Archive for the ‘Bone Marrow Stem Cells’ Category

INTRODUCTION

Programmed cell death protein 1 (PD-1) is a major inhibitor of T cell responses expressed on activated T cells. It is also expressed on natural killer cells, B cells, regulatory T cells, T follicular helper cells, and myeloid cells (1). The current model supports that a key mechanism dampening antitumor immune responses is the up-regulation of PD-1 ligands in cancer cells and antigen-presenting cells (APCs) of the tumor microenvironment (TME), which mediate ligation of PD-1 on tumor-infiltrating CD8+ T cells, leading to the development of T incapable of generating antitumor responses (2). Therapeutic targeting of the PD-1 pathway with antibodies blocking the PD-1 receptor or its ligands induces expansion of oligoclonal CD8+ tumor-infiltrating lymphocytes that recognize tumor neoantigens (3). Thus, in the context of cancer, PD-1 is considered a major inhibitor of T effector cells, whereas on APC and cancer cells, emphasis has been placed on the expression of PD-1 ligands. PD-1 ligand-1 expression in the TME is often a prerequisite for patient enrollment to clinical trials involving blockade of the PD-1 pathway. However, responses do not always correlate with PD-L1 expression, and it remains incompletely understood how the components of the PD-1:PD-L1/2 pathway suppress antitumor immunity.

Recent studies indicated that PD-1 can be induced by Toll-like receptor (TLR) signaling in macrophages (M) and negatively correlates with M1 polarization (4). PD-1 expression in macrophages plays a pathologic role by suppressing the innate inflammatory response to sepsis (5) and inhibiting Mycobacterium tuberculosis phagocytosis in active tuberculosis (6). Our knowledge about the function of PD-1 on myeloid cells in the context of cancer is very limited. However, similar to its role in infections, PD-1 expression inversely correlates with M1 polarization and phagocytic potency of tumor-associated M (TAM) against tumor (7, 8). The mechanisms of PD-1 expression in myeloid cells and the role of PD-1expressing myeloid cells in tumor immunity remain unknown.

The rapid increase in myeloid cell output in response to immunologic stress is known as emergency myelopoiesis. Terminally differentiated myeloid cells are essential innate immune cells and are required for the activation of adaptive immunity. Strong activation signals mediated by pathogen-associated molecular pattern or danger-associated molecular pattern molecules lead to a transient expansion and subsequent differentiation of myeloid progenitors to mature monocytes and granulocytes to protect the host. In contrast, during emergency myelopoiesis mediated by continuous low-level stimulation mediated by cancer-derived factors and cytokines, bone marrow common myeloid progenitors (CMPs) but, predominantly, granulocyte/macrophage progenitors (GMPs) undergo modest expansion with hindered differentiation, and a fraction of myeloid cells with immunosuppressive and tumor-promoting properties, named myeloid-derived suppressor cells (MDSCs), accumulates. MDSCs suppress CD8+ T cell responses by various mechanisms (9). In the mouse, MDSCs consist of two major subsets, CD11b+Ly6ChiLy6G (thereafter named CD11b+Ly6C+) monocytic (M-MDSC) and CD11b+Ly6CloLy6G+ (hereafter named CD11b+Ly6G+) polymorphonuclear (PMN-MDSC) (10). These cells have similar morphology and phenotype to normal monocytes and neutrophils but distinct genomic and biochemical profiles (9). In humans, in addition to M-MDSC and PMN-MDSC, a small subset of early-stage MDSC has been identified (10).

Although PMN-MDSCs represent the major subset of circulating MDSC, they are less immunosuppressive than M-MDSC when assessed on a per cell basis (1113). Current views support the two-signal requirement for MDSC function. The first signal controls MDSC generation, whereas the second signal controls MDSC activation, which depends on cues provided by the TME and promotes MDSC differentiation to TAM (14). Proinflammatory cytokines and endoplasmic reticulum stress response in the TME contribute to pathologic myeloid cell activation that manifests as weak phagocytic activity, increased production of reactive oxygen species and nitric oxide (NO) and expression of arginase-1 (ARG1), and convert myeloid cells to MDSC (9). MDSCs are associated with poor outcomes in many cancer types in patients and negatively correlate with response to chemotherapy, immunotherapy, and cancer vaccines (1519).

In the present study, we examined how PD-1 regulates the response of myeloid progenitors to cancer-driven emergency myelopoiesis and its implications on antitumor immunity. We determined that myeloid progenitors, which expand during cancer-driven emergency myelopoiesis, express PD-1 and PD-L1. PD-L1 was constitutively expressed on CMPs and GMPs, whereas PD-1 expression displayed a notable increase on GMPs that arose during tumor-driven emergency myelopoiesis. PD-1 was also expressed on tumor-infiltrating myeloid cellsincluding M-MDSCs and PMN-MDSCs, CD11b+F4/80+ M, and CD11c+major histocompatibility complex class II-positive (MHCII+) dendritic cells (DCs) in tumor-bearing miceand on MDSCs in patients with refractory lymphoma. Ablation of PD-1 signaling in PD-1 knockout (KO) mice prevented GMP accumulation and MDSC generation and resulted in increase of Ly6Chi effector monocytes, M and DC. We generated mice with conditional targeting of the Pdcd1 gene (PD-1f/f) and selectively eliminated PD-1 in myeloid cells or T cells. Compared with T cellspecific ablation of PD-1, myeloid-specific PD-1 ablation more effectively decreased tumor growth in various tumor models. At a cellular level, only myeloid-specific PD-1 ablation skewed the myeloid cell fate commitment from MDSC to effector Ly6Chi monocytes M and DC and induced T effector memory (TEM) cells with improved functionality. Our findings reveal a previously unidentified role of the PD-1 pathway and suggest that skewing of myeloid cell fate during emergency myelopoiesis and differentiation to effector APCs, thereby reprogramming T cell responses, might be a key mechanism by which PD-1 blockade mediates antitumor function.

For our studies, we selected the murine B16-F10 melanoma tumor model because it has been informative in dissecting mechanisms of resistance to checkpoint immunotherapy (20). First, we examined whether B16-F10 induces tumor-driven emergency myelopoiesis similarly to the MC17-51 fibrosarcoma, a mouse tumor model well established to induce cancer-driven emergency myelopoiesis (21). We assessed the expansion of myeloid progenitors in the bone marrow and the increase of CD11b+CD45+ myeloid cells in the spleen and tumor (figs. S1 and S2). Both tumor types induced increase of myeloid progenitors in the bone marrow and systemic increase of CD45+CD11b+ myeloid cells (fig. S3), providing evidence that B16-F10 melanoma is an appropriate tumor model to study tumor-driven emergency myelopoiesis and its consequences in tumor immunity. In the spleen of nontumor-bearing mice, few myeloid cells constitutively expressed very low levels of PD-L1, whereas PD-1 was very low to undetectable (Fig. 1, A and B). In B16-F10 tumor-bearing mice, expression of PD-1 and PD-L1 was up-regulated on myeloid cells of the spleen (Fig. 1, C to F). PD-1 and PD-L1 were also expressed on myeloid cells at the tumor site (Fig. 1, G to I). All subsets of myeloid cells expanding in tumor-bearing mice including M-MDSCs, PMN-MDSCs, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs expressed PD-1 (Fig. 1, D and G). Kinetics studies of PD-1 expression on myeloid cells in the spleen of tumor-bearing mice showed a gradual increase over time (Fig. 1, J to M).

(A and B) Expression of PD-1 and PD-L1 on CD11b+Ly6C+ monocytes and CD11c+MHCII+ DC in the spleen of nontumor-bearing C57BL/6 mice. FMO, fluorescence minus one. (C) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and at the indicated time points, expression of PD-1 was examined by flow cytometry in the spleen after gating on the indicated myeloid populations; contour plots depicting the percentage of positive cells are shown. On day 16 after tumor inoculation, expression of PD-1 and PD-L1 was assessed in the spleen (D) and the tumor site (G) after gating on the indicated myeloid populations. (D and G) Fluorescence-activated cell sorting (FACS) histograms and contour plots depicting the percentage of positive cells and bar graphs (E, F, H, and I) of mean SEM positive cells. Results are representative of 12 independent experiments with six mice per group. (J to M) Kinetics of PD-1 up-regulation on CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ of the spleen after tumor inoculation. **P < 0.01, ***P < 0.005, ****P < 0.001.

Because myeloid cells that give rise to MDSC and TAM are generated from myeloid progenitors in the bone marrow during tumor-driven emergency myelopoiesis, we examined PD-1 and PD-L1 expression in these myeloid progenitors. In nontumor-bearing mice, PD-1 was detected at very low levels on GMPs (Fig. 2A), whereas PD-L1 was constitutively expressed in CMPs but mostly on GMPs (Fig. 2B). In tumor-bearing mice, PD-L1 was up-regulated in CMPs and GMPs, and its expression levels remained elevated during all assessed time points (Fig. 2, F to J). PD-1 expression was induced on CMPs but more prominently on GMPs (Fig. 2, C to I). Kinetics studies showed that PD-1 expression on GMPs peaked early after tumor inoculation (Fig. 2, C, E, and I), at a time point when tumor growth was not yet measurable. Thus, induction of PD-1 expression in myeloid progenitors is an early event during tumor development.

(A and B) Expression of PD-1 and PD-L1 on CMPs and GMPs of nontumor-bearing mice. (C to J) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and expression of PD-1 and PD-L1 on CMPs and GMPs was examined on days 9, 12, 14, and 16 after implantation. FACS histograms (C and F) and contour plots (D, E, G, and H) indicating the percentage of positive cells and bar graphs of mean SEM positive cells (I and J) are shown. Results are representative of four independent experiments with six mice per group. (K and L) Kinetics of PD-1 (K) and PD-L1 (L) expression on CMPs (blue) and GMPs (orange) during tumor-driven emergency myelopoiesis. Results are representative of four separate experiments with six mice per group. *P < 0.05, ***P < 0.005, ****P < 0.001.

To determine whether PD-1 expression on GMPs was mediated by growth factors regulating emergency myelopoiesis, we cultured bone marrow cells from nontumor-bearing mice with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony growth factor (GM-CSF), and the TLR4 ligand lipopolysaccharide. PD-1 that was constitutively expressed at low levels in GMPs was up-regulated by culture with each of these factors (fig. S4A), consistent with our findings that PD-1 expression was rapidly induced on GMPs of tumor-bearing mice in vivo (Fig. 2, C, E, and I). Quantitative polymerase chain reaction (qPCR) in purified Linneg bone marrow cells showed that PD-1 mRNA was constitutively expressed in myeloid progenitors and was up-regulated by culture with G-CSF or GM-CSF (fig. S4B). Together, these in vivo and in vitro studies provide evidence that PD-1 expression on myeloid progenitors is regulated by a direct cell-intrinsic effect of factors driving cancer-mediated emergency myelopoiesis.

To examine whether PD-1 was expressed in MDSCs in humans, we used samples from healthy donors and patients with malignant non-Hodgkins lymphoma (NHL) (figs. S5 and S6). A high level of PD-1expressing M-MDSCs was detected in the peripheral blood of three patients with treatment-refractory NHL but not in two patients who responded to treatment or five healthy donors (fig. S6). These results show that PD-1 expression is detected in human MDSCs and serve as a paradigm, suggesting that PD-1 expression in MDSCs of patients with cancer might be a clinically relevant event.

To examine whether PD-1 might have an active role in tumor-induced stress myelopoiesis, we used PD-1deficient (PD-1/) mice. PD-1 deletion, which resulted in decreased tumor growth (Fig. 3, A and B), substantially altered tumor-induced stress myelopoiesis (Fig. 3, C to E). Although accumulation of CMPs was comparable, accumulation of GMPs was significantly diminished in PD-1/ mice (Fig. 3, C and D), indicating that GMPs might be a key target on which PD-1 mediated its effects on myeloid progenitors (Fig. 3E). Kinetics studies showed sustained GMP expansion in wild-type (WT) tumor-bearing mice. In contrast, in PD-1/ tumor-bearing mice, GMPs displayed a rapid expansion and subsequent decline (fig. S7). In parallel, in PD-1/ mice, there was an increase of differentiated CD11b+Ly6Chi monocytic cells not only in the tumor (Fig. 3H) but also in the spleen and the small intestine, which also displayed an increase in CD11c+MHCII+ DCs (Fig. 3, F and G). Moreover, at these sites, there was a significant increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 3, I to K), indicating a shift of myelopoiesis output toward monocytic lineage dominance. These Ly6Chi monocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs in PD-1/ tumor-bearing mice expressed interferon (IFN) regulatory factor 8 (IRF8), and all myeloid subsets had elevated expression of the retinoic acid receptor-related orphan receptor (RORC or ROR) (Fig. 3, L to N, and fig. S8). Similar results were observed in two additional tumor models, the MC38 colon adenocarcinoma and the MC17-51 fibrosarcoma model (fig. S9), both of which induced cancer-driven emergency myelopoiesis (fig. S3).

(A and B) WT and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). Mice were euthanized on day 16, and tumor weight was measured (B). Data shown are means SEM of six mice per group and are representative of six independent experiments. (C) Mean percentages SEM of LSK (Linneg, Sca1pos, CD127neg, c-kitpos) and LK (Linneg, Sca1neg, CD127neg, c-kitpos) hematopoietic precursors, CMP, and GMP in the bone marrow of nontumor-bearing and tumor-bearing WT and PD-1/ mice. GMPs in PD-1/ mice were significantly lower compared with GMPs in WT mice (**P < 0.01). (D) Representative contour plots of FACS analysis for CMP and GMP in the bone marrow of tumor-bearing WT and PD-1/ mice. (E) Schematic presentation of myeloid lineage differentiation. The arrowhead indicates GMP, the key target population of PD-1 during emergency myelopoiesis. HSC, hematopoietic stem cells; MPP, multi-potent progenitor; MDP, monocyte/macrophages and DC precursors; CDP, common dendritic cell progenitors; CLP, common lymphoid progenitors. (F to H) Mean percentages of CD45+CD11b+, CD11b+Ly6C+, CD11b+Ly6G+, and CD11c+MHCII+ in the spleen (F), small intestine (G), and B16-F10 site (H) of tumor-bearing WT and PD-1/ mice. (I to K) Representative plots of FACS analysis for CD11b+Ly6Chi and CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen (I), small intestine (J), and B16-F10 site (K). (L to N) Mean percentages SEM of RORC and IRF8 expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD45+CD11b+ gate in the spleen (L), small intestine (M), and B16-F10 site (N). Data from one representative experiment of three independent experiments with six mice per group are shown. (O and P) Diminished suppressive activity (O) and NO production (P) of CD11b+Ly6C+ cells isolated from PD-1/ tumor-bearing mice. CD11b+Ly6C+ cells were isolated from tumor-bearing WT and PD-1/ mice and cultured at various ratios with OTI splenocytes stimulated with OVA257264. Data show means SEM of one representative of two experiments (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.001).

IRF8 regulates myeloid cell fate to monocyte/macrophage and DC differentiation versus granulocyte differentiation (22, 23), explaining the increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio that we observed in tumor-bearing PD-1 KO mice. IRF8 is designated as one of the terminal selectors that control the induction and maintenance of the terminally differentiated state of these myeloid cells (22, 23). Moreover, IRF8 shifts the fate of myeloid cells away from immature MDSC, which are characterized by a restriction in IRF8 expression (24, 25). Retinoid-related orphan nuclear receptors not only are required for myelopoiesis and are mediators of the inflammatory response of effector Ly6Chi monocytes and macrophages (21, 26) but also can be expressed by MDSC (21). For these reasons, we examined the functional properties of CD11b+Ly6C+ cells in PD-1/ tumor-bearing mice. A key mechanism by which CD11b+Ly6C+ M-MDSCs mediate suppression of T cell responses involves the production of NO (27). We assessed the immunosuppressive function and found diminished NO production and diminished suppressor capacity of CD11b+Ly6C+ myeloid cells isolated from tumor-bearing PD-1/ mice compared with their counterparts isolated from tumor-bearing WT control mice (Fig. 3, O and P). Thus, PD-1 ablation switches the fate and function of myeloid cells away from immunosuppressive MDSC and promotes the generation of differentiated monocytes, M, and DC. The expansion of CD11b+Ly6Chi monocytes, the increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio, and the up-regulation of RORC in myeloid cells of the spleen of PD-1/ mice were already observed on day 9 after tumor inoculation, when tumors were not yet measurable, and on day 12, when tumors in WT and PD-1/ mice had comparable size (fig. S10). These results indicate that the effects of PD-1 ablation on the myeloid compartment of PD-1/ tumor-bearing mice preceded the differences in tumor growth.

To determine the potential therapeutic relevance of these findings, we examined whether changes in the myeloid compartment might be detected during treatment with PD-1blocking antibody. Compared with the control treatment group, mice receiving antiPD-1 antibody (fig. S11A) had diminished accumulation of GMP in the bone marrow (fig. S11B) and increased expansion of Ly6C+ monocytes and DC in the tumor site (fig. S11D), with effector features characterized by the expression of RORC, IRF8, and IFN- (fig. S11, E to G and I). In contrast, cells expressing interleukin-4 receptor (IL-4Ra), a marker of MDSC (10, 28), were significantly decreased (fig. S11H). Thus, treatment with antiPD-1blocking antibody promotes the differentiation of myeloid cells with effector features while suppressing expansion of MDSC in tumor-bearing mice.

