 (LTB4).
Three patients with severe (nephrotic range proteinuria and elevated soluble C5b-9) HSCT-TMA have been enrolled in the clinical trial. One patient completed more than 60 days of nomacopan treatment and subsequently was discharged from the hospital. Another patient died from multi-organ failureunrelated to nomacopan treatment.Dosing has begun in the third patient.
This is promising news for children and families facing hematopoietic stem cell transplant-related TMAs who have unmet needs that are significant and urgent because there are no approved treatment options, said Rachelle Jacques, President and CEO of Akari Therapeutics. Recruitment into a study of treatment for a rare and emergent complication of stem cell transplants in children has inherent challenges, and it is testament to the passion and commitment of everyone involved that this important Phase III clinical trial is progressing on behalf of patients and their families.
Nomacopan was granted Orphan Drug and Fast Track designations by the U.S. Food and Drug Administration (FDA) for pediatric HSCT-TMA. Data from the Phase III Part A study of nomacopan in HSCT-TMA will inform the pivotal Phase III Part B study that will be the basis for potential regulatory submissions in the U.S. and Europe.
The six-year-old patient who was discharged wastreated at a clinical trial site in Manchester, England by investigator Rob Wynn, M.D. Thrombotic microangiopathy following a stem cell transplant procedure is a rare but devastating complication made even more tragic because there are currently no approved treatments, said Professor Rob Wynn, of Royal Manchester Childrens Hospital, part of Manchester University NHS Foundation Trust. As we advance this important clinical trial and offer treatment to children in Manchester where formerly there was none, we are bringing new hope to families who are in desperate need, and to other clinicians who very much want to offer a treatment option.
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Thrombotic microangiopathy following a stem cell transplant procedure is a rare but serious complication of HSCT that appears to involve complement activation, inflammation, tissue hypoxia and blood clots, leading to progressive organ damage and death. The mortality rate in patients who develop severe transplant-related TMAs is 80%.1 Currently, there are no approved treatment options in the U.S. or Europe.
Sites are open and recruiting in the U.S, U.K., and Poland for the Phase III Part A clinical trial of investigational nomacopan in pediatric patients who have undergone allogeneic or autologous HSCT and develop HSCT-TMA within a year of transplant. Patient dosing is underway in the multi-center, open-label study that has a recruitment goal of seven pediatric patients over six months old.
The primary study endpoints are either independence of red blood cell transfusion or urine protein creatinine ratio of 2 mg/mg maintained over 28 days immediately prior to any scheduled clinical visit up to Week 24. According to the study protocol, patients may discontinue therapy sooner than 24 weeks, if one, or both, of the primary endpoint components has been met and the treating clinician determines there is no longer a need for continued treatment with nomacopan. Patients who have achieved the primary endpoint and are no longer receiving nomacopan will have a follow-up clinic visit 30 days after the last dose, at 24 weeks and for long-term follow-up at one and two years.
References
Rosenthal J. Hematopoietic cell transplantation-associated thrombotic microangiopathy: a review of pathophysiology, diagnosis, and treatment.J Blood Med. 2016;7:181-186. Published 2016 Sep 2. doi:10.2147/JBM.S102235
About Akari Therapeutics
Akari Therapeutics, plc (Nasdaq: AKTX) is a biotechnology company focused on developing advanced therapies for autoimmune and inflammatory diseases. Akari's lead asset, investigational nomacopan, is a bispecific recombinant inhibitor of C5 complement activation and leukotriene B4 (LTB4) activity. The Akaripipeline includes two late-stage programs for bullous pemphigoid (BP) and thrombotic microangiopathy (TMA), as well as earlier stage research and development programs in eye and lung diseases with significant unmet need. For more information about Akari, please visit akaritx.com.
