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.

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

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Colleen LeCours lay in a hospital bed at the General campus of The Ottawa Hospital on August 12, 2016, waiting for the only thing that could save her life a stem cell transplant from a stranger.

The donor could be anywhere in the world if a related blood donor cant be found, the call to find a match goes out to registries all over the globe and the donated stem cells are rushed across international borders.

What LeCours didnt know is that her donor, an 18-year-old Carleton University student named Timothy White, was just one floor below. Similarly, White didnt know that his recipient was in the same hospital.

There are currently more than 450,000 people on the Canadian Blood Services Stem Cell Registry formerly known as OneMatch and 36 million on affiliated international registries. Still, some people never find a match. There are more than 900 Canadians in need of a transplant who have not found a match anywhere in the world.

What were the odds that the match for LeCours, now 57, would be found in the same city?

Astronomical, she said.

The chances that White would even ever be asked to donate were also very low only about one in a thousand. After he agreed to donate, he was not told where the recipient might be. I was told the recipient could be anywhere. They could be in Africa, said White, now 22 and a recent graduate in computer science.

White had signed up for the registry through a cheek swab booth at ComiCon less than six months earlier. A smart place to recruit would-be stem cell donors, he notes. The optimal donor is a male between the age of 17 and 35 and thats the ComiCon demographic.

He decided to register as a potential donor because he grew up in the scouting movement. One of the main philosophies is to do a good turn every day, he said.

The donation was a non-surgical procedure in which Whites blood was removed though a needle, the stem cells were separated from his blood and the remaining blood components returned to his body through another needle. The procedure started at about 8 a.m. and was over by about 5 p.m.

I figured if I gave someone a day for a thousand more days (of life) then I felt it was a fair trade. I have many years of life. Why not spend one day? said White.

LeCourss medical journey started in 2009 with an emergency room visit for abdominal pain. She was eventually diagnosed with Stage 4 follicular lymphoma, a blood cancer that affects infection-fighting white blood cells. At the time, LeCours was working for Gov.-Gen. Michalle Jean and was able to stay on the job most of the time during her six months of treatment.

Four years later, the lymphoma returned. It was back again two years after that, in a more aggressive form. The only treatment was stem cell transplant.

There are two main kinds of stem cell transplants autologous and allogenic. In an autologous transplant, stem cells are collected from a patients own blood and reintroduced after being treated to remove cancer cells. In an allogenic stem cell transplant, the stem cells come from a donor.

At this point, LeCours was a candidate for an autologous transplant. Once again, she underwent aggressive chemotherapy. A year later, the cancer returned.

Doctors told LeCours there wasnt much else they could do and advised her to get her affairs in order. But the hospitals transplant team felt she could be a candidate for an allogenic transplant. Theres risk rejecting donated stem cells can be fatal to the patient.

LeCours learned that her brother was a match. But the medical work-up would last about three months and she couldnt wait that long.

I wasnt sure I wanted to do it but I didnt have much choice, she said. They said, We have someone waiting in the wings.

And I said, He probably has wings.

After the transplant, LeCours recovered as an outpatient in the home of her brother and sister-in-law. It took three months to rebuild her immune system. Her only rejection symptoms were a bit of skin irritation.

In January 2018, LeCours received an email asking if she would like to exchange contact information with her donor. She replied that she would.

A few months later, she got a message with Whites co-ordinates and was astonished to find that her donor was in Ottawa. It took her a few weeks to formulate an email.

I didnt want to scare him. I just wanted him to know how incredibly grateful I was. And I wanted to pay it forward, said LeCours.

After careful consideration, she sent White an email on Oct. 8, 2018.

Today, being Thanksgiving, I have so much to be thankful for, namely you giving your stem cells and saving my life and the success of the stem cells grafting to my bone marrow, LeCours wrote. I cant thank you enough for your wonderful selfless act.

Stem cell donor 18-year-old Carleton University student Timothy White at The Ottawa Hospital, General campus, donating stem cells for Colleen LeCours in August 2016. At the time he did not know that LeCours would be the recipient. Courtesy Timothy White.jpg

She added that she didnt know anything about him except for his name and email address, and asked if they could meet. They got together for the first time over lunch in a burger restaurant.