To determine whether these changes on myeloid cell fate in PD-1/ mice were mediated by myeloid cellintrinsic effects of PD-1 ablation or by the effects of PD-1neg T cells on myeloid cells, we generated mice with conditional targeting of Pdcd1 gene (PD-1f/f) (fig. S12A) and crossed them with mice expressing cre recombinase under the control of the lysozyme (LysM) promoter to induce selective ablation of the Pdcd1 gene in myeloid cells (PD-1f/fLysMcre) or with mice expressing cre recombinase under the control of the CD4 promoter to induce selective ablation of the Pdcd1 gene in T cells (PD-1f/fCD4cre) (fig. S12, B and C). In PD-1f/fLysMcre mice, tumor growth was significantly diminished (Fig. 4, A and B), indicating that despite the preserved PD-1 expression in T cells, myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice was sufficient to inhibit tumor growth. Tumor-driven emergency myelopoiesis was selectively affected in PD-1f/fLysMcre mice. Although myeloid-specific PD-1 ablation resulted in expansion of CMPs, accumulation of GMPs was prevented (Fig. 4C). In contrast, no change on cancer-driven emergency myelopoiesis was detected in PD-1f/fCD4cre mice, which had comparable expansion of CMP and GMP to PD-1f/f control mice (Fig. 5A).

(A and B) PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). After mice were euthanized, tumor weight was measured (B). (C) Mean percentages SEM of CMP and GMP in the bone marrow of tumor-bearing PD-1f/f and PD-1f/fLysMcre mice. (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen of tumor-bearing mice. (E) Mean percentages SEM of CD11b+CD45+, CD11b+Ly6C+, and CD11b+Ly6G+ cells and (F) representative contour plots of FACS analysis for CD11b+CD45+ and CD11b+Ly6C+ cells at the tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (G) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, and CD80+ cells and IFN-expressing myeloid cell subsets within the CD45+CD11b+ gate in B16-F10 tumors from PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (H) Mean percentages SEM and (I) FACS histograms of IL-4Ra, CD206, and ARG1 expression in CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD11b+CD45+ gate in the spleen of tumor-bearing PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. Data are from one representative of three independent experiments with six mice per group are shown in all the panels (*P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001).

PD-1f/f and PD-1f/fCD4cre mice were inoculated with B16-F10 melanoma. (A) On day 16, mice were euthanized, and bone marrow CMPs and GMPs were examined by flow cytometry. Mean percentages SEM of CMP or GMP are shown. (B and C) Tumor size was assessed every other day from inoculation (B). On the day of euthanasia, tumor weight was measured (C). (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+ and CD11b+Ly6G+ populations within the CD11+CD45+ gate in the spleen. (E) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ cells within the CD11b+CD45+ gate in the tumor site. (F) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, CD80+, and IFN- expression in the indicated myeloid subsets (CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+) within the CD11b+CD45+ gate in the tumor site. (G to J) Mean percentages SEM of CD4+ and CD8+ TCM and TEM (G), as well as IFN-, IL-2, and IL-17 (H to J) expression in CD4+ and CD8+ TEM and TCM at the tumor site, and respective contour plots (K to M). Results are from one representative of two independent experiments with six mice per group are shown (*P < 0.05 and **P < 0.01).

Myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice not only shifted the differentiation of CD11b+Ly6C+ and CD11b+Ly6G+ myeloid subsets and increased the CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen and tumor site as in PD-1/ mice (Fig. 4, D to F) but also resulted in a notably different immunological profile of CD11b+Ly6C+ monocytic myeloid cells, consistent with effector myeloid function as indicated by the expression of effector myeloid cell markers including CD80, CD86, CD16/32 (Fc receptor II/III), and CD88 (C5aR) (Fig. 4G). Consistent with the improved function of myeloid cells, PD-1f/fLysMcre mice also had higher levels of IFN-expressing CD11b+Ly6Chi monocytes and CD11b+F4/80+ Ms (Fig. 4G and fig. S13, A and B) and increase of IRF8+ and RORC+ CD11b+Ly6Chi monocytes (fig. S13, C and D). In contrast, cells expressing IL-4Ra, CD206, and ARG1which are markers of MDSC, immunosuppressive neutrophils, and tolerogenic DCs (2933)were diminished (Fig. 4, H and I). Thus, myeloid-intrinsic PD-1 ablation skews the fate of myeloid cells away from immunosuppressive MDSCs; promotes the differentiation of functional effector monocytes, Ms, and DCs; and has a decisive role in systemic antitumor immunity despite PD-1 expression in T cells.

We studied antitumor responses in mice with T cellspecific PD-1 ablation and found that PD-1f/fCD4cre mice had diminished antitumor protection (Fig. 5, B and C). Consistent with the causative role of myeloid cellspecific PD-1 targeting in the differentiation and function of myeloid cells, T cellspecific PD-1 ablation did not induce expansion of CD11b+CD45+ leukocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs and increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 5, D and E) or immunological features of functional effector myeloid cells (Fig. 5F) in PD-1f/fCD4cre tumor-bearing mice, compared with control tumor-bearing mice. Moreover, despite PD-1 ablation, tumor-bearing PD-1f/fCD4cre mice did not have quantitative differences in tumor-infiltrating TEM cells compared with control tumor-bearing mice (Fig. 5G) or features of enhanced effector function as determined by assessment of cytokine-producing cells (Fig. 5, H to M).

Similar outcomes to those observed with B16-F10 tumor in the differentiation of myeloid cells toward myeloid effectors versus MDSC were obtained when PD-1f/fLysMcre and PD-1f/fCD4cre mice were inoculated with MC38 colon adenocarcinoma cells (Fig. 6, B to I). Moreover, PD-1f/fLysMcre but not PD-1f/f CD4cre mice inoculated with MC38 had functional differences in tumor-infiltrating TEM and T central memory (TCM) cells compared with control tumor-bearing mice (Fig. 6, J to L). In the context of this highly immunogenic tumor, PD-1 ablation in myeloid cells resulted in complete tumor eradication, whereas mice with PD-1 ablation in T cells showed progressive tumor growth (Fig. 6A). Together, these results suggest that by preventing the differentiation of effector myeloid cells and promoting generation of MDSC, myeloid-specific PD-1 expression has a decisive role on T cell function. Thus, although PD-1 is an inhibitor of T cell responses (2, 34, 35), ablation of PD-1 signaling in myeloid cells is an indispensable requirement for induction of systemic antitumor immunity in vivo.

(A) PD-1f/f, PD-1f/fCD4cre, and PD-1f/fLysMcre mice were inoculated with MC38 colon adenocarcinoma, and tumor size was monitored daily. Mice were euthanized on day 21, and mean percentages SEM of CD45+CD11b+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen (B) and tumor site (C) were determined. (D) Mean percentages SEM of RORC- and IRF8-expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F/480+, and CD11c+MHCII+ myeloid cells and (E) mean percentages SEM of ARG1, IL-4Ra, CD88, and CD80 cells within the same myeloid subsets in the spleen. (F and G) Representative flow cytometry plots for RORC and IRF8 expression. (H) Mean percentages SEM and (I) representative flow cytometry plots of IFN- and ARG1-expressing CD11b+Ly6C+ and CD11b+Ly6G+ myeloid cells at the tumor site. (J to L) Mean percentages SEM of CD4+ and CD8+ TCM and TEM cells (J) and IFN-expressing CD4+ and CD8+ TEM and TCM at the tumor site (K) and respective contour plots (L). Data are from one representative of three experiments with six mice per group (*P < 0.05, **P < 0.01, and ***P < 0.001).

To further investigate the direct effects of PD-1 on myeloid cell fate in the absence of T cells, we used recombination activating gene 2 (RAG2) KO mice (lacking mature T cells and B cells). Treatment of RAG2 KO tumor-bearing mice with antiPD-1blocking antibody resulted in decreased accumulation of GMPs during tumor-driven emergency myelopoiesis (fig. S14A), myeloid cell expansion in the spleen and tumor site (fig. S14, B and C), and enhanced generation of effector myeloid cells (fig. S14, D to G), providing evidence that blockade of PD-1mediated signals skews myeloid lineage fate to myeloid effector cells in a myeloid cellintrinsic and T cellindependent manner. In RAG2 KO mice treated with antiPD-1 antibody, despite the absence of T cells, a decrease of tumor growth was also observed (fig. S14, H and I), suggesting that ablation of PD-1 signaling promotes myeloid-specific mechanisms that induce tumor suppression, one of which might involve increased phagocytosis (8).

To understand mechanisms that might be responsible for the significant differences of myeloid cell fate commitment induced by myeloid-specific PD-1 targeting, we examined whether PD-1deficient bone marrow myeloid progenitors might have distinct signaling responses to the key hematopoietic growth factors that mediate cancer-driven emergency myelopoiesis, which also induced PD-1 expression in GMP during in vitro culture. To avoid any potential impact of bone marrowresiding PD-1/ T cells or mature myeloid cells on the signaling responses of myeloid progenitors, we used Linneg bone marrow from PD-1f/fLysMcre mice because LysMcre is expressed in CMPs and GMPs (36), allowing us to take advantage of the selective deletion of PD-1 in these myeloid progenitors. PD-1deficient GMPs (fig. S15) had enhanced activation of extracellular signalregulated kinase 1/2 (Erk1/2), mammalian target of rapamycin complex 1 (mTORC1), and signal transducer and activator of transcription 1 (STAT1) in response to G-CSF, a main mediator of emergency myelopoiesis (37, 38). These results are notable because each of these signaling targets has a decisive role in the differentiation and maturation of myeloid cells while preventing the generation of immature immunosuppressive MDSC (3942). These findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis.

Metabolism has a decisive role in the fate of hematopoietic and myeloid precursors. Stemness and pluripotency are regulated by maintenance of glycolysis (43). Switch from glycolysis to mitochondrial metabolism and activation of oxidative phosphorylation and trichloroacetic acid (TCA) cycle are associated with differentiation (44). This is initiated by glycolysis-mediated mitochondrial biogenesis and epigenetic regulation of gene expression (43). The structural remodeling of the mitochondrial architecture during differentiation is characterized by increased replication of mitochondrial DNA to support production of TCA cycle enzymes and electron transport chain subunits, linking mitochondrial metabolism to differentiation (45).

We examined whether PD-1 ablation, which promoted the differentiation of myeloid cells in response to tumor-mediated emergency myelopoiesis, might affect the metabolic properties of myeloid precursors. Linneg bone marrow myeloid precursors were cultured with the cytokines G-CSF/GM-CSF/IL-6 that drive tumor-mediated emergency myelopoiesis in cocktail (Fig. 7, A and B) or individually (Fig. 7, C and D). Hematopoietic stem cell differentiation was documented by decrease of Linneg, which was more prominent in the cultures of PD-1deficient bone marrow cells, and coincided with increase of CD45+CD11b+ cells (Fig. 7, A and B). Ly6C+ monocytic cells dominated in the PD-1f/fLysMcre cultures, whereas Ly6G+ granulocytes were decreasing compared with PD-1f/f control cultures (Fig. 7, C and D), providing evidence for a cell-intrinsic mechanism of PD-1deficient myeloid precursors for monocytic lineage commitment. Glucose uptake, but more prominently, mitochondrial biogenesis, was elevated in PD-1deficient CMP and GMP (Fig. 7, E and F). Bioenergetics studies showed that PD-1deficient cells developed robust mitochondrial activity (Fig. 7G) and increase of oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio during culture (Fig. 7H), indicating that mitochondrial metabolism progressively dominated over glycolysis. This bioenergetic profile is consistent with metabolism-driven enhanced differentiation of hematopoietic and myeloid precursors (45, 46).

(A and B) Linneg bone marrow from PD-1f/f and PD-1f/fLysMcre mice was cultured with GM-CSF, G-CSF, and IL-6 for the indicated time intervals. Mean percentages SEM of CD11b+CD45+ (A) and Linneg cells (B) are shown. (C and D) Bone marrow cells purified as in (A) and (B) were cultured with the indicated growth factors, and mean percentages SEM of CD11b+Ly6C+ and CD11b+Ly6G+ cells were examined after 48 hours of culture. (E to H) Bone marrow cells were prepared and cultured as in (A) and (B), and at 48 hours of culture, glucose uptake was assessed using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) (E), and mitochondrial biogenesis was assessed by MitoGreen staining and flow cytometry (F). (G) At 24, 48, and 72 hours of culture, OCR and ECAR were measured by a Seahorse extracellular flux analyzer, and mitostress responses at each time point of culture were examined. (H) OCR/ECAR ratio was measured at these time points, and the increase of OCR/ECAR ratio during stimulation was calculated. (I) Linneg bone marrow cells from PD-1f/f and PD-1f/fLysMcre mice were cultured with G-CSF and GM-CSF for 48 hours, and metabolite analysis was performed by mass spectrometry. The unsupervised hierarchical clustering heat map of the top 50 metabolites is shown. (J) At 24, 48, and 72 hours of culture with G-CSF and GM-CSF, mRNA was extracted and analyzed for the expression of the indicated genes by qPCR. Results of the 48-hour culture are shown and are presented as the fold increase over the mRNA level expressed by PD-1f/f cells. Results are from one of three independent experiments. (K to M) At 24 hours of culture with GM-CSF, G-CSF, or IL-6, the content of neutral lipid droplets, including triglycerides and cholesterol esters, was assessed by flow cytometry using boron-dipyrromethene (BODIPY) 493/503. Mean percentages SEM (K) of BODIPY 493/503positive cells within the CD11b+CD45+ gate, representative contour plots (L), and histograms of FACS analysis (M) are shown. (N) PD-1f/f and PD-1f/fLysMcre DC were differentiated in the presence of B16-F10 tumor supernatant, and the content of neutral lipids was assessed. Mean percentage SEM of BODIPY 493/503positive DC within the CD45+CD11b+ gate is shown. Results are representative of three experiments. *P < 0.05, **P < 0.01, and ***P < 0.005.

We performed unbiased global metabolite analysis to determine whether PD-1deficient myeloid precursors developed a distinct metabolic program. Compared with control, PD-1deficient cells had elevated metabolic intermediates of glycolysis and pentose phosphate pathway (PPP), acetylcoenzyme A (coA), and the TCA cycle metabolites citrate and -ketoglutarate, but the most prominent difference was the elevated cholesterol (Fig. 7I, figs. S16 and S17, and table S1). Abundant cytosolic acetyl-coA can be used for fatty acid and cholesterol biosynthesis (fig. S17) (43). Moreover, mTORC1 activates de novo cholesterol synthesis via sterol regulatory element-binding protein 1 (SREBP1), which regulates transcription of enzymes involved in cholesterol synthesis (47, 48). Because acetyl-coA was elevated (Fig. 7I and fig. S17) and mTORC1 activation was enhanced in PD-1deficient myeloid progenitors in response to growth factors driving emergency myelopoiesis (fig. S15), we examined whether activation of the mevalonate pathway that induces cholesterol synthesis (fig. S18A) might be involved. In PD-1deficient myeloid progenitors cultured with growth factors of emergency myelopoiesis, mRNA of genes regulating cholesterol synthesis and uptake was increased, mRNA of genes promoting cholesterol metabolism was decreased (Fig. 7J and fig. S18B), whereas cellular cholesterol and neutral lipid content was elevated (Fig. 7, K to M). PD-1deficient DC not only differentiated in vitro in the presence of B16-F10 tumor supernatant but also had a significant increase of cholesterol and neutral lipids compared with similarly differentiated DC from control mice (Fig. 7N). Consistent with these in vitro findings, glucose uptake and content of cholesterol and neutral lipids were elevated in GMPs of tumor-bearing PD-1 KO mice compared with control mice at days 7 or 9 after tumor inoculation, respectively, when tumors were not yet detectable or tumors in WT and PD-1 mice had equal size (fig. S19). Thus, features associated with metabolism-driven differentiation of myeloid progenitors are enhanced early in tumor-bearing PD-1 KO mice.

In addition to cholesterol synthesis, mevalonate also leads to the synthesis of isoprenoids, including geranylgeranyl pyrophosphate (GGPP) (fig. S17), which is required for protein geranylgeranylation catalyzed by geranylgeranyltransferase and has an active role in the up-regulation of RORC expression (49). Our metabolite analysis showed increased GGPP (Fig. 7I), providing a mechanistic explanation for the up-regulation of RORC in PD-1deficient myeloid cells. Cholesterol accumulation is associated with skewing of hematopoiesis toward myeloid lineage and monocytosis, induces a proinflammatory program in monocytes/macrophages and DC, and amplifies TLR signaling (5052). Together, these results unravel a previously unidentified role of PD-1 targeting in regulating myeloid lineage fate commitment and proinflammatory differentiation of monocytes, macrophages, and DC during tumor-driven emergency myelopoiesis, through metabolic reprogramming.

Previously, it was determined that monocyte/macrophage terminal differentiation is controlled by the combined actions of retinoid receptors and the nuclear receptor peroxisome proliferatoractivated receptor (PPAR), which is regulated by cholesterol and promotes gene expression and lipid metabolic processes, leading to terminal macrophage differentiation (26, 53). Because our in vitro studies showed that PD-1deficient myeloid progenitors developed a distinct metabolic program with elevated cholesterol metabolism, we examined whether PD-1 ablation might alter the expression of PPAR in addition to RORC. We found that the expression of PPAR was elevated in CD11b+Ly6C+ monocytic cells and M isolated from tumors of PD-1/ and PD-1f/fLysMcre mice (Fig. 8, A to C). Because PD-1deficient myeloid progenitors developed robust mitochondrial activity during culture in vitro (Fig. 7, G and H) and PPAR is involved in mitochondrial function (53), we examined whether myeloid cells in tumor-bearing mice have improved mitochondrial metabolism, a feature that has an important role in supporting antitumor function of other immune cells (54). Monocytes, M, and DC isolated from tumor of PD-1/, and PD-1f/fLysMcre mice had increased mitochondrial membrane potential compared with myeloid cells from control tumor-bearing mice, consistent with enhanced mitochondrial metabolism (Fig. 8, D to G).