Cautionary Note Regarding Forward-Looking Statements
Certain statements in this press release constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward- looking statements reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward- looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a variety of risks and factors that are beyond our control. Such risks and uncertainties for our company include, but are not limited to: needs for additional capital to fund our operations, our ability to continue as a going concern; uncertainties of cash flows and inability to meet working capital needs; an inability or delay in obtaining required regulatory approvals for nomacopan and any other product candidates, which may result in unexpected cost expenditures; our ability to obtain orphan drug designation in additional indications; risks inherent in drug development in general; uncertainties in obtaining successful clinical results for nomacopan and any other product candidates and unexpected costs that may result there; difficulties enrolling patients in our clinical trials; failure to realize any value of nomacopan and any other product candidates developed and being developed in light of inherent risks and difficulties involved in successfully bringing product candidates to market; inability to develop new product candidates and support existing product candidates; the approval by the FDA and EMA and any other similar foreign regulatory authorities of other competing or superior products brought to market; risks resulting from unforeseen side effects; risk that the market for nomacopan may not be as large as expected risks associated with the impact of the COVID-19 pandemic; inability to obtain, maintain and enforce patents and other intellectual property rights or the unexpected costs associated with such enforcement or litigation; inability to obtain and maintain commercial manufacturing arrangements with third- party manufacturers or establish commercial scale manufacturing capabilities; the inability to timely source adequate supply of our active pharmaceutical ingredients from third party manufacturers on whom the company depends; unexpected cost increases and pricing pressures and risks and other risk factors detailed in our public filings with the U.S. Securities and Exchange Commission, including our most recently filed Annual Report on Form 20-F filed with the SEC. Except as otherwise noted, these forward-looking statements speak only as of the date of this press release and we undertake no obligation to update or revise any of these statements to reflect events or circumstances occurring after this press release. We caution investors not to place considerable reliance on the forward-looking statements contained in this press release.
For more information
Investor Contact:Mike MoyerLifeSci Advisors(617) 308-4306mmoyer@lifesciadvisors.com
Media Contact:Eliza SchleifsteinSchleifstein PR (917) 763-8106eliza@schleifsteinpr.com
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Akari Therapeutics Announces First Patient to Complete Course of Treatment in the Phase III Part A Clinical Trial of Investigational Nomacopan in...
The U.S. Supreme Court's June 24 ruling ending federal abortion rights under Roe v. Wade could inspire groups that seek to protect embryos to urge greater restrictions on in vitro fertilization (IVF) and embryonic stem cell research, according to Henry T. (Hank) Greely, director of the Stanford Law School Center for Biomedical Ethics.
Assisted reproductive technologies such as IVF aren't constitutionally protected and neither is preimplantation genetic testing, which screens for certain traits and DNA-caused conditions in embryos that haven't yet been implanted in the uterus, he said in a recent interview prior to the landmark ruling.
The court's ruling doesn't ban these technologies, which assist people seeking to have children, but it is likely to inspire some groups and states to seek to preserve unused embryos or ban embryonic stem cell research, Greely said.
His paper about the potential short- and long-term impacts of the decision is in preprint publication and is expected to be published in the Journal of Law and Biosciences in the coming weeks. In the short term, the technologies that embryo-protection groups might seek to ban or limit might be an alternative for women who can no longer receive an abortion in their home state.
Prenatal testing currently can determine if the fetus has a serious DNA defect that would cause disease or disability; a woman can then decide whether to continue with or terminate the pregnancy. That choice would likely disappear in states that restrict abortions, Greely said.
But a genetic testing technique that is used during in vitro fertilization could be utilized to prevent IVF pregnancies with fetal abnormalities. Preimplantation genetic testing, or PGT, screens out embryos with DNA-causing birth defects before the embryos are transferred to the uterus. The procedure can determine with a high degree of accuracy whether an embryo would develop into a baby who might have one of a large number of conditions. The decision not to transfer an embryo with genes that could cause a disability, condition or trait isn't illegal in the U.S., he said.
In states where abortion is illegal, it's likely there would be an increased interest in using PGT. The embryos are screened while outside the womb and prior to implantation and pregnancy.
"I think some people, some couples will say, well, if we have an embryo for the pregnancy that would have a severe disability as a child, our state wouldn't allow us to abort it. So let's go through preimplantation," he said.
But Greely doesn't think using PGT will skyrocket after the court's abortion decision. The technique requires that prospective parents use IVF, which is unpleasant and risky due to egg harvesting, he said.
IVF is also expensive. Most couples seeking the technique do so due to infertility and the decision isn't made lightly. Anyone with enough money to afford IVF would likely be able to afford to travel to another state for an abortion, he said.
Greely thinks it is unlikely embryo-protection groups would advocate for any kind of legislation that has a negative effect on IVF, however.
