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Atopy: Weighing Risk With the Possibility of Cure Using Hematopoietic Cell Transplantation – Hematology Advisor

By daniellenierenberg

Contraryto previous research, some patients with atopy who undergo allogeneichematopoietic cell transplantation (AHCT) may be cured even if the donor isatopic, according to research published in Bone Marrow Transplantation.

Investigatorsaimed to determine whether atopic disease could be cured or transferred fromdonor to recipient, as there is evidence, though unconfirmed, that AHCT caneither transfer atopy from donor to recipient when the donor has the conditionand the recipient does not (D+R-), or cure atopy in a recipient with thecondition when the donor does not have it (D-R+).

Of the 54 participants including in the study, the median age at transplant was 46 years (range, 4-64 years), one-third of patients had acute myeloid leukemia, and 50% had a human leukocyte antigenmatched sibling. The median donor age at transplant was 34 years (range, 7-60 years).

Amongall AHCT procedures included in this study, 18 (33%) had an atopic donor andrecipient (D+R+), 13 (24%) had a nonatopic donor and recipient (D-R-), 11(20.4%) had an atopic donor and nonatopic recipient, and 12 (22.2%) had anonatopic donor and an atopic recipient.

At afollow-up of at least 2-years post-HCT, 7 of 12 (58%) D-R+ patients becamenonatopic, while only 1 of 11 (9%) D+R- patients became atopic. While 11 of 13(85%) D-R- patients remained nonatopic, 11 of 18 (61%) D+R+ patients became nonatopic,as well.

Inconclusion, cure of atopy with HCT occurs in about half patients, albeitprobably not due to the replacement of atopic with nonatopic immune system butpossibly due to an immune reset analogous to that observed in some autoimmunedisease patients after autologous HCT, the authors concluded. They added thatprospective trials are needed to confirm these findings.

Reference

Whiteside S, Chin A, Tripathi G, et al. Curtability and transferability of atopy with allogeneic hematopoietic cell transplantation [published online March 30, 2020]. Bone Marrow Transplant. doi: 10.1038/s41409-020-0876-7

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Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance – Science Advances

By daniellenierenberg

Abstract

Dyskeratosis congenita is a cancer-prone inherited bone marrow failure syndrome caused by telomere dysfunction. A mouse model recently suggested that p53 regulates telomere metabolism, but the clinical relevance of this finding remained uncertain. Here, a germline missense mutation of MDM4, a negative regulator of p53, was found in a family with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. Using a mouse model, we show that this mutation (p.T454M) leads to increased p53 activity, decreased telomere length, and bone marrow failure. Variations in p53 activity markedly altered the phenotype of Mdm4 mutant mice, suggesting an explanation for the variable expressivity of disease symptoms in the family. Our data indicate that a germline activation of the p53 pathway may cause telomere dysfunction and point to polymorphisms affecting this pathway as potential genetic modifiers of telomere biology and bone marrow function.

TP53 is the gene most frequently mutated in human tumors (1), and germ lineinactivating p53 mutations cause the Li-Fraumeni syndrome of cancer predisposition (2). In addition, accelerated tumorigenesis has been associated with polymorphisms increasing the expression of MDM2 or MDM4, the essential p53 inhibitors (3, 4). Alterations of the p53/MDM2/MDM4 regulatory node are, thus, mainly known to promote cancer. Unexpectedly, however, we recently found that mice expressing p5331, a hyperactive mutant p53 lacking its C terminus, recapitulated the complete phenotype of patients with dyskeratosis congenita (DC) (5).

DC is a telomere biology disorder characterized by the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia; patients are also at very high risk of bone marrow failure, pulmonary fibrosis, and cancer, especially head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukemia (AML) (6). Patients with DC are known to exhibit disease diversity in terms of age of onset, symptoms, and severity due to the mode of inheritance and causative gene (7, 8). DC is caused by germline mutations in genes encoding key components of telomere biology: the telomerase holoenzyme (DKC1, TERC, TERT, NOP10, and NHP2), the shelterin telomere protection complex (ACD, TINF2, and POT1), telomere capping proteins (CTC1 and STN1), and other proteins interacting with these cellular processes (RTEL1, NAF1, WRAP53, and PARN) (6). Twenty to 30% of affected individuals remain unexplained at the molecular level.

Our finding that p5331/31 mice were remarkable models of DC was initially unexpected for two reasons. First, an increased p53 activity was not expected to cause telomere dysfunction, given the well-accepted notion that p53 acts as the guardian of the genome. However, p53 is now known to down-regulate the expression of many genes involved in genome maintenance (5, 9, 10), and this might actually contribute to its toolkit to prevent tumor formation (11). Second, telomere biology diseases are usually difficult to model in mice because of differences in telomere length and telomerase expression between mice and humans. Mice that lack telomerase exhibited short telomeres only after three or four generations (G3/G4) of intracrosses (12, 13). However, mice with a telomerase haploinsufficiency and a deficient shelterin complex exhibited telomere dysfunction and DC features in a single generation (G1) (14). Because DC features were observed in G1 p5331/31 mice, we supposed that p53 might exert pleiotropic effects on telomere maintenance. Consistent with this, we found that murine p53 down-regulates several genes implicated in telomere biology (5, 9). Because some of these genes were also down-regulated by p53 in human cells (5, 9), our data suggested that an activating p53 mutation might cause features of DC in humans. However, this conclusion remained speculative in the absence of any clinical evidence.

Here, we report the identification of a germline missense mutation in MDM4, encoding an essential and specific negative regulator of p53, in a family presenting some DC-like phenotypic traits. We used a mouse model to demonstrate that this mutation leads to p53 activation, short telomeres, and bone marrow failure. Together, our results provide compelling evidence that a germline mutation affecting a specific p53 regulator may cause DC-like features in both humans and mice.

Family NCI-226 first enrolled in the National Cancer Institute (NCI) inherited bone marrow failure syndrome (IBMFS) cohort in 2008 (Fig. 1A and table S1). At the time, the proband (226-1) was 17 years of age and had a history of neutropenia, bone marrow hypocellularity, vague gastrointestinal symptoms, and chronic pain. His mother (226-4) also had intermittent neutropenia and a hypocellular bone marrow. Notably, his maternal aunt (226-7) had a history of melanoma and died at age 52 because of AML. The maternal aunts daughter (probands cousin, 226-8) had HNSCC at age 27 years, intermittent neutropenia, and bone marrow hypocellularity, while her son (probands cousin, 226-9) was diagnosed with metastatic HNSCC at 42 years of age. The probands father (226-3) was healthy with the exception of hemochromatosis. An IBMFS was suspected on the basis of the family history of cancer and neutropenia. Chromosome breakage for Fanconi anemia was normal, while lymphocyte telomeres were between the 1st and 10th percentiles in the proband and maternal cousin (226-8) (Fig. 1, B and C). The proband was tested for mutations in known DC-causing genes, and a TERT variant (p.W203S) was identified. Unexpectedly, however, the variant was found to be inherited from his father. TERT p.W203S is not present in gnomAD, but it is predicted to be tolerated by MetaSVM (15).

(A) Pedigree of family NCI-226. Arrow indicates proband. Cancer histories include oral squamous cell carcinoma for 226-8 at age 27 years and for 226-9 at age 42 years, and melanoma at 51 years and AML at 52 years for 226-7 (see table S1 for further details). 226-5 had lung cancer at age 69 years. 226-6 had non-Hodgkin lymphoma at age 91 years. In addition, four siblings of 226-6 had cancer: one with breast, two with lung, and one with ovary or uterus (not specified). Sequencing of 226-5, 226-6, 226-7, and 226-9 was not possible because of lack of available DNA. (B and C) Lymphocyte telomere lengths (TL) of study participants. Total lymphocyte telomere lengths are shown and were measured by flow cytometry with in situ hybridization. (B) Graphical depiction of telomere length in relation to age. Four individuals had telomeres measured twice. Legend is in (C). Percentiles (%ile) are based on 400 healthy individuals (50). (C) Age at measurement(s) and telomere length in kilobases. (D) Sequence of the MDM4 RING domain (residues 436 to 490) with secondary structure residues indicated (black boxes). The P-loop motif is highlighted in gray, and the mutated residue in red. (E) The mutant RING domain retains ATP-binding capacity. Wild-type (WT) and mutant (TM) glutathione S-transferase (GST)RING proteins, or GST alone, were incubated with 10 nM ATP and 5 Ci ATP-32P for 10 min at room temperature, filtered through nitrocellulose, and counted by liquid scintillation CPM, counts per minute. Results from two independent experiments. (F) The mutant MDM4 RING domain has an altered capacity to dimerize with the MDM2 RING. Two-hybrid assays were carried out as described (47). -LW, minus leucine and tryptophan; -LWHA, minus leucine, tryptophan, histidine and adenine; OD, optical density. Growth on the -LWHA medium indicates protein interaction, readily observed between MDM2 (M2-BD) and WT MDM4 (M4-AD WT) but faintly visible between MDM2 and MDM4T454M (M4-AD TM). (G) Impact of the mutation in transfected human cells. U2OS cells were transfected with an empty vector (EV) or an expression plasmid encoding a Myc-tagged MDM4 (WT or T454M) protein and then treated or not with cycloheximide (CHX) to inhibit protein synthesis, and protein extracts were immunoblotted with antibodies against Myc, p21, or actin. Bands were normalized to actin, and a value of 1 was assigned to cells transfected with the WT MDM4 expression plasmid (for Myc) or with the empty vector (for p21).

Since the TERT variant did not track with disease inheritance, whole-exome sequencing (WES) was performed to search for a causal gene. The whole-exome data were filtered by maternal autosomal inheritance and revealed three genes with heterozygous missense mutations potentially deleterious according to bioinformatics predictions: MDM4, KRT76, and REM1 (table S2). Given the limited knowledge of the function of KRT76 and REM1, and our prior knowledge of a DC-like phenotype in p5331/31 mice, we chose to focus on the mutation affecting MDM4 because it encodes a major negative regulator of p53. Although the T454M mutation does not affect the p53 interaction domain of MDM4, it might affect p53 regulation because it affects the MDM4 RING domain: Residue 454 is both part of a P-loop motif thought to confer adenosine triphosphate (ATP)binding capacity (16) and part of a strand important for MDM2-MDM4 heterodimerization (Fig. 1D) (17). The mutant RING domain had fully retained its capacity to bind ATP specifically (Fig. 1E and fig. S1A) but exhibited an altered capacity to interact with the MDM2 RING domain in a yeast two-hybrid assay (Fig. 1F). We next used transfection experiments to evaluate the consequences of this mutation on the full-length protein in human cells. We transfected U2OS cellsknown to have a functional but attenuated p53 pathway due to MDM2 overexpression (18)with either an empty vector or an expression plasmid encoding a Myc-tagged MDM4WT or MDM4T454M protein. Compared with cells transfected with the empty vector, cells transfected with a MDM4WT or a MDM4T454M expression plasmid exhibited decreased p21 levels, indicating MDM4-mediated p53 inhibition in both cases (Fig. 1G). However, the decrease in p21 levels was less pronounced in cells expressing MDM4T454M than in cells expressing MDM4WT (Fig. 1G) despite similar transfection efficiencies (fig. S1B). The lower expression levels of the MDM4T454M protein likely contributed to its decreased capacity to inhibit p53 (Fig. 1G). In this experimental setting, the treatment with cycloheximide did not reveal any significant difference in stability between the mutant and wild-type (WT) MDM4 proteins (Fig. 1G and quantification in fig. S1C), raising the possibility that the observed lower MDM4T454M protein levels might result from differences in mRNA translation efficiency. Together, these preliminary results argued for an impact of the mutation on MDM4 function, leading to p53 activation.

The MDM4 RING domain is remarkably conserved throughout evolution, e.g., with 91% identity between the RING domains of human MDM4 and mouse Mdm4 (19). Thus, we decided to create a mouse model to precisely evaluate the physiological impact of the human mutation. We used homologous recombination in embryonic stem (ES) cells to target the p.T454M mutation at the Mdm4 locus (Fig. 2A). Targeted recombinants were identified by long-range polymerase chain reaction (PCR) (Fig. 2B), confirmed by DNA sequencing (Fig. 2C), and the structure of the recombinant allele was further analyzed by Southern blots with probes located 5 and 3 of the targeted mutation (Fig. 2D). Recombinant ES clones were then microinjected into blastocysts to generate chimeric mice, and chimeras were mated with PGK-Cre mice to excise the Neo gene. PCR was used to verify transmission through the germ line of the Mdm4T454M (noted below Mdm4TM) mutation and to genotype the mouse colony and mouse embryonic fibroblasts (MEFs) (Fig. 2E). We first isolated RNAs from Mdm4TM/TM MEFs and sequenced the entire Mdm4 coding sequence: The Mdm4TM sequence was identical to the WT Mdm4 sequence except for the introduced missense mutation (not shown). Furthermore, like its human counterpart, the Mdm4 gene encodes two major transcripts: Mdm4-FL, encoding the full-length oncoprotein that inhibits p53, and Mdm4-S, encoding a shorter, extremely unstable protein (20, 21). We observed, in unstressed cells as well as in cells treated with Nutlin [a molecule that activates p53 by preventing Mdm2-p53 interactions (22) without altering Mdm4-p53 interactions (23, 24)], that the Mdm4TM mutation affected neither Mdm4-FL nor Mdm4-S mRNA levels (Fig. 2F). In Western blots, however, Mdm4-FL was the only detectable isoform, and it was expressed at lower levels in the mutant MEFs (Fig. 2G).

(A) Targeting strategy. Homologous recombination in ES cells was used to target the T454M mutation at the Mdm4 locus. For the Mdm4 WT allele, exons 9 to 11 are shown [black boxes, coding sequences; white box, 3 untranslated region (3UTR)] and Bam HI (BH) restriction sites. Above, the targeting construct contains the following: (i) a 2.9-kb-long 5 homology region encompassing exon 10, intron 10, and exon 11 sequences upstream the mutation; (ii) the mutation (asterisk) within exon 11; (iii) a 2.6-kb-long fragment encompassing the 3 end of the gene and sequences immediately downstream; (iv) a neomycin selection gene (Neo) flanked by loxP sequences (gray arrowheads) and an additional BH site; (v) a 2.1-kb-long 3 homology region containing sequences downstream Mdm4; and (vi) the Diphtheria toxin a gene (DTA) for targeting enrichment. (B to D) screening of G418-resistant ES clones as described in (A), with asterisks (*) indicating positive recombinants: (B) PCR with primers a and b; (C) sequencing after PCR with primers c and d: the sequence for codons 452 to 456 demonstrates heterozygosity at codon 454; (D) Southern blot of Bam HIdigested DNA with the 5 (left) or 3 (right) probe. (E) Examples of fibroblast genotyping by PCR with primers e and f. (F) The Mdm4T454M mutation does not alter Mdm4 mRNA levels. Mdm4-FL (left) and Mdm4-S (right) mRNAs were extracted from WT and Mdm4TM/TM MEFs before or after treatment for 24 hours with 10 M Nutlin, quantified using real-time PCR, and normalized to control mRNAs, and then the value in Nutlin-treated WT MEFs was assigned a value of 1. Results from five independent experiments and >4 MEFs per genotype. ns, not significant in a Students t test. (G) Decreased Mdm4 protein levels in Mdm4TM/TM MEFs. Protein extracts, prepared from MEFs treated as in (F), were immunoblotted with antibodies against Mdm4 or actin. Bands were normalized to actin, and then the values in Nutlin-treated WT cells were assigned a value of 1. p53P/P Mdm4E6/E6 MEFs do not express a full-length Mdm4 protein (20): They were loaded to unambiguously identify the Mdm4(-FL) band in the other lanes.

Mdm4TM/TM MEFs contained higher mRNA levels for the p53 targets p21(Cdkn1a) and Mdm2, indicating increased p53 activity (Fig. 3A). Consistent with this, Mdm4TM/TM MEFs exhibited increased p21 and Mdm2 protein levels (Fig. 3B and fig. S2). Moreover, Mdm4TM/TM MEFs prematurely ceased to proliferate when submitted to a 3T3 protocol (Fig. 3C), which also suggests an increased p53 activity. The mean telomere length was decreased by 11% in Mdm4TM/TM MEFs, and a subset of very short telomeres was observed in these cells, hence demonstrating a direct link between the Mdm4TM mutation, p53 activation, and altered telomere biology (Fig. 3D). In p5331/31 MEFs, subtle but significant decreases in expression were previously observed for several genes involved in telomere biology, and in particular, small variations in Rtel1 gene expression were found to have marked effects on the survival of p5331/31 mice (5, 9). Similarly, Mdm4TM/TM MEFs exhibited subtle but significant decreases in expression for Rtel1 and several other genes contributing to telomere biology (Fig. 3E). We previously showed that p53 activation correlates with an increased binding of the E2F4 repressor at the Rtel1 promoter (9). Hence, the decreased Rtel1 mRNA levels in Mdm4TM/TM MEFs most likely resulted from increased p53 signaling. Consistent with this, a further increase in p53 activity, induced by Nutlin, led to further decreases in Rtel1 mRNA and protein levels, in both WT and Mdm4TM/TM cells (fig. S3A). Recently, in apparent contradiction with our finding that p53 activation can cause telomere shortening (5), p53 was proposed to prevent telomere DNA degradation by inducing subtelomeric transcripts, including telomere repeat-containing RNA (TERRA) (25, 26), which suggested a complex, possibly context-dependent impact of p53 on telomeres (27). This led us to compare TERRA transcripts in WT and Mdm4TM/TM cells. Consistent with an earlier report (26), p53 activation led to increased TERRA at the mouse Xq subtelomeric region in WT cells (fig. S3B). However, Mdm4TM/TM cells failed to induce TERRA in response to stress (fig. S3B). Together, our data suggest that the telomere shortening observed in Mdm4TM/TM cells results from a p53-dependent decrease in expression of several telomere-related genes and, notably, Rtel1, a gene mutated in several families with DC (6). In addition, although evidence that altered TERRA levels can cause DC is currently lacking, we cannot exclude that an altered regulation of TERRA expression might contribute to telomere defects in Mdm4TM/TM cells.