As soon as I saw him, I broke down, said LeCours.

It has been three and a half years since the transplant and LeCours remains in remission. She invited White to her familys Thanksgiving this year, and the two meet to catch up every few months. Its one of the quirks of stem cell donation that the recipient assumes the blood type of the donor. LeCours, once O-positive, now has blood type A-negative, like White.

Im a grandmother. The fact that my grandson has his moma is huge.

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ASTRONOMICAL ODDS: Stem cell recipient and her donor both from Ottawa - Ottawa Sun

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Military personnel walk past the Raytheon Missile stand.

Carl De Souza | AFP | Getty Images

Check out the companies making headlines in midday trading:

Raytheon, Lockheed Martin, L3Harris Equity of major aircraft and weapons manufacturers Raytheon, Lockheed Martin and L3Harris rose 1.6%, 3.8% and 3.3%, respectively, in midday trading as U.S.-Iranian tensions flare in the Middle East. The U.S. confirmed it was responsible for a drone strike in Baghdad on Friday that killed Iranian Gen. Qasem Soleimani, Tehran's top military commander and a prominent political fixture in the region.

Incyte Shares of Incyte plunged 10% Friday after the company announced that a Phase III study showed one of its developmental drugs failed to show results that were statistically superior to a placebo. The drug was aimed at treating a disease that arises when donated bone marrow or stem cells attack their new host.

Tesla Tesla's stock climbed 3.8% on Friday after the automaker reported better-than-expected deliveries for its most recent quarter. The electric car company delivered 112,000 vehicles during the fourth quarter, topping consensus estimates of 106,000. Tesla delivered roughly 367,500 vehicles for the full year, a 50% increase from 2018 and within the range that it had given as guidance.

Bank of America Shares of the top U.S. bank fell 1.5% in afternoon trading after BMO Capital Markets downgraded the equity to market perform from outperform, telling clients its valuation re-rating has "run its course." Analyst James Fotheringham added that Bank of America shares now trade at a premium to their long-term average and suggested investors look to cheaper names like Citi and Morgan Stanley in the big-bank space.

Concho Resources, Apache, Devon Energy Shares of Concho, Apache and Devon all traded higher, following crude prices, after the U.S. killed a top Iranian military leader in an airstrike. Concho and Apache each traded higher by more than 1% while Devon advanced 0.8%.

L Brands Shares of L Brands rose nearly 8% after Bank of America upgraded the retail and apparel company to buy from neutral. The bank's analysts cited a strong Bath & Body Works business, potential for a more stable Victoria's Secret and a high dividend yield as reasons for the upgrade. The bank also raised its price target on the stock to $25 per share from $21, which would be a 49% increase from where the stock closed on Thursday.

Humana Humana rose 1.5% after Goldman Sachs added the health care company to its "Conviction Buy" list and told clients it sees sizable upward revisions to earnings estimates due to the recent repeal of a fee on health insurers.

CNBC's Fred Imbert and Jesse Pound contributed to this report.

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Stocks making the biggest moves midday: L3Harris, Tesla, Apache & more - CNBC

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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.

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Targeted deletion of PD-1 in myeloid cells induces antitumor immunity - Science

Bone Marrow Stem Cells Comments Off on Targeted deletion of PD-1 in myeloid cells induces antitumor immunity – Science | January 4th, 2020

Researchers at Baylor College of Medicine have discovered a new mechanism that helps maintain and repair bones in adults. Ultimately, this could help develop new therapeutic strategies to improve bone healing.

Knee Bones

Osteoporosis is a skeletal disease characterized by reduced bone density and changes in the microarchitecture of bones. These changes weaken the bone and increase the risk of fracture. This disease develops particularly in older people. Today, a new study could eventually lead to the development of therapeutic strategies to improve bone healing in these patients. According to the results published in the journal Cell Stem Cell on the 5th December, 2019 researchers have discovered a new mechanism that contributes to the maintenance and repair of bones in adults.