"Americans like IVF; almost everybody knows somebody or will know somebody who's either gone through IVF or who's actually the product of IVF. Two percent of the babies born every year in the U.S. with the product of IVF, and particularly the wealthier people are, the more likely they are to have either used IVF or know somebody who uses IVF, and also, the more likely they are to be politically powerful," he said.
There's a certain sort of law Greely thinks might be politically viable: limiting the selection or deselection of an embryo for IVF for a specific reason such as race, gender or disability.
"We've already seen it in abortion state statutes. A lot of abortion laws ban abortion for the purpose of discriminating on race, sex or disability status. And some of them explicitly say Down syndrome status.
"I can imagine the disability community coming together with protection groups to try to pass laws banning using PGT to select against embryos based on race, sex or disability. The important part of that would probably be disability and maybe even with the focus just on Down syndrome, which has a very strong support group and has some political sympathy," he said.
There isn't much political support for eliminating embryos that would have a fatal disease, however, he said.
"There's a more attractive case for protecting embryos that might become people with Down syndrome compared to protecting embryos that might become babies who would die within a year from Tay-Sachs disease," he said.
The court's decision on Roe v. Wade could invigorate efforts to pass new legislation to protect embryos outside the uterus among people who believe embryos are viable far earlier than at the 15 weeks in the Mississippi case that challenged Roe v. Wade. Some groups have claimed that human life starts far earlier and even at fertilization, which would make, in their view, all embryos for IVF "viable" regardless of whether they are implanted in the womb.
In the normal medical standard of care, no more than two embryos should be transferred into a woman's uterus at a time to minimize the chances of multiple pregnancies, Greely noted in his paper.
Most IVF cycles produce more than two eggs. Prospective parents can choose to have the extra embryos frozen for possible later use, donated to other couples, designated for research or destroyed and discarded.
Some legislation advocated by embryo-protection groups could limit or change the practice, he said. With the exception of Louisiana, there are no limitations on destroying embryos that aren't implanted, he said, though some other states have considered the legislation.
"The only limitation that I know of is the Louisiana law where you're not allowed to destroy embryos. So leftover embryos are kept frozen indefinitely in IVF clinics there," he said.
Legislation could lead clinics to build facilities to freeze and store unused embryos in perpetuity, he said, adding that the Louisiana law hasn't caused IVF clinics to close.
Embryo-protection groups might also try to get a law passed that's similar to a 2004 Italian law, which was subsequently limited by a court decision, Greely noted.
"They said you have to transfer for possible implantation every viable embryo you make, which means in Italy they typically only make one or two embryos at a time.
The embryo-protection groups "might try that, but all that would do is make IVF more difficult or expensive, and I don't think there's going to be political support for it. I don't think there'll be enough political support for it for people to adopt it," he said.
Greely noted that there could potentially be a significant change in embryo research as opposed to clinical treatments in an IVF clinic.
"Actually, embryo research in particular has really nothing to do with Roe v. Wade. As a matter of law, Roe v. Wade never protected embryo research, but I think it's connected in terms of the political dynamics after the death of Roe v. Wade," Greely said.
There's a good chance that at some stage, states will pass laws that eliminate human embryo research, in part because it is a huge issue, he said. Embryonic stem cells are taken from embryos created and then not used for pregnancy at IVF clinics.
"Twenty years ago, a number of states banned it; a number of states like California encouraged that research. But research into Type 1 diabetes and other major diseases has been disappointing.
"I think it has been useful, but there have been no miracles from it so far," he said.
The discovery in 2007 of a method to turn regular body cells into cells that can become any cell type in the human body makes the argument for using embryonic stem cells less compelling, he noted in his paper. Called induced pluripotent stem cells or iPSCs, these cells take away some of the urgency about using embryonic stem cells.
But iPSCs aren't exactly like human embryonic stem cells, Greely noted. Researchers would likely argue that human embryos are still required for research on embryonic development that would lead to ways for couples to succeed in having babies.
iPSCs might also play a role in the same types of research, since scientists have been creating "embryo-like things" or "embryo models" that provide more information about human embryonic development, he wrote.
How these laws might affect funding for embryonic research is also unknown.