(A) Quantification of p21 and Mdm2 mRNAs extracted from WT, Mdm4+/TM, and Mdm4TM/TM MEFs, treated or not for 24 hours with 10 M Nutlin. mRNA levels were quantified using real-time PCR and normalized to control mRNAs, and then the value in Nutlin-treated WT MEFs was assigned a value of 1. Results from 10 independent experiments. (B) Protein extracts, prepared from p53/, WT, and Mdm4TM/TM MEFs treated as in (A), were immunoblotted with antibodies against Mdm2, Mdm4, p53, p21, or actin. Bands were normalized to actin, and then the values in Nutlin-treated WT MEFs were assigned a value of 1. (C) Proliferation of MEFs in a 3T3 protocol. Each point is the average value of three independent MEFs. (D) Decreased telomere length in Mdm4TM/TM MEFs, as measured by quantitative FISH with a telomeric probe. Results from two MEFs per genotype, and 68 to 75 metaphases per MEF [means + 95% confidence interval (CI) are shown in yellow]. a.u., arbitrary units. (E) Telomere-related genes down-regulated in Mdm4TM/TM MEFs. mRNAs were extracted from unstressed WT and Mdm4TM//TM MEFs, quantified using real-time PCR, and normalized to control mRNAs, and the value in WT MEFs was assigned a value of 1. Results from >3 independent experiments and two MEFs per genotype. In relevant panels: P = 0.08, *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by Students t (A, C at passage 7, and E) or Mann-Whitney (D) statistical tests.

Mdm4TM/TM mice were born in Mendelian proportions from Mdm4+/TM intercrosses (Fig. 4A) but were smaller than their littermates and died within 0 to 30 min after birth, with signs of severe respiratory distress (Fig. 4, B and C). Consistent with this, Mdm4TM/TM pups at postnatal day 0 (P0) appeared hypoxic (Fig. 4C), and their lungs were very small and dysfunctional (Fig. 4D). Thus, Mdm4TM/TM pups most likely died from neonatal respiratory failure. Tissues from Mdm4TM/TM pups exhibited increased p21 mRNA levels, suggesting an increase in p53 activity in these animals (fig. S4). We next used flowFISH (fluorescence in situ hybridization) with a telomere-specific probe to evaluate the impact of the mutation on telomere length in vivo. Lung cells from Mdm4TM/TM pups (and control G3 Terc/ mice) exhibited a 25% decrease in mean telomere length compared with cells from WT or Mdm4+/TM littermates, indicating altered telomere biology in G1 homozygous mutants (Fig. 4E). Notably, p53 loss or haploinsufficiency rescued the perinatal lethality of Mdm4TM/TM pups, illustrating that the premature death of Mdm4TM/TM mice likely resulted from increased p53 activity (Fig. 4F). However, p53/ and Mdm4TM/TM p53/ mice exhibited similar survival curves, with a fraction of the mice (respectively 4 of 12 and 1 of 6) succumbing to thymic lymphoma in less than 180 days. In contrast, after 180 days, all the p53+/ mice remained alive, whereas most Mdm4TM/TM p53+/ mice had died. Mdm4TM/TM p53+/ mice were smaller than their littermates (Fig. 4G) and exhibited hyperpigmentation of the footpads (Fig. 4H), and 120-day-old Mdm4TM/TM p53+/ mice exhibited abnormal hemograms (Fig. 4I). Furthermore, the Mdm4TM/TM p53+/ mice that died 60 to 160 days after birth exhibited bone marrow hypocellularity (Fig. 4J), indicating bone marrow failure as the likely cause for their premature death.

(A) Mendelian distribution of the offspring from 8 Mdm4+/TM intercrosses. (B) Mdm4TM/TM mice die at birth. Cohort sizes are in parentheses. (C) Mdm4TM/TM neonates are smaller than their littermates and appear hypoxic. (D) Lungs from Mdm4TM/TM P0 pups are hypoplastic and sink in phosphate-buffered saline owing to a lack of air inflation. (E) Flow-FISH analysis of P0 lung cells with a telomere-specific peptide nucleic acid (PNA) probe. Top: Representative results from a WT, a Mdm4+/TM, a Mdm4TM/TM, and a G3 Terc/ mouse are shown. Right: Green fluorescence (fluo.) with black histograms for cells without the probe (measuring cellular autofluorescence) and green histograms for cells with the probe. The shift in fluorescence intensity is smaller in Mdm4TM/TM and Terc/ cells (c or d < a or b), indicating reduced telomere length. Left: Propidium iodide (PI) fluorescence histograms are superposed for cells with or without the probe. Below: Statistical analysis of green fluorescence shifts (see Materials and Methods). Means + 95% CI are shown; data are from two to three mice and >3800 cells per genotype. (F) Impact of decreased p53 activity on Mdm4TM/TM animals. Cohort sizes are in parentheses. (G) Examples of littermates with indicated genotypes. (H) Hind legs of mice with indicated genotypes. (I) Mdm4TM/TM p53+/ mice exhibit abnormal hemograms. Counts for white blood cells (WBC), red blood cells (RBC), and platelets (PLT) for age-matched (120 days old) animals are shown. (J) Hematoxylin and eosin staining of sternum sections from WT and Mdm4TM/TM p53+/ mice. In relevant panels: ns, not significant; *P < 0.05, ***P < 0.001, and ****P < 0.0001 by Mantel-Cox (B and F), Students t (C, D, G, and I), or Mann-Whitney (E) statistical tests. Photo credits: E.T. and R.D., Institut Curie (C, G, and H); R.D., Institut Curie (D).

Although Mdm4TM/TM MEFs and mice were useful to demonstrate that the Mdm4T454M mutation leads to p53 activation and short telomeres, a detailed analysis of Mdm4+/TM mice appeared more relevant to model the NCI-226 family, in which all affected relatives were heterozygous carriers of the MDM4T454M mutation. Unlike Mdm4TM/TM mice, most Mdm4+/TM animals remained alive 6 months after birth and had no apparent phenotype, similarly to WT mice (Fig. 5A). This was consistent with our analyses in fibroblasts because Mdm4+/TM MEFs behaved like WT cells in a 3T3 proliferation assay (Fig. 3C). However, p53 target genes appeared to be transactivated slightly more efficiently in Mdm4+/TM than in WT cells (Fig. 3A), and 30% of Mdm4+/TM mice exhibited a slight hyperpigmentation of the footpads, suggesting a subtle increase in p53 activity (Fig. 5B). We reasoned that a further, subtle increase in p53 activity might affect the survival of Mdm4+/TM mice. We tested this hypothesis by mating Mdm4+/TM animals with p53+/31 mice. p53+/31 mice were previously found to exhibit a slight increase in p53 activity and to remain alive for over a year (5). Notably, unlike Mdm4+/TM or p53+/31 heterozygous mice, Mdm4+/TM p53+/31 compound heterozygotes died in less than 3 months (Fig. 5A) and exhibited many features associated with strong p53 activation. Mdm4+/TM p53+/31 mice exhibited intense skin hyperpigmentation (Fig. 5C), were much smaller than their littermates (Fig. 5D), and exhibited heart hypertrophy (Fig. 5E) and thymic hypoplasia (Fig. 5F) and the males had testicular hypoplasia (Fig. 5G). Bone marrow failure was the likely cause for the premature death of Mdm4+/TM p53+/31 mice, as indicated by abnormal hemograms of 18-day-old (P18) compound heterozygotes (Fig. 5H) and bone marrow hypocellularity in the sternum sections of moribund Mdm4+/TM p53+/31 animals (Fig. 5I). We next used flow-FISH to analyze telomere length in the bone marrow cells of P18 WT, Mdm4+/TM, p53+/31, and Mdm4+/TM p53+/31 mice. We found no significant difference between telomere lengths in cells from five WT and three Mdm4+/TM mice with normal skin pigmentation, whereas cells from two Mdm4+/TM mice with increased skin pigmentation (or from p53+/31 mice) exhibited marginal (5 to 7%) decreases in mean telomere length. Notably, in G1 Mdm4+/TM p53+/31 cells, the average telomere length was decreased by 34% (Fig. 5J). Together, these results demonstrate that Mdm4+/TM mice are hypersensitive to subtle increases in p53 activity. Consistent with this, Mdm4+/TM p53+/31 MEFs also exhibited increased p53 signaling and accelerated proliferation arrest in a 3T3 protocol (fig. S5). In sum, the comparison between Mdm4TM/TM and Mdm4TM/TM p53+/ mice, or between Mdm4+/TM and Mdm4+/TM p53+/31 animals, indicated that subtle variations in p53 signaling had marked effects on the phenotypic consequences of the Mdm4T454M mutation (table S3).

(A) Impact of increased p53 activity on Mdm4+/TM animals. Cohort sizes are in parentheses. (B) Footpads from Mdm4+/TM mice appear normal (top) or exhibit a subtle increase in pigmentation (bottom). (C) Mdm4+/TM p53+/31 mice exhibit strong skin hyperpigmentation. (D) Mdm4+/TM p53+/31 mice are smaller than age-matched WT mice. (E to G) Mdm4+/TM p53+/31 mice exhibit heart hypertrophy (E) as well as thymic (F) and testicular (G) hypoplasia. (H) Mdm4+/TM p53+/31 mice exhibit abnormal hemograms. Counts for white blood cells, red blood cells, and platelets for five age-matched (P18) animals per genotype are shown. (I) Hematoxylin and eosin staining of sternum sections from mice of the indicated genotypes. (J) Flow-FISH analysis of P18 bone marrow cells with a telomere-specific PNA probe. Top: Representative results for a WT, a Mdm4+/TM with normal skin pigmentation (nsp), a Mdm4+/TM with increased footpad skin pigmentation (isp), a p53+/31, and a Mdm4+/TM p53+/31 mouse are shown; black histograms, cells without the probe; green histograms, cells with the probe. The smallest shift in fluorescence intensity (e) was observed with Mdm4+/TM p53+/31 cells. Bottom: Statistical analysis of green fluorescence shifts. Means + 95% CI are shown; data are from >1500 cells per genotype. In relevant panels: ns, not significant; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by Mantel-Cox (A), Students t (D and E to H), or Mann-Whitney (J) statistical tests. Photo credits: R.D. and P.L., Institut Curie (B); E.T. and R.D., Institut Curie (C and D).

The carriers of the MDM4T454M mutation exhibited considerable heterogeneity in their phenotypes (Fig. 1 and table S1). The data from our mouse model suggested that variations in p53 activity might account for the variable expressivity and penetrance of clinical features among the NCI-226 MDM4+/T454M relatives. Hence, we analyzed nine known common polymorphisms reported to affect p53 activity and tumorigenesis (four at the TP53 locus, two at the MDM2 locus, and three at the MDM4 locus) (3,4,2832). Among the four MDM4+/T454M relatives, the proband (NCI-226-1) is more difficult to interpret because the potential contribution of the TERT p.W203S variant to his phenotype cannot be ruled out (even though it appears unlikely according to in silico predictions). The MDM4 allele encoding the mutant protein (p.T454M) appears associated with the C allele of single-nucleotide polymorphism (SNP) rs4245739, the G allele of SNP rs11801299, and the G allele of SNP rs1380576 (Fig. 6A). These three MDM4 variant alleles are associated with increased p53 activity (4,32) and might, thus, synergize with the MDM4T454M mutation in this family.

(A) Genotyping of polymorphisms that may affect the p53 pathway. The SNPs rs1800371 and rs1042522 modify the p53 protein sequence (28,29), whereas rs17878362 and rs17880560 are singlets (A1) or doublets (A2) of G-rich sequences in noncoding regions of TP53 that affect p53 expression (30). SNPs rs117039649 and rs2279744, in the MDM2 promoter, affect MDM2 mRNA levels (3,31). Three SNPs are at the MDM4 locus: rs4245739 in the 3UTR region affects MDM4 protein levels (4), whereas rs11801299 and rs1380576 were associated with an increased risk of developing retinoblastoma (32), a cancer type with frequent MDM4 alterations (51). Polymorphisms that differ among family members are in bold, with the allele (or haplotype) associated with increased p53 activity in green (because it may synergize with the effects of the MDM4T454M mutation). Alleles (or haplotypes) for which there is evidence of decreased p53 activity, or for which the effect is uncertain, are highlighted in red or blue, respectively. Please note that the clinical effects of the TP53 rs1042522 SNP have recently been contested (33), so that all alleles for this SNP were labeled in blue. MAF, minor allele frequency reported for all gnomAD populations combined. https://gnomad.broadinstitute.org (52). (B) Comparative analysis of primary fibroblasts from family members 226-4 and 226-8. p21 and RTEL1 mRNAs, extracted from cells from relatives NCI 226-4 and NCI 226-8 or two unrelated patients with DC carrying a TINF2 or a TERT mutation, were quantified using real-time PCR, normalized to control mRNAs, and then expressed relative to the mean values in TINF2 and TERT mutant cells. ns, not significant, **P < 0.01 and ***P < 0.001 in a Students t test.

The probands affected cousin (226-8) exhibited a very early onset of disease, with lymphocyte telomere length within or below the first percentile of age-matched control participants and tongue squamous cell carcinoma at age 27 (Fig. 1 and table S1). The WT MDM4 allele of 226-8 carried the rs4245739 C, the rs11801299 G, and the rs1380576 G variants associated with increased p53 activity. This suggests a potential disease-modifying effect of these MDM4 SNPs. In contrast, the probands mother (226-4) was much less severely affected, with telomere length between the 10th and 50th percentiles (Fig. 1). Although we cannot rule out that disease anticipation might contribute to her milder phenotype, note that her WT MDM4 allele carried variants that might correlate with decreased p53 activity and could antagonize the MDM4T454M mutation (rs4245739 A, rs11801299 A, and rs1380576 C; Fig. 6A). Family members 226-4 and 226-8 shared the same genotypes for all the other tested variants, except for TP53 rs1042522, a SNP first reported to affect apoptotic or cell cycle arrest responses (28), but with a clinical effect that now appears controversial (33). The probands sister (226-2), with a B cell deficiency and telomere lengths around the 10th percentile, also appeared less affected than 226-8. All the tested variants at the MDM2 and MDM4 loci were identical between 226-2 and 226-8. However, unlike 226-8, 226-2 exhibited a TP53 allele with an A1A1 haplotype for variants rs17878362 and rs17880560 that might decrease p53 activity (30) and antagonize the effects of the MDM4T454M mutation (Fig. 6A).

We had primary fibroblasts available for two of these family members, 226-4 and 226-8, allowing us to directly assess the functional effect of the MDM4T454M variant in these cells. These fibroblasts were grown in parallel with primary fibroblasts from patients with DC carrying either a TINF2K280E mutation or a TERTP704S mutation, and mRNA levels for p21 and RTEL1 were quantified. In agreement with the notion that a MDM4T454M heterozygous mutation activates p53 signaling in NCI-226 family members, fibroblasts from both 226-4 and 226-8 exhibited increased p21 mRNA levels compared with TINF2 or TERT mutant cells (Fig. 6B). However, cells from 226-4 only exhibited a 2-fold increase in p21 levels, whereas a 12-fold increase was observed for cells from 226-8, consistent with the notion that SNPs affecting the p53 pathway might counteract (for 226-4) or strengthen (for 226-8) the effect of the MDM4T454M mutation. Furthermore, we previously showed that RTEL1 mRNA levels are down-regulated upon p53 activation in human cells (5). RTEL1 mRNA levels appeared normal in cells from 226-4 but were markedly decreased in cells from 226-8, raising the possibility that a threshold in p53 activation might be required to affect RTEL1 expression (Fig. 6B).