(A to C) Expression of PPAR in myeloid cells at the B16-F10 site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by flow cytometry. Mean percentages SEM (A), representative histograms (B), and contour plots (C) of PPAR-expressing CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets. (D to G) Mitochondrial metabolic activity of myeloid cells at the B16-F10 tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by assessing mitochondrial membrane potential using MitoRed. Mean fluorescence intensity (MFI) SEM of MitoRedpositive CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets within the CD45+CD11b+ gate (D to F) and representative plots of FACS analysis (G) are shown. (H to L) In parallel, expression of IFN-, IL-17A, IL-2, IL-10, RORC, and ICOS in CD8+ TCM and TEM isolated from B16-F10bearing PD-1f/f and PD-1f/fLysMcre mice was assessed by flow cytometry. Representative histograms (H), contour plots (I and K), and mean percentages SEM (J, L, and M) within the CD44hiCD62Lhi gate (for TCM) and CD44hiCD62lo gate (for TEM) cells are shown. Data are from one representative of four independent experiments (*P < 0.05, **P < 0.01, and ***P < 0.005).

We investigated whether these significant immunometabolic changes of myeloid cells, induced by myeloid-specific PD-1 targeting, affected immunological properties of T cells that have key roles in their antitumor function. Compared with control PD-1f/f tumor-bearing mice, PD-1f/fLysMcre tumor-bearing mice had no quantitative differences in CD4+ or CD8+ TEM and TCM cells (fig. S20A) but had significant functional differences. There was an increase of IFN-, IL-17, and IL-10producing CD8+ TEM cells and IL-2producing CD8+ TCM cells (Fig. 8, H to J). Inducible T cell costimulator (ICOS) and lymphocyte-activation gene 3 (Lag3) were elevated in T cells from PD-1f/fLysMcre tumor-bearing mice but cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T cell immunoglobulin and mucin domain 3 (Tim3), CD160, and PD-1/PD-L1 were comparable in T cells from PD-1f/f and PD-1f/fLysMcre tumor-bearing mice (Fig. 8, K to M, and fig. S20B). These findings are significant because IL-17producing T helper cell 17 (TH17)/ T cytotoxic cell 17 (Tc17) cells have enhanced antitumor function and mediate durable tumor growth inhibition (55). Moreover, T cells with a hybrid phenotype producing both IFN- and IL-17 might have superior antitumor properties by combining the enhanced effector function of TH1/Tc1 and the longevity and stemness of TH17/Tc17 cells (56). In our studies, these properties of TEM cells correlated with improved antitumor function in PD-1f/fLysMcre mice.

To examine experimentally whether PD-1deficient myeloid cells differentiated in tumor-bearing mice in vivo have improved capacity of inducing antigen-specific T cell responses, we assessed responses of the same primary CD4+ or CD8+ T cells to antigen-loaded DCs isolated from PD-1/ or control mice bearing B16-F10 tumors (fig. S21A). DCs isolated from the spleen of tumor-bearing WT and PD-1/ mice were pulsed with ovalbumin (OVA) and cocultured with OVA-specific CD4+ or CD8+ T cells from OTI or OTII T cell receptor (TCR)transgenic mice. DCs from tumor-bearing PD-1/ mice had superior ability to induce OTI and OTII T cell proliferation and IFN- expression (fig. S21, B and C). Together, our data provide evidence that myeloid cellintrinsic PD-1 ablation induces potent antitumor immunity by decreasing accumulation of MDSC and promoting proinflammatory and effector monocytic/macrophage and DC differentiation, thereby leading to enhanced effector T cell responses.

Our present studies reveal a previously unidentified role of the PD-1 pathway in regulating lineage fate commitment and function of myeloid cells that arise from tumor-driven emergency myelopoiesis. These outcomes are mediated by myeloid-intrinsic effects of PD-1 ablation, leading to altered signaling and metabolic reprogramming of myeloid progenitors characterized by enhanced differentiation and elevated cholesterol synthesis. Consequently, the accumulation of immature immunosuppressive and tumor-promoting MDSC is diminished, and the output of differentiated, inflammatory effector monocytes, M, and DC is enhanced. These immunometabolic changes of myeloid cells promote the differentiation of TEM cells and systemic antitumor immunity in vivo despite preserved PD-1 expression in T cells.

We found that PD-1deficient myeloid progenitors had enhanced activation of Erk1/2 and mTORC1 in response to G-CSF. These results indicate that Erk1/2 and mTORC1, a downstream mediator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling, which are major targets of PD-1 in T cells (2), are subjected to PD-1mediated inhibition in myeloid cells. These results are revealing because Erk1/2 phosphorylation subverts MDSC-mediated suppression by inducing M-MDSCs differentiation to APC (39). Erk and PI3K regulate glycolysis in response to G-CSF (57). PI3K/Akt/mTORC1 signaling is critical in myeloid lineage commitment. Expression of constitutively active Akt in CD34+ cells induces enhanced monocyte and neutrophil development, whereas a dominant negative Akt has the opposite effect (58). mTORC1 is necessary for the transition of hematopoietic cells from a quiescent state to a prepared alert state in response to injury-induced systemic signals (59), for G-CSFmediated differentiation of myeloid progenitors (40), and for M-CSFmediated monocyte/macrophage generation (41). mTORC1 stimulates translation initiation through phosphorylation of 4E (eIF4E)binding protein 1 (4E-BP1) and ribosomal S6 kinases and has a decisive role in the expression of glucose transporters and enzymes of glycolysis and PPP (47). Consistent with these, our studies showed that PD-1deficient myeloid progenitors had elevated expression of glycolysis and PPP intermediates after culture with emergency cytokines in vitro and enhanced monocytic differentiation in tumor-bearing mice in vivo. Together, our findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis. Further studies will identify how receptor-proximal signaling events mediated by hematopoietic growth factors are targeted by PD-1 in a manner comparable to PD-1mediated targeting of signaling pathways in T cells (2, 34, 35).

Our metabolite analysis showed that a notable difference of PD-1deficient myeloid progenitors was the increased expression of mevalonate metabolism enzymes and the elevated cholesterol. mTORC1 activates SREBP1, which induces transcription of enzymes involved in fatty acid and cholesterol synthesis (48), thereby leading to glycolysis-regulated activation of the mevalonate pathway. Our signaling studies showing enhanced mTORC1 activation and our metabolic studies showing enhanced mitochondrial metabolism and increased cholesterol content in PD-1deficient myeloid cells provide a mechanistic link between the altered differentiation of PD-1deficient myeloid progenitors and the altered immunophenotypic and functional program of PD-1deficient monocytes, M, and DC in tumor-bearing mice. Cholesterol drives myeloid cell expansion and differentiation of macrophages and DC (50, 51, 60) and promotes antigen-presenting function (61). These properties are consistent with the metabolic profile and the increased cholesterol of PD-1deficient myeloid progenitors; the inflammatory and effector features of differentiated monocytes, M, and DC; and the enhanced T effector cell activation in tumor-bearing mice with myeloid-specific PD-1 ablation that we identified in our studies. By such mechanism, PD-1 might centrally regulate antitumor immunity, independently of the expression of PD-1 and its ligands in the TME. Our studies showed that PD-1 expression on myeloid progenitors is an early event during tumor-mediated emergency myelopoiesis and indicate that PD-1 blockade at early stages of cancer might have a decisive effect on antitumor immunity by preventing MDSC generation from myeloid progenitors and inducing the systemic output of effector myeloid cells that drive antitumor T cell responses.

In addition to its expression in myeloid progenitors, in the bone marrow, we found that PD-1 is expressed in all myeloid subsets including M-MDSC, PMN-MDSC, CD11b+F4/80+ M, and CD11c+MHCII+ DC in the tumor and the spleen of tumor-bearing mice, albeit at different levels. This difference might be related to gradient of tumor-derived factors responsible for PD-1 induction such as G-CSF and GM-CSF that we found to induce PD-1 transcription in myeloid progenitors. This possibility would be consistent with the gradual up-regulation of PD-1 expression in splenic myeloid cells, determined by our kinetics studies, which correlates with tumor growth that might be responsible for the increase of systemic levels of tumor-derived soluble factors that induce PD-1. Other cues of the TME known to mediate the activation step of MDSC (14) might also be responsible for the induction of higher PD-1 expression level in the tumor versus the splenic myeloid cells. Our findings unravel a previously unidentified role of PD-1 in myeloid cell fate commitment during emergency myelopoiesis, a process that is involved not only in antitumor immunity but also in the control of pathogen-induced innate immune responses and sterile inflammation (62).

An additional important finding of our studies is that the nuclear receptors RORC and PPAR are up-regulated in myeloid cells by PD-1 ablation. RORs were initially considered retinoic acid receptors but were subsequently identified as sterol ligands. RORC not only is induced by sterols and isoprenoid intermediates (49) but also serves as the high-affinity receptor of the cholesterol precursor desmosterol (63, 64), a metabolic intermediate of cholesterol synthesis via the mevalonate pathway that regulates inflammatory responses of myeloid cells (52, 60). Desmosterol and as sterol sulfates function as endogenous RORC agonists and induce expression of RORC target genes (63, 64). Our studies showed that, in addition to cholesterol, the mevalonate metabolism product GGPP that has an active role in the up-regulation of RORC expression (49) was elevated in PD-1deficient myeloid cells, providing a mechanistic basis for our finding of the elevated RORC expression. Retinoid receptors and PPAR together regulate monocyte/macrophage terminal differentiation (26). Although initially thought to be involved in proinflammatory macrophage differentiation, it was subsequently understood that PPAR predominantly promotes macrophage-mediated resolution of inflammation by inducing expression of the nuclear receptor liver X receptor and the scavenger receptor CD36, thereby regulating tissue remodeling (65). PPAR also regulates macrophage-mediated tissue remodeling by efferocytosis and production of proresolving cytokines (66), which can suppress cancer growth (67). The combined actions of RORC and PPAR induced by myeloid-specific PD-1 ablation might be involved in the antitumor function by promoting both proinflammatory and tissue remodeling properties of myeloid cells. Future studies will dissect the specific role of each of these nuclear receptors on the antitumor immunity induced by myeloid cellspecific ablation of PD-1.

In conclusion, our results provide multiple levels of evidence that myeloid-specific PD-1 targeting mediates myeloid cellintrinsic effects, which have a decisive role on systemic antitumor responses. This might be a key mechanism by which PD-1 blockade induces antitumor function. Recapitulating this immunometabolic program of myeloid cells will improve the outcome of cancer immunotherapy.

immunology.sciencemag.org/cgi/content/full/5/43/eaay1863/DC1

Materials and Methods

Fig. S1. Gating strategy of hematopoietic and myeloid precursors in the bone marrow.

Fig. S2. Gating strategy of myeloid subsets in the spleen and tumor site.

Fig. S3. Cancer-induced emergency myelopoiesis in three different mouse tumor models.

Fig. S4. PD-1 expression is induced on myeloid progenitors by emergency cytokines.

Fig. S5. Gating strategy for identification of MDSC in human blood samples.

Fig. S6. PD-1 expression in human MDSC.

Fig. S7. PD-1 ablation alters tumor-driven emergency myelopoiesis.

Fig. S8. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in response to tumor-driven emergency myelopoiesis.

Fig. S9. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in mice-bearing MC38 or MC17-51 tumors.

Fig. S10. PD-1 ablation increases the output of RORChi effector-like myeloid cells at early stages of tumor growth.

Fig. S11. Therapeutic targeting of PD-1 increases effector features of myeloid cells and decreases tumor growth.

Fig. S12. Myeloid-specific and T cellspecific PD-1 deletion.

Fig. S13. Myeloid-specific PD-1 ablation promotes expansion of IRF8hi and RORChi monocytes and IFN-producing monocytes and macrophages in the tumor site.

Fig. S14. Tumor-induced emergency myelopoiesis and myeloid effector differentiation in Rag2-deficient mice treated with PD-1 antibody.

Fig. S15. PD-1 ablation reduces the threshold of growth factormediated signaling in GMP.

Fig. S16. Myeloid-specific PD-1 ablation induces a distinct metabolic profile characterized by elevated cholesterol.

Fig. S17. Metabolic pathways linking glycolysis to PPP, fatty acid, and cholesterol synthesis.

Fig. S18. Schematic presentation of the mevalonate pathway.

Fig. S19. Increase of glucose uptake and neutral lipid content in PD-1deficient myeloid progenitors early after tumor implantation.

Fig. S20. Myeloid-specific PD-1 deletion alters the immunological profile of CD8+ TEM cells.

Fig. S21. PD-1 ablation enhances antigen presentation ex vivo by tumor-matured DC.

Table S1. List of significantly different metabolites.

Table S2. List of antibodies used for surface staining.

Table S3. List of antibodies used for intracellular staining.

Table S4. List of antibodies used for phenotype of human MDSC.

Table S5. Raw data in Excel spreadsheet.

References (6871)

Acknowledgments: Funding: This work was supported by NIH grants CA183605, CA183605S1, and AI098129-01 and by the DoD grant PC140571. Author contribution: L.S. participated in the conceptualization of the project and experimental design, performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. M.A.A.M. performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. J.D.W., N.M.T.-O., A.C., R.P., Q.W., and M.Y. participated in various steps of the experimental studies. J.A. participated in the experimental design of metabolite studies and the formal analysis and the validation of the data and participated in the preparation of the manuscript. N.P. participated in the conceptualization of the project, designed and performed the bioenergetics studies, and participated in experiments, the analysis and validation of the data, and the preparation of the manuscript. V.A.B. had the overall responsibility of project conceptualization, experimental design, investigation, data analysis and validation, and preparation of the manuscript and figures. Competing interests: V.A.B. has patents on the PD-1 pathway licensed by Bristol-Myers Squibb, Roche, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, and Dako. The authors declare no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.

See more here:
Targeted deletion of PD-1 in myeloid cells induces antitumor immunity - Science

For its promising investigational therapeutic approach to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), BrainStorm Cell Therapeutics is theBuzz of BIO 2020 winnerin the Public Therapeutic Biotech category.

The Buzz of BIO contest identifies U.S. companies with groundbreaking, early-stage potential to improve lives. The event also is anopportunity to make investor connections that could take products to the next phase.

Ten biotechnology companies are nominated in each of the three categories ofBuzz of BIO: Public Therapeutic Biotech, Private Therapeutic Biotech, and Diagnostics and Beyond. In the Public Therapeutic Biotech category that BrainStorm won, nominated companies must be actively developing a publicly traded human treatment intended for review by theU.S. Food and Drug Administration (FDA).

As a developer of autologous cellular therapies treatments that use a patients own cells and tissues for debilitating neurodegenerative diseases, BrainStorm is now testing its NurOwn therapy for safety and effectiveness. The treatment involves extracting, from human bone, marrow-derived mesenchymal stem cells (MSCs), which are capable of differentiating into other cell types. The MSCs are then matured into a specific cell type that produces neurotrophic factors compounds that promote nervous tissue growth and survival. They are then reintroduced to the body via injection into muscles and/or the spinal canal.

Backed by a California Institute for Regenerative Medicine grant, Brainstorm has fully enrolledits randomized, double-blind, placebo-controlled Phase 3 clinical trial (NCT03280056) at six U.S. sites in California, Massachusetts, and Minnesota. Some 200 ALS patients are participating. A secondary safety analysis by the trials independent Data Safety Monitoring Board (DSMB) revealed no new concerns. Every two months, study subjects will be given three injections into the spinal canal of either NurOwn or placebo.

The trial is expected to conclude late this year. Results will be announced shortly afterward.

In a Phase 2 study (NCT02017912), which included individuals with rapidly progressing ALS, NurOwn demonstrated a positive safety profile as well as prospective efficacy.

The use of autologous MSC cells to potentially treat ALS was given orphan drug status by both the FDA and the European Medicines Agency.

Thanks to everyone who voted for BrainStorm during the Buzz of BIO competition,Chaim Lebovits, BrainStorm president and CEO, said in a press release. The entire management team at BrainStorm was very pleased with the results of this competition, and we look forward to presenting to an audience of accredited investors who may benefit from the companys story. We thank the BIO[Biotechnology Innovation Organization] team for singling out BrainStorms NurOwn as a key technology with the potential to improve lives.

As a contest winner, BrainStorm is invited to givea presentation at theBio CEO & Investor Conference, to be held Feb. 1011 in New York City, along with exposure to multiple industry elites and potential investors.

NurOwn cells also are being tested in a Phase 2 clinical study (NCT03799718) in patients with progressive multiple sclerosis.

Mary M. Chapman began her professional career at United Press International, running both print and broadcast desks. She then became a Michigan correspondent for what is now Bloomberg BNA, where she mainly covered the automotive industry plus legal, tax and regulatory issues. A member of the Automotive Press Association and one of a relatively small number of women on the car beat, Chapman has discussed the automotive industry multiple times of National Public Radio, and in 2014 was selected as an honorary judge at the prestigious Cobble Beach Concours dElegance. She has written for numerous national outlets including Time, People, Al-Jazeera America, Fortune, Daily Beast, MSN.com, Newsweek, The Detroit News and Detroit Free Press. The winner of the Society of Professional Journalists award for outstanding reporting, Chapman has had dozens of articles in The New York Times, including two on the coveted front page. She has completed a manuscript about centenarian car enthusiast Margaret Dunning, titled Belle of the Concours.