The federal government has had little appetite for funding embryonic research and has refused to fund research that "destroys, discards, or knowingly subject(s) to risk of injury of death" embryos, Greely noted in his paper.
Yet, the federal government doesn't limit or ban the research itself; its actions have solely been about research it funds. Federal funds can be used for research on cells created from embryos that were destroyed somewhere else, he noted.
At least 11 states, however, have banned (or effectively banned) human embryo research on cells created from destroyed embryos that came from somewhere else, he wrote.
Some states allow such research, including California, Connecticut, Michigan, Montana and New York, Greely noted. California in particular continues to support stem cell research without a ban on the use of embryonic cells. In 2020, the state's voters passed Proposition 14 for $5.5 billion in bonds to advance the research.
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How abortion ruling could affect IVF and embryonic research - The Almanac Online
Viewers of today's This Morning programme have been left 'in tears' after a boy had the chance to meet the donor who saved his life. Jose flew all the way from Brazil to meet 10-year-old Finley Hill who was searching for a life-saving donor to cure a rare immune disease.
Finley and his family appeared on the show to share the news that he has now been cured. A pre-recorded message from Jose was then shown, before Phillip revealed he had been flown from Brazil to meet them in the studio.
And viewers were loving the sweet moment, taking to Twitter to share their reaction. @jmclean514 said: "What a beautiful story in real time. Brought tears to my eyes. This just goes to show that there's kindness in humankind" and @RachelWalker35 said: "I was in tears! Beautiful. Well done."
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@debbuecoates65 also added: "Awww well done this morning you made me cry." and @BushraA89302368 said: "So adorable! What a truly extraordinary story"
Finley Hill first appeared on This Morning in summer 2019 as he searched for a stem cell donor to cure a rare immune disease.
Following his appearance, Finley had a transplant in the November and since then has gone from strength-to-strength with the This Morning team following his journey all the way.
Talking on the programme about Jose saving her son's life, mum Jo said: "Thank you is never going to be enough. How do you thank the person that has saved your world? So thankfully, he's sent messages back and he's the most humble, beautiful man."
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This Morning viewers 'in tears' after boy meets donor who saved his life - Devon Live
News Photo by Julie RiddleDetective Sgt. Steve Davis works at his computer at the Alpena Police Department on Wednesday.
ALPENA Police work hinges on relationships, said Detective Sgt. Steve Davis, retiring on Friday from the Alpena Police Department.
In 14 years of responding to complaints in Alpena and another 11 years as Alpena detective, Davis has met some of the strongest people he knows.
Those resilient people often encountered as they reeled from the devastation of a recent trauma gave him strength to do the job he now leaves after 32 years, Davis said, reflecting on his career in an Alpena Police Department conference room on Wednesday.
Davis stepped into law enforcement in 1990, moving to Montmorency County in 1991.
Six years later, he joined the Alpena Police Department as a road patrol officer, from which he was promoted to road sergeant in 2001.
Since 2011, Davis has served as detective, chasing leads and digging deep into Alpenas most serious crimes.
That transition meant learning to slow down, looking over things not once, not twice, but three times, Davis said.
Unlike road patrol work which often involves hustling from complaint to complaint a detective has to step back and examine the big picture surrounding stabbings, suicides, rapes, assaults, and other major crimes, following leads and studying patterns and interviewing residents.
Last summer, during what Davis called one of the most complex cases of his career, he had to call in the help of the Michigan State Police during a months-long investigation into the disappearance of missing Alpena teenager Brynn Bills.
Police later found Bills body buried in a back yard in Alpena Township. No charges have been filed related to her death.
That investigation, now turned into a death investigation by the State Police, required pursuing numerous angles and talking to hundreds of people, Davis said.
Since his young days as a patrol officer, Davis has noted an alarming loss of communication skills within multiple age groups, a change he chalks up to social medias enabling of faceless retorts and insults without consequences.
When I was a kid, if you wanted to talk to someone, you rode your bike over to their house and talked to them, face to face, he said. As a society, weve lost a lot of that. And thats pretty unfortunate.
Society feels the brunt of that loss when people with differing viewpoints dont know how to listen to one another and resort to violence and then police have to step in, Davis said.
Since his career started, inpatient mental health facilities have closed and budget-strapped mental health agencies have struggled to keep up with a seeming increase in mental health struggles and police not trained as mental health workers have to pick up the pieces, Davis said.