Although MDM4 is primarily known for its clinical relevance in cancer biology, our study shows that a germline missense MDM4 mutation may cause features suggestive of DC. In humans, the MDM4 (p.T454M) mutation was identified in this family with neutropenia, bone marrow hypocellularity, early-onset tongue SCC, AML, and telomeres between the 1st and 10th percentiles in the younger generation. In mice, the same Mdm4 mutation notably correlated with increased p53 activity, short telomeres, and bone marrow failure. In both human transfected cells and MEFs, the mutant protein was expressed at lower levels than its WT counterpart, likely contributing to increased p53 activity. Together, these results demonstrate the importance of the MDM4/p53 regulatory axis on telomere biology and DC-like features in both species. Notably, p5331/31 mice were previously found to phenocopy DC (5), but whether this finding was relevant to human disease had remained controversial. When a mutation in PARN was found to cause DC (34), it first appeared consistent with the p5331 mouse model because PARN, the polyadenylate-specific ribonuclease, had been proposed to regulate p53 mRNA stability (35). However, whether PARN regulates the stability of mRNAs is now contested (36). Rather, PARN would regulate the levels of over 200 microRNAs, of which only a few might repress p53 mRNA translation (37). Furthermore, PARN regulates TERC, the telomerase RNA component (38), and TERC overexpression increased telomere length in PARN-deficient cells (39). Thus, whether a germline mutation that specifically activates p53 can cause DC-like features remained to be demonstrated in humans, and our report provides compelling evidence for this, because unlike PARN, MDM4 is a very specific regulator of p53.

A germline antiterminating MDM2 mutation was recently identified in a patient with a Werner-like syndrome of premature aging. Although multiple mechanisms might contribute to the clinical features in that report, a premature cellular senescence resulting from p53 hyperactivation was proposed to play a major role in his segmental progeroid phenotype (40). In that regard, our finding that increased p53 activity correlates with short telomeres appears relevant because telomere attrition is a primary hallmark of aging, well known to trigger cellular senescence (41). Furthermore, germline TP53 frameshift mutations were recently reported in two patients diagnosed with pure red blood cell aplasia and hypogammaglobulinemia, resembling but not entirely consistent with Diamond Blackfan anemia (DBA) (42). In addition to the pure red cell aplasia diagnostic of DBA, those patients were found to exhibit relatively short telomeres (although not as short as telomeres from patients with DC), which may also seem consistent with our results. Our finding of an MDM4 missense mutation in a DC-like family, together with recent reports linking an antiterminating MDM2 mutation to a Werner-like phenotype and TP53 frameshift mutations to DBA-like features, indicates that the clinical impact of germline mutations affecting the p53/MDM2/MDM4 regulatory network is just emerging. An inherited hyperactivation of the p53 pathwayvia a germline TP53, MDM2, or MDM4 mutationmay thus cause either DBA, Werner-like, or DC-like features, but additional work will be required to determine whether mutations in any of these three genes can cause any of these three syndromes. Likewise, several mouse models have implicated p53 deregulation in features of other developmental syndromes including the CHARGE, Treacher-Collins, Waardenburg, or DiGeorge syndrome (43), and it will be important to know whether germline mutations in TP53, MDM2, or MDM4 may cause these additional syndromes in humans.

Heterozygous Mdm4+/TM mice appeared normal but were hypersensitive to variations in p53 activity, and, perhaps most notably, Mdm4+/TM p53+/31 compound heterozygous mice rapidly died from bone marrow failure. Thus, the p5331 mutation acted as a strong genetic modifier of the Mdm4TM mutation. It is tempting to speculate that similarly, among the NCI-226 family members heterozygous for the MDM4T454M allele, differences in the severity of phenotypic traits (e.g., lymphocyte telomere length and bone marrow cellularity) may result, in part, from modifiers affecting the p53 pathway and synergize or antagonize with the effects of the MDM4T454M mutation. To search for potentially relevant modifiers, we looked at nine polymorphisms at the TP53, MDM2, and MDM4 loci that were previously reported to affect p53 activity. Notably, we found that the family member most severely affected (226-8, the probands cousin) carried a TP53 haplotype, as well as SNPs on the WT MDM4 allele, that might synergize with the effects of the MDM4T454M mutation. Conversely, a TP53 haplotype for the probands sister (226-2), or SNPs at the WT MDM4 locus for the probands mother (226-4), might antagonize the impact of MDM4T454M allele. Consistent with this, primary fibroblasts from 226-4 and 226-8 exhibited increased p53 activity, but p53 activation was much stronger in cells from 226-8. Our data, thus, appear consistent with the existence of genetic modifiers at the TP53 and MDM4 loci that may affect DC-like phenotypic traits among family members carrying the MDM4 (p.T454M) mutation. However, this remains speculative given the small number of individuals that could be analyzed. Furthermore, nonexonic variants affecting other genes might also contribute to DC-like traits (44). Last, the TP53 and MDM4 polymorphisms considered here were previously evaluated for their potential impact on tumorigenic processes, rather than DC-like traits such as telomere length or bone marrow hypocellularity. Our data suggest that polymorphisms at the TP53 and MDM4 (and possibly MDM2) loci should be evaluated for their potential impact on bone marrow function and telomere biology.

The individuals in this study are participants in an Institutional Review Boardapproved longitudinal cohort study at the NCI entitled Etiologic Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes (www.marrowfailure.cancer.gov, ClinicalTrials.gov NCT00027274) (7). Patients and their family members enrolled in 2008 and completed detailed family history and medical history questionnaires. Detailed medical record review and thorough clinical evaluations of the proband, his sister, parents, and maternal cousin were conducted at the National Institutes of Health (NIH) Clinical Center. Telomere length was measured by flow cytometry with in situ hybridization (flow-FISH) (45) in leukocytes of all patients and family members reported. DNA was extracted from whole blood using standard methods. DNA was not available from 226-7 or 226-9 (Fig. 1). Given the time frame of participant enrollment, Sanger sequencing of DKC1, TINF2, TERT, TERC, and WRAP53 was performed first, followed by exome sequencing.

WES of blood-derived DNA for family NCI-226 was performed at the NCIs Cancer Genomics Research Laboratory as previously described (46). Exome enrichment was performed with NimbleGens SeqCap EZ Human Exome Library v3.0 + UTR (Roche NimbleGen Inc., Madison, WI, USA), targeting 96 Mb of exonic sequence and the flanking untranslated regions (UTRs) on an Illumina HiSeq. Annotation of each exome variant locus was performed using a custom software pipeline. WES variants of interest were identified if they met the following criteria: heterozygous in the proband, his mother, and maternal cousin; nonsynonymous; had a minor allele frequency <0.1% in the Exome Aggregation Consortium databases; and occurred <5 times in our in house database of 4091 individuals. Variants of interest were validated to rule out false-positive findings using an Ion 316 chip on the Ion PGM Sequencer (Life Technologies, Carlsbad, CA, USA).

Primers flanking the MDM4 RING domain were used to amplify RING sequences, and PCR products were cloned (or cloned and mutagenized) in the pGST-parallel2 plasmid. Glutathione S-transferase (GST) fusion proteins were expressed in BL21 (DE3) cells. After induction for 16 hours at 20C with 0.2 mM IPTG (isopropyl--d-thiogalactopyranoside), soluble proteins were extracted by sonication in lysis buffer [50 mM tris (pH 7.0), 300 mM LiSO4, 1 mM dithiothreitol (DTT), 0.5 mM phenylmethylsulfonyl fluoride (PMSF), 0.2% NP-40, complete Protease inhibitors (Roche) 1]. The soluble protein fraction was incubated with Glutathione Sepharose beads (Pharmacia) at 4C for 2 hours, and the bound proteins were washed with 50 mM tris (pH 7.0), 300 mM LiSO4, and 1 mM DTT and then eluted with an elution buffer [50 mM tris-HCl (pH 7.5), 300 mM NaCl, 1 mM DTT, and 15 mM glutathione]. WT and mutant GST-RING proteins (0, 1, 2, 4, or 8 g) or GST alone (0 or 8 g) was incubated with 10 nM ATP and 5 Ci ATP-32P for 10 min at room temperature, filtered through nitrocellulose, and counted by liquid scintillation. Alternatively, 7 g of either WT or mutant GST-RING proteins was incubated with 5 Ci ATP-32P for 10 min at room temperature and increasing amounts (0, 0.02, 2, 20, and 200 M) of ATP or guanosine triphosphate (GTP), filtered through nitrocellulose, and counted by liquid scintillation.

The yeast two-hybrid assays were performed as described (47). Briefly, MDM4 and MDM2 RING open reading frames were cloned in plasmids derived from the two-hybrid vectors pGADT7 (Gal4-activating domain) and pGBKT7 (Gal4-binding domain) creating N-terminal fusions and transformed in yeast haploid strains Y187 and AH109 (Clontech). Interactions were scored, after mating and diploid selection on dropout medium without leucine and tryptophan, as growth on dropout medium without leucine, tryptophan, histidine, and adenine.

U2OS cells (106) were transfected by using Lipofectamine 2000 (Invitrogen) with pCDNA3.1 (6 g), or 5 106 cells were transfected with 30 g of pCDNA3.1-MycTag-MDM4WT or pCDNA3.1-MycTag-MDM4TM. Twenty-four hours after transfection, cells were treated with cycloheximide (50 g/ml; Sigma-Aldrich, C4859), then scratched in phosphate-buffered saline (PBS) after 2, 4, or 8 hours, pelleted, and snap frozen in liquid nitrogen before protein or RNA extraction with standard protocols.

The targeting vector was generated by recombineering from the RP23-365M5 BAC (bacterial artificial chromosome) clone (CHORI BACPAC Resources) containing mouse Mdm4 and downstream sequences of C57Bl6/J origin. A loxP-flanked neomycin cassette (Neo) and a diphtheria toxin gene (DTA) were inserted downstream of the Mdm4 gene, respectively, for positive and negative selections, and a single-nucleotide mutation encoding the missense mutation T454M (TM) was targeted in the exon 11 of Mdm4. The targeting construct was fully sequenced before use.

CK-35 ES cells were electroporated with the targeting construct linearized with Not I. Recombinant clones were identified by long-range PCR, confirmed by Southern blot, PCR, and DNA sequencing (primer sequences in table S4). Two independent recombinant clones were injected into blastocysts to generate chimeras, and germline transmission was verified by genotyping their offspring. Reverse transcription PCR (RT-PCR) of RNAs from Mdm4TM/TM MEFs showed that the mutant complementary DNA (cDNA) differed from an Mdm4 WT sequence only by the engineered missense mutation. The genotyping of p53+/, p53+/31, and G3 Terc/ mice was performed as previously described (5, 12). All experiments were performed according to Institutional Animal Care and Use Committee regulations.

MEFs isolated from 13.5-day embryos were cultured in a 5% CO2 and 3% O2 incubator, in Dulbeccos modified Eagles medium GlutaMAX (Gibco), with 15% fetal bovine serum (Biowest), 100 M 2-mercaptoethanol (Millipore), 0.01 mM Non-Essential Amino Acids, and penicillin/streptavidin (Gibco) for five or fewer passages, except for 3T3 experiments, performed in a 5% CO2 incubator for seven passages. Cells were treated for 24 hours with 10 M Nutlin 3a (Sigma-Aldrich) (22) or 15 M cisplatin (Sigma-Aldrich). Primary human fibroblasts at low passage (p.2 for TINF2K280E, p.3 for NCI-226-4 and NCI-226-8, and p.4 for TERTP704S) were thawed and cultured in fibroblast basal medium (Lonza) with 20% fetal calf serum, l-glutamin, 10 mM Hepes, penicillin/streptavidin, and gentamicin before quantitative PCR (qPCR) analysis.

Total RNA, extracted using NucleoSpin RNA II (Macherey-Nagel), was reverse transcribed using SuperScript IV (Invitrogen), with, for TERRA quantification, a (CCCTAA)4 oligo as described (48). Real-time qPCRs were performed with primer sequences as described (5, 9, 48) on a QuantStudio using Power SYBR Green (Applied Biosystems).

Protein detection by immunoblotting was performed using antibodies against Mdm2 (4B2), Mdm4 (M0445; Sigma-Aldrich), p53 (AF1355, R&D Systems), actin (A2066; Sigma-Aldrich), p21 (F5; Santa Cruz Biotechnology), Myc-Tag (SAB2702192; Sigma-Aldrich), and Rtel1 (from J.-A.L.-V.). Chemiluminescence revelation was achieved with SuperSignal West Dura (Perbio). Bands of interest were quantified by using ImageJ and normalized with actin.

Cells were treated with colcemide (0.5 g/ml) for 1.5 hours, submitted to hypotonic shock, fixed in an (3:1) ethanol/acetic acid solution, and dropped onto glass slides. Quantitative FISH was then carried out as described (5) with a TelC-Cy3 peptide nucleic acid (PNA) probe (Panagene). Images were acquired using a Zeiss Axioplan 2, and telomeric signals were quantified with iVision (Chromaphor).

Flow-FISH with mouse cells was performed as described (45). For each animal, either the lungs were collected or the bone marrow from two tibias and two femurs was collected and red blood cells were lysed; then, 2 106 cells were fixed in 500 l of PNA hybridization buffer [70% deionized formamide, 20 mM tris (pH 7.4), and 0.1% Blocking reagent; Roche] and stored at 20C. Either nothing (control) or 5 l of probe stock solution was added to cells [probe stock solution: 10 M TelC-FAM PNA probe (Panagene), 70% formamide, and 20 mM tris (pH 7.4)], and samples were denatured for 10 min at 80C before hybridization for 2 hours at room temperature. After three washes, cells were resuspended in PBS 1, 0.1% bovine serum albumin, ribonuclease A (1000 U/ml), and propidium iodide (12.5 g/ml) and analyzed with an LSR II fluorescence-activated cell sorter. WT and G3 Terc/ mice were included in all flow-FISH experiments, respectively, as controls of normal and short telomeres. For fluorescence shift analyses, the green histograms (corresponding to cells with the telomeric probe) were sliced into 18 windows of equal width and numbered 0 to 17 according to their distance from the median value in cells without the probe, and the number of cells in each window was quantified with ImageJ. The data from two to five mice per genotype were typically used to calculate mean telomere lengths, expressed relative to the mean in WT cells.

Organs were fixed in formol 4% for 24 hours and then ethanol 70% and embedded in paraffin wax. Serial sections were stained with hematoxylin and eosin using standard procedures (49). For hemograms, 100 l of blood from each animal was recovered retro-orbitally in a 10-l citrate-concentrated solution (S5770; Sigma-Aldrich) and analyzed using an MS9 machine (Melet Schloesing Laboratoires).

DNA extracted from Epstein-Barr virustransformed lymphocytes of NCI-226 family members was amplified with primers flanking nucleotide polymorphisms of interest (primer sequences in table S5), and then PCR products were analyzed by Sanger DNA sequencing.

Analyses with Students t, Mann-Whitney, or Mantel-Cox statistical tests were performed by using GraphPad Prism, and values of P < 0.05 were considered significant.

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Acknowledgments: We are grateful to the family for valuable contributions to this study. We thank I. Grandjean, C. Caspersen, A. Fosse, and M. Garcia from the Animal Facility, C. Alberti and C. Roulle from the Transgenesis Platform, M. Richardson and A. Nicolas from the Pathology Service, and Z. Maciorowski from the Cell-Sorting Facility of the Institut Curie. We thank A. Chor for help with qPCRs, A. Pyanitskaya, C. Adam, V. Borde, M. Schertzer, and M. Perderiset for plasmids and technical advices, and A. Fajac for comments on the manuscript. F.T. would like to acknowledge the talent, kindness, and loyal support of I. Simeonova and S.J., two exceptional PhD students whose pioneering work led to this study. Funding: The Genetics of Tumor Suppression laboratory received funding from the Ligue Nationale contre le Cancer (Labellisation 2014-2018 and Comit Ile-de-France), the Fondation ARC and the Gefluc. PhD students were supported by fellowships from the Ministre de lEnseignement Suprieur et de la Recherche (to S.J., E.T., and R.D.), the Ligue Nationale contre le Cancer (to S.J.), and the Fondation pour la Recherche Mdicale (to E.T.). The work of S.A.S., N.G., and B.P.A. was supported by the intramural research program of the Division of Cancer Epidemiology and Genetics, NCI, and the NIH Clinical Center. Author contributions: V.L. created the Mdm4T454M mouse model, genotyped mouse cohorts, and performed transfections, yeast two-hybrid assays, protein purifications, and molecular cloning. E.T., R.D., and V.L. managed mouse colonies. E.T., R.D., and P.L. performed mouse anatomopathology. I.D., E.T., R.D., F.T., and J.-A.L.-V. determined mouse telomere lengths. V.L. and S.J. genotyped human polymorphisms and analyzed human fibroblasts. E.T. and R.D. genotyped MEFs and performed 3T3 assays. V.L., R.D., and E.T. performed Western blots. E.T., R.D., V.L., S.J., and P.L. performed qPCRs. B.B. and V.L. performed ATP-binding assays. B.P.A. supervised the NCI IBMFS study. N.G. and S.A.S. evaluated study participants. S.A.S. analyzed the exome sequencing data. F.T. and S.A.S. supervised the project and wrote the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. The human samples can be provided by S.A.S. pending scientific review and a completed material transfer agreement. Requests for human cells should be submitted to S.A.S.