Total Posts: 6

Ins holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Cincias e Tecnologias and Instituto Gulbenkian de Cincia. Ins currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.

Read more:
BrainStorm Cell Therapeutics Wins 2020 'Buzz of BIO' Award for ALS Investigational Therapy - ALS News Today

Meet the inflammation and immunity researcher studying the fundamental cellular mechanisms behind uncontrolled inflammatory responses to allergens

As the prevalence of allergic disease continues to rise worldwide, the work of immunologist Dr. Adam MacNeil has never been more important. By identifying novel targets in allergic inflammation to enable the development of innovative therapies, MacNeil and his team are pushing toward a healthier future. Were interested in allergic inflammation from two different branches, firstly, how the cells that contribute to inflammation emerge from the bone marrow, and secondly, how mature mast cells contribute to inflammatory mechanisms at the site of exposure, explains MacNeil, associate professor in the interdisciplinary Health Sciences department at Brock University, Canada.

Dr. Adam J. MacNeil, Associate Professor of Immunologyat Brock University's Department of Health Sciences.Pictured from left to rightare;Melissa Rouillard, Aindriu Maguire, Rob Crozier, Adam MacNeil, Jeremia Coish, Katie Hunter, Colton Watson, and Natalie Hicks. Image courtesy of theMacNeil Lab.

The MacNeil Lab investigates mechanisms in hematopoietic stem cells directing the maturation of the most well-known allergic mediator cellsmature mast cellsthat drive allergic inflammation. A key research goal for the team is to identify how an allergen activates a mast cell to create an inflammatory response.

Seeking to understand the signals that stimulate a progenitor cell to become a mast cell in different tissues, this research looks to determine the signaling pathways directing the epigenetic, and ultimately proteomic, profile of these cells1-3. To do this, cells are isolated and matured from bone marrow to create functional, phenotypical mast cells, which are primed with allergen-specific IgE molecules before addition of the allergen to activate the cells. The inflammatory response to the allergen, and the cell signaling processes that contribute to the inflammatory mechanisms, can then be measured through the secretion of histamines in degranulation mechanisms, or release of pro-inflammatory mediators such as cytokines, chemokines, and lipid metabolites.

Brock University

Being able to identify and sort cells with a specific immune profile requires tools capable of precision sorting of heterogeneous populations of cells. MacNeil expands: Were working with a heterogeneous population of cells in the bone marrow and trying to take only the stem cells out. So, it's a very small population within the total population of cells. Many of the assays that we want to do with that small population of cells are very well-suited to being sorted directly onto a 96-well plate where we can then actually conduct the experiment directly, knowing exactly how many cells are in each well and what the particular profile of those cells is. That makes the Sony SH800S a really strong tool for our lab.

When it comes to optimizing and streamlining the lab's work, Sony technology offers advantages over traditional methods. The traditional flow cytometer or cell sorter in any core lab is operated by a technician, and they're the only one allowed to touch it. That doesn't make for great learning opportunities for graduate students, and it's much better if they can actually interface with the instrument themselves, says MacNeil. The software and automation really allow for that to happen, but also adds to the robustness of the instrument. The way in which it has been designed means that it's pretty difficult to break it.

With an epigenetic approach to understanding how mast cells differentiate, and the effect of inhibiting specific signaling pathways in those cells, the MacNeil Lab uses sorted cells in functional assays such as immune cell profiling and cytokine secretion. Also, the cells can be sorted into plate-based assays for ChIP or RNA-Seq to assess their genetic profile. We're not only interested in sorting. We bought the device because it's robustly dynamic, explains MacNeil, referring to the Sony SH800S. You can look at data acquisition and not have to even use the sorting function at all in certain scenarios. There are many times that were simply interested in looking at the phenotype of our cells and not worried about sorting necessarily. Weve found this instrument to be very easy to use and to give us robust data in terms of the immune profile of our cells.

In addition, the SH800S microfluidic sorting chip helps to automate key stages of instrument setup and demonstrates versatility with a wide range of chip sizes, ranging from 70130 m, for sorting a variety of cells. The chip ultimately gets to the robustness of the instrument, explains MacNeil. Because of the chip, we have such peace of mind about how the instrument functions that we don't even worry about clogging of the instrument and all of the problems that the chip ultimately solves. If we do run into a problem, we can just change the chip. I certainly find the chip technology to be really well suited to our type of lab environment.

For MacNeil, the Sony SH800S Cell Sorter is a great fit for the lab, with a seamless software interface and great overall instrument design and modularity for easy plate-based sorting.MacNeil lab logocourtesy of the MacNeil Lab.

Working within the diverse multidisciplinary department at Brock University opens unique and fascinating research avenues not available to all immunologists and has led MacNeil to interesting collaborations and knowledge exchange on transdisciplinary projects.

As part of these broader research avenues, working with sociologist Prof. Terrance Wade and cardiovascular biologist Prof. Deborah OLeary, MacNeil also studies adverse experiences in childhood. The team is investigating whether such events may set the immunological stage for dysregulated inflammation in later life, through mechanisms involving stress-stimulated cortisol release that can shape how the immune system is responding4.

In another stream of collaborative immunological research, MacNeil collaborates with psychologist Prof. Anthony Bogaert to look at the role of the immune system in shaping sexual orientation as part of the fraternal birth order effect. This research looks at how early pregnancies stimulate the immune system to make antibodies against brain proteins in fetal males that may then affect their social behaviors in later life5. Its something I may not have expected to ever work on, says MacNeil. But when you come to a diverse department with a wide lens on health, these kinds of opportunities emerge. Were now interested in using the SH800S to test hypotheses for particular mechanisms underlying this phenomenon.

Looking ahead, MacNeil expects tissue heterogeneity to be a key issue to tackle in the field of immunology. Cell populations simply aren't uniform, he says. Mast cells in different locations in the body don't have exactly the same phenotype, and so, as our research proceeds and we continue to probe the role of the mast cell in allergic inflammation, we're very conscious that tissue heterogeneity is going to be a factor. But with such challenges come opportunities. Were ultimately interested in going into those tissues and trying to pull mast cells out. To do this, we would require an instrument like a cell sorter. Once the cells are sorted, we can interrogate their functional phenotype, including how they degranulate, secrete cytokines and metabolize lipids etc. toward one day potentially modulating their phenotype for the hundreds of millions affected by this inappropriate immune response, MacNeil concludes.

Originally posted here:
Innovative therapies: Novel targets in allergic inflammation - SelectScience

McLean (United States) (AFP)

When a person's immune system is impaired by a genetic disease, a bone-marrow transplant can be a powerful therapeutic tool, but with a major downside: during the first few months the recipient's defenses against viruses are severely weakened. The slightest infection can lead to a hospital trip.

A still-experimental type of treatment known as T-cell therapy aims to assist during this vulnerable period -- the months during which the body is rebuilding its natural defenses. After two decades of clinical trials, the technology has been refined, and is being used to treat more and more patients, many of them children.

A boy named Johan is one of them.

Today he is a mischievous, smiling toddler with a thick shock of light-brown hair, who never tires, playfully tormenting the family's puppy, Henry.

There is no sign of the three-year-long medical and emotional roller-coaster ride he and his family, who live in an affluent Washington suburb, have been on.

The first traumatic surprise came with the results of a pregnancy test: Johan was not planned.

"That was a huge shock. I cried," said his mother, 39-year-old Maren Chamorro.

- Risky procedure -

She had known since childhood that she carried a gene that can be fatal in a child's first 10 years, chronic granulomatous disease (CGD).

Her brother died of it at the age of seven. The inexorable laws of genetics meant that Maren had a one in four chance of transmitting it to her child.

For their first children, she and her husband Ricardo had chosen in-vitro fertilization, allowing the embryos to be genetically tested before implantation.

Their twins Thomas and Joanna were born -- both disease-free -- seven and a half years ago.

But in Johan's case, a post-birth genetic test quickly confirmed the worst: he had CGD.

After conferring with experts at Children's National Hospital in Washington, the couple took one of the most important decisions of their lives: Johan would receive a bone-marrow transplant, a risky procedure but one that would give him a chance of a cure.

"Obviously, the fact that Maren had lost a sibling at a young age from the disease played a big role," Ricardo confided.

Bone marrow, the spongy tissue inside bones, serves as the body's "factory" for the production of blood cells -- both red and white.

- His brother's immune system -

Johan's white blood cells were incapable of fighting off bacteria and fungal infections. A simple bacterial infection, of negligible concern in a healthy child, could spread out of control in his young body.

Luckily, Johan's brother Thomas, six years old at the time, was a perfect match. In April 2018, doctors first "cleansed" Johan's marrow using chemotherapy. They then took a small amount of marrow from Thomas's hip bones using a long, thin needle.

From that sample they extracted "supercells," as Thomas calls them -- stem cells, which they reinjected into Johan's veins. Those cells would eventually settle in his bone marrow -- and begin producing normal white blood cells.

The second step was preventive cell therapy, under an experimental program led by immunologist Michael Keller at Children's National Hospital.

The part of the immune system that protects against bacteria can be rebuilt in only a matter of weeks; but for viruses, the natural process takes at least three months.

- Hurdles remain -

From Thomas's blood, doctors extracted specialized white blood cells -- T-cells -- that had already encountered six viruses.

Keller grew them for 10 days in an incubator, creating an army of hundreds of millions of those specialized T-cells. The result: a fluffy white substance contained in a small glass vial.

Those T-cells were then injected into Johan's veins, immediately conferring protection against the six viruses.

"He has his brother's immune system," said Keller, an assistant professor at Children's National.

Johan's mother confirmed as much: today, when Thomas and Johan catch a cold, they have the same symptoms, and for nearly the same amount of time.

"I think it's pretty cool to have immunity from your big brother," Maren Chamorro said.

This therapeutic approach -- boosting the body's immune system using cells from a donor or one's own genetically modified cells -- is known as immunotherapy.

Its main use so far has been against cancer, but Keller hopes it will soon become available against viruses for patients, like Johan, who suffer from depressed immune systems.

The chief obstacles to that happening are the complexity of the process and the costs, which can run to many thousands of dollars. These factors currently restrict the procedure to some 30 medical centers in the United States.

For Johan, a year and a half after his bone marrow transplant, everything points to a complete success.

"It's neat to see him processing things, and especially play outside in the mud," his mother said.

"You know, what a gift!"

Her only concern now is the same as any mother would have -- that when her son does fall ill, others in the family might catch the same bug.

2020 AFP

Read the original post:
The 'supercells' that cured an infant's grave genetic illness - FRANCE 24

"One reason that cats are happier than people is that they have no newspapers. Gwendolyn Brooks

I had a question from a follower last week about a small biotech firm based near one of my residences in New York City. This $4 developmental firm is focused on diseases of the central nervous system. I had not looked at this name in quite some time, and there is very little research posted on this company, so we will revisit it in the paragraphs below.

Brainstorm Cell Therapeutics (BCLI) is a small biotech concern out of New York. The company is developing adult stem cell therapeutic products. It focuses on utilizing the patients own bone marrow stem cells to generate neuron-like cells that may provide an effective treatment initially for amyotrophic lateral sclerosis, Parkinsons disease, multiple sclerosis and spinal cord injury. It develops these therapies with its proprietary NurOwn platform. The shares currently trade at the $4 level and have an approximate market cap of $90 million.

Source: June Company Presentation

Pipeline:

Source: June Company Presentation

As can be seen above, the company has several mostly early stage assets it is developing in its pipeline.

By far the most advance therapy in the company's pipeline is its product aimed at ALS which is also known as Lou Gehrig's Disease. This rare condition affects some 450,000 individual worldwide, including some 30,000 in the United States.

Source: June Company Presentation

The company posted a second safety analysis around this Phase 3 trial in late October. Much more important top-line results from this key study should be out sometime in the fourth quarter of next year. 200 people have been enrolled in this critical study. Here are the company's conclusions about its Phase II trial.

Source: June Company Presentation

Top-line data from a Phase 2 NurOwn trial to treat Progressive Multiple Sclerosis should be out mid-year in 2020 as the only other trial milestone on the horizon.

It is hard to find many small biotech firms that get less coverage than Brainstorm. I can find only one analyst firm that has 'chimed in' on BCLI in 2019. That was Maxim Group five weeks ago which maintained its Buy rating and $9 price target.

Notably, no insiders have sold shares in this firm since late in 2015. Earlier this month, the CEO, CFO and CMO purchased just over $65,000 in shares in aggregate. Although this is hardly a big insider buy, this was the first insider activity in the stock since January of this year.

The company ended the third quarter with just over $2 million in cash and marketable securities on the balance. It also has remaining non-dilutive CIRM and IIA grants that amount to approximately $5.9 million. Given Brainstorm burned through just over $5 million, some sort of capital raise is very likely on the horizon.

According to a recent interview posted on Seeking Alpha with the company's CEO, there are several other potential competitors in the ALS also conducting late stage trials. Brainstorm's leaders believe NurOwn's effort stands out in 'by being autologous and because it can produce high levels of neurotrophic factors. Moreover, unlike most stem cell competitors, it's delivered directly into the spinal fluid through bimonthly lumbar punctures, unlike others that need an invasive surgical procedure "that carries considerable morbidity".'

The company's platform is intriguing. However, there simply doesn't seem to be enough information to make an informed decision around this name especially in light of a coming capital raise. I offer up this analysis in response to an inquiry and because there is little posted here on Seeking Alpha on this name.

"There is, incidentally, no way of talking about cats that enables one to come off as a sane person. Dan Greenberg

Bret Jensen is the Founder of and authors articles for the Biotech Forum, Busted IPO Forum, and Insiders Forum

I present and update my best small-cap biotech stock ideas only to subscribers of my exclusive marketplace, The Biotech Forum. Try a free 2-week trial today by clicking on our logo below!

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Read the original:
Reading Up On Brainstorm Cell Therapeutics - Seeking Alpha

Soft tissue injuries in muscles, tendons and ligaments, andosteoarthritis, can make moving around painful and limit your physical activity. ButDr. James Presley,a Mayo Clinic physical medicine specialist, says two specialized treatments are growing more common and can help you heal faster.

Platelet-rich plasmais a specialized treatment that Dr. Presley says can bring relief for many patients dealing with soft tissue injuries.

Platelet-rich plasma is a way of trying to harness the bodys immune system or the bodys own ability to heal tissues, Dr. Presley says. [We] concentrate it and then spot-shoot it into the area of injury.

Dr. Presley says the process involves taking blood from your arm, processing it to concentrate the platelets, then injecting it directly into the affected area.

These treatments seem to be helpful in helping the healing process move along when it comes to tendon and ligament injuries, and potentially to help decrease pain and improve function in a joint that has some arthritis, Dr. Presley says.

The second treatment is calledbone marrow aspirate concentrateand involves extracting cells, including stem cells, from bone marrow in the pelvis; processing them into a solution; and injecting them into a painful joint.

The studies that have been done with this have shown patients have decreased pain and thereby improved function of a joint with mild to moderate osteoarthritis, Dr. Presley says.

But he says the best thing you can do is protect your muscles, tendons, and ligaments from injury by finding a happy medium between staying active and avoiding overuse.

Original post:
Advances In Treatment Of Soft Tissue Injuries (Video) - South Florida Reporter

The 2010s are coming to an end, and looking back there have been some pretty amazing advances and innovations in health and science.

Advances in prosthetic limbs

Prosthetic limbs have been around since ancient times. In Egypt, a prosthetic wooden toe was found on a mummy dating back 3,000 years. By the Dark Ages, inventors could incorporate hinges on prosthetic arms used by knights. In modern times, the field of prosthetics has turned to incorporating more technology into physical stand-ins for limbs. In the last several years, theres been a boom in advances that have led to the best and most useful prosthetics weve ever seen.

Reports from the early 2010s talked about the potential for new technology to allow people to control prosthetics with their minds and to receive sensory information from their devices. It may have been a reach in the early part of the decade, but now it is literally within grasp. There are new prosthetic hands being tested that give the user the ability to grab objects with their thoughts and even to sense the texture of what they are touching. New bionic hands allow the user to feel again by sending signals back to the brain about the things they are touching, like whether its hard or soft. Other research groups have been working on bionic arms that can move based on the users thoughts through a brain-computer interface. While these have demonstrated its possible to accomplish these goals in the lab, theres still more to be done before people can use these devices outside in the real world.

Many of these advanced prosthetics are still prototypes and may not reach the general population for a while. Luckily, cheaper 3D printers have made simple prosthetics more accessible. These are important because a prosthetic device can improve the quality of life for people. For example, this person has been printing prosthetic hands and arms for people in Africa after watching an online tutorial. New materials that go into 3D printers are cheaper than they used to be and are being used in prosthetics to provide a more affordable option for patients.

Although prosthetics have been around for ages in some form or another, they arent always used. One variable to consider is the social acceptance of having a prosthetic. Theres still a lot of stigma around disabilities and many people may reject prosthetics even if they are available. In 2012, an athlete with both feet amputated competed in the mens 400 meter race at the Olympics in London. There was some controversy over whether the runner with a prosthetic foot should be allowed to run in races with people who dont have prosthetics or if they should only be allowed in competitions specifically for people who have them. Prosthetics also need to be comfortable and usable in order to be successfully adopted. In one study, about 4.5 percent of people rejected prosthetics and 13.4 percent stopped using their prosthetics. As the new prosthetics that are more natural and intuitive to use come to market, hopefully more people will benefit, and the social barriers to acceptance will disappear.