Untreated mental illness paired with the inability to deal with an opposing viewpoint puts everyone in danger when people burst into schools or churches or parades ready to kill, he said.
Like many police officers, Davis mourns a changed public perception of police work that makes hiring officers harder and wears out officers who have to work overtime.
News reports of police doing wrong do not reflect the attitude or actions of most police officers, Davis said.
Then again, he added, neither do depictions of people hating and distrusting police reflect the way Alpena treats its police force.
In a community largely supportive of its public safety workers, he cant walk into a sandwich shop without someone offering to buy him lunch.
As a young officer, he sometimes took a cynical view of the community. Age and time have made him less judgemental and more ready to see positives, even while embroiled in the citys worst crimes.
Theres a lot of good people out there, he said. Weve just got to remember that.
Several years ago, Davis donated stem cells to save a woman from another country, someone whose name he will never know.
Asked if he was willing to undergo the procedure to help the woman, Davis assented readily.
Thats kinda why I got into law enforcement, he said.
His wife is making him celebrate his retirement with a party, Davis said, waving off a suggestion that a police retirement deserves special recognition.
We all put our part into this community, he said. Im just one little piece.
Julie Riddle can be reached at 989-358-5693 or jriddle@thealpenanews.com. Follow her on Twitter @jriddleX.
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Alpena detective: 'Good people out there' | News, Sports, Jobs - Alpena News
A five-year-old boy has raised over 500 for charity after losing his best friend.
Rowan Lyons took part in five 2k junior park runs to honour the youngster who lost her battle with brain cancer this year. Rowan's best friend, Sophie Welburn, was diagnosed with a rare and aggressive brain tumour in July, last year, when she was just four-years-old, Chronicle Live reports.
She was given nine months to live after her diagnoses and lost her battle with the disease in March. The pair met in September at Abbey Infant School, on Cleveland Terrace in Darlington, where they became best friends.
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After Sophie's death, young Rowan decided to complete park runs to honour each year of the youngsters short life. The schoolboy has raised 502 for brain tumour research.
Rowan said: "I felt really sad when Sophie died, and I miss my best friend. I wanted to do something good, and I like running. I felt very tired afterwards."
Despite Sophies illness, she continued to go to school until March, this year. Sophie's condition quickly deteriorated and on March 18 she died peacefully at home with her loving family by her side.
Rowans mum, Marianne Lyons, said: "My husband, Rob, and I are really proud of him. We still talk about Sophie, and the fundraising has helped Rowan to understand what has happened."
Sophie was diagnosed with a brain tumour known as a diffuse intrinsic pontine glioma (DIPG). It forms in glial cells in a part of the brain stem called the pons.
The pons controls the nerves and muscles that help us perform basic but vital functions such as walking, talking, breathing and swallowing. A DIPG takes over this area of the brain and gradually stops these functions working.
Sophies Mum, Louise Wray, said: "Rowan didnt know Sophie was poorly and he embraced her like any other child. Although Sophie only attended a few mornings each week when she was well enough to, Rowan would wait for her by the door of the classroom.
"They were so close, she even made him a Valentines card." Sophies dad, Chris Welburn, added: "Sophie and Rowan were such good friends, and I think what hes done is so lovely.
"He is a little superstar. I think Sophie would be so proud of Rowan, and she would be cheering him on."
According to Brain Tumour Research, brain tumours kill more children and adults under the age of 40 than any other cancer. Yet historically, just 1% of the national spend on cancer research has been allocated to the disease.
Brain Tumour Research funds sustainable research at dedicated centres in the UK. It also campaigns for the Government and the larger cancer charities to invest more research into brain tumours in order to speed up new treatments for patients and find a cure.
Matthew Price, community development manager at Brain Tumour Research, said: "We also think Rowan is a superstar, and were really grateful to him as its only with the support of people like him that were able to progress our research into brain tumours and improve the outcome for patients like Sophie who are forced to fight this awful disease.
"Unlike many other cancers, brain tumours are indiscriminate. They can affect anyone at any time. Too little is known about the causes and that is why increased investment in research is vital."
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'I miss my best friend': Five-year-old runs 10k to honour girl who died from rare brain tumour - Teesside Live