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Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance - Science Advances

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Stem Cells Market Expected to Boost the Global Industry Growth in the Near Future – Germany English News

By daniellenierenberg

Advance Market Analyticsreleased the research report ofGlobal Stem CellsMarket, offers a detailed overview of the factors influencing the global business scope.Global Stem Cells Market research report shows the latest market insights with upcoming trends and breakdown of the products and services.The report provides key statistics on the market status, size, share, growth factors of the Global Stem Cells.This Report covers the emerging players data, including: competitive situation, sales, revenue and global market.

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The stem cell is used for treating chronic diseases such as cardiovascular disorders, cancer, diabetes, and others. Growing research and development in stem cell isolation techniques propelling market growth. For instance, a surgeon from Turkey developed a method for obtaining stem cells from the human body without enzymes which are generally used for the isolation of stem cells. Further, growing healthcare infrastructure in the developing economies and government spending on the life science research and development expected to drive the demand for stem cell market over the forecasted period.

The Global Stem Cellsis segmented by following Product Types:

Type (Adult Stem Cells (Neuronal, Hematopoietic, Mesenchymal, Umbilical Cord, Others), Human Embryonic Stem Cells (hESC), Induced Pluripotent Stem Cells, Very Small Embryonic-Like Stem Cells), Application (Regenerative Medicine (Neurology, Orthopedics, Oncology, Hematology, Cardiovascular and Myocardial Infraction, Injuries, Diabetes, Liver Disorder, Incontinence, Others), Drug Discovery and Development), Technology (Cell Acquisition (Bone Marrow Harvest, Umbilical Blood Cord, Apheresis), Cell Production (Therapeutic Cloning, In-vitro Fertilization, Cell Culture, Isolation), Cryopreservation, Expansion and Sub-Culture), Therapy (Autologous, Allogeneic)

Region Included are: North America, Europe, Asia Pacific, Oceania, South America, Middle East & Africa

Country Level Break-Up: United States, Canada, Mexico, Brazil, Argentina, Colombia, Chile, South Africa, Nigeria, Tunisia, Morocco, Germany, United Kingdom (UK), the Netherlands, Spain, Italy, Belgium, Austria, Turkey, Russia, France, Poland, Israel, United Arab Emirates, Qatar, Saudi Arabia, China, Japan, Taiwan, South Korea, Singapore, India, Australia and New Zealand etc.Enquire for customization in Report @:https://www.advancemarketanalytics.com/enquiry-before-buy/72815-global-stem-cells-market-1

Strategic Points Covered in Table of Content of Global Stem Cells Market:

Chapter 1: Introduction, market driving force product Objective of Study and Research Scope the Global Stem Cells market

Chapter 2: Exclusive Summary the basic information of the Global Stem Cells Market.

Chapter 3: Displayingthe Market Dynamics- Drivers, Trends and Challenges of the Global Stem Cells

Chapter 4: Presenting the Global Stem Cells Market Factor Analysis Porters Five Forces, Supply/Value Chain, PESTEL analysis, Market Entropy, Patent/Trademark Analysis.

Chapter 5: Displaying the by Type, End User and Region 2013-2018

Chapter 6: Evaluating the leading manufacturers of the Global Stem Cells market which consists of its Competitive Landscape, Peer Group Analysis, BCG Matrix & Company Profile

Chapter 7: To evaluate the market by segments, by countries and by manufacturers with revenue share and sales by key countries in these various regions.

Chapter 8 & 9: Displaying the Appendix, Methodology and Data Source

Finally, Global Stem Cells Market is a valuable source of guidance for individuals and companies.

Data Sources & Methodology

The primary sources involves the industry experts from the Global Stem Cells Market including the management organizations, processing organizations, analytics service providers of the industrys value chain. All primary sources were interviewed to gather and authenticate qualitative & quantitative information and determine the future prospects.

In the extensive primary research process undertaken for this study, the primary sources Postal Surveys, telephone, Online & Face-to-Face Survey were considered to obtain and verify both qualitative and quantitative aspects of this research study. When it comes to secondary sources Companys Annual reports, press Releases, Websites, Investor Presentation, Conference Call transcripts, Webinar, Journals, Regulators, National Customs and Industry Associations were given primary weight-age.

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Stem Cells Market Expected to Boost the Global Industry Growth in the Near Future - Germany English News

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Mount Sinai Leading the Way in Innovative Stem Cell Therapy for COVID-19 Patients – Newswise

By daniellenierenberg

Newswise (New York, NY April 9, 2020) Mount Sinai Health System is the first in the country to use an innovative allogeneic stem cell therapy in COVID-19 patients and will play a central role in developing and conducting a rigorous clinical trial for patients with severe acute respiratory distress syndrome, the breathing illness that afflicts people who have severe cases of COVID-19.

The therapy, known as remestemcel-L, has previously been tested in bone marrow transplant patients, who can experience an overactive immune response similar to that seen in severe cases of COVID-19.

Mount Sinai began administering the therapy, known as remestemcel-L, to patients in late March under the Food and Drug Administrations compassionate use program, which allows patients with an immediately life-threatening condition to gain access to an investigational therapy. Ten patients with moderate to severe cases of COVID-19-related acute respiratory distress syndrome (ARDS), most of whom were on ventilators, were given the therapy and doctors saw encouraging results.

We are encouraged by what we have seen so far and look forward to participating in the randomized controlled trial starting soon that would better indicate whether this is an effective therapy for patients in severe respiratory distress from COVID-19, said Keren Osman, MD, Medical Director of the Cellular Therapy Service in the Bone Marrow and Stem Cell Transplantation Program at The Tisch Cancer Institute at Mount Sinai and Associate Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai. Dr. Osman oversaw the treatment of the first Mount Sinai patients with this innovative therapy.

Under the leadership of Annetine Gelijns, PhD, Alan Moskowitz, MD, and Emilia Bagiella, PhD, of Mount Sinais Institute of Transformative Clinical Trials, Mount Sinai will serve as the clinical and data coordinating center for a randomized clinical trial evaluating the therapeutic benefit and safety of this stem cell therapy in 240 patients with COVID-related ARDS in the United States and Canada. The trial will be conducted as a public-private partnership between the Cardiothoracic Surgical Trials Network, which was established as a flexible clinical trials platform by the National Heart, Lung, and Blood Institute, and Mesoblast, the manufacturer of the cells.

The coronavirus pandemic has caused exponential increases of people suffering with acute respiratory distress syndrome, requiring intubation and mechanical ventilation with many dying, said Dr. Gelijns, who is also the Edmond A. Guggenheim Professor of Health Policy at the Icahn School of Medicine at Mount Sinai. We have designed a clinical trial that will expeditiously determine whether the stem cell therapy will offer a life-saving therapy for a group of patients with a dismal prognosis.

We are interested to study the potential of this anti-inflammatory cell therapy to make an impact on the high mortality of lung complications in COVID-19 patients, said CSTN Chairman A. Marc Gillinov, MD. This randomized controlled trial is in line with our mandate to rigorously evaluate novel therapies for public health imperatives.

The therapy consists of mesenchymal stem cells. These cells are found in bone marrow and serve many functions including aiding tissue repair and suppressing inflammation. The therapy was previously tested in a phase 3 trial in children who had an often-fatal inflammatory condition called graft-versus-host disease (GVHD) that can occur after bone marrow transplants.

The inflammation that occurs in GVHD is the result of a cytokine storm, which activates immune cells that attack healthy tissue. A similar cytokine storm that causes damage to the lungs and other organs appears to be taking place in COVID-19 patients who develop acute respiratory distress syndrome, said John Levine, MD, Professor of Medicine (Hematology and Medical Oncology), and Pediatrics, at the Icahn School of Medicine at Mount Sinai, who helped implement the compassionate use of the drug at Mount Sinai.

These stem cells have shown excellent response rates in severe graft-versus-host disease in children, said Dr. Levine, who is also the co-director of the Mount Sinai Acute GVHD International Consortium (MAGIC). Mesenchymal stem cells have a natural property that dampens excessive immune responses.

Several people were instrumental in quickly and efficiently working through the complex application process for each patient to gain compassionate use of the therapy. Three key players involved were Stacey-Ann Brown, MD, MPH, Assistant Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine) at the Icahn School of Medicine at Mount Sinai; Tiffany Drummond, Assistant Director of Regulatory Affairs at The Tisch Cancer Institute at Mount Sinai; and Camelia Iancu-Rubin, PhD, Director of the Cellular Therapy Laboratory at the Icahn School of Medicine at Mount Sinai.

About the Mount Sinai Health System

The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai is a national and international source of unrivaled education, translational research and discovery, and collaborative clinical leadership ensuring that we deliver the highest quality carefrom prevention to treatment of the most serious and complex human diseases. The Health System includes more than 7,200 physicians and features a robust and continually expanding network of multispecialty services, including more than 400 ambulatory practice locations throughout the five boroughs of New York City, Westchester, and Long Island. The Mount Sinai Hospital is ranked No. 14 onU.S. News & World Report's"Honor Roll" of the Top 20 Best Hospitals in the country and the Icahn School of Medicine as one of the Top 20 Best Medical Schools in country. Mount Sinai Health System hospitals are consistently ranked regionally by specialty and our physicians in the top 1% of all physicians nationally byU.S. News & World Report.

For more information, visithttps://www.mountsinai.orgor find Mount Sinai onFacebook,TwitterandYouTube.

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Turkey opens airspace to save Italian toddler’s life – Anadolu Ajans

By daniellenierenberg

ANKARA

Amid the closure of Turkish airspace due to the coronavirus outbreak, it opened it up to an Italian jet to save the life of a 2-year-old Italian child.

On March 14, Dr. Massimo Cardillo, the head of Italys National Transplant Center, sent an email asking Turkish authorities for help with the ailing toddler, according to Turkish healthcare sources.

The mail said that after a comprehensive search of international donor banks, the compatible donor for the toddler awaiting a stem cell transplant was found in Turkey, added the sources, who asked not to be named due to restrictions on speaking to the media.

Although by that time Turkey had closed its airspace due to the COVID-19 threat, Turkeys Health Ministry and Foreign Ministry made a special exception in this case to save the toddlers life.

The compatible donor was found and provided by Turkey's Stem Cell Coordination Center.

On March 31, a jet took off from Rome and was allowed to land at Istanbul Airport.

The stem cells were then delivered to the Italian team by Turkish doctors in an isolated room at the airport.

The Italian team took the cells to Rome without incident and delivered them to the hospital for transplantation to the toddler.

Nicoletta Sacchi, director of the Italian Bone Marrow Donor Registry, said they will never forget Turkeys help during this difficult period.

"I extend my thanks to the donor, the main hero of the event. Were grateful to both Turkey and the donor," he said.

Due to the coronavirus pandemic, which has killed tens of thousands of people worldwide since emerging last December, many countries, including Turkey, have closed their airspace to both international and domestic flights.

*Writing by Fahri Aksut

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Cellect Biotechnology Reports Fourth Quarter and Full Year 2019 Results – Yahoo Finance

By daniellenierenberg

Achieved Primary Investigational New Drug (IND) Approval in the U.S.; Positioned to Commence Patient Enrollment

Maintained Clinical Progress in Israel and Nearing Completion of Phase 1/2 Trial

Strategic Commercial Agreement with Canndoc Anticipated to Generate Significant Revenue; Closing of Merger Transaction Progressing as Planned

TEL AVIV, Israel, April 3, 2020 /PRNewswire/ -- Cellect Biotechnology Ltd. (Nasdaq: APOP), a developer of a novel stem cell production technology, today announced operating and financial results for the fourth quarter and full year ended December 31, 2019.

"We achieved a number of strategic priorities in 2019, including the IND approval to commence our first-ever trial in the U.S.," commented Dr. Shai Yarkoni, Chief Executive Officer."We plan to begin enrolling patients for this trial and completing the trial in Israel when the COVID-19 pandemic is mitigated. While these near-term events are value-enhancers, I believe that our recently announced prospective partnership with Canndoc could be a game-changer for Cellect and change our growth trajectory. It has the potential to significantly enhance our short and long term business prospects and shareholder value. As a player in the fast-growing pain management market, we would anticipate significant revenue opportunities already this year."

Recent Strategic Development

As previously announced, on March 4, 2020, the Company entered into a commercial binding Letter Of Intent (LOI) with Canndoc Ltd, a leading pharma grade medical cannabis pioneer and a wholly owned subsidiary of publicly-traded Intercure Ltd. (TASE: INCR),to acquire from Canndoc all rights to the use and sell Canndoc products for the reduction of opioid usage, including accumulated data, as well as on-going and pipeline of clinical trials. This commercial arrangement is subject to negotiation and approval by each company's board of directors and definitive agreements.

Additionally, the two companies signed a non-binding LOI for a full merger. Under preliminary details, Cellect will acquire from Intercure all of Canndoc outstanding shares, in exchange for additional Cellect ADRs to be in total ~95% (~93% on a fully diluted basis) of the merged company. The proposed merger is subject to independent valuation of both companies, fairness opinion by a third party, negotiation of a definitive agreement, approval of the agreement by the Company's Board of Directors and shareholders, internal approvals by Canndoc and Intercure, and customary closing conditions, including the approval of the IMCA (Israeli Medical Cannabis Agency). Upon the closing of the merger, Cellect and Canndoc will aim to fulfill all of the requirements to ensure the Company's ADRs and warrants continue trading on the Nasdaq Stock Market (Nasdaq) and, for this purpose, Intercure would commit to invest a cash sum of at least $3.0 million in any public offering that is undertaken by the Company, at a price of not less than $4.50 per ADR.

Based on the progress to date, the Company continues to expect the commercial and merger transactions will close in the second quarter of 2020.

Additional Operating Highlights:

Clinical Progress Update:

Due to the ongoing COVID-19 pandemic, the Company is experiencing clinical disruption such as:

The Company continues to take all the necessary precautions advised by global health officials to ensure the health and safety of its employees and partners. The Company is unaware of any impact on employees from pandemic related exposure or illness and is continuing to perform in-house research, including in the opioid/pain management area.

Fourth Quarter and Full Year 2019 Financial Results:

Balance Sheet Highlights:

For the convenience of the reader, the amounts have been translated from NIS into U.S. dollars, at the representative rate of exchange on December 31, 2019 (U.S. $1 = NIS 3.456).

About Cellect Biotechnology Ltd.

Cellect Biotechnology (NASDAQ: APOP) has developed a breakthrough technology, for the selection of stem cells from any given tissue, that aims to improve a variety of stem cell-based therapies.

The Company's technology is expected to provide researchers, clinical community and pharma companies with the tools to rapidly isolate stem cells in quantity and quality allowing stem cell-based treatments and procedures in a wide variety of applications in regenerative medicine. The Company's current clinical trial is aimed at bone marrow transplantations in cancer treatment.

Story continues

Forward Looking Statements

This press release contains forward-looking statements about the Company's expectations, beliefs and intentions. Forward-looking statements can be identified by the use of forward-looking words such as "believe", "expect", "intend", "plan", "may", "should", "could", "might", "seek", "target", "will", "project", "forecast", "continue" or "anticipate" or their negatives or variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical matters. For example, forward-looking statements are used in this press release when we discuss Cellect's intent regarding the future potential of Cellect's technology. These forward-looking statements and their implications are based on the current expectations of the management of the Company only and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. In addition, historical results or conclusions from scientific research and clinical studies do not guarantee that future results would suggest similar conclusions or that historical results referred to herein would be interpreted similarly in light of additional research or otherwise. The following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: the Company's history of losses and needs for additional capital to fund its operations and its inability to obtain additional capital on acceptable terms, or at all; the Company's ability to continue as a going concern; uncertainties of cash flows and inability to meet working capital needs; the Company's ability to obtain regulatory approvals; the Company's ability to obtain favorable pre-clinical and clinical trial results; the Company's technology may not be validated and its methods may not be accepted by the scientific community; difficulties enrolling patients in the Company's clinical trials; the ability to timely source adequate supply of FasL; risks resulting from unforeseen side effects; the Company's ability to establish and maintain strategic partnerships and other corporate collaborations; the scope of protection the Company is able to establish and maintain for intellectual property rights and its ability to operate its business without infringing the intellectual property rights of others; competitive companies, technologies and the Company's industry; unforeseen scientific difficulties may develop with the Company's technology; and the Company's ability to retain or attract key employees whose knowledge is essential to the development of its products. Any forward-looking statement in this press release speaks only as of the date of this press release. The Company undertakes no obligation to publicly update or review any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by any applicable securities laws. More detailed information about the risks and uncertainties affecting the Company is contained under the heading "Risk Factors" in Cellect Biotechnology Ltd.'s Annual Report on Form 20-F for the fiscal year ended December 31, 2019 filed with the U.S. Securities and Exchange Commission, or SEC, which is available on the SEC's website, http://www.sec.gov, and in the Company's periodic filings with the SEC.