CRISPR

The genome modification technique called Clustered Regularly Interspaced Short Palindromic Repeats, aka CRISPR, was a culmination of a few decades of work by scientists, and major studies explaining the method were published in 2013. The version of it called CRISPR-associated protein 9 or CRIPSR-Cas9 is what most researchers are specifically using in most cases. It involves a regular gene editing mechanism that happens in bacteria. The bacteria can take sections of DNA from attacking viruses and essentially use that to remember the viruses if they return. When the virus is back, the bacteria can target the matching sections of DNA in the virus, cut it and disable the virus.

Though 2013 was only six years ago, as far as science goes, CRISPR has been moving at lightning speed towards practical applications. Using CRISPR to edit a gene sequence, researchers can now add, delete or modify DNA segments more quickly and accurately than ever before. Since the technique was developed, researchers have used CRISPR to target diseases caused by a single gene like cystic fibrosis or sickle cell disease.

Probably the most infamous use of CRISPR are the CRISPR babies. In late 2018, a Chinese researcher, He Jiankui, claimed to have used CRISPR to modify the genomes of two babies to include a mutated version of a gene that protects against HIV. This case was and is highly controversial for the ethical concerns with genetically modifying a human genome at the embryo level, or germline, meaning it can be passed down to future generations and has not been done before in humans. Recently, MIT Technology Review obtained excerpts from Hes research, and experts say that the report and data may be untrustworthy. This means it is still unclear if He and collaborators actually successfully modified the babies genomes. The scientific community overall condemns this way of using CRISPR to edit a human germline genome and has called for an international moratorium on it until a framework can be agreed on.The researcher has been sentenced to three years in prison in Shenzhen, China.

As fraught with controversy as the CRISPR babies may be, CRISPR technology still holds a lot of promise and can be used responsibly, supporters say. For example, researchers are using it to target cancer cells by taking a patients immune cells, modifying them using CRISPR and then infusing the patient with the modified cells. For blood diseases, a patient with sickle cell disease is reported to be responding well to a CRISPR treatment that has allowed her body to produce a crucial protein.

Another area that has boomed this decade partly because of CRISPR technology is stem cell therapy, which well get into in the next section.

Stem cell therapy

Technically, the only Federal Drug Administration (FDA)-approved stem cell therapies are blood-forming stem cells derived from umbilical cord blood. Blood-forming stem cells are used to treat patients with cancer after chemotherapy has depleted blood cells, as well as patients with blood disorders like leukemia whose bone marrow tissues are damaged. These types of treatments have been around for about 30 years, but in the 2010s weve seen potential for more uses of stem cells in health care.

The main idea behind stem cell therapy is that because the cells are pluripotent meaning they can become many other types of cells they can be introduced into parts of the body that are damaged and need new cells. On top of that, researchers can now extract some types of stem cells from a persons body, so no need for umbilical cords. This opens up the possibilities for highly personalized treatment where one person can be treated with stem cells from their own body.

Researchers are exploring how stem cells can be used to treat liver disease, cerebral palsy, stroke, brain injury and others. There are many ongoing research-backed clinical trials for stem cell therapy. A quick search for stem cell therapy on the governments clinical trial database turns up 5,638 results. And because of the work necessary to even get to the clinical trial stage, theres likely an order of magnitude more stem cell therapy studies in the pre-clinical trial stages.

Stem cell therapy is also being offered in for-profit clinics around the U.S. In these cases, the clinics are typically taking fat tissue from a patient, isolating the stem cells and then administering the stem cells back to the patient. In some cases, the treatments may lead to health complications, like blindness in a few extreme cases, and the FDA warns that such treatments are unapproved and potentially harmful. The FDA is ramping up regulation of stem cell clinics and earlier this year took a specific clinic in Florida to court.

Although there are many stem cell clinics offering unproven stem cell therapies, its not all hype. Granted that its difficult to pass the clinical trial stage to get FDA approval, stem cell research may lead to new treatments for several health conditions that could completely change the health care landscape.

You can follow Chia-Yi Hou on Twitter.

More here:
The 3 most important health innovations of the past decade - The Hill

Doctor close-up of a doctor showing a picture of a kidney on a tablet in a hospital

With a float in this years Rose Bowl parade celebrating organ donation, there are a lot of questions many have about the process and why they should donate their organs.

Legacy of Hope, the Alabama organ donation alliance, said over 1,400 Alabama residents are waiting for a life-saving transplant, with 471 lives saved in 2018.

2.9 million residents across the state are on the registry.

Can I become an organ donor?

The federal government organ donation website, Organdonor.gov, says anyone 18 and older can join the national and state organ donor registries and donate as long as they and their organs are in healthy condition.

The Tennessee donor registry also allows anyone between 13 and 17 to join as long as they have a state ID, drivers license, or leaners permit. However, their parents will have the final say on organ and tissue donation if that decision needs to be made.

Even if you have health issues, you could still donate even one organ, which could save or improve a life.

What can be donated?

How do I register to donate?

There are two registries: The National Donor Registry and the state registry.

In Alabama and Tennessee, if you checked yes to organ donation when applying for or renewing your license, youre already on the state list.

If you didnt check yes, you can make your decision when applying for or renewing your drivers license or state ID at your local DMV or visit your states registry online.

In Alabama, Legacy of Hope manages the state registry, and you can sign up here.

In Tennessee, Donate Life Tennessee manages the state registry donation registry, and you can sign up here.

Youll need to check yes every time you renew to stay on the list.

You can join the national registry hereor in the iPhone Health app.

Who will get my organs if I decide to donate?

Its possible anybody could get your organs if you donate. People of different races match frequently, according to organdonor.gov.

The matching process includes many factors such as location, how long a recipient has been on the list, medical need, and determining blood and tissue type.

The Organ Procurement and Transplantation Network handles the matching process and it varies based on the organ being transplanted.

Does my decision to donate affect the care I get in the hospital?

No. The medical teams saving your life will do everything in their power before donation becomes a possibility. A separate team handles organ retrieval should it be necessary.

The donation process only begins once brain death is confirmed. In those cases, a potential donor must have no brain activity and be unable to breathe without a machine.

Legacy of Hope says in Alabama, two doctors have to mutually agree that a patient is brain dead before the process starts.

Where can I find more information?

If youre trying to decide or just want more information, there are multiple resources.

View original post here:
Curious about organ donation? Heres what you need to know - WHNT News 19

Stem Cell Therapy Market 2019 report is a proficient and in-depth research report on the worlds major regional market conditions, focusing on the main regions (North America, Europe and Asia-Pacific). It covers the market landscape and its growth prospects over the coming years. The report also includes a discussion of the Key Vendors operating in this Global market.

The data and the information that was gathered was checked and approved by the subject matter experts. The users will discover this report for a better understanding of the Stem Cell Therapy market inside and out. The prime goal of this report is to help the user to comprehend the Stem Cell Therapy market as far as its definition, division, market potential, compelling patterns, and the difficulties that the market is facing.

Major companies in Stem Cell Therapy market analysis:Osiris Therapeutics, Inc., Medipost Co., Ltd., Anterogen Co., Ltd., Pharmicell Co., Ltd., Holostem Terapie Avanzate Srl, JCR Pharmaceuticals Co., Ltd., Nuvasive, Inc., RTI Surgical, Inc., Allosource

By Therapeutic ApplicationMusculoskeletal disorders, Wounds and Injuries, Cardiovascular Diseases, Surgeries, Gastrointestinal Diseases, Other Therapeutic Applications

By Cell SourceAdipose Tissue-derived Mesenchymal Stem Cells, Bone Marrow-derived Mesenchymal Stem Cells, Cord Blood/Embryonic Stem Cells, Other Cell Sources

Points Covered in The Report:

Get a sample copy of the report at @https://www.360researchreports.com/enquiry/request-sample/12900039

The information and the data with respect to the market are taken from solid sources, for example, sites, yearly reports of the companies, journals, and others. The facts and information are mentioned in the report utilizing outlines, diagrams, pie graphs, and other pictorial portrayals. This upgrades the visual portrayal and furthermore helps in understanding the facts much better. The properties that are clarified in the report are the technological progressions that are made in the Stem Cell Therapy market, the business made in the worldwide market, the annual production, the profit made by the business, the ventures made by the manufacturers and the measures that are taken by the government to boost the development of the market.

The Stem Cell Therapy market revenue generation is also included in the report. The different sections from which significant offers of the market is acquired is incorporated inside the report with the regional division. The regional division encourages the market players to comprehend where to make investments and where there will be support from both the consumers and government.

Major regions in Stem Cell Therapy market analysis:

Detailed TOC of 2019 Global Stem Cell Therapy market Depth Research Report:

Chapter 1 Industry Overview

Chapter 2 Production Market Analysis

Chapter 3 Sales Market Analysis

Chapter 4 Consumption Market Analysis

Chapter 5 Production, Sales and Consumption Market Comparison Analysis

Chapter 6 Major Manufacturers Production and Sales Market Comparison Analysis

Chapter 7 Major Type Analysis

Chapter 8 Major Application Analysis

Chapter 9 Industry Chain Analysis

9.2 Manufacturing Analysis

9.3 Industry Chain Structure Analysis

Chapter 10 Global and Regional Market Forecast

10.2 Sales Market Forecast

10.3 Consumption Market Forecast

Chapter 11 Major Manufacturers Analysis

11.1 Company 3

11.2 Company 2

11.3 Company 3

Chapter 12 New Project Investment Feasibility Analysis

Continued.

Look into Table of Content of Stem Cell Therapy Market Report @ https://www.360researchreports.com/TOC/12900039#TOC

Key Reasons to Purchase:

Look into Table of Content of Stem Cell Therapy Market Report @https://www.360researchreports.com/TOC/12900039#TOC

Key questions answered:

Purchase this report (Price 3500 USD for a single-user license) @ https://www.360researchreports.com/purchase/12900039

This report revolves around Global and regional market, giving data on significant players like producers, providers, wholesalers, brokers, clients, investors, significant types, significant applications and so forth. Information type capacity, production, market share, price, revenue, cost, gross, gross margin, growth rate, consumption, import, export, etc. Industry chain, producing process, cost structure, promoting direct are also analysed in this report.

About Us:

360 Research Reports is the credible source for gaining the market reports that will provide you with the lead your business needs. At 360 Research Reports, our objective is providing a platform for many top-notch market research firms worldwide to publish their research reports, as well as helping the decision makers in finding most suitable market research solutions under one roof. Our aim is to provide the best solution that matches the exact customer requirements. This drives us to provide you with custom or syndicated research reports.

Contact Us:

Name: Mr. Ajay More

Email:[emailprotected]

Organization: 360 Research Reports

Phone: +44 20 3239 8187/ +14242530807

Check Out Our Other Related Reports-

Dental Lasers Market Research 2020 | Industry Analysis by Trends, Scope, Stake, Business Overview, Growth and Forecast by 2023

Polyurethane Sealants Market trends and forecast to 2023 | Report based on reviewed data and important sources by Size, Share, regional and geographical predictions till 2023

Global Proppant Market Analysis 2019 Industry Analysis, Size, production, scenarios, intake and cost structure Study and forecast to 2023

Solar Photovoltaic Material market growth and detailed insights 2020 by types, applications, trends, and forecast to 2023

Drilling Tools Market 2018 Industry Price Trend, Size Estimation, Industry Outlook, Business Growth, Report Latest Research, Business Analysis and Forecast 2023 Analysis Research

Cannula Market Report 2019 | Competitive analysis, trends, stake, challenges and forecast to 2023

Continue reading here:
Stem Cell Therapy Market Report to 2020 | Analysis and forecast of market till 2023 by key players(companies), applications and classification of the...

Sickle cell disease is a genetic condition in which red blood cells, which should be circular, adopt a crescent shape and are sticky and rigidALAMY

The first patients to receive gene-editing treatments for inherited blood diseases will enter the new year free of agonising symptoms.

The experiments suggest that altering DNA could treat sickle cell disease (SCD) and beta thalassemia, conditions both caused by faulty genes that hamper the bloods ability to carry oxygen.

The companies behind the trials said that a patient in the US with SCD had been well since July. A thalassemia patient in Germany had been free of symptoms for nine months. Previously she had 16 blood transfusions a year.

British patients could be offered similar experimental therapies next year. The treatment for both conditions involved a high-precision gene-editing tool called Crispr-Cas9. It was used to alter the DNA of some of the cells of Victoria

Want to read more?

Subscribe now and get unlimited digital access on web and our smartphone and tablet apps, free for your first month.

Link:
Sickle cell patient is pain free after geneediting trial altered her DNA - The Times

Of all blood cancers, leukaemia and lymphoma are among the most curable.

However, many people, including doctors, still believe the disease leads to immediate death.

This is no longer true today as they are not fatal.

With optimal treatment, the majority of patients go into remission and are considered cured.

These two cancers have been more extensively studied than other forms of cancer, due to the ease in obtaining samples from blood, bone marrow or lymph nodes, spurring the advent of novel targeted therapies for a cure, says consultant haematologist Dr Ng Soo Chin.

Most blood cancers start in the bone marrow, where blood is produced.

Bone marrow contains stem cells, which mature and develop into red blood cells, white blood cells or platelets.

In most blood cancers, normal cell development is interrupted by the uncontrolled growth of an abnormal type of a particular blood cell.

These abnormal blood cells, which are cancerous, prevent your blood from performing many of its functions, like fighting off infections or preventing serious bleeding.

Leukaemia or white blood is classified into acute and chronic disease, which is then divided further into subtypes: acute lymphocytic leukaemia, acute myeloid leukaemia, chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML).

The presentation between acute and chronic leukaemia differs.

The acute person will tell you he was well a week ago and is now down with symptoms such as lethargy, anaemia and recurrent infection.

Suddenly, he may look pale, so we check his blood count for any abnormalities. A bone marrow exam will further confirm whether it is acute.

With chronic leukaemia, the patient can be unwell for a couple of months.

We are increasingly picking up cases early because of blood test availability.

The survival rate has improved tremendously for acute leukaemia, with more than 50% fully cured because bone marrow transplants are easily available in the country.

For CLL and CML, 95% of patients are alive at the 10-year mark, says Dr Ng.

Generally, chronic leukaemia patients belong to the older age group (50 years and above), but acute leukaemia can occur in all ages.

Leukaemia symptoms are often vague and not specific, so its easy to overlook them as they may resemble symptoms of the flu and other common illnesses.

In fact, chronic leukaemia may initially produce no symptoms and can go unnoticed or undiagnosed for years.

Lymphomas, a type of blood cancer that begins in a subset of white blood cells called lymphocytes, can be classified into Hodgkins and non-Hodgkins.

The main difference between Hodgkins and non-Hodgkins lymphoma is the specific lymphocyte each involves.

Lymphocytes are an integral part of your immune system, which protects you from germs.

Five-year survival rates are high with Hodgkins lymphoma at 86% and non-Hodgkins lymphoma at 70%.

You can beat the disease even if it is detected at a late stage.

Multiple myeloma, which is the third kind of blood cancer, forms in a type of white blood cell called a plasma cell.

Patients often complain of bone pain, and unfortunately, this type of cancer has no cure.

Blood cancers typically involve abnormal white blood cells and can affect paople of all ages, depending on the type of cancer. 123rf.com

Fear of treatment

Chemotherapy is a much dreaded word among cancer patients.

But with advances in medicine, newer chemotherapy-free treatments are now available.

Dr Ng says, Traditionally, cancer is treated via surgery or radiation the layman says we fry and poison them, which is not far from the truth!

Radiation means burning the cancerous area, but a lot of times, the cancer can also be present elsewhere, so there is limitation to this treatment.

With chemotherapy, we use cytotoxic (cell-killing) drugs they go in and knock off both cancer and normal cells.

The short-term effects include vomiting, hair loss, appetite loss and weight loss.

But as doctors, we are looking at a different perspective. We are more worried about white cells dropping (neutropenia) because the patient can pick up an infection that can potentially kill him.

Neutropenia is a condition that results when the body does not have enough neutrophils, a type of white blood cell that is an essential first line of defence against infections.

Thats one risk of chemotherapy, although we can now improve neutropenia by giving a growth factor injection.

But for certain cancers, we need to step up the drugs.

He adds: We are scared of neutropenia, but patients are more concerned about bodily changes.

The older ones get upset over losing hair because they cannot take it when others ask them what has happened to their hair.

Young people are not as concerned with hair loss because it can be trendy.

We understand that chemotherapy is less than pleasant and strong doses can impair fertility in young patients, especially women.

Despite current technology, only one-third of patients are successful in freezing their eggs.

What he is concerned about is that chemotherapy can actually increase the patients risk of getting another cancer, especially blood cancer.

It can happen the day after! says Dr Ng.

Most experts believe chemotherapy damages stem cells, so if youre unlucky, you might get acute myeloid leukaemia after undergoing chemotherapy for breast cancer.

Its just like crossing the road there is always a risk of being knocked down.

All our cells have a biological clock and there is an orderly exchange of old and new cells.

But with blood cancers such as leukaemia, there is a clone of abnormal cells.

Cancer cells have an advantage over normal cells because they can survive longer.

Chemotherapy is still needed to treat most acute blood cancers, although if the mutation is known, targeted therapies can be applied.

For chronic blood cancers, there is no need for chemotherapy. Oral drugs are enough to combat the disease.

Eventually, many patients are able to wean off the drugs.