Read Also: HGH Is Now A Solid Treatment For Osteoporosis According To Studies

Adult bone repair relies on the activation of bone stem cells, which still remain poorly characterized. Bone stem cells have been found both in the bone marrow inside the bone and also in the periosteum the outer layer of tissue that envelopes the bone. Previous studies have shown that these two populations of stem cells, although they share many characteristics, also have unique functions and specific regulatory mechanisms. said Dr. Dongsu Park, assistant professor of molecular and human genetics, pathology and immunology at Baylor College of Medicine, where the study was conducted.

Of these two populations, periosteal stem cells are the least known. Although the scientists know that this is a heterogeneous population of cells that can contribute to the thickness, formation and repair of bone fractures, no one has yet been able to distinguish between the different subtypes of bone stem cells in order to study the regulation of their different functions.

Here, however, Dongsu Park and colleagues were able to develop a technique in mice to identify different subpopulations of periosteal stem cells, define their contribution to the repair of bone fractures and identify the specific factors that regulate their migration and proliferation under physiological conditions.

In rats, they discovered specific markers for this class of cells. They identified a specific subset of stem cells that contribute to lifelong bone regeneration in adults. They also observed that periosteal stem cells react to inflammatory molecules, chemokines, which are normally produced in bone injuries.

Read Also: The Exciting Future of Joint and Cartilage Repair

In detail, periosteal stem cells have receptors that bind to the CCL5 chemokine. The CCL5 chemokine sends a signal to the cells to migrate to the injured bone and repair it. By suppressing the CCL5 gene in rats, the researchers found defects in bone repair that delayed healing. However, when they gave CCL5 to rats that had lost CCL5, the bones recovered faster.

Our findings contribute to a better understanding of the healing of adult bones. We believe this is one of the first studies to show that bone stem cells are heterogeneous and that different subtypes have unique properties that are regulated by specific mechanisms, said Dongsu Park. We have identified markers that allow us to distinguish between the subtypes of bone stem cells and have investigated what each subtype contributes to bone health. The understanding of how the functions of bone stem cells are regulated offers the possibility of developing new therapeutic strategies for the treatment of bone damage in adults.

Read Also: Implants from Own Stem Cells May Offer Solution to Back Pain, Researchers Say

In the long term, these findings may therefore have potential therapeutic applications, particularly in people with osteoporosis or diabetes.Indeed, people with diabetes may be prone to falls and fractures due to possible neurological, visual or renal complications. In addition, bone fragility in diabetics is likely to be due to changes in bone remodeling and, in particular, an increase in bone resorption.

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30458-8?

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Researchers at Baylor College of Medicine Discover How to Improve Bone Repair - Gilmore Health News

Bone Marrow Stem Cells Comments Off on Researchers at Baylor College of Medicine Discover How to Improve Bone Repair – Gilmore Health News | January 4th, 2020

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

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The 'supercells' that cured an infant's grave genetic illness - FRANCE 24

Bone Marrow Stem Cells Comments Off on The ‘supercells’ that cured an infant’s grave genetic illness – FRANCE 24 | January 2nd, 2020

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.

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Innovative therapies: Novel targets in allergic inflammation - SelectScience

Bone Marrow Stem Cells Comments Off on Innovative therapies: Novel targets in allergic inflammation – SelectScience | January 2nd, 2020

After years of ethical debates and breakthroughs in the lab, CRISPR has finally made its way to clinical trials. Researchers are now looking at whether the DNA-editing tool, as well as more conventional gene therapies, can effectively treat a wide array of heritable disorders and even cancers.

Theres been a convergence of the science getting better, the manufacturing getting much better, and money being available for these kinds of studies, says Cynthia Dunbar, a senior investigator at the National Heart, Lung, and Blood Institute. Its truly come of age.

CRISPR formally known as CRISPR-Cas9 has been touted as an improvement over conventional gene therapy because of its potential precision. CRISPR (clustered regularly interspaced short palindromic repeats) is a genetic code that, contained in a strand of RNA and paired with the enzyme Cas9, acts like molecular scissors that can target and snip out specific genes. Add a template for a healthy gene, and CRISPRs cut can allow the cell to replace a defective gene with a healthy one.