Cellect Biotechnology Ltd

Consolidated Statement of Operation

Convenience

translation

Twelve months

ended

Twelve months ended

Three months ended

December 31,

December 31,

December 31,

2019

2019

2018

2019

2018

Unaudited

Audited

Audited

Unaudited

Unaudited

U.S. dollars

NIS

(In thousands, except share and pershare data)

Research and development expenses

3,508

12,122

13,513

2,571

4,040

General and administrative expenses

2,954

10,210

15,734

2,378

4,733

Operating loss

6,462

22,332

29,247

4,949

8,773

Financial expenses (income) due towarrants exercisable into ADS

(2,032)

(7,022)

(7,719)

998

(4,784)

Other financial expenses (income), net

433

1,498

(1,415)

129

(238)

Total comprehensive loss

4,863

16,808

20,113

6,076

3,751

Loss per share:

Basic and diluted loss per share

0.023

0.079

0.155

0.027

0.029

Weighted average number of sharesoutstanding used to compute basic anddiluted loss per share

212,642,505

212,6432,505

129,426,091

224,087,799

130,274,953

Cellect Biotechnology Ltd

Consolidated Balance Sheet Data

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MSC-based therapies from Mesoblast, Cynata advance to tackle COVID-19 ARDS – BioWorld Online

By daniellenierenberg

PERTH, Australia Australian stem cell therapy company Mesoblast Ltd. announced that the FDA gave it the green light to test its allogeneic mesenchymal stem cell (MSC) product candidate remestemcel-L in patients with acute respiratory distress syndrome (ARDS) caused by coronavirus (COVID-19).

Were going to be evaluating whether an injection of our cells intravenously can tone down the immune system just enough so it gets rid of the virus but doesnt destroy your lungs at the same time, Mesoblast CEO Silviu Itescu told BioWorld.

What people are dying of is acute respiratory distress syndrome, which is the bodys immune response to the virus in the lungs, and the immune system goes haywire, and in its battle with the virus it overreacts and causes severe damage to the lungs, Itescu said.

The FDA clearance provides a pathway in the United States for use of remestemcel-L in patients with COVID-19 ARDS, where the prognosis is very dismal, under both expanded access compassionate use and in a planned randomized controlled trial.

The company is in active discussions with various governments, regulatory authorities, medical institutions and pharmaceutical companies.

Recently published results from an investigator-initiated clinical study conducted in China reported that allogeneic MSCs cured or significantly improved functional outcomes in all seven treated patients. A post-hoc analysis of a randomized, placebo-controlled study in 60 patients with chronic obstructive pulmonary disease demonstrated that remestemcel-L significantly improved respiratory function in patients with the same elevated inflammatory biomarkers that are also observed in patients with COVID-19 ARDS.

Remestemcel-L is being developed for various inflammatory conditions and is believed to counteract the inflammatory processes implicated in those diseases by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

The safety and therapeutic effects of remestemcel-L intravenous infusions have been evaluated in more than 1,100 patients in various clinical trials.

The stem cell therapy was successful in a phase III trial for steroid-refractory acute graft-vs.-host disease (aGVHD) in children, a potentially fatal inflammatory condition due to a similar cytokine storm process as is seen in COVID-19 ARDS.

Cynata in preclinical ARDs studies

Fellow Aussie regenerative medicine company Cynata Therapeutics Ltd. is studying the utility of its Cymerus MSCs as a treatment for ARDS associated with COVID-19 with the Critical Care Research Group at Prince Charles Hospital in Brisbane, Australia.

Acute respiratory distress syndrome is a huge problem worldwide and is prevalent aside from COVID-19, but suddenly it is on the front page because people are dying of this. The data behooves us to see if MSC treatment can rescue people from this, Cynata CEO Ross Macdonald told BioWorld.

The Critical Care Research Group has long seen the need to improve interventions in patients who have ARDS, and they have an interest in MSCs and came to us, he said.

ARDS is an inflammatory process leading to the build-up of fluid in the lungs and respiratory failure. It can occur due to infection, trauma and inhalation of noxious substances. ARDS often affects previously healthy individuals and accounts for roughly 10% of all ICU admissions, with almost 25% of patients requiring mechanical ventilation. Survivors of ARDS are often left with severe long-term illness and disability.

The study will investigate Cynatas Cymerus MSCs as a treatment for ARDS, in combination with extracorporeal membrane oxygenation (ECMO). ECMO circulates blood through an artificial lung, oxygenating the blood before putting it back into the bloodstream of a patient. ECMO has emerged as a treatment adjunct to support the vital organs in patients with severe ARDS, which can provide short- to medium-term mechanical pulmonary support.

MSC therapy could be used as a possible treatment for ARDS due to the ability of MSCs to reduce inflammation, enhance clearance of pathogens and stimulate tissue repair.

The study will first seek to determine if Cymerus MSC treatment improves oxygenation in sheep with ARDS supported by ECMO, and to evaluate the effects on lung mechanics, blood flow, inflammation and lung injury, as well as safety.

If the study is successful, the data would support progression to a clinical trial of Cymerus MSCs in humans with ARDS undergoing ECMO support.

The study is being funded by the Queensland State Government, the National Health and Medical Research Council (NHMRC), the Intensive Care Society UK, and the Prince Charles Hospital Foundation.

If the FDA or TGA wants us to step in, were all ears. Our product is manufactured in the United States, and supply is not an issue. In theory, were ready to go, Macdonald said.

He was quick to point out that what differentiates Cynatas stem cell product from competitors is that its MSCs are derived from induced pluripotent stem cells (iPSCs), and most stem cell companies rely on multiple donors to donate either bone marrow or adipose tissue as their primary tissue sources. From those sources they derive a small number of MSCs, which represent the starting material of their manufacturing process.

Cynatas Cymerus MSC therapy comes from a single donor and can be produced in limitless quantities, giving it the potential to create a new standard, Macdonald said. The platform technology is based on versatile stem cells known as mesenchymoangioblasts (MCAs), which are a precursor of mesenchymal stem cells.

That process allows the company to make MSCs derived from iPSCs in large amounts without losing their potency, and that forms the basis for the companys platform technology, which it calls Cymerus.

Cynata is gearing up for three phase II trials with its Cymerus MSCs in graft-vs.-host disease (GVHD), critical limb ischemia and osteoarthritis.

Mesoblasts remestemcel-L is being studied in clinical trials across several inflammatory conditions, including in elderly patients with lung disease and adults and children with steroid-refractory aGVHD, heart failure and chronic low back pain due to intervertebral disc degeneration.

The FDA recently accepted Mesoblasts BLA for priority review for remestemcel-L for children with aGVHD. It has a PDUFA date of Sept. 30 for the product branded as Ryoncil.

Mesoblast shares (ASX:MSB) were up nearly 34% to AU$1.78 from AU$1.32 per share by market close April 6.

Cynatas shares (ASX:CYP) were trading at AU86 cents on April 7.

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COVID-19 Tips for Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia – Curetoday.com

By daniellenierenberg

The COVID-19 pandemic has created a unique challenge for patients with myelodysplastic syndromes and acute myeloid leukemia, creating many questions that experts tried to answer in a recent webinar from The Aplastic Anemia and MDS International Foundation.

The Aplastic Anemia and MDS International Foundation (AAMDSIF) recently hosted a webinar to address the questions of this patient population by connecting them with Dr. Gail J. Roboz, professor of medicine and director of the clinical and translational leukemia program at the Weill Medical College of Cornell University in the New York Presbyterian Hospital in New York City.

Over the course of the webinar, Dr. Roboz, also a member of the AAMDSIF Medical Advisory Board, answered questions from the audience about the various ways that COVID-19 is impacting patients, from treatment delays to transplant and beyond.

Audience: If a patient with MDS were to be diagnosed with COVID-19, what are the most important things that they should let their medical team know, as they may not be familiar with MDS?Roboz: I think that it's important that if you're being seen in a facility where they don't know you very well or they don't know much about MDS, you can tell them that MDS is a is a bone marrow failure problem. You can tell them about your own blood counts, do I usually run low neutrophils or low hemoglobin or low platelets or all three, so you can tell them about what your specific experience is. But with respect to therapy, it is not completely clear that the underlying diagnosis, in this case MDS, is going to change what they do.

I think one of the questions is going to be about potential interactions with any medications that you're taking for MDS. And that's, of course, something that would be discussed if you're hospitalized.

If you are not getting hospitalized and you are patient with MDS, I certainly think it's reasonable to have, if at all possible, a daily or every other day telemedicine visit, either by video or by phone or by email, or however you're communicating with your doctor as a check in to just see how you're doing, see how your symptoms are evolving.

Should I continue with routine blood tests under the conditions or should I hunker down and not leave the house? If the previous blood test that the patient has had is looking absolutely perfect, and if there is a track record over a period of time that we know that this patient is tolerating the drug well and hasn't had any issues, I would be willing to consider skipping a routine blood test.

That said, I think it's really important to discuss this individually with the physician. First of all, depending on where you are, I'm hearing that in some parts of the country, you can actually drive to the doctor's office and they have a check in system that's allowing you to check in from your car, so that you could actually get into the office, get a lab check and get out without seeing really anybody.

Is there a change in patient protocol for when patient should be concerned about a fever?That is a really important question, especially for neutropenic patients. I think that if you are neutropenic and running a fever, neutropenic fevers do have to be evaluated, especially in hematologic malignancy patients.

If you don't feel too bad, and you're not having shaking chills and you think you can get your doctor's office on the phone quickly, it's not unreasonable to try that. That said, most of the time, it's really tough to get seen urgently in an office at this point. Again, it depends on where you are.

If you're going into the ER, you have to be very specific with them and say, hey, listen, I have leukemia, or I have MDS. This is my doctor. I'm neutropenic. I'm coming in with neutropenic fever, and they will evaluate you simultaneously for all of the routine things for neutropenic fever, as well as for coronavirus.

What are the recommendations regarding patients moving forward with transplant?I think that the issue is that the intensive care units in many areas, and the infectious disease doctors and many of the pulmonary specialists and other supportive specialties that are so critical to get patients safely through transplant, are very occupied at the moment.

But we want to make sure that when you come in for a procedure with curative intent, that all of the backup that we need to get you through the procedure safely is 100% available. So, it is definitely the case that patients are being delayed in their transplant. However, there are situations in which people might proceed. And I think again, this has to be a very individual discussion with the physician.

In the New York area, we are anticipating a surge in mid-April. So we definitely have been making decisions for our transplant patients that we don't want to bring you in here literally at the moment when they're predicting that things are going to get much worse, because maybe things will be better at the end of the month or at the beginning of the next month. And then we can hopefully start breathing a sigh of relief and bring you in much more safely.

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Life ‘hanging by a thread’ for Italian cancer patients in coronavirus crisis – The Guardian

By daniellenierenberg

Since the coronavirus outbreak hit Italy, Francesca Masi has felt her life has been hanging by a thread. She was diagnosed with myelofibrosis, a rare bone marrow cancer, in 2016 and was due to have a transplant this month, but now fears it will be postponed as the country deals with the pandemic.

Access for thousands of cancer patients in need of chemotherapy, scans, transplants and surgery has become difficult, if not impossible, in Italys Covid-19 emergency.

Across the country, dozens of specialist cancer wards and hospitals have been transformed to treat coronavirus, while others have closed after medical staff and patients were infected. There are now fewer beds in intensive care units for cancer patients.

At the beginning of my diagnosis I underwent other treatments with success, but since my conditions worsened, transplant became my only option. So to be stuck in this situation make me living in a constant state of anxiety, says Masi, who lives and works in Pontedera, in the province of Pisa. She is 46 and the mother of a 10-year-old boy. I now run the risk of dying, which isnt fair, because my doctors had finally located two foreign donors whose marrow was 100% compatible with mine. International flight restrictions to halt the spread ofcoronavirus mean marrow from overseas donors risks not arriving in Italy.

Research led by Codice Viola, a charity that supports pancreatic cancer patients, and seen exclusively by the Guardian, found that of 500 mostly breast or pancreatic patients appointments for chemotherapy or radiotherapy were postponed for 24% (11% with no arranged date), while 64% of surgical procedures were postponed indefinitely. More than half have had follow-up appointments rescheduled.

Dozens of patients and doctors who spoke to the Guardian fear that the restrictive measures to contain the virus are limiting access to proper medical care for cancer patients, who also represent 17% of Italian coronavirus fatalities, according to a recent study.

Francesca Pesce, 54, a professional translator and member of Codice Viola, has been living with metastatic pancreatic cancer for almost three years. This week she will leave Rome for a follow-up in Milan, one of the cities worst affected by the virus.

At least I have this option, which others dont, she said. On the one hand, cancer patients are afraid of contracting the virus in hospitals, so they forgo their treatments; on the other, hospitals have been forced to cancel their appointments as many oncologists and anaesthetists have been moved to other wards to assist in the Covid-19 emergency.

Paolo Ascierto, an oncologist at Naples Pascale hospital now treating coronavirus patients, said converting cancer wards to Covid-19 units could be risky. I understand the state of emergency, but we mustnt forget that cancer patients require dedicated and specialised treatments. There are special conditions, like patients in follow-up, that can be managed safely using online consultations to monitor the patients progress.

But there are other conditions, such as metastatic patients, that must be prioritised, because a lack of constant attention can mean the difference between life and death.

In Ortona, Abruzzo, protests erupted following the announcement by local authorities that the only hospital in the region specialised in womens cancer treatments was to be entirely converted to treat Covid-19 patients.

Where cancer wards are functioning, certain diagnostic procedures, such as endescopies, may be limited, and a decrease in blood donations is limiting surgical options. At the moment, only urgent surgical procedures are being performed, says Pesce. And even urgent procedures are now stymied, because of a shortage of blood due to the coronavirus emergency.

The closure of air routes to and from Italy has also made it virtually impossible for thousands of cancer patients to access treatment in other European hospitals.

Alessandra Capone, 47, a dancer, feminist and human rights activist, has been living with breast cancer for 10 years. In 2015 it spread to her liver and lymph nodes and last year she began a series of treatments at University Hospital in Frankfurt with just 5% of her liver cancer-free. She is now facing enormous difficulties travelling to Germany.

I contacted the Ministry of Foreign Affairs and International Cooperation but the line is always busy and I couldnt speak to anybody. Then I contacted the Italian consulate in Frankfurt. They told me I need a number of certifications for travelling to another country, even for health reasons. Not to mention that in Germany very few hotels are accepting reservations, especially from Italians, during this emergency. Its very stressful.

For the first time, however, the Italian government last week authorised an air force flight to Turkey to secure haemopoietic stem cells from a donor for a two-year-old boy whose condition had worsened.

Travel is also limited within Italy, where patients from Sicily, Puglia and Calabria often undergo treatments and operations in richer Veneto and Lombardy, which are among the worst affected regions in the country for Covid-19.

Grazia De Michele, 39, a blogger and researcher in the history of medicine, lives in Foggia, in Puglia, and has been living with breast cancer since 2010. A few months ago, her mother was diagnosed with pancreatic cancer. My mother was supposed to have a CT scan in March to see if the chemo shes on is working, but the scan was postponed, she says. I was supposed to undergo an oophorectomy, and my operation was postponed as well.

You have to imagine what its like for cancer patients, says Capone. Many live in a constant state of anxiety, with the fear of dying. The situation caused by the coronavirus emergency has put them under enormous psychological and physical distress. You see, you can protect yourself from coronavirus by staying at home, but its not the same with cancer. Cancer doesnt follow the diktat of quarantines or decrees. It keeps going, in war and in peace.

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Life 'hanging by a thread' for Italian cancer patients in coronavirus crisis - The Guardian

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India Based Stem Cell Research Firm To Test Its Stem Cell Product For Acute Respiratory Disease Syndrome (ARDS) COVID-19 – IndianWeb2.com

By daniellenierenberg

Stempeutics Research, a group company of Manipal Education and Medical Group (MEMG), announced today that it has partnered with Global Consortium of cell therapy companies seeking European Commission Funding to Fight Against Corona! (FAC!). Under this partnership, Stempeutics will export its stem cell product Stempeucel (subject to regulatory approvals) for treating critically ill COVID-19 patients with lung disease. First the product will be clinically tested and upon successful outcomes, it intends to export the product on a regular basis. In this connection it is signing up an alliance with Educell Ltd, Slovenia.

Currently, no specific drugs or vaccines are available to cure the patients with COVID-19 infection. Mortality in COVID-19 infected patients with the inflammatory lung condition ARDS (Acute Respiratory Distress Syndrome)is reported to approach 50%, and is associated with older age, co-morbidities such as diabetes, cardiovascular disease, COPD (chronic obstructive pulmonary disease), higher disease severity, and elevated markers of inflammation. Current therapeutic interventions (with the exception of ventilators/respirators which are in very short supply) do not appear to be improving in-hospital survival. Hence, there is a large unmet need for a safe and effective treatment for COVID-19 infected patients, especially in severe cases. A promising new therapy for the ARDS, the terminal stage of COVID-19, using MSCs can quickly (2-4 days) reduce inflammation of the lung tissue, and allow patients to more quickly come off of the ventilatory support and hopefully fully recover with less significant lung damage.