As we may be aware, immunotherapy is the buzzword in cancer treatment today.

Also called biologic therapy, it is a type of cancer treatment that boosts the bodys natural defences to fight cancer.

It uses substances made by the body or in a laboratory to improve or restore immune system function.

One of the latest treatment modalities is the CAR T-cell therapy, a form of immunotherapy that uses specially altered T cells a part of the immune system to fight cancer.

A sample of a patients T cells are collected from the blood, then modified to produce special structures called chimeric antigen receptors (CARs) on their surface.

When these CAR T-cells are reinfused into the patient, the new receptors enable them to latch onto a specific antigen on the patients tumour cells and kill the cells.

At the moment, this intravenous therapy is available in the United States and hasnt reached our shores yet. It has to be properly regulated first, says Dr Ng.

A volunteer is having his head shaved to donate hair to make wigs for cancer patients in this filepic. Hair loss is one of the side effects of chemotherapy that affect patients the most.

Following natural remedies

The consultant haematologist errs on the side of caution when patients ask about natural cancer remedies, or the dos and donts during treatment.

We always believe there should be a scientific approach to the problem.

If patients are doing okay while undergoing treatment and there is no weight loss, I tell them to go ahead and do what they always do.

However, just be particular about food hygiene, as there is a chance you may get food poisoning.

If youre undergoing chemotherapy, then youll land yourself in hospital, and if your luck is bad, you may even land up in the ICU (intensive care unit).

So make sure the food is cooked and not left overnight to reduce your chances of infection.

Eat a balanced diet, he advises.

When it comes to exercise, he says to work out within your limit.

Instead of pushing the body and running marathons or climbing mountains, go for walks.

Dr Ng says, Life should go on, but be sensible.

Dont go to crowded places because you may pick up an infection, but dont be withdrawn either. All humans need social interaction.

With the billion-dollar dietary supplements industry, companies are constantly trying to lure customers into buying their products.

A lot of supplements are just glorified vitamins in different packaging.

The more expensive they are, the more people will buy them, thinking they are good.

There are people with good intentions, but unfortunately, there are also a lot of scammers out there that is life.

For the amount you spend on supplements, why not keep the money aside and go for a trip once your treatment is over? he suggests.

Often, the late diagnosis is due to preference for alternative treatment.

These alternative treatments are like fashion shows, after some time, they go out of trend.

For me, youre wasting valuable time because cancer is not your friend.

Yes, chemotherapy is tough, but with the latest chemo-free regimen, patients are more willing to come forward.

The earlier it is treated, the higher your chances of recovering, he says.

To share his 30-odd years of knowledge and experience in the field, Dr Ng has written his third book titled Understanding Blood Disorders.

Intended for patients, caregivers and healthcare professionals, proceeds from the sales of the 270-page book will go to the newly set-up Faith Hope Love Hospice Care Malaysia in Petaling Jaya, Selangor.

We're sorry, this article is unavailable at the moment. If you wish to read this article, kindly contact our Customer Service team at 1-300-88-7827. Thank you for your patience - we're bringing you a new and improved experience soon!

Article type: metered

User Type: anonymous web

User Status:

Campaign ID: 7

Cxense type: free

User access status: 3

See the article here:
Leukaemia and lymphoma have a good survival rate - The Star Online

December 2017, and the Christmas party season is in full flow. Everywhere I look are scenes from some hilariously awful Dickens pastiche: revellers squeezed into warm pubs; joyful chatter spilling out on to the street; the sound of carols and the scent of mulled wine in the air. Its as if I am peering in at it all through frosted glass, wishing my own Christmas could be as carefree.

Instead, I have spent a morning turned on my side on a hospital bed while a nervous-looking young doctor works up a sweat attempting to force a long needle into my hipbone. He needs it to go deep enough that he can suck out some of the marrow inside, but my tough bones are making life difficult for him.

I dont feel so tough. My wife and I spend the next fortnight anxiously waiting for the results. Results that should confirm why my body is behaving in unexpected ways: the unusual infections; the crushing fatigue; the old jeans that suddenly slip off my waist.

Christmas is never a nice time to feel alone. Yet, despite the fact I am surrounded by loved ones, that is how I feel: terrifyingly alone. The emotions of the season get warped and amplified. I attempt to go to one party, see a friend who is going through her own hellish time, and we both sob on each others shoulders for five minutes straight. Everything feels raw and heavy. My little girl is not even 18 months old, and I love her more than anything but I find it hard to even be in the same room as her. Its all too much.

If Christmas has lost its religious meaning, then it hasnt for me. I try praying for the first time in about three decades: Er, yes, it has been a while sorry about that but could you just help me out with this one thing? I promise God and Santa Ill be all sorts of good if things turn out OK.

***

My results arrive on 22 December. There is a wait in a hospital corridor that is still too triggering to think about properly. And then a doctor calls me in, sits me down and tells me that I have a rare blood cancer called essential thrombocythemia, which sounds like some cult artist signed to Warp Records in the 90s (the doctor doesnt say that bit). There is no known cure. But dont worry, he says, its manageable. I just need to take some aspirin and keep an eye on it. You will lead a normal life, he says. My wife tells me my face instantly changed colour, the pallid grey lifting for the first time in weeks.

My little girl throws up all over the seat when we pull out of the drive, and it doesnt even feel slightly annoying

Its a strange gift, receiving blood cancer for Christmas. In some ways I preferred the Mr Frosty slushy-making kit I got when I was eight, and maybe even the Scalextric that never quite played out the way you hoped it would from the adverts. And yet what the doctor is telling me you will lead a normal life feels like the biggest and best present I have ever received. Queueing up to be discharged, I let wave after wave of euphoria run through me and think to myself: This has to be the weirdest cancer diagnosis ever.

A day later, we pack up the car and head off to my parents. My little girl throws up all over the back seat as soon as we pull out of the drive, and it doesnt even feel slightly annoying. We laugh. Life is good. That Christmas, for the first time since I can remember, I am truly happy; just living in the moment. The light seems brighter and more beautiful. I notice dew drops on plants and the smell of fresh air. I hug my wife and daughter even more tightly than usual.

***

All this relief is not to last long. In the first week of 2018, I attend a follow-up appointment and am told that, sorry, they hadnt seen all of the bone marrow samples before. My condition is, in fact, developing into a much more serious disease called myelofibrosis, which needs treatment.

A week on from that, I turn up at the hospital, steeled to start chemotherapy. But there is worse news: a team of specialists have discussed my case and they believe I am at high risk of developing acute myeloid leukaemia, a swift and deadly cancer. They recommend you have a stem cell transplant, says the doctor. I ask when. As soon as possible. If I can find a match on the stem cell donor register, then I will be dosed up with drugs so intense that my entire immune system will be wiped out; then a strangers cells will be fed into me and we will all cross our fingers and hope that my body doesnt reject them. The chance of survival and the disease not returning does not seem to me to be all that much better than 50/50. Even if it all succeeds, the recovery process will be long and gruelling.

I spend the next few weeks in a state of catatonic depression. Or do I? Because I am somehow getting things done: I organise a will, I arrange a sperm bank visit (the transplant, even if successful, will leave me infertile), I cry myself senseless writing a letter to my daughter in case the worst should happen. I also drink all the good bottles of wine I had been saving for special occasions. A bottle of Domaine Dujac Morey Saint-Denis 2012 on a Tuesday night with defrosted Quorn chilli not the pairing Id had in mind, but saving it for the future seems silly.

Through all the gloom I see something with startling clarity. I realise that what Im mourning is not so much my old life before all this started a life of pointless anxieties, petty rivalries and overthinking but rather the carefree, optimistic version of life I had briefly glimpsed over Christmas. And yet no sooner have I understood all this than the chance to enact it has been snatched away. I feel like an old professor who has finally unravelled the mysteries of the universe with his dying breath.

***

Over the next few months, something happens that I still find hard to believe. I am transferred to a new hospital with a more specialist team on the case. There are more blood tests and scans, and another long needle is forced into my hip. And then I get another gift, this one in time for Christmas 2018: my condition is not so serious as I was led to believe. It appears to be a peculiar version of a peculiar cancer caught somewhere between the relatively benign essential thrombocythemia and the more concerning myelofibrosis. But it is stable, at least for now, with no signs to suggest it will progress any time soon.

***

I like to think that this year I have made good on my promise to live like I did during the Christmas of 2017. My outlook has certainly changed. When people ask how, I always say the same thing: that its great to get older. The idea of panicking about a milestone such as my imminent 40th seems so ridiculous now. Instead, just think what a privilege it is to be able to get there.

I am more present for my family these days, and less consumed with things I cant control. I have returned to the volunteering role I thought I didnt have time for; I have got fit; I dont let work define my happiness; I am kinder to myself. I have bought lots more nice wine to replace the nice wine I drank with defrosted Quorn chilli.

Do I still get annoyed by delayed trains, lost keys or the fact my daughter is taking half an hour to put on a pink tutu, the only item of clothing in the house that shell wear? It would be a lie to say no. But the second I think: But youre not quite likely to die any more, the problem disappears. I am, undeniably, a happier person.

I still have a malfunction inside me and I still have to think about it every day. Its hard not to my spleen, inflated with excess blood cells, gently nudges against my ribs like an annoying acquaintance who would hate me to forget that all is not quite right. At some point in the future and not even the best doctors can predict exactly when the disease might whirr into life and start scarring my bone marrow, turning it into a barren wasteland that can no longer produce enough blood to keep me alive. Im hopeful that science will find a fix before that time comes. There are encouraging signs on the horizon. And if not? Well, these days I try not to dwell on the future. I am here, instead, for the present. I am alive. I am alive with the spirit of Christmas.

MPN Voice provides information and emotional support to people diagnosed with a myeloproliferative neoplasm

See more here:
A blood cancer diagnosis helped me find true happiness - The Guardian

Dec. 24 (UPI) Those with weak and brittle bones caused by a rare genetic disorder have reason for new hope with the discovery of a cell transplant treatment that may finally resolve the underlying cause of their disease.

In an article published Tuesday in the journal STEM CELLS, researchers show how they transplanted healthy donor bone marrow cells directly into the femur of mice with osteogensis imperfecta, or OI, a rare disease that affects bone strength.

One month following transplantation, the researchers found 18 percent of the surface that was injected with the donor cells expressed osteoblasts cells that help form new bone tissue an indication of engraftment, or growth.

In addition, long-term engraftment was then observed at three and six months post-transplantation.

This is a basic research study with potential for future translation into practice, study co-author Ivo Kalajzic, a researcher at the Center for Regenerative Medicine and Skeletal Development at the University of Connecticut, said in a statement.

Kalajzic and his colleagues also found that healthy donor cells replacing mutant collagen have the ability to improve bone strength and structure in transplant recipients.

OI are genetic disorders that mainly affect the bone. Patients with OI have bones that break easily, sometimes with no obvious cause.

In recent years, research has shown that the disorders are caused by genetic mutations associated with type 1 collagen molecules. These molecules help the body process collagen, and damage to them results in defective bone structure.

Currently, treatments for OI attempt to correct the defective bone structure, but dont focus on the underlying collagen defect.

The new findings demonstrate, however, that healthy donor stem cells that produce normal collagen in OI patients have the potential to increase bone mass and correct the collagen defect causing the condition.

Read more here:
Stem cells effective against rare bone disorder in trial with mice - Breitbart

The Galloping Ghosts are looking beyond the scoreboard to help classmate Juwan Adams battle pediatric cancer.

Khalis Whiting and her Abington girls basketball teammates have a different perspective this holiday season. A perspective that changed when through Kisses for Kyle they were put in touch with two area families who have a child battling pediatric cancer.

One George Hamlin is a student in Upper Dublin High School. The other, Juwan Adams, is a senior at Abington. Both families were on the receiving end of gifts and gift cards at the Abington-Upper Moreland game last week. It is the 10th annual giving back game since coach Dan Marsh initiated the project.

It was an amazing experience, said Whiting, the Ghosts sophomore point guard. I was not familiar with the families, but I have seen (Adams) a few times in school, but I never really knew the story until this came up and I researched him.

He has a powerful story, and hes such a strong young man to be going through this. Every time I see him in the hallways, hes always smiling and so positive. So you know give it to his family.

Adams, who has been battling Hodgkins Lymphoma since April of 2016, is in need of a match for an allogeneic stem cell transplant.

Right now, he is out of options, his mother, Andrea Adams, said. We know for sure that an allo stem cell transplant will cure him, but unfortunately, in order to do that, we need a donor.

We have tested everyone in our family, and no one is a full match, so were relying on the Be the Match registry to locate a donor. Sadly, for minorities theres a very slim chance to actually find a full 10-out-of-10 match because we dont have enough minorities on the registry.

Hes had almost every treatment available for Hodgkins, including an auto stem cell transplant, which is where he gave himself his own cells in February of 2017. He was in remission for about a year, and unfortunately, in May of this year, we found out the cancer is back, and its been spreading consistently since May.

Despite missing more than half of the last three-and-a-half years of school, Juwan maintains a 4.25 GPA and is a member of the National Honor Society.

Abington School District has been really great with accommodating him, giving him tutors, and whenever hes an in-patient, he does hospital school, Andrea said.

Juwan is the drum captain and lieutenant of Abingtons marching band, and since September is Pediatric Cancer Awareness month, for the past four years, the marching band has worn gold ribbons on their uniforms.

Since his diagnosis in eighth grade, Juwan has been active in pediatric cancer awareness events, and for the past four years, he has held toy and book drives that he presents to the children at CHOP on his birthday in July.

Last week, Juwan and his family were on the receiving end.

It was great because Juwan never wants gifts, Andrea said. Having a child with cancer, financially its tough, especially now that we have only have one person working fulltime, and that lifted a tremendous burden, and it was so unexpected.

To have him honored by his school and his peers, he was super excited about it, and he really appreciated it because a lot of kids (battling cancer) have to give up school, or their friends tend to abandon them.

I want to thank the team and the Abington students because it is very easy to turn your back on kids that are going through these things. These kids have really rallied around him. This is one of the reasons he fights so hard to be in school. He sometimes sneaks to school because he feels the love from his school and his peers. That was one thing he definitely wanted to do to finish his senior year with his class. They have really rallied around him, and this kind of thing gives him the extra push he needs to keep fighting.

Statistics say Juwan has a 23 percent chance of finding a perfect match, but the Abington senior has been proactive.

When they told him the odds of finding his match, he said he had to do something about it, Andrea said. He set a goal to register a thousand people on the national registry, half of those being minorities.

We have gone around holding bone marrow drives. Hes now an ambassador for Be the Match, and hes been an ambassador for CHOP for about two years.

Juwan is inviting everyone to join his fight.

"People are starting to wake up and realize kids with cancer more and more are dying each day, and if they have a chance to do something, they should take every step they can," Juwan said earlier this fall. It's been hard sometimes, but I have my friends and family to support me.

Read more:
Abington working toward big win - Sports - The Intelligencer

For its promising investigational therapeutic approach to neurodegenerative diseases, including progressive multiple sclerosis (MS), BrainStorm Cell Therapeutics is theBuzz of BIO 2020 winnerin the Public Therapeutic Biotech category.

The Buzz of BIO contest identifies U.S. companies with groundbreaking, early-stage potential to improve lives. The event also is anopportunity to make investor connections that could take products to the next phase.

Ten biotechnology companies are nominated in each of the three categories of Buzz of BIO: Public Therapeutic Biotech, Private Therapeutic Biotech, and Diagnostics and Beyond. In the Public Therapeutic Biotech category that BrainStorm won, nominated companies must be actively developing a publicly traded human treatment intended for review by theU.S. Food and Drug Administration.

As a developer of autologous cellular therapies for debilitating neurodegenerative diseases, BrainStorm is testing its investigational therapy,NurOwn, in progressive MS patients, for whom treatment options are limited.

The therapy is based on patients own bone marrow-derived mesenchymal stem cells that are engineered to secrete growth factors. Such factors are thought to protect nerves from damage, promote the repair of myelin (the protective coat of neurons that is destroyed in MS), and ultimately slow or stabilize disease progression.

BrainStorms current open-label Phase 2 clinical study (NCT03799718) is enrolling up to 20 adults with either secondary progressive or primary progressive MS at three U.S. sites:theKeck School of Medicine of USC, the Stanford School of Medicine, and theCleveland Clinic. After undergoing a bone marrow aspiration to collect cells, each participant will receive three intrathecal (injected into the spinal cord) NurOwn cell transplants within 16 weeks, and will be tracked for at least another 12 weeks to assess safety and effectiveness. Contact information for the trial centers is available here.

Thanks to everyone who voted for BrainStorm during the Buzz of BIO competition,Chaim Lebovits, BrainStorm president and CEO, said in a press release.

As the winner of the contest, BrainStorm also was invited to givea presentation at theBio CEO & Investor Conference, to be held Feb. 1011 in New York City.

The entire management team at BrainStorm was very pleased with the results of this competition, and we look forward to presenting to an audience of accredited investors who may benefit from the companys story, said Lebovits. We thank the BIO[Biotechnology Innovation Organization] team for singling out BrainStorms NurOwn as a key technology with the potential to improve lives.

NurOwn cells also are being tested in a Phase 3 trial (NCT03280056) in patients with amyotrophic lateral sclerosis (ALS).

Total Posts: 1,053

Patrcia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

More:
BrainStorm Cell Therapeutics Wins 2020 'Buzz of BIO' Award - Multiple Sclerosis News Today

SEATTLE--(BUSINESS WIRE)--According to Coherent Market Insights, the global bone graft and substitutes market is estimated to be valued at US$ 3,046.7 million in 2019, and is expected to exhibit a CAGR of 5.5% during the forecast period (2019-2027).