In April, scientists at the University of Pennsylvania announced they had begun using CRISPR for cancer treatments. The first two patients one with multiple myeloma, the other with sarcoma had cells from their immune systems removed. Researchers used CRISPR to genetically edit the cells in the lab, and then returned them back into their bodies.

On the other side of the country, Mark Walters, a blood and bone marrow transplant specialist at the University of California, San Francisco, Benioff Childrens Hospital in Oakland, is gearing up for trials that will use CRISPR to repair the defective gene that causes sickle cell disease. With CRISPR, once youve made that type of correction, [that cell] is 100 percent healthy, says Walters.

Another team is tackling the same disease using a type of hemoglobin, a protein in red blood cells, thats normally made only in fetuses and newborn babies. Researchers found that some adults continue to produce these proteins throughout their lives, and when those adults also have sickle cell disease, their symptoms are mild. So the international team used CRISPR to disable the gene that interferes with production of this hemoglobin, resuming its production and protecting the adult patients against sickle cell disease.

Several other CRISPR studies are in the works to treat a range of inherited disorders, including hemophilia and SCID-X1 (also known as X-linked severe combined immunodeficiency, the so-called bubble boy disease in which babies are born without a functioning immune system).

At St. Jude Childrens Research Hospital, a gene therapy trial cured Gael Jesus Pino Alva (pictured with his mother, Giannina) of SCID-X1, the bubble boy disease. (Credit: St. Jude Children's Research Hospital/Peter Barta)

The past year also saw success in a handful of experiments on conventional gene therapy. Instead of using CRISPR to repair disease-causing genes, these treatments use hollowed-out viruses to ferry healthy versions of genes into cells. Millions of these altered cells are released into the bloodstream or bone marrow in hopes that enough will land in the right places. But because scientists cant predict where the circulating genes may end up, this shotgun approach has had unintended, sometimes fatal, consequences including, in an earlier study, inadvertently activating leukemia-causing genes in patients treated for SCID-X1.

But in 2019, researchers learned that using a different type of virus one related to HIV to transport the genes may prevent these side effects. In an April study, researchers at St. Jude Childrens Research Hospital in Memphis, Tennessee, and UCSF Benioff Childrens Hospital in Oakland collected bone marrow from eight newborns with SCID-X1. They loaded corrective genes into the disabled HIV-related virus, which carried them into the patients bone marrow stem cells. The infants also received low doses of busulfan, a chemotherapy that gave the doctored stem cells room to grow. So far, we havent seen anything worrisome, says Ewelina Mamcarz, a pediatric oncologist at St. Jude who led the research team. The study recently added its 12th patient.

Gene therapy does have its momentum [back], says Mamcarz, reflecting on the fields setback after the earlier studys leukemia side effects. Theres so much that still needs to be done, and so many questions, she says. [But] this is how medicine evolves. We always want to be better than we were a week ago.

In the future, the hope is that gene therapy technologies will move beyond mending simple genetic mistakes and be used to combat big killers like diabetes or heart disease. [Those diseases are] more challenging, but a lot of them would benefit from knocking out a bad gene, says Dunbar.

For now, though, researchers are optimistic about the progress thats already been made. All of this has been very encouraging, says Dunbar. [And] for sickle cell in the U.S. and hemophilia in the developed world, these diseases may soon be solved.

[This story originally appeared in print as "Gene Therapy Gets Clinical."]

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Gene Therapies Make it to Clinical Trials - Discover Magazine

Bone Marrow Stem Cells Comments Off on Gene Therapies Make it to Clinical Trials – Discover Magazine | December 31st, 2019

In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering -- by editing her genome. Victoria Gray's recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research -- gene therapy. "I have hoped for a cure since I was about 11," the 34-year-old told AFP in an email.

"Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency." Over several weeks, Gray's blood was drawn so doctors could get to the cause of her illness -- stem cells from her bone marrow that were making deformed red blood cells. The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 -- pronounced "Crisper" -- a new tool informally known as molecular "scissors." The genetically edited cells were transfused back into Gray's veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured. "This is one patient. This is early results. We need to see how it works out in other patients," said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville. "But these results are really exciting." In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden. For decades, the DNA of living organisms such as corn and salmon has been modified. But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs. The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself. "It's all developing very quickly," said French geneticist Emmanuelle Charpentier, one of Crispr's inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Cures

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy. Scientists practising the technique insert a normal gene into cells containing a defective gene. It does the work the original could not -- such as making normal red blood cells, in Victoria's case, or making tumor-killing super white blood cells for a cancer patient. Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union. They join several other gene therapies -- bringing the total to eight -- approved in recent years to treat certain cancers and an inherited blindness. Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution. "Twenty-five, 30 years, that's the time it had to take," he told AFP from Paris.

"It took a generation for gene therapy to become a reality. Now, it's only going to go faster." Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a "breakthrough period." "We have hit an inflection point," said Carrie Wolinetz, NIH's associate director for science policy.These therapies are exorbitantly expensive, however, costing up to $2 million -- meaning patients face grueling negotiations with their insurance companies. They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion -- and fighting a general infection. "You cannot do this in a community hospital close to home," said her doctor. However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers. They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

Bioterrorism

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who don't necessarily share the medical ethics of Western medicine. Last year in China, scientist He Jiankui triggered an international scandal -- and his excommunication from the scientific community -- when he used Crispr to create what he called the first gene-edited humans. The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process. "That technology is not safe," said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr "scissors" often cut next to the targeted gene, causing unexpected mutations. "It's very easy to do if you don't care about the consequences," Musunuru added. Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability. There is also the temptation to genetically edit entire animal species -- malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US. The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesn't believe in the more dystopian scenarios predicted for gene therapy, including American "biohackers" injecting themselves with Crispr technology bought online. "Not everyone is a biologist or scientist," she said. And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies' crops? Charpentier thinks that technology generally tends to be used for the better. "I'm a bacteriologist -- we've been talking about bioterrorism for years," she said. "Nothing has ever happened."

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Year in Review: Gene Therapy Technology and a Milestone 2019 for Medical Research - News18

Bone Marrow Stem Cells Comments Off on Year in Review: Gene Therapy Technology and a Milestone 2019 for Medical Research – News18 | December 31st, 2019

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.

Read more:
The 3 most important health innovations of the past decade - The Hill

Bone Marrow Stem Cells Comments Off on The 3 most important health innovations of the past decade – The Hill | December 31st, 2019

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.

Visit link:
Curious about organ donation? Heres what you need to know - WHNT News 19

Bone Marrow Stem Cells Comments Off on Curious about organ donation? Heres what you need to know – WHNT News 19 | December 31st, 2019

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.

Go here to see the original:
Advances In Treatment Of Soft Tissue Injuries (Video) - South Florida Reporter

Bone Marrow Stem Cells Comments Off on Advances In Treatment Of Soft Tissue Injuries (Video) – South Florida Reporter | December 31st, 2019

For decades, the DNA of living organisms such as corn and salmon has been modified, but Crispr, invented in 2012, made gene editing more widely accessible. Image: YinYang/IStock.com via AFP Relaxnews

In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering by editing her genome.

Victoria Grays recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research gene therapy.

I have hoped for a cure since I was about 11, the 34-year-old told AFP in an email.

Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency.

Over several weeks, Grays blood was drawn so doctors could get to the cause of her illness stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 pronounced Crisper a new tool informally known as molecular scissors.

The genetically edited cells were transfused back into Grays veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured.

This is one patient. This is early results. We need to see how it works out in other patients, said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

But these results are really exciting.

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified.

But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

Its all developing very quickly, said French geneticist Emmanuelle Charpentier, one of Crisprs inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Cures

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practicing the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not such as making normal red blood cells, in Victorias case, or making tumor-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the United States and a blood disease in the European Union.

They join several other gene therapies bringing the total to eight approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

Twenty-five, 30 years, thats the time it had to take, he told AFP from Paris.

It took a generation for gene therapy to become a reality. Now, its only going to go faster.

Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a breakthrough period.

We have hit an inflection point, said Carrie Wolinetz, NIHs associate director for science policy.