Stempeucel is an allogeneic, off the shelf, pooled mesenchymal stromal cells having anti- inflammatory and immune-modulatory properties which prevents the over activation of the immune system. Stempeucel product exhibits a wide range of potent therapeutic properties. The product exhibits potent immunomodulatory and anti-inflammatory properties which could help in reducing the inflammation caused due to the cytokine storm elicited by the bodys immune cells in response to SARS-CoV-2 (COVID-19) related infection in the lungs. Also, the growth factor, Angiopoietin-1 (Ang-1) is effective in reducing alveolar epithelium permeability in the lung. Hence it is envisaged, Stempeucel will reduce the fatal symptoms of COVID 19 induced pneumonia and its progression to ARDS.

Commenting on this initiative, Dr. Miomir Knezevic, Leader of the Global Consortium and Founder of Educell said, We are happy to partner with Stempeutics since its product Stempeucel is already designated as an ATMP1 in Europe and also Stempeucel technology has been patented in many countries in Europe. Stempeutics manufacturing process is scalable and the product is affordable which are key to meet the demands of COVID-19 patients

Mr. BN Manohar, CEO of Stempeutics said, From the clinical data using Stempeucel in different clinical trials in other indications it may be postulated that Stempeucel has the potential capability for treating COVID-19 infection. Together with the safety profile observed from DCGI approved clinical trials involving more than 350 patients injected with Stempeucel by different routes of injection, this therapy may help in mitigating the lung tissue damaging effects of COVID-19 infection.

Dr. Stephen Minger, Scientific Advisor for the Global Consortium and ex Global Director of R&D, Cell Technologies GE Healthcare added The most severely affected CV-2 infected patients will often go on to develop ARDS which necessitates assisted ventilation to preserve breathing and lung function. Moreover, many ARDS patients will also experience an acute but severe life-threatening inflammatory response (cytokine storm) which can result in long-term damage to lung tissue and lung function. Treating ARDS patients with allogeneic expanded bone marrow derived MSCs could alleviate and ameliorate lung inflammation and compromised lung function and significantly reduce the time required for patients to be ventilated.

Dr. Raviraja N S, Sr. Director Business Development and Innovation, Stempeutics, said, Given the severe shortage of ventilators in the world, and the high mortality rate of patients who develop ARDS (approx. 50%), the clinical use of MSCs in COVID-19 ADRS patients could drastically impact on the healthcare burden currently occurring due to very large patient numbers, limited equipment and overworked medical personnel.

Mr. B N Manohar MD & CEO, Stempeutics Research

Manohar is the MD & CEO of Stempeutics Research a leading stem cell research and product development company in India. He earned his B.E. degree in Electronics & Communication from REC Trichy in 1977. Post that he did M.E. in Computer Science from College of Engineering, Guindy. Manohar has transformed Stempeutics a life science start-up from R&D to Commercialization stage with Global recognition. Stempeutics has developed an innovative drug called Stempeucel for addressing major unmet medical needs in India and Globally.

This drug developed by an Indian company has received many Global Recognitions. Fourteen countries including US & Japan has granted patent for the novelty and inventiveness of the drug. Europe has recognized this drug by granting Advanced Therapy Medicinal Product classification and Orphan Drug Designation. Recently it became the FIRST stem cell product to be approved by DCGI for conditional marketing for treating patients suffering from life threatening disease call Buergers Disease. Stempeutics has put India on the World map of Regenerative Medicine. Under Manohars leadership Stempeutics has been recognized as Indias hottest start-ups by Business Today in 2008 and Karnataka Government bestowed Emerging Company of the Year award in 2011 and 2013. In 2017 Manohar was awarded Biotechnologist of the Year award by Wockhardt Foundation, India. He raised US$ 10M in 2009 by establishing business alliance with major pharma company Cipla. Recently Stempeutics has tied up with Alkem Labs for Osteoarthritis indication. Prior to Joining Manipal Group, Manohar has had 12 years successful stints at Wipro GE Medical Systems. At GE Medical he has handled multiple senior assignments including Vice President Customer Service where he received GE Asia Service Award for highest revenue growth in 1998. Currently Manohar serves in the Boards of Stempeutics and MentisSoft.

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Roma woman tells of her ‘life-changing’ MS treatment – Observer

By daniellenierenberg

THERES a 70 per cent chance youre going to get a mum without MS for the first time.

Those were the words Amanda Weyman-Jones told her daughter before they hopped on a plane, in a last ditch-attempt for Amanda to take her future back.

In January, Amanda and daughter Chloe travelled halfway across the globe to Moscow, Russia for a life changing and experimental treatment in hopes it would effectively stop her three decade battle with multiple sclerosis in its tracks.

The trip was made possible with the support from the Roma community who banded together to help Amanda raise $80,000 to pay for the treatment only available in the Russian capital.

And according to Amanda, she has already seen a massive improvement with her condition.

Im walking and I would say I have improved 70 per cent already, and its only expected to get better as time goes on, the 58-year-old mother of six said.

They say that the treatment gives you an 80 per cent (chance) of curing your MS and at the moment, I feel like Im in that 80 per cent Im feeling really good about my chances.

Amanda underwent an experimental procedure called Autologous haematopoietic stem cell transplant (AHSCT) treatment, which rebuilds the patients immune system.

Seven weeks on and Amanda says she feels like a new person, and has been walking around the football field everyday, which she states is a miracle as she couldnt even walk to the field before the treatment.

Ever since returning to Roma from Russia in February, all she has wanted to do is shout from the rooftops that others living with MS can also have their lives changed.

I heard about a man on a property in Blackall with MS and hes young so I want him to know he doesnt have to have this disease, you can get better, Mrs Weyman-Jones said.

This treatment gives you that infinity with people. Its life saving stuff.

Amandas brother Hayward and sister Diana were both diagnosed with MS too; Hayward died last year, and Diana is now in a wheelchair.

All too familiar with the devastating effects of MS, Amanda is determined to not become a burden on her loved ones.

Amanda who has Primary Progressive MS was given an Expanded Disability Status Scale (EDSS) score of 4.5 which notes a limited walking mobility to approximately 300m without aide prior to treatment. With no action taken, she would probably have continued to progress until she was wheelchair bound. The EDSS is scored zero to 10, with 10 marking a person has died from MS.

Now, with more improvements expected to continue in the next six to 12 months, Amanda is hopeful her quality of life will improve and once her immunity has built up, to continue working at the family-owned-and-run Overlander Motel.

I will be forever grateful to Dr Frederinco, the brilliant medical team in Russia, Roma, its local businesses and the wider community for blessing me with a new life, Amanda said.

Through the generosity and support by all, I have realised how lucky I am to be surrounded by such a caring community.

Amanda said she knew that while there is a long road ahead of her, every passing day she is more feeling more hopeful.

I was told that recovery can be like a rollercoaster, so I will accept the bad days and make sure I remember the good, she said.

My walking is slowly getting safer and less hazardous to myself . and to all other pedestrians. Every morning I wake up, knowing that every days a better day.

I am a new person, it is just a miracle.

Stats about MS

With MS Queensland aware of nearly 4000 people living with Multiple Sclerosis in Queensland and over 25,600 people in Australia living with the neurological condition.

Most people with MS in Australia experience their first symptoms between 20 and 40 years of age, with about three quarters of people living with MS, female.

MS is not considered a classic genetic disease in that there is not one single gene that causes the condition. Rather, there are more than 200 different known genetic factors which contribute to the risk of developing MS. It has been estimated that genes may account for around half of the risk for MS, and those with a family history of MS are at greater risk than the general population. Even so, the majority of people with a family member with MS will not develop the disease so genes on their own are not enough.

MS is caused by a complex interaction between a persons genetics and environment factors.

Autologous haematopoietic stem cell transplant (AHSCT) is an immunosuppressive chemotherapy treatment combined with reinfusion of blood stem cells to help rebuild the immune system.

AHSCT has been used for decades for the treatment of blood cancers. However in the past ten or so years a number of international observational studies of several hundred patients have been published with some patients being followed for five to eight years.

The treatment consisted of four days of stimulation before the stem cells were collected and then Amanda was pumped full of high dose chemotherapy.

Amanda then had a rest day, and on January 29, her harvested stem cells were returned to her MS ravaged body, signalling the rebirth of her immune system with no memory of MS.

After that she was given daily steroid infusions and was put into isolation for six nights before one final dose of chemotherapy.

Response from MS Queensland about the treatment

CEO of MS Queensland Zane Ali said MS Queensland and MS Research Australia are continuing to support Australian research in the use of AHSCT to treat multiple sclerosis.

Rigorous evidence for the efficacy and safety of AHSCT in relation to other MS therapies, and the most appropriate circumstances for its use, is required for Australian hospitals and clinicians to provide this intervention with equity and with greater confidence in the potential outcomes, he said.

Australian hospitals and doctors are likely to recommend AHSCT as a possible treatment only if the other approved MS therapies are not working for an individual with MS or cannot be used in an individual for other reasons.

Despite Amandas MRI revealing her Central Nervous System was so progressed (with 35 lesions or more on the spine), she met the criteria for the treatment because of her mobility.

You have to be at a very healthy besides having MS, patients are tested from head to toe when they first arrive in hospital to ensure that they dont have any cancers or illnesses that could effect the viability of the treatment, said daughter Chloe.

The doctor was surprised after he saw how mobile mum still was considering the damage that he saw in her brain.

People arent accepted all of the time, some are told before they go and some are only told after all of the testing is completed in Moscow, then they are then sent home. International studies also suggest AHSCT does not halt or reverse progressive forms of the disease, and is therefore unlikely that

AHSCT would be recommended as a treatment for patients with secondary progressive or primary progressive MS.

Currently the treatment is provided in Australia through two observational clinical trials, at St Vincents, Sydney and Austin Health, Melbourne and by a small number of other centres on a case-by-case basis.

These centres have strict eligibility requirements that have been set by the hospital ethics committees and may only apply to limited numbers of patients with MS, Mr Ali said.

It is for this reason patients need to be referred to these centres by a neurologist, who can provide a detailed clinical history and MRI findings, Mr Ali said.

Mr Ali said that data from the large European Bone Marrow Transplant Registry suggests that in approximately 55 per cent of people with MS, treated with a range of different chemotherapy regimens, at three years of follow-up, inflammatory disease is halted with no evidence during the follow-up period of relapses, active brain lesions or disability progression.

After five years approximately 45 per cent of people remain progression free.

This case series included patients with both relapsing remitting and progressive disease, he said.

Other smaller studies have shown similar results, with remission of disease seen in these studies in at least 63 per cent of patients followed for a minimum of three years.

Most studies also show that the risk of disease activity returning gradually increases over longer periods of follow-up.

Mr Ali said in some but not all, of the people with MS who respond to AHSCT, some reversal of disability has been noted in some studies.

Other patients may continue to experience disease activity and disability progression (worsening) despite treatment with AHSCT, he said.

In people with progressive forms of MS or relapsing remitting MS of longer duration, the benefits of the procedure have been much less clear and accumulation of disability usually continues.

Amanda said they chose Moscow for the treatment because despite other countries offering the experimental procedure, after thorough research they found Russia had the highest rate of treatment success.

They accept advanced progressive MS where most of the other clinics offering it only treat relapsing remitting MS, she said.

I was still on my feet (only just) but people went over in wheelchairs, walkers, walking sticks and many were older than me.

For Chloe, who is training to become a nurse and who spent every spare moment researching AHSCT treatment said while they mostly compared the options available in Mexico and Russia, Russia stood out to them because it was cheaper and they had more experience.

One of the major influencing factors was that in Mexico patients stayed in a complex with they carer and in Russia patients stayed in a hospital, so we felt more reassured knowing that mum would have 24 hour care provided to her at the touch of a buzzer, she said.

Great lengths of a loving daughter

Although Amanda has lived with MS for 34 years, she feels like she is one of the lucky ones.

None of this would have been possible without Chloe. Her drive and determination surprises me every day, she said.

Researching, booking, fundraising and organising the whole trip, proves to me that I am the luckiest mum on earth.

Chloe was the driving force behind the push for treatment and the GoFundMe campaign which raised over half the $80,000 goal was with her mum every step of the journey.

I have found spending a month in Russia very interesting, the first couple of weeks for easy, but after that I just wanted to come home to Australia, the 19-year-old said.

Every day I would go and visit Mum in the morning and stay there with her until dark and then head on back to the hotel, I basically just did that every day.

I made some great friends with some other patients carers and so often we would catch up at the end of the day to recuperate and support each other.

Although the month spent away from her loved ones began to take its toll, Chloe has high hopes for the future.

It was very draining being over there, I felt like I wasnt doing much but I was just always so tired, she said.

Its amazing to see how quickly mum is healing after the treatment, but it will take some time to see what the true outcome for her is going to be.

In the end, we dont know what the future holds for mum and her MS, we are just thinking positively and hope that we see improvements over the next 12 months.

We feel very lucky that we had the opportunity to go over and are now advocating for other people to have the treatment as well.

Chloe and Amanda Weyman-Jones sightseeing in Moscow before the treatment began.

During the treatment.

Amanda Weyman-Jones with Greta and Theresa who were also going through the treatment.

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Roma woman tells of her 'life-changing' MS treatment - Observer

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Stem Cell Therapy for Colon Cancer – The Ritz Herald

By daniellenierenberg

An article published in Experimental Biology and Medicine(Volume 245, Issue 6, March 2020)examines the safety of stem cell therapy for the treatment of colon cancer.The study, led by Dr. J. Liu in the State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design at the East China University of Science and Technology in Shanghai (China), reports that mesenchymal stem cells from a variety of sources promote the growth and metastasis of colon cancer cells in an animal model.

Mesenchymal stem (MSCs), a category of adult stem cells, are being evaluated as a therapy for numerous cancers.MSCs are excellent carriers for tumor treatment because they migrate to tumor tissues, can be genetically modified to secrete anticancer molecules and do not elicit immune responses.Clinical trials have shown that MSCs carrying modified genes can be used to treat colon cancer as well as ulcerative colitis. However, some studies have demonstrated MSCs can differentiate into cancer-associated fibroblasts and promote tumor growth.Therefore, additional studies are needed to evaluate the safety of MSCs for targeted treatment of colon cancer.

In the current study, Dr. Liu and colleagues examined the effects of mesenchymal stem cells (MSCs) from three sources (bone marrow, adipose, and placenta) on colon cancer cells.MSCs from all three sources promoted tumor growth and metastasis in vivo. In vitro studies demonstrated that MSCs promote colon cancer cell stemness and epithelial to mesenchymal transition, which would enhance tumor growth and metastasis respectively.Finally, the detrimental effects of MSCs could be reversed by blocking IL-8 signaling pathways. Dr. Ma, a co-author of the study, said that Mesenchymal stem cells have a dual role: promoting and/or suppressing cancer. Which effect is dominant depends on the type of tumor cell, the tissue source of the MSC and the interaction between the MSC and the cancer cell. This is the major issue in the clinical application research of MSCs, and additional preclinical experimental data will be needed to evaluate the safety of MSCs for colon cancer treatment.

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology & Medicine, said: Lui and colleagues have performed elegant studies on the impact of mesenchymal stem cells (MSCs), from various sources, upon the proliferation, stemness, and metastasis of colon cancer stem cells (CSCs) in vitro and in vivo. They further demonstrate that IL-8 stimulates the interaction between colon CSCs and MSCs, and activates the MAPK signaling pathway in colon CSCs.This provides a basis for the further study of MSCs as a biologic therapy for colon cancer.

Experimental Biology and Medicine is a global journal dedicated to the publication of multidisciplinary and interdisciplinary research in the biomedical sciences. The journal was first established in 1903. Experimental Biology and Medicine is the journal of the Society of Experimental Biology and Medicine. To learn about the benefits of society membership, visit sebm.org.

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First Two Patients Enrolled in Randomized Phase 2, COVID-19 Trial with Leronlimab; Five More Severely Ill COVID-19 Patients Treated Under Emergency…

By daniellenierenberg

DetailsCategory: AntibodiesPublished on Monday, 06 April 2020 18:54Hits: 142

Fifteen (15) severely ill COVID-19 patients have been treated under an EIND;

7-day results from the first four patients are available and are very promising;

7-day results for the first 10 patients will be available this week

VANCOUVER, Canada I April 06, 2020 I CytoDyn Inc. (OTC.QB: CYDY), (CytoDyn or the Company"), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today that the first two COVID-19 patients have been treated with leronlimab under the Companys Phase 2 randomized clinical trial, which is for patients with mild-to-moderate indications. The Company anticipates that enrollment of more patients will accelerate this week at multiple clinical sites.

In addition, the Companys investigational new drug, leronlimab, has now been administered to 15 severely ill COVID-19 patients atfour hospitals, 10 patients treated at a leading medical center in the New York City area and five patients at three other hospitals, all under an emergency investigational new drug (EIND), which were granted by the U.S. Food and Drug Administration (FDA) for each individual patient.