Key Trends and Analysis of the Global Bone Graft and Substitutes Market:

Key players in the market are focusing on receiving product approvals for bone grafts and bone graft substitutes are expected to fuel growth of the global bone graft and substitutes market over the forecast period. For instance, in December 2016, CoreBone, an Israel-based company manufacturing bone grafts from corals received approval from European Medicines Agency (EMA) for use this product in Europe, which is expected to generate a significant revenue for the region through its sales.

Request your Sample PDF copy @ https://www.coherentmarketinsights.com/insight/request-sample/1050

Moreover, adoption of inorganic growth strategies by major key players is expected to boost the market growth over the forecast period. For instance, in February 2019, Orthofix Medical acquired Options Medical, LLC, a medical device distributor based in Florida, U.S. The acquisition aims to enhance the sales force. Moreover, in 2017, LifeNet Health acquired Austria-based tissue bank- AlloTiss Gemeinntzige Gewebebank GmbH. The acquisition enabled LifeNet Health to establish training and distribution center in Vienna, Austria to support the use of allograft in Europe.

Furthermore, rising road accidents and injuries is expected to propel the market growth over the forecast period. For instance, in 2018, as per the World Health Organization (WHO) estimation, around 1.35 million people are reported to die each year due to road traffic crashes, globally.

Among regions, Asia Pacific is expected to show significant growth in the global bone graft and substitutes market, owing to increasing road accidents in the region. For instance, according to the World Health Organization report in 2013, Asia Pacific region reported around 153,000 fatalities due to road accidents or around 400 deaths each day. It also stated that road traffic death rate in South-East Asia region was 17.0 per 100,000 population, compared to the global rate of 17.4, where there was considerable variation seen within the region ranging from 3.5 in the Maldives to 36.2 in Thailand in 2015.

Key Market Takeaways:

Buy this Report (Single User License) @ https://www.coherentmarketinsights.com/insight/buy-now/1050

Market Segmentation:

Read more:
Global Bone Graft and Substitutes Market to Surpass US$ 4673.5 Million by 2027 Coherent Market Insights - Business Wire

Gurugram/New Delhi: In a ground-breaking procedure, Haematologists and Bone Marrow Transplant specialists successfully treated Anurag Mishra, a 47-year-old man from New Delhi, suffering from Multiple Sclerosis (MS) from the past seven years.

Multiple sclerosis (MS) is a life-long condition, known to reduce life-expectancy. MS affects the brain and spinal cord that leads to serious disabilities.

The most common symptoms of MS include loss of sensation and balance, restricted arm or leg movement and vision loss in one or both the eyes.

Mishra, who was bedridden earlier, is back to his normal routine life, was diagnosed with MS an autoimmune neurodegenerative disease, where the body's own defence system starts attacking its nervous system, without any specific reason

Dr Rahul Bhargava, Director, Department of Clinical Hematology & Bone Marrow Transplant, Fortis Hospital in Gurugram with his team performed autologous bone marrow transplant where they used Mishra's stem cells for transplant, thereby reducing the chances of rejection and infections.

"In an autologous BMT procedure, the healthy stem cells from the patient are taken out and preserved. Chemotherapy is then administered to reset the body's immunity and then the stem cells are injected back to rescue the person from the side effects of chemotherapy," said Bhargava.

After the surgery, the patient is kept under isolation for a few months to ensure he/she does not contract any infection. In this case, when Mr Anurag approached us, he was entirely dependent on others for his basic needs. But within six months after the treatment, he is back on his legs and is carrying on with his normal life," Bhargava added.

According to the patient, the attacks are sudden and may affect any part of your body, limiting your abilities.

"Extreme pain and disabilities this disease gave, made me very scary and depressing. I think I am very lucky to get to know about Dr Rahul Bhargava and team, who cured me miraculously," Mishra said.

"Too much delay in the procedure can considerably affect the clinical outcomes. In the case of Mr Anurag, recovery is 90 per cent, which means he received the treatment within recovery time-frame," Dr Bhargava said.

See more here:
Delhi: 47-year-old successfully treated with bone marrow transplant - ETHealthworld.com

Bipartisan legislation provides record funding for lifesaving cellular transplants and eliminates a Medicare payment barrier for seniors.

Washington, DC, December 20, 2019 --(PR.com)-- National Marrow Donor Program (NMDP)/Be The Match applauds Congress for passing bipartisan legislation that provides record levels of funding to increase access for patients to cellular transplants, which can be the only curative treatments for blood cancers such as leukemia or lymphoma and other blood diseases. The bill also increases access to these same therapies for senior citizens by fixing a Medicare reimbursement issue that can be a barrier for them to these life-saving procedures.

Increasing funding levels for these programs and bringing Medicare payment policies for these procedures up to date represents major victories for the 1.3 million Americans fighting blood cancers, said Brian Lindberg, Chief Legal Officer and General Counsel of NMDP/Be The Match. By increasing funding for life-saving cellular transplants and removing Medicare barriers that inhibit access to care, Congress has given hope to patients in need of these curative treatments.

We are honored to have broad support from members in the House and Senate who stand with us and our mission to find matched donors for every patient in need of these cellular therapies, Lindberg added. Increasing patient access to life-saving bone marrow and cord blood transplant is NMDP/Be The Matchs top priority.

The program works closely with organizations throughout the nation to recruit volunteer donors for the registry and with public and private insurers to ensure that all patients have equal access to treatment.

The $30 million included in the final legislation for the C.W. Bill Young Cell Transplantation Program, an increase of $5.4 million over last year, and the $17.3 million for the National Cord Blood Inventory, an increase of $1.0 million, will help reduce barriers to transplant by:

Advancing new and innovative methods of providing the best possible transplant to every patient in need, regardless of socioeconomic status, age, ethnic ancestry, or any other individually defining characteristic; Continuing to simplify processes and systems to reduce time to transplant, providing the patient and their physician the therapy the patient needs exactly when he/she needs it; and Protecting access to transplant by allowing NMDP to pursue our vision of achieving equal outcomes for all.

In the case of older Americans, inadequate Medicare transplant reimbursement, primarily for donor-related costs, poses a significant barrier to patient access.

Unlike Medicare payment policies for the acquisition of solid organs for transplant, Medicare does not provide separate payments for the cost of acquiring the cells for transplant (which can include the cost of identifying genetically matched donors, collecting the cells, and transporting them to the transplant hospital). As a result, hospitals take substantial financial losses on these life-saving procedures, which often require a 20-to-30-day hospital stay on average, because the reimbursement rate does not come close to covering the true costs of treatment.

NMDP/Be The Match looks forward to working closely with the Centers for Medicare & Medicaid Services (CMS), which operates the Medicare program, to ensure that this critical payment reform is implemented as quickly as possible, so that Medicare beneficiaries are not at risk of being denied the bone marrow, peripheral blood stem cell, or cord blood transplant they need to survive.

About National Marrow Donor Program/Be The MatchFor people with life-threatening blood cancers such as leukemia and lymphoma, a cure exists. National Marrow Donor Program(NMDP)/Be The Match connects patients with their donor match for a life-saving marrow or umbilical cord blood transplant and works to identify and eliminate financial and other barriers faced by these patients. NMDP also provides patients and their families one-on-one support, education, and guidance before, during and after transplant.

Contact Information:National Marrow Donor ProgramEllen Almond(703) 548-0019Contact via Emailhttps://bethematch.org/

Read the full story here: https://www.pr.com/press-release/802090

Press Release Distributed by PR.com

Here is the original post:
National Marrow Donor Program/Be The Match Applauds Congress for Its Support of Patients with Blood Cancers and Other Diseases - Benzinga

Last Christmas a student from London received what he says was the best Christmas present ever the chance to save a strangers life.

Will Briant, 23, from Kennington, was found to be the best match for a patient with blood cancer in desperate need of a stem cell transplant. Will recently received a letter informing him that his anonymous recipients transplant had been a success and that he is now doing well.

Will initially joined the Anthony Nolan stem cell register in 2014. His girlfriend, who volunteered with Edinburg Universitys Blood, Bone Marrow and Transplant Society, which is part of blood cancer charity Anthony Nolans student volunteer network called Marrow, suggested that he sign up.

Will said: My girlfriend, Libby, told me this amazing statistic that a quarter of all stem cell donors sign up through Marrow at university, so I couldnt not join.

If it wasnt for Marrow and for Libby, I wouldnt have become a donor and given someone hope of a second chance of life just before Christmas.

After Will joined the Anthony Nolan register the charity confirmed his tissue type. Every time the charity was informed that someone needed a transplant it compared the patients tissue type to Wills and over 750,000 others on the register, as well as registers across the world.

In December last year, Will received an email from Anthony Nolan, informing him that he had come up as a potential match for a blood cancer patient in desperate need of a stem cell transplant. Will then went to his GP for blood tests, to confirm that he was in fact the best possible match.

Will said: Just a week before Christmas, I got the best Christmas present ever. I was told that I was the best match for the patient, and I would be donating early in the new year!

I was so excited. When you sign up you know that its such a tiny chance that youll be found as the best match for someone, so to actually be chosen felt really exciting. Also, because it was just before Christmas, it felt quite exciting to know that the patient would find out that they had a match just in time for Christmas!

On average, people who join the stem cell register have around a 1 in 800 chance of being asked to donate in the next five years, but for men aged 16-30, its 1 in 200. This is why Anthony Nolan need more young men to join the register.

At the beginning of this year, having spent Christmas at home with his family, Will donated his stem cells at The London Clinic.

Will said: For four days before the donation I had a course of G-CSF injections to increase the number of stem cells I was producing. This caused mild flu-like symptoms, I just felt a bit tired and achy really. The whole way through, I kept thinking about the recipient, and how, in this context, I was absolutely delighted to have mild flu-like symptoms! It was quite strange to be doing it for real, after talking to so many potential donors when I volunteered with Marrow at university!

Libby, the same girlfriend who had suggested Will consider signing up to the register four years earlier, accompanied him to his donation.

Will said: I sat in a hospital bed for four hours and was so pampered by the staff there! There was a huge choice of different lunches, endless coffees and I got to watch programmes on my iPad.

Following his donation Will then went back to his studies and his job, barely giving a second thought to what hed just done. However, this all changed when a month after the donation he received a letter of thanks from the recipient of his stem cells.

Will said: It was honestly the best letter Ive ever received. It was especially powerful because it really hit home, that not only had I given him a second chance of life, but also, I had given his wife, his children, his grandchildren and his friends more precious time with him.

Patients and recipients must remain anonymous for two years following a transplant, but they are able to communicate via anonymous letters and cards. After the two-year period, if both parties agree, they are allowed to meet.

Just recently, Will also received a letter from the hospital at which his recipient received their stem cell transplant to say that the donation had been successful and even though recovery can be a long process, he is currently recovering well. Will is hoping that they will both exchange Christmas cards this year.

Anthony Nolan is the charity that finds matching stem cell donors for people with blood cancer and blood disorders and gives them a second chance of life. It costs 40 for Anthony Nolan to add each new donor to the register, so the charity needs financial support to help it continue to give patients, their family and their friends hope.

Terence Lovell, Director of Engagement at Anthony Nolan told Charity Today: Our amazing stem cell donors, like Will, continue to enable many patients with blood cancer to spend Christmas with their loved ones, who wouldnt be here without their act of kindness.

Anyone wanting to support our work can visit our website and make a donation, which will help give someone like Wills recipient, a second chance of life in the future. Without your support, there is no cure.

Anthony Nolan also carries out ground-breaking research to save more lives and provide information and support to patients after a stem cell transplant, through its clinical nurse specialists and psychologists, who help guide patients through their recovery. Find out more about Anthony Nolan this Christmas by visitinghttps://www.anthonynolan.org/

Read more:
'Last Christmas...' London student saved a stranger's life, this year he is alive and celebrating his gift of life - Charity Today News

https://www.projectlifemovement.org/impact/https://www.projectlifemovement.org/impact/

Our Impact

The Project to Save Lives Leukemia, Sickle Cell anemia and other diseases can often be cured with a bone marrow transplant. However, African American patients with leukemia and Sickle Cell have only a 23% chance of finding a bone marrow match on the National Registry. For mixed race patients the chance of finding a match is even lower. Conversely, African American and mixed race patients with leukemia or Sickle Cell have a 77% or more chance of dying if the only treatment that will save their lives is a bone marrow match and transplant. Compare this to the 41% chance of finding a match for Asian or Pacific Islanders, 46% for Hispanics or Latinos, 57% for American Indian and Alaska Natives, and 77%f for whites. The only reason for these discrepancies is the lack of bone marrow donors from the African American and mixed race communities. The solution to this problem is simple. We can save lives by having more African American and mixed race bone marrow donors, and providing supportservices to African American and mixed race children and adults in need of bone marrow transplants. This is the mission of The Project to Save Lives.

Doctors also use bone marrow transplants to treat aplastic anemia, autoimmune diseases (including scleroderma and multiple sclerosis), Hodgkin lymphoma, immune deficiency disorders, inborn errors of metabolism, non-hodkin lympohma, myelodysplastic syndrome, myeleproliferative neoplasms, multiple myeloma, myelofibrosis.

Thousands of patients with these diseases will need a bone marrow transplant to survive. Given the lack of African American and mixed race donors, the shortage of diverse donors costs lives. With ethnicity being the key to a perfect match between donor and recipient, we can change the odds only by increasing donors from the African American and mixed race communities. Increase the donors and the odds of finding matching donors will increase. You could save a life and become a hero by being a donor, and being a donor can be as simple as donating blood platelets.

ligible donors must be 18-44 years of age and in general good health. Donors must be willing and committed to donate to any patient they might match. Registration involves completing a consent form and a simple cheek swab test. Cheek swabbing is free. This can be done at an actual drive or by requesting a kit online to complete your swab. This places you on the Be The Match Registry for anyone you might match. While the current method of registration is digital The Project to Save Lives is working on a method of registration for those not equipped to register digitally.

If you match a patient in need, there are two ways to donate. The patients doctor chooses the method of donation that is best for the patient. 80% of the time Peripheral blood stem cell (PBSC) donation is used. This is the method of collecting blood-forming cells for transplants. The same blood forming cells that are found in marrow are also found in the circulating (peripheral) blood. PBSC is a non-surgical procedure, called apheresis. The donation takes place at an experienced facility that participates in PBSC collections. For 5 days leading up to donation you will be given injections of a drug called filgrastim to increase the number of cells in your bloodstream that are used for transplant. Some of your blood is then removed through a needle in one arm and passed through a machine that separates out the blood-forming cells. The remaining blood is returned to you through the other arm. The other 20% of marrow donations take place in a hospital under general anesthesia. Doctors use a needle to withdraw liquid marrow from the back of your pelvic bone. Donors feel no pain or discomfort during the donation. The procedure is out-patient. There is small discomfort to save a life. Further, donors never pay for donating and are never paid to donate. The amount of cells donated will not weaken your immune system. Most donors are back to their usual routine in a few days and your marrow naturally replaces itself within 4-6 weeks.

Some believe that donors are usually found in their family. This is not true. 70% of patients do not have a matching donor in the family. Adding more registry members increases the ethnic diversity of the registry which increases the variety of tissue types available, which helps more people of ethnicity and ethnic diversity find the match they need. Additionally, members of the LGBTQ+ community can join the registry and donate. The African American and mixed race communities need members who are committed to helping save a life. This means being willing to donate to anyone in need. If you are called as a potential match for a patient, your commitment means that youre willing to take up to 20-30 hours spread over 4-6 weeks to: attend an information session, attend appointments, and donate. You are also committing to keeping your contact information up-to-date so that the registry can find you to quickly get a blood sample for further match testing.

There are many myths about bone marrow donation:MYTH: Donating is very painful.FACT: Donating is less painful than you think.MYTH: Donating involves opening up or removing bones.FACT: This is not true. Most blood stem cell donors (80%) give PBSC a process similar to platelet donation. This is a non-surgical, out-patient procedure and no bone is removed. The donorreceives a drug for 5 days to increase the number of cells in the bloodstream. The cells are then collected during donation. The donor may experience head or muscle aches that disappearshortly after the donation, and are typically back to their normal routine in 1 to 2 days.

The other procedure (20%) is a surgical, out-patient procedure that takes place in a hospital operating room. While the donor is under anesthesia, the doctors collect marrow from the back ofthe donors pelvic bone. After donation, donors may feel soreness in the lower back. Donors are typically back to their normal routine in 2 to 7 days.MYTH: Donating is dangerous.FACT: There are few risks to donating.MYTH: Donating takes a long time.FACT: It doesnt take long to save someones life.MYTH: Donating is expensive and you need medical insurance.FACT: Donating is absolutely free to the donor.MYTH: Sharing your personal information and DNA is risky.FACT: Be the Match and HIPPA will protect your privacy andconfidentiality.MYTH: Asking about a donors ethnic background is racist.FACT: Ethnic background is an important factor for matching donors to patients. When it comes to matching human leukocyte antigen (HLA) types,a patients ethnic background is important inpredicting the likelihood or finding a match. This is because HLA markers used in matching are inherited.MYTH: Gay men cannot join or donate.FACT: Gay men and others in the LGBTQ+ community CAN join the registry and donate.MYTH: Be the Match discriminates against people age 45+.FACT: Age guidelines protect the safety of the donor and provide the best possible outcome for the patient. They are not meant to discriminate.

More Important Facts:1. Every 3 minutes, someone is diagnosed with a blood cancer like Leukemia. For many of these and other patients with diseases like Sickle Cell anemia, a marrow transplant is the only lifesaving treatment-their only chance for a cure.2. Every year, more than 14,000 patients are diagnosed with life-threatening blood cancerslike leukemia and lymphomaor other diseases for which a marrow or cord blood transplant from an unrelated donor may be their best or only hope of a cure.3. 70% of all patients who need a transplant do not have a matched donor in their family. They depend on Be The Match Registry to find an unrelated donor or cord blood unit.4. Approximately 70 % of transplants facilitated by the National Marrow Donor Program are for patients diagnosed with leukemia or lymphoma.5. Every 10 minutes, someone dies from a blood cancer. Thats more than six people each hour, or 148 people each day.6. More than 70 diseases can be treated & cured by an unrelated donor transplant.7. Leukemia causes more deaths than any other cancer among children and young adults under the age of 20.8. Be The Match Registry works tirelessly on behalf of patients in need of a life-saving transplant. Through successful partnerships with organizations, more volunteer donors step forward, more funding becomes available to support critical outreach and more advances are made in the science of transplants. We all have the power to heal, the power to save a life. Take the first step.9. African Americans and people of mixed race are particularly at risk of dying due to inability to find a match.10. Due to significant medical achievements in recent decades, survival rates are higher than ever for bone marrow and PBSC transplants. There are Health Benefits of Diets That Increase Bone Marrow in Donors. There are health benefits to diets that will increase your Red Blood Count to make you a more valuable donor. The Be the Match registry can give you information on what to eat to increase your Red Blood Count which will, in turn, greatly improve you health.

Join the Be The Match RegistryBe the Match is the largest, most diverse registry of potential marrow donors and cord blood units in the world. Be the Match offers one-on-one support, education and guidance before, during and after transplants. But first a marrow match must be found. And there are many patients in need of a donor. The ICLA DA SILVA FOUNDATION, INC. is A Recruitment Center for the Be the Match Registry. The Icla da Silva Foundation is the largest recruitment center for the Be The Match Registry in the United States. It recruits over 38,000 new potential bone marrow donors every year, with a strong focus on minority communities. The Icla da Silva Foundation was established in 1992, in memory of the 13-year-old Brazilian girl named Icla da Silva. After two years of fighting leukemia, Icla passed away in New York City, where she came hoping to get her life saving treatment: a bone marrow transplant. The young girl never found a matching donor.

With offices across the United States and Puerto Rico, the Foundation is continuously expanding its efforts in providing assistance and hope to thousands of families in the United States and all over the world. The mission of the Icla da Silva Foundation is to save lives by recruiting bone marrow donors and providing support services to children and adults with leukemia and other diseases treatable by marrow transplants. The Icla da Silva Foundation is a nonprofit organization under section 501(c) 3 of the IRS Code. Eligible donors must be 18-44 years of age and in general good health. Be willing and committed to donate to any patient that you might match. Registration involves completing a consent form and a simple cheek swab test. This places you on the Be The Match Registry for anyone you might match. You can contact the ICLA/Be the Match organization through the following:

https://bethematch.org/support-thecause/donate-bone-marrow/donation-faqs/. You can also contact The Project to

Save a Life through its two community volunteers: John-Michael Lawrence atlawrencejohnmichael9@gmail.com and Rhoda London at diversitydonordrive@aol.com.

What You Can Do Besides Being a Donor:If you are not able to donate or are younger than 18 or older than 44, you can:1. Host an actual cheek swabbing drive in you place of worship, school, business organization;2. Publicize a digital drive in any of the above on Facebook or any other social media;3. Share the information with other groups,family and friends;4. Make a financial donation in honor of your own good health or in honor of your recovery from and illness. Since swabbing and medical expenses are free, financial donations go to support analyzing the swabs and medical expenses for the donor and recipient;5. For a PHYSICAL Drive, register online at Join.Bethematch.org/JaxDonors for information and videos on how to hold a drive. Please join the effort, you can save a life.

Read more here:
The Project to Save Lives Free Press of Jacksonville - Jacksonville Free Press

Gurugram/New Delhi, Dec 19 : In a ground-breaking procedure, Haematologists and Bone Marrow Transplant specialists successfully treated Anurag Mishra, a 47-year-old man from New Delhi, suffering from Multiple Sclerosis (MS) from the past seven years.

The most common symptoms of MS include loss of sensation and balance, restricted arm or leg movement and vision loss in one or both the eyes.

Mishra, who was bedridden earlier, is back to his normal routine life, was diagnosed with MS an autoimmune neurodegenerative disease, where the body's own defence system starts attacking its nervous system, without any specific reason

Unlike the current line of MS treatment, which mainly includes steroid therapy, physiotherapy and symptom management, doctors used Bone Marrow Transplant (BMT).

Dr Rahul Bhargava, Director, Department of Clinical Hematology iamp; Bone Marrow Transplant, Fortis Hospital in Gurugram with his team performed autologous bone marrow transplant where they used Mishra's stem cells for transplant, thereby reducing the chances of rejection and infections.

"In an autologous BMT procedure, the healthy stem cells from the patient are taken out and preserved. Chemotherapy is then administered to reset the body's immunity and then the stem cells are injected back to rescue the person from the side effects of chemotherapy," said Bhargava.

After the surgery, the patient is kept under isolation for a few months to ensure he/she does not contract any infection. In this case, when Mr Anurag approached us, he was entirely dependent on others for his basic needs. But within six months after the treatment, he is back on his legs and is carrying on with his normal life," Bhargava added.

According to the patient, the attacks are sudden and may affect any part of your body, limiting your abilities.

"Extreme pain and disabilities this disease gave, made me very scary and depressing. I think I am very lucky to get to know about Dr Rahul Bhargava and team, who cured me miraculously," Mishra said.

"Too much delay in the procedure can considerably affect the clinical outcomes. In the case of Mr Anurag, recovery is 90 per cent, which means he received the treatment within recovery time-frame," Dr Bhargava said.

Continued here:
47-year-old successfully treated with bone marrow transplant | newkerala.com News #267197 - New Kerala

At just 13 years old,Charlie Knuth, of Darboy, Wisc., has known more pain than most others do in a lifetime. The teen, who suffers from epidermolysis bullosa, a rare disease that causes his skin to blister incredibly easily, is near-constantly wrapped in bandages to protect his fragile skin. He takes special baths to soothe his sores, which can form from the slightest touch and are lanced before he is covered in fresh dressings.But the so-called butterfly child a name often given to EB sufferers as their skins fragility is similar to that of a butterfly wing has another battle ahead: cancer.

Its unimaginable, Trisha Knuth, Charlies mother, told Fox News. Even as his mom, when I see him taking it in stride, I cant even believe that he can.

BOY, 2, HAS RARE 'SCALE'-LIKE SKIN CONDITION THAT AFFECTS 1 IN 500,000: 'HES OVERCOME SO MUCH'

Charlies biological parents abandoned him at the hospital shortly after his birth. Knuth and her husband, Kevin, had long fostered children with complex medical needs. But just weeks before they received a call about Charlie, they were readying to let their license expire; the tragic cases were simply becoming too much. Even so, Knuth said shecouldnt say no to Charlie she knew to do so was likely a death sentence. They began the lengthy adoption process shortly after bringing him home.

Trisha Knuth and Charlie, 13. (Trisha Knuth/Facebook)

When I went to the children's hospital in Milwaukee, he was slathered from head-to-toe in Vaseline," she recalled."Nobody ever came for him. I worked with the nurses and learned his care but EB is so rare that many hospitals don't know how to care for those with [the condition]. They sent me home with morphine and a few things and it was a learning process from there.

Thirteen years later, Charlie didnt end up dying, he ended up thriving, she said. When he was 5 years old, he underwent an experimental skin grafting procedure at the University of Minnesota in an attempt to make his skin stronger and less prone to blistering. Knuth called it a transformation for her young son, who had two really good years before his body rejected the graft and he began to suffer from aplastic anemia, a potentially deadly condition that occurs when the body doesn't produce enough red blood cells.

In 2012, he underwent a stem cell transplant in an attempt to treat his severe EB. He was hospitalized for six months but eventually pulled through.

Charlie, who suffers from EB, was recently diagnosed with cancer. (Trisha Knuth/Facebook)

Hes done pretty well after that second time. But he is constantly wounded, very fragile, said Knuth.

But in recent months, Charlie began to complain of a sore throat not uncommon for those with EB, as blisters can form on the inside of the body as well on the outside. The mouth and throat are commonly affected.But there were no visible blisters, raising his doctor's suspicions. ACT scan later revealed enlarged lymph nodes in his neck and armpits. A biopsy later confirmed lymphoma, a type of cancer that affects the bodys lymphatic system. Knuth called the diagnosis another hurdle in his very hard life.

The pain was masked by EB. Its hard to tell whats what because EB causes so much pain, she said.

Cancer treatment often consisting of chemotherapy, radiation, and surgery is hard enough on an average persons body. But those with EB face an entirely different battle; Knuth said nurses inserting an IV cant use medical tape to help attach the drip, as the adhesive ripsher sons skin when removed. Oxygen and anesthesia masks are often a struggle as well, as are blood pressure cuffs.

Charlie (R) when he was younger. (Trisha Knuth/Facebook)

How do you treat someone who cant be touched? Knuth questioned, noting she has gone into the operating room with Charlie in times past to ensure he is not injured. You cant even imagine. [Its like] being burned every day, and then bandaged, and nowundergoing cancer treatment it boggles the mind.

When speaking to Fox News, Knuth and Charlie were in Minnesota, where doctors are working to build atreatment plan. The day after Christmas which the pair are celebrating in an Airbnb Charlie is slated to undergo a procedure to remove fluid from his spine and bone marrow from his hips. One of his affected lymph nodes will be taken for further testing.

In the meantime, Kevin is home with the couples 2-year-old adopted daughter, who also suffers from EB.

"He puts on a great outward attitude, but I know there is trauma."

CLICK HERE TO GET THE FOX NEWS APP

He is very brave and resilient and funny, said Knuth of Charlie. But in addition to the physical pain, He does have emotional pain; he puts on a great outward attitude, but I know there is trauma.

When asked how she and Kevin manage it all, Knuth acknowledged theirs is a crazy life. But, she quickly noted, I am very happy with this life. Its hard. But when I die, I'll know my life was fulfilled and great.

Link:
Wisconsin teen diagnosed with cancer while battling rare 'butterfly skin' disease: 'He is resilient' - Fox News

MELVILLE, N.Y., Dec. 16, 2019 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (BioRestorative or the Company) (OTC: BRTX), a life sciences company focused on stem cell-based therapies, announced today feature coverage in the news outlet, IEEE Pulse, a magazine of the IEEE Engineering in Medicine and Biology Society. According to IEEE, it is the worlds largest technical professional organization for the advancement of technology.

To view the IEEE Pulse Magazines article featuring BioRestorative, click here.

The published cover-story article features commentary from Francisco Silva, Chief Scientist and Vice President of Research and Development for BioRestorative, regarding BRTX-100, the Companys lead therapeutic candidate for chronic lumbar disc disease. Once the U.S. Food and Drug Administration (FDA) authorizes the sale of BRTX-100, we would ship it to your doctor, and with a 30-minute procedure the material would be injected into your disc in a 1.5 ml solution, explains Silva. He elaborates on the product, discussing growing and expanding stem cells from the patients bone marrow under hypoxic conditions that mimic those in the normal intervertebral space. We are enriching the cells to be able to survive in this harsh environment, says Silva.

In addition to BRTX-100, the magazine article also highlights BioRestoratives other research pursuit, its ThermoStem program, utilizing brown adipose (fat) derived stem cells to target treatment of metabolic diseases and disorders, like diabetes, obesity and hypertension.

About BioRestorative Therapies, Inc.

BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:

Disc/Spine Program (brtxDISC): Our lead cell therapy candidate, BRTX-100, is a product formulated from autologous (or a persons own) cultured mesenchymal stem cells collected from the patients bone marrow. We intend that the product will be used for the non-surgical treatment of painful lumbosacral disc disorders. The BRTX-100 production process utilizes proprietary technology and involves collecting a patients bone marrow, isolating and culturing stem cells from the bone marrow and cryopreserving the cells. In an outpatient procedure, BRTX-100 is to be injected by a physician into the patients damaged disc. The treatment is intended for patients whose pain has not been alleviated by non-invasive procedures and who potentially face the prospect of surgery. We have received authorization from the Food and Drug Administration to commence a Phase 2 clinical trial using BRTX-100 to treat persistent lower back pain due to painful degenerative discs.

Metabolic Program (ThermoStem): We are developing a cell-based therapy to target obesity and metabolic disorders using brown adipose (fat) derived stem cells to generate brown adipose tissue (BAT). BAT is intended to mimic naturally occurring brown adipose depots that regulate metabolic homeostasis in humans. Initial preclinical research indicates that increased amounts of brown fat in the body may be responsible for additional caloric burning as well as reduced glucose and lipid levels. Researchers have found that people with higher levels of brown fat may have a reduced risk for obesity and diabetes.

Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, whether the Company will be able to consummate the private placement and the satisfaction of closing conditions related to the private placement and those set forth in the Company's Form 10-K filed with the Securities and Exchange Commission. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this release are made as of the date hereof and the Company undertakes no obligation to update such statements.

CONTACT:Email: ir@biorestorative.com

Originally posted here:
BioRestorative Therapies Featured in IEEE Pulse Magazine's Cover Story About Stem Cell Therapies for Low Back Pain - GlobeNewswire

GREEN BAY, Wi. (WBAY) - More than 10,000 people couldn't find a match for a bone marrow transplant last year. The family of one Wisconsin teenager in desperate need of a match decided to host their own donor drive during Sunday's Packers game.

Nick Parins, who lives in Land O Lakes, Wisconsin, has T-Cell Lymphoma and needs a bone marrow transplant, but currently there is no match for him.

Its very frustrating for us, his family and friends, that theres so many people out there and so many people in the bank right now but theres just not the match for him, said Erick St. Aubin, Nicks cousin.

On the same day Nick turned 18, Eric St. Aubin and other family and friends gathered just outside Lambeau Field to host a bone marrow donor drive in his honor.

Right after kickoff today we facetimed with him to sing him happy birthday and it was pretty emotional, said St. Aubin.

The family partnered with Be The Match to set up the registration booth. People interested in putting themselves on the global donor registry only needed to provide some basic information and take a cheek swab test.

Its not saying youre signing up today and youre going to donate tomorrow. Thats really far from the truth, said Be The Match Community Engagement Specialist. The reality is its pretty rare to become a match and if you are its a very special thing.

Klingberg says there arent enough people on the registry to help all the patients who need bone marrow transplants.

This is their last hope. So its really frustrating when you hear people Oh, its really painful or It requires a lot of time or whatever, said Klingberg.

Klingberg says if you are a match, the donation process isnt actually all that painful, and it saves a life.

When somebody comes through and honors that commitment to donate some stem cells, thats all it took, and then this person is coming out of the hospital and going to overcome their disease, said Klingberg. Its amazing and it gives me goosebumps every time.

St. Aubin hopes the event will spread awareness and possibly lead to a life saved.

You could be a match [with someone] across the world, or you might be a match for Nick.

To register as a bone marrow donor, or for more information CLICK HERE.

Visit link:
Bone marrow donor drive held in Green Bay for teen who needs a match - WBAY

Bone marrow aspiration and trephine biopsy are usually performed on the back of the hipbone, or posterior iliac crest. An aspirate can also be obtained from the sternum (breastbone). For the sternal aspirate, the patient lies on their back, with a pillow under the shoulder to raise the chest. A trephine biopsy should never be performed on the sternum, due to the risk of injury to blood vessels, lungs or the heart.

The need to selectively isolate and concentrate selective cells, such as mononuclear cells, allogeneic cancer cells, T cells and others, is driving the market. Over 30,000 bone marrow transplants occur every year. The explosive growth of stem cells therapies represents the largest growth opportunity for bone marrow processing systems.Europe and North America spearheaded the market as of 2016, by contributing over 74.0% to the overall revenue. Majority of stem cell transplants are conducted in Europe, and it is one of the major factors contributing to the lucrative share in the cell harvesting system market.

Get More Information:https://www.trendsmarketresearch.com/report/sample/3184

In 2016, North America dominated the research landscape as more than 54.0% of stem cell clinical trials were conducted in this region. The region also accounts for the second largest number of stem cell transplantation, which is further driving the demand for harvesting in the region.Asia Pacific is anticipated to witness lucrative growth over the forecast period, owing to rising incidence of chronic diseases and increasing demand for stem cell transplantation along with stem cell-based therapy.

Request For Table of Contents:https://www.trendsmarketresearch.com/report/requesttoc/3184

Japan and China are the biggest markets for harvesting systems in Asia Pacific. Emerging countries such as Mexico, South Korea, and South Africa are also expected to report lucrative growth over the forecast period. Growing investment by government bodies on stem cell-based research and increase in aging population can be attributed to the increasing demand for these therapies in these countries.

Major players operating in the global bone marrow processing systems market are ThermoGenesis (Cesca Therapeutics inc.), RegenMed Systems Inc., MK Alliance Inc., Fresenius Kabi AG, Harvest Technologies (Terumo BCT), Arthrex, Inc. and others

Report Description:https://www.trendsmarketresearch.com/report/bone-marrow-processing-system-market

More here:
Bone Marrow Processing System Market Expected to Witness an Imperishable Growth over 2025 - Guru Online News