CytoDyn also anticipates initiating its other COVID-19 trial this week. This trial is a Phase 2b/3 for severely ill COVID-19 patients and is for 342 patients, double-blinded with a 2:1 ratio (drug to placebo ratio). Patients enrolled in this trial are expected to be administered leronlimab for two weeks, with the primary endpoint being the mortality rate at 14 days. The Company will perform an interim analysis on the data from 50 patients following two weeks of leronlimab therapy.

Bruce Patterson, M.D., Chief Executive Officer and founder of IncellDx, a diagnostic partner and advisor to CytoDyn, commented, We are encouraged by the positive results demonstrated with leronlimab in the New York patients. Our team is working hard to distribute leronlimab to multiple clinical sites to initiate therapy in patients with severe COVID-19 disease. While every patient is experiencing different comorbidities, we are seeing similar clinical responses, which we believe is a reflection of leronlimabs mechanism of action.

Nader Pourhassan, Ph.D., President and Chief Executive Officer of CytoDyn, said, Our partnership with the New York medical team and now other hospitals has been exemplary. We are collaborating in every aspect to deliver leronlimab to patients in order to provide proof of concept as soon as possible. The outstanding coordination among the physicians, the hospital administrators, the FDA, and our team, will hopefully help mitigate the deleterious effects from this pandemic should we prove leronlimab as a solution. The lead physician in New York is a true medical hero, who deserves to be recognized for his contribution to humanity in the pandemic of COVID-19. We are very hopeful of sending the day three and day seven results of the first ten EIND patients to the FDA by the end of this week.

About Coronavirus Disease 2019SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain, and the virus is highly contagious. COVID-19 typically transmits person to person through respiratory droplets, commonly resulting from coughing, sneezing, and close personal contact. Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals. For confirmed COVID-19 infections, symptoms have included fever, cough, and shortness of breath. The symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure. Clinical manifestations in patients have ranged from non-existent to severe and fatal. At this time, there are minimal treatment options for COVID-19.

About Leronlimab (PRO 140) The FDA has granted a Fast Track designation to CytoDyn for two potential indications of leronlimab for deadly diseases. The first as a combination therapy with HAART for HIV-infected patients and the second is for metastatic triple-negative breast cancer.Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases, including NASH.Leronlimab has completed nine clinical trials in over 800 people, including meeting its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab could significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

In the setting of cancer, research has shown that CCR5 may play a role in tumor invasion, metastases, and tumor microenvironment control. Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting aPhase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation. It may be crucial in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells. CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to support further the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD, blocking the CCR5 receptor from recognizing specific immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted orphan drug designation to leronlimab for the prevention of GvHD.

About CytoDynCytoDyn is a late-stage biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a critical role in the ability of HIV to enter and infect healthy T-cells.The CCR5 receptor also appears to be implicated in tumor metastasis and immune-mediated illnesses, such as GvHD and NASH. CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. CytoDyn plans to seek FDA approval for leronlimab in combination therapy and plans to complete the filing of a Biologics License Application (BLA) in April of 2020 for that indication. CytoDyn is also conducting a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients. CytoDyn plans to initiate a registration-directed study of leronlimab monotherapy indication. If successful, it could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV with no reported drug-related serious adverse events (SAEs). Moreover, a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients; some patients on leronlimab monotherapy have remained virally suppressed for more than five years. CytoDyn is also conducting a Phase 2 trial to evaluate leronlimab for the prevention of GvHD and a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is atwww.cytodyn.com.

SOURCE: Cytodyn

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First Two Patients Enrolled in Randomized Phase 2, COVID-19 Trial with Leronlimab; Five More Severely Ill COVID-19 Patients Treated Under Emergency...

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BioIVT Opens New Blood Donor Center to Support Boston-area Research into COVID-19 Therapies, Vaccines and Diagnostics – Yahoo Finance

By daniellenierenberg

Located on the Tufts University Medford, MA campus, this new donor center will enable delivery of fresh blood, leukopaks and buffy coats for COVID-19, cell and gene therapy research within hours of collection

WESTBURY, N.Y., April 6, 2020 /PRNewswire/ --BioIVT, a leading provider of research models and services for drug and diagnostic development, today announced the opening of its new blood donor center on the Tufts University campus in Medford, MA to support academic and pharmaceutical researchers involved in COVID-19, cell and gene therapy research.

"BioIVT wants to play a leading role in supporting COVID-19 research efforts and blood donations are a vital resource for the research and development of new therapies, vaccines, and diagnostics. We have many years' experience developing blood products, including blood-derived immune cells for cell and gene therapy research, and we want to make that expertise count," said BioIVT CEO Jeff Gatz. "Researchers recognize and appreciate BioIVT's rapid response and commitment to high quality, fresh blood products and this new donor center will allow us to offer those attributes and services to additional US clients."

BioIVT's new Boston blood donor center is its seventh. The company has similar facilities located in California, Tennessee and Pennsylvania to serve US clients and in London, UK for EU-based clients.

"While the initial focus at our Boston donor center will be on delivering fresh blood, leukopaks and buffy coats within hours of collection, we plan to add more capabilities and donors over time," said Jeff Widdoss, Vice President of Donor Center Operations at BioIVT.

Leukopaks, which contain concentrated white blood cells, are used to help identify promising new drug candidates, assess toxicity levels, and conduct stem cell and gene therapy research. They are particularly useful for researchers who need to obtain large numbers of leukocytes from a single donor.

BioIVT blood products can be supplied with specific clinical data, such as the donor age, ethnicity, gender, BMI and smoking status. Its leukopaks are also human leukocyte antigen (HLA), FC receptor and cytomegalovirus typed. HLA typing is used to match patients and donors for bone marrow or cord blood transplants. FC receptors play an important role in antibody-dependent immune responses.

COVID-19-related Precautions Blood donor centers are considered essential businesses and will remain open during the COVID-19 quarantine. BioIVT is taking additional safety measures to protect both blood donors and its staff during this difficult time. It has instituted several social distancing measures, including increasing the space between chairs in the waiting room and between donor beds, and limiting the entrance of non-essential personnel. The screening rooms are disinfected between donors and all areas of the center continue to be cleaned at regular intervals.

As soon as each blood donor signs their informed consent form, their temperature is taken. If they have a fever, their appointment is postponed, and they are referred to their physician. Any donor who develops COVID-19 symptoms after donating blood is required to inform the center immediately.

All BioIVT blood collections are conducted under institutional review board (IRB) oversight and according to US Food and Drug Administration (FDA) regulations and American Association of Blood Banks (AABB) guidelines.

Those who would like to donate blood at BioIVT's new Boston-area donor center should call 1-833-GO-4-CURE or visit http://www.biospecialty.com to make an appointment.

Further information about the products available from BioIVT's new donor center can be found at https://info.bioivt.com/ma-donor-ctr-req.

About BioIVTBioIVT is a leading global provider of research models and value-added research services for drug discovery and development. We specialize in control and disease-state biospecimens including human and animal tissues, cell products, blood and other biofluids. Our unmatched portfolio of clinical specimens directly supports precision medicine research and the effort to improve patient outcomes by coupling comprehensive clinical data with donor samples. Our PHASEZERO Research Services team works collaboratively with clients to provide target and biomarker validation, phenotypic assays to characterize novel therapeutics, clinical assay development and in vitro hepatic modeling solutions. And as the premier supplier of hepatic products, including hepatocytes and subcellular fractions, BioIVT enables scientists to better understand the pharmacokinetics and drug metabolism of newly-discovered compounds and their effects on disease processes. By combining our technical expertise, exceptional customer service, and unparalleled access to biological specimens, BioIVT serves the research community as a trusted partner in elevating science. For more information, please visit http://www.bioivt.com or follow the company on Twitter @BioIVT.

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FDA ACCEPTS MESOBLAST’S BIOLOGICS LICENCE APPLICATION FOR RYONCIL AND AGREES TO PRIORITY REVIEW – GlobeNewswire

By daniellenierenberg

NEW YORK, April 01, 2020 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq: MESO; ASX:MSB), global leader in cellular medicines for inflammatory diseases, today announced that the United States Food and Drug Administration (FDA) has accepted for priority review the Companys Biologics License Application (BLA) filing for RYONCILTM (remestemcel-L), its allogeneic cell therapy for the treatment of children with steroid-refractory acute graft versus host disease (SR-aGVHD). The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of September 30, 2020, and if approved, Mesoblast will make RYONCIL immediately available in the United States.

A Priority Review designation will direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. The FDA has advised that they are planning to hold an Advisory Committee Meeting to discuss this application.

Mesoblast Chief Executive Dr Silviu Itescu stated: There is a critical need to improve survival outcomes in children suffering from the more advanced stages of this devastating disease. The acceptance of the BLA represents an important milestone for the Company. Mesoblast is on track in its preparation for the potential launch of RYONCIL, including meeting its target inventory build and commercial team roll-out.

About Acute GVHD Acute GVHD occurs in approximately 50% of patients who receive an allogeneic bone marrow transplant (BMT). Over 30,000 patients worldwide undergo an allogeneic BMT annually, primarily during treatment for blood cancers, and these numbers are increasing.1 In patients with the most severe form of acute GVHD (Grade C/D or III/IV) mortality is as high as 90% despite optimal institutional standard of care.2,3. There are currently no FDA-approved treatments in the US for children under 12 with SR-aGVHD.

About RYONCILTM Mesoblasts lead product candidate, RYONCIL (remestemcel-L), is an investigational therapy comprising culture- expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor. It is administered to patients in a series of intravenous infusions. RYONCIL is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in SR- aGVHD by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

References

About Mesoblast Mesoblast Limited(Nasdaq: MESO; ASX:MSB) is a world leader in developing allogeneic (off-the-shelf) cellular medicines. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of commercial products and late-stage product candidates. Mesoblasts proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblast has filed a Biologics License Application to theUnited States Food and Drug Administration(FDA) to seek approval of its product candidate RYONCIL (remestemcel-L) for steroid-refractory acute graft versus host disease (acute GvHD). Remestemcel-L is also being developed for other rare diseases. Mesoblast is completing Phase 3 trials for its product candidates for advanced heart failure and chronic low back pain. If approved, RYONCIL is expected to be launched inthe United Statesin 2020 for pediatric steroid-refractory acute GVHD. Two products have been commercialized inJapanandEuropeby Mesoblasts licensees, and the Company has established commercial partnerships inEuropeandChinafor certain Phase 3 assets.

Mesoblast has a strong and extensive global intellectual property (IP) portfolio with protection extending through to at least 2040 in all major markets. This IP position is expected to provide the Company with substantial commercial advantages as it develops its product candidates for these conditions.

Mesoblast has locations inAustralia,the United StatesandSingaporeand is listed on theAustralian Securities Exchange(MSB) and on the Nasdaq (MESO). For more information, please seewww.mesoblast.com, LinkedIn:Mesoblast Limitedand Twitter: @Mesoblast

Forward-Looking Statements This announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward- looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward-looking statements include, but are not limited to, statements about the timing, progress and results of Mesoblasts preclinical and clinical studies; Mesoblasts ability to advance product candidates into, enroll and successfully complete, clinical studies; the timing or likelihood of regulatory filings and approvals; and the pricing and reimbursement of Mesoblasts product candidates, if approved. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

Release authorized by the Chief Executive.

For further information, please contact: Julie Meldrum Corporate Communications T: +61 3 9639 6036 E: julie.meldrum@mesoblast.com

Schond Greenway Investor RelationsT: +1 212 880 2060E: schond.greenway@mesoblast.com

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FDA ACCEPTS MESOBLAST'S BIOLOGICS LICENCE APPLICATION FOR RYONCIL AND AGREES TO PRIORITY REVIEW - GlobeNewswire

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BrainStorm Awarded $1.5 Million Non-Dilutive Grant for 2020 by the Israel Innovation Authority – Yahoo Finance

By daniellenierenberg

NEW YORK and PETACH TIKVAH, Israel, April 03, 2020 (GLOBE NEWSWIRE) -- BrainStorm Cell Therapeutics Inc. (BCLI), a leading developer of adult stem cell technologies for neurodegenerative diseases, today announced that its wholly-owned subsidiary, Brainstorm Cell Therapeutics Ltd., has been awarded a new grant of approximately $1.5 million by the Israel Innovation Authority (IIA). The grant enables Brainstorm to continue development of advanced cellular manufacturing capabilities, furthers development of MSC-derived exosomes as a novel therapeutic platform, and will ultimately enable Brainstorm to expand the therapeutic pipeline in neurodegenerative disorders.

BrainStorm's CEO Chaim Lebovits, commented, "The Israel Innovation Authority's support of our programs provides further validation for the potential of our treatments to help patients suffering from neurodegenerative disorders. The continued financial support for our research and development will further our ability to execute our strategic objectives, as we finalize our Phase 3 pivotal trial with NurOwn in ALS patients and advance our cellular technology pipeline."

The IIA has supported BrainStorm Cell Therapeutics Ltd. since 2007, providing grants totaling approximately 11.4 million USD in support of the development of NurOwn and other projects. BrainStorm will be required to pay mid-single digit royalties to the IIA based on sales of the products, up to a total of the cumulative amount of IIA grants received plus accumulated interest.

About NurOwnNurOwn (autologous MSC-NTF cells) represent a promising investigational approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors. Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression. NurOwn is currently being evaluated in a Phase 3 ALS randomized placebo-controlled trial and in a Phase 2 open-label multicenter trial in Progressive MS.

Story continues

AboutBrainStorm Cell Therapeutics Inc.BrainStorm Cell Therapeutics Inc.is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwnCellular Therapeutic Technology Platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement as well as through its own patents, patent applications and proprietary know-how. Autologous MSC-NTF cells have received Orphan Drug status designation from theU.S. Food and Drug Administration(U.S.FDA) and theEuropean Medicines Agency(EMA) in ALS. BrainStorm has fully enrolled the Phase 3 pivotal trial in ALS (NCT03280056), investigating repeat-administration of autologous MSC-NTF cells at six sites in theU.S., supported by a grant from theCalifornia Institute for Regenerative Medicine(CIRM CLIN2-0989). The pivotal study is intended to support a BLA filing for U.S.FDAapproval of autologous MSC-NTF cells in ALS. BrainStorm received U.S.FDAclearance to initiate a Phase 2 open-label multi-center trial of repeat intrathecal dosing of MSC-NTF cells in Progressive Multiple Sclerosis (NCT03799718) inDecember 2018and has been enrolling clinical trial participants sinceMarch 2019. For more information, visit the company'swebsite.

Safe-Harbor Statement Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could causeBrainStorm Cell Therapeutics Inc.'sactual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may", "should", "would", "could", "will", "expect", "likely", "believe", "plan", "estimate", "predict", "potential", and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorms need to raise additional capital, BrainStorms ability to continue as a going concern, regulatory approval of BrainStorms NurOwn treatment candidate, the success of BrainStorms product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorms NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorms ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorms ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation,; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

CONTACTSInvestor Relations:Preetam Shah, MBA, PhDChief Financial OfficerBrainStorm Cell Therapeutics Inc.Phone: + 1.862.397.1860pshah@brainstorm-cell.comMedia:Sean LeousWestwicke/ICR PRPhone: +1.646.677.1839sean.leous@icrinc.com

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Cellect Biotechnology Reports Fourth Quarter and Full Year 2019 Results – P&T Community

By daniellenierenberg

TEL AVIV, Israel, April 3, 2020 /PRNewswire/ -- Cellect Biotechnology Ltd. (Nasdaq: APOP), a developer of a novel stem cell production technology, today announced operating and financial results for the fourth quarter and full year ended December 31, 2019.

"We achieved a number of strategic priorities in 2019, including the IND approval to commence our first-ever trial in the U.S.," commented Dr. Shai Yarkoni, Chief Executive Officer."We plan to begin enrolling patients for this trial and completing the trial in Israel when the COVID-19 pandemic is mitigated. While these near-term events are value-enhancers, I believe that our recently announced prospective partnership with Canndoc could be a game-changer for Cellect and change our growth trajectory. It has the potential to significantly enhance our short and long term business prospects and shareholder value. As a player in the fast-growing pain management market, we would anticipate significant revenue opportunities already this year."

Recent Strategic Development

As previously announced, on March 4, 2020, the Company entered into a commercial binding Letter Of Intent (LOI) with Canndoc Ltd, a leading pharma grade medical cannabis pioneer and a wholly owned subsidiary of publicly-traded Intercure Ltd. (TASE: INCR),to acquire from Canndoc all rights to the use and sell Canndoc products for the reduction of opioid usage, including accumulated data, as well as on-going and pipeline of clinical trials. This commercial arrangement is subject to negotiation and approval by each company's board of directors and definitive agreements.

Additionally, the two companies signed a non-binding LOI for a full merger. Under preliminary details, Cellect will acquire from Intercure all of Canndoc outstanding shares, in exchange for additional Cellect ADRs to be in total ~95% (~93% on a fully diluted basis) of the merged company. The proposed merger is subject to independent valuation of both companies, fairness opinion by a third party, negotiation of a definitive agreement, approval of the agreement by the Company's Board of Directors and shareholders, internal approvals by Canndoc and Intercure, and customary closing conditions, including the approval of the IMCA (Israeli Medical Cannabis Agency). Upon the closing of the merger, Cellect and Canndoc will aim to fulfill all of the requirements to ensure the Company's ADRs and warrants continue trading on the Nasdaq Stock Market (Nasdaq) and, for this purpose, Intercure would commit to invest a cash sum of at least $3.0 million in any public offering that is undertaken by the Company, at a price of not less than $4.50 per ADR.

Based on the progress to date, the Company continues to expect the commercial and merger transactions will close in the second quarter of 2020.

Additional Operating Highlights:

Clinical Progress Update:

Due to the ongoing COVID-19 pandemic, the Company is experiencing clinical disruption such as:

The Company continues to take all the necessary precautions advised by global health officials to ensure the health and safety of its employees and partners. The Company is unaware of any impact on employees from pandemic related exposure or illness and is continuing to perform in-house research, including in the opioid/pain management area.

Fourth Quarter and Full Year 2019 Financial Results:

Balance Sheet Highlights:

For the convenience of the reader, the amounts have been translated from NIS into U.S. dollars, at the representative rate of exchange on December 31, 2019 (U.S. $1 = NIS 3.456).

About Cellect Biotechnology Ltd.

Cellect Biotechnology (NASDAQ: APOP) has developed a breakthrough technology, for the selection of stem cells from any given tissue, that aims to improve a variety of stem cell-based therapies.

The Company's technology is expected to provide researchers, clinical community and pharma companies with the tools to rapidly isolate stem cells in quantity and quality allowing stem cell-based treatments and procedures in a wide variety of applications in regenerative medicine. The Company's current clinical trial is aimed at bone marrow transplantations in cancer treatment.

Forward Looking Statements

This press release contains forward-looking statements about the Company's expectations, beliefs and intentions. Forward-looking statements can be identified by the use of forward-looking words such as "believe", "expect", "intend", "plan", "may", "should", "could", "might", "seek", "target", "will", "project", "forecast", "continue" or "anticipate" or their negatives or variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical matters. For example, forward-looking statements are used in this press release when we discuss Cellect's intent regarding the future potential of Cellect's technology. These forward-looking statements and their implications are based on the current expectations of the management of the Company only and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. In addition, historical results or conclusions from scientific research and clinical studies do not guarantee that future results would suggest similar conclusions or that historical results referred to herein would be interpreted similarly in light of additional research or otherwise. The following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: the Company's history of losses and needs for additional capital to fund its operations and its inability to obtain additional capital on acceptable terms, or at all; the Company's ability to continue as a going concern; uncertainties of cash flows and inability to meet working capital needs; the Company's ability to obtain regulatory approvals; the Company's ability to obtain favorable pre-clinical and clinical trial results; the Company's technology may not be validated and its methods may not be accepted by the scientific community; difficulties enrolling patients in the Company's clinical trials; the ability to timely source adequate supply of FasL; risks resulting from unforeseen side effects; the Company's ability to establish and maintain strategic partnerships and other corporate collaborations; the scope of protection the Company is able to establish and maintain for intellectual property rights and its ability to operate its business without infringing the intellectual property rights of others; competitive companies, technologies and the Company's industry; unforeseen scientific difficulties may develop with the Company's technology; and the Company's ability to retain or attract key employees whose knowledge is essential to the development of its products. Any forward-looking statement in this press release speaks only as of the date of this press release. The Company undertakes no obligation to publicly update or review any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by any applicable securities laws. More detailed information about the risks and uncertainties affecting the Company is contained under the heading "Risk Factors" in Cellect Biotechnology Ltd.'s Annual Report on Form 20-F for the fiscal year ended December 31, 2019 filed with the U.S. Securities and Exchange Commission, or SEC, which is available on the SEC's website, http://www.sec.gov, and in the Company's periodic filings with the SEC.

Cellect Biotechnology Ltd

Consolidated Statement of Operation

Convenience

translation

Twelve months

ended

Twelve months ended

Three months ended

December 31,

December 31,

December 31,

2019

2019

2018

2019

2018

Unaudited

Audited

Audited

Unaudited

Unaudited

U.S. dollars

NIS

(In thousands, except share and pershare data)

Research and development expenses

3,508

12,122

13,513

2,571

4,040

General and administrative expenses

2,954

10,210

15,734

2,378

4,733

Operating loss

6,462

22,332

29,247

4,949

8,773

Financial expenses (income) due towarrants exercisable into ADS

(2,032)

(7,022)

(7,719)

998

(4,784)

Other financial expenses (income), net

433

1,498

(1,415)

129

(238)

Total comprehensive loss

4,863

16,808

20,113

6,076

3,751

Loss per share:

Basic and diluted loss per share

0.023

0.079

0.155

0.027

0.029

Weighted average number of sharesoutstanding used to compute basic anddiluted loss per share

212,642,505

212,6432,505

129,426,091

224,087,799

130,274,953

Cellect Biotechnology Ltd

Consolidated Balance Sheet Data

ASSETS

Convenience

translation

December 31,

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Cellect Biotechnology Reports Fourth Quarter and Full Year 2019 Results - P&T Community

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Is There a New CAR T-Cell Treatment for Mantle Cell Lymphoma? – AJMC.com Managed Markets Network

By daniellenierenberg

Maggie L. Shaw

Mantle cell lymphoma is a type of B-cell non-Hodgkin lymphoma with a typically poor prognosis. Even with an allogeneic stem cell transplant, patients can become resistant to chemotherapy. Most do not survive 4 or 5 years after diagnosis, and the 10-year survival rate hovers between 5% and 10%.

Chimeric antigen receptor (CAR) T-cell therapy has been making great inroads as targeted treatment for many types of cancers highly resistant to other treatments, by prolonging patient survival and increasing their quality of life. Until now, similar results have not been seen in patients with MCL. However, with their successful phase 2 ZUMA-2 trial results just published in the New England Journal of Medicine, a group of researchers led by Michael Wang, MD, from The University of Texas MD Anderson Cancer Center, are able to show that these patients can benefit from the specialized therapy.

In this study conducted in the United States and Europe, the patient population had relapsed/refractory progressive disease despite receiving Brutons tyrosine kinase (BTK) inhibitor therapy and from 3 to 5 prior therapies.

BTK inhibitor therapy has greatly improved outcomes in patients with relapsed or refractory mantle cell lymphoma, yet patients who have disease progression after receiving the treatment are likely to have poor outcomes, with median overall survival of just 6 to 10 months, the authors said.

The median patient age was 65 years (range, 38-79). They were evaluated for response to a single infusion of KTE-X19, an anti-CD19 CAR T-cell therapy, that was dosed at 2106 CAR T cells/kg of body weight. Seventy-four patients were enrolled between October 24, 2016, and April 16, 2019; the treatment was manufactured for 71 and ultimately administered to 68.

There was a follow-up after 60 patients were monitored for 7 months, at which time a primary efficacy analysis was conducted. The primary endpoint was objective response (complete [CR] or partial [PR]), which was confirmed via bone marrow evaluation and positron emission tomography-computed tomography.

Overall, 85% of the entire study cohort of 74 patients was able to reach an objective response to KTE-X19, 59% of whom had a CR. These numbers were even higher among the group of 60 patients. Ninety-three percent (95% CI, 84%-98%) achieved an objective response, which was evaluated by an independent radiologic review committee. And of this group, 67% (95% CI, 53%-78%) had a CR.

The median times to response were impressive, with there being 1 month (range, 0.8-3.1) to initial response and 3 months (range, 0.9-9.3) to CR. In addition, of the 42 patients who initially had a PR or stable disease (SD), 24 (21 who had a PR, 3 who had SD) progressed to a CR in a median 2.2 months (range, 1.8-8.3).

Progression-free (PFS) and overall survival (OS) results also show promise to treatment with KTE-X19. As of the data cutoff date, there was evidence of remission in 78% patients who had a CR, with similar results seen in 57% of patients from the primary efficacy analysis. Overall, at 12 months, the PFS and OS were 61% and 83%, respectively.

Common adverse events to the treatment of grade 3 or higher included cytopenias (94%) and infections (32%). Ninety-one percent also experienced cytokine release syndrome, with a median time to onset of 2 days (range, 1-13) for any grade and 4 days (range, 1-9) for at least grade 3, but none died as a result. According to the study authors, most symptoms were reversible.

ZUMA-2 is the first multi-center, phase 2 study of CAR T-cell therapy for relapsed/refractory mantle cell lymphoma, and these efficacy and safety results are encouraging, stated Wang. Although this study continues, our reported results, including a manageable safety profile, point to this therapy as an effective and viable option for patients with relapsed or refractory mantle cell lymphoma.

Reference

Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382;1331-1342. doi: 10.1056/NEJM0a1914347.

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CytoDyn CEO Dr. Pourhassan to Appear on Fox Business Network Friday, April 3, 2020 at 2:00 pm ET to Discuss Leronlimab Treatment of 10 Severely Ill…

By daniellenierenberg

Both Phase 2 and Phase 2b/3 trials for COVID-19 patients will be discussed

VANCOUVER, Washington, April 03, 2020 (GLOBE NEWSWIRE) -- CytoDyn Inc. (CYDY), (CytoDyn or the Company"), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today that Nader Pourhassan, Ph.D., President and Chief executive Officer of CytoDyn will appear on Fox Business Network on the Making Money with Charles Payne program. The program will air from 2:00 pm ET to 3:00 pm ET (11:00 am PT to 12 noon PT) and is also available via live streaming at https://www.foxbusiness.com/shows/making-money-with-charles-payne.

The Companys investigational new drug, leronlimab, has been administered to 10 severely ill patients with COVID-19 at a leading medical center in the New York City area under an emergency IND recently granted by the FDA. The Company recently initiated enrollment in a Phase 2 trial for leronlimab treatment of COVID-19 patients with mild-to-moderate indications and under the same IND, is now proceeding with its second COVID-19 clinical, a Phase 2b/3 trial for the treatment of critically ill patients.

About Coronavirus Disease 2019SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain, and the virus is highly contagious. COVID-19 typically transmits person to person through respiratory droplets, commonly resulting from coughing, sneezing, and close personal contact. Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals. For confirmed COVID-19 infections, symptoms have included fever, cough, and shortness of breath. The symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure. Clinical manifestations in patients have ranged from non-existent to severe and fatal. At this time, there are minimal treatment options for COVID-19.

About Leronlimab (PRO 140) The FDA has granted a Fast Track designation to CytoDyn for two potential indications of leronlimab for deadly diseases. The first as a combination therapy with HAART for HIV-infected patients and the second is for metastatic triple-negative breast cancer.Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases, including NASH.Leronlimab has completed nine clinical trials in over 800 people, including meeting its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab could significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

In the setting of cancer, research has shown that CCR5 may play a role in tumor invasion, metastases, and tumor microenvironment control. Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting aPhase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation. It may be crucial in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells. CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to support further the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD, blocking the CCR5 receptor from recognizing specific immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted orphan drug designation to leronlimab for the prevention of GvHD.

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About CytoDynCytoDyn is a late-stage biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a critical role in the ability of HIV to enter and infect healthy T-cells.The CCR5 receptor also appears to be implicated in tumor metastasis and immune-mediated illnesses, such as GvHD and NASH. CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. CytoDyn plans to seek FDA approval for leronlimab in combination therapy and plans to complete the filing of a Biologics License Application (BLA) in April of 2020 for that indication. CytoDyn is also conducting a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients. CytoDyn plans to initiate a registration-directed study of leronlimab monotherapy indication. If successful, it could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV with no reported drug-related serious adverse events (SAEs). Moreover, a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients; some patients on leronlimab monotherapy have remained virally suppressed for more than five years. CytoDyn is also conducting a Phase 2 trial to evaluate leronlimab for the prevention of GvHD and a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is atwww.cytodyn.com.

Forward-Looking StatementsThis press releasecontains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as believes, hopes, intends, estimates, expects, projects, plans, anticipates and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. The Companys forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties including: (i)the sufficiency of the Companys cash position, (ii)the Companys ability to raise additional capital to fund its operations, (iii) the Companys ability to meet its debt obligations, if any, (iv)the Companys ability to enter into partnership or licensing arrangements with third parties, (v)the Companys ability to identify patients to enroll in its clinical trials in a timely fashion, (vi)the Companys ability to achieve approval of a marketable product, (vii)the design, implementation and conduct of the Companys clinical trials, (viii)the results of the Companys clinical trials, including the possibility of unfavorable clinical trial results, (ix)the market for, and marketability of, any product that is approved, (x)the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Companys products, (xi)regulatory initiatives, compliance with governmental regulations and the regulatory approval process, (xii)general economic and business conditions, (xiii)changes in foreign, political, and social conditions, and (xiv)various other matters, many of which are beyond the Companys control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form10-K, and any risk factors or cautionary statements included in any subsequent Form10-Q or Form8-K, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release.

CYTODYN CONTACTSInvestors: Dave Gentry, CEORedChip CompaniesOffice: 1.800.RED.CHIP (733.2447)Cell: 407.491.4498dave@redchip.com

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CytoDyn CEO Dr. Pourhassan to Appear on Fox Business Network Friday, April 3, 2020 at 2:00 pm ET to Discuss Leronlimab Treatment of 10 Severely Ill...

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Explained: Why are cancer patients more vulnerable to coronavirus? – The Indian Express

By daniellenierenberg

By: Explained Desk | New Delhi | Updated: April 3, 2020 7:55:52 pm What are the risks if those suffering from cancer contract coronavirus? Image source: Pixabay

The number of people infected with COVID-19 across the world has now reached a million. It is well known now that while people of all age groups are vulnerable to infection from the disease caused by the SARS-CoV-2 virus, the people likely to develop severe COVID-19 are those above the age of 60 years.

Especially vulnerable are those people who have comorbidities such as heart disease, hypertension, diabetes, chronic respiratory disease and cancer.

For some cancer patients receiving treatment, the global pandemic poses a different set of challenges, even if they do not have COVID-19. Heres a look at some of those challenges and how doctors and cancer specialists have been advised to alter treatments during this time.

Are cancer patients at higher risk of developing serious illness due to COVID-19?

Yes, a subset of cancer patients are more vulnerable to developing serious illness due to COVID-19. This subset includes people with cancer who are undergoing active chemotherapy, those undergoing radical radiotherapy for lung cancer, people with cancers of the blood or bone marrow such as leukaemia, lymphoma or myeloma (at any stage of treatment), those getting immunotherapy or antibody treatments for cancer, those having other types of targetted cancer treatments which may affect the immune system and cancer patients who have undergone bone marrow or stem cell transplants in the last six months or who are still taking immunosuppressive drugs.

Further, a cancer patient who is over the age of 60 and has comorbodities such as cardiovascular or respiratory issues will also be especially vulnerable to illness due to COVID-19. As per a recent analysis of patients in Italy, 20 percent of those who died in the country had active cancer.

Also in Explained: The cancer crisis in India

Some cancer patients are more vulnerable because of their weakened immune systems. The immune system has an important role to play to fight off infection or repair an injured tissue. With COVID-19 as well, the role of the immune system is to try and fight off the virus. For this to happen, the immune system should not be overstimulated so as to cause hyper inflammation caused when more than necessary number of white blood cells are deployed by the immune system, which can lead to sepsis or even death. The immune system should also not be weak that it is unable to fight off the infection.

Some cancer treatments such as chemotherapy and radiotherapy might weaken the immune system of the patient, since such treatments can stop the bone marrow from making enough white blood cells. Due to this, the immune system is weakened, reducing the persons ability to fight off infection.c

Also Read: How to make a face mask a step-by-step guide

What about cancer patients who do not have COVID-19?

The UKs National Health Service (NHS) has placed guidelines for treatment of cancer patients who do not have COVID-19. These guidelines state that cancer patients may need to consider if the risks of beginning or continuing their cancer treatment could outweigh the benefits, since patients receiving therapies are more at risk from becoming seriously ill if they were to contract COVID-19. When deciding on whether a particular cancer treatment should be undertaken, doctors may also take into account the exposure of the patient to the virus during hospital visits.

Further doctors dealing with cancer patients will also have to consider the overall impact of the coronavirus on health services, Cancer Research UK points out. For example, its likely that there will be staff and bed shortages. This means they might need to delay or rearrange treatments. Because of this, they might need to prioritise some treatments over others, it says.

Heres a quick Coronavirus guide from Express Explained to keep you updated: What can cause a COVID-19 patient to relapse after recovery? | COVID-19 lockdown has cleaned up the air, but this may not be good news. Heres why | Can alternative medicine work against the coronavirus? | A five-minute test for COVID-19 has been readied, India may get it too | How India is building up defence during lockdown | Why only a fraction of those with coronavirus suffer acutely | How do healthcare workers protect themselves from getting infected? | What does it take to set up isolation wards?

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Explained: Why are cancer patients more vulnerable to coronavirus? - The Indian Express

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