These therapies are exorbitantly expensive, however, costing up to $2 million meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion and fighting a general infection.

You cannot do this in a community hospital close to home, said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

Bioterrorism

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who dont necessarily share the medical ethics of Western medicine.

Last year in China, scientist He Jiankui triggered an international scandal and his excommunication from the scientific community when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process.

That technology is not safe, said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr scissors often cut next to the targeted gene, causing unexpected mutations.

Its very easy to do if you dont care about the consequences, Musunuru added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesnt believe in the more dystopian scenarios predicted for gene therapy, including American biohackers injecting themselves with Crispr technology bought online.

Not everyone is a biologist or scientist, she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies crops?

Charpentier thinks that technology generally tends to be used for the better.

Im a bacteriologist weve been talking about bioterrorism for years, she said. Nothing has ever happened.IB/JB

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2019: The year gene therapy came of age - INQUIRER.net

Bone Marrow Stem Cells Comments Off on 2019: The year gene therapy came of age – INQUIRER.net | December 29th, 2019

A mum whose ex bludgeoned her teenage son to death with a hammer before killing himself is making a heartfelt plea to strangers to try and save her own life.

Tania Morris fears this Christmas may be her last after being diagnosed with Hodgkin's Lymphoma shortly after the tragedy in Burslem, Stoke-on-Trent.

The 49-year-old, who was the only survivor of the brutal attack, was later told that her only chance of survival is a stem cell transplant, StokeonTrentLive revealed.

In the most cruel twists of fate, her only hope would have been heronly child, 19-year-old Nathan Bates, who was murdered just weeks before she was diagnosed with the deadly blood disease.

Tania and her loved-ones are now desperately urging people to join the Antony Nolan register in the hope they can get their very own Christmas miracle.

Tests on other family members including Tania's mum Viv, 69, and dad Robert, aged 70, showed they are not suitable as they are too old and one has a pacemaker.

And her brother Darren Morris, 48, was not a match either.

Meanwhile, her younger brother Adam Morris, who could have fitted the bill, died of a heart attack at the age of 41 four years ago.

Brave Tania, of Burlsem. told StokeonTrentLive: "It's heartbreaking. The doctors just keep saying we need a fit-and-healthy 19-year-old and that breaks my heart as that's how old Nathan was when he was murdered.

"My younger brother could have been a match but he died of a heart attack.

"My other brother Darren was devastated when he was tested and wasn't a match. He wanted so much to help me.

"Dad's only a half match. He's too poorly himself to go ahead but if and when it becomes life or death he could be a last roesort. They're worried it would kill both me and him.

"It would really be desperate measures if it comes to that. It would be my last option because it could kill me.

"My mum's not even been tested because she's had a heart bypass.

"We are just hoping that someone comes forward. It's my only chance of beating this."

Tania's ex, Robert Goodwin, attacked Nathan as he slept at his home, knowing Nathans mum would be out.

An inquest heard Goodwin then left the property and hanged himself in nearby woodland at a spot where Tania would routinely walk her dogs.

It is believed he did so with the intentions that his ex would discover not just her sons body, but also his.

At the time of Nathan's murder, Goodwin was on bail after being charged with assaulting Tania and had retained his liberty despite having breached a condition not to contact her.

And it was while she was coping with the stress of organising Nathan's funeral the following December that she first noticed her own health decline.

The official blood cancer diagnosis then came in January this year.

She has since endured endless rounds of chemotherapy - but has just been told the latest treatment is not working.

Tania said: "He's just a coward for what he did to Nathan. He wouldn't accept any responsibility for what he did. He wanted me to drop the charges but I refused because I was scared he would do it to someone else.

"He just couldn't cope with the thought of going to prison so he killed Nathan, killed himself and if I don't find a donor, he may yet kill me. All the stress he's put our family through also led to my mum's heart attack.

"He had no reason to do what he did, he just wanted to upset me in the worst possible way.

"He said he loved me to pieces but then he did this.

"Since the day he attacked me, it's just been one thing after another."

Tania, who is currently too sick to work at Churchill China, added: "I haven't properly grieved for Nathan because of the cancer.

"I'm up at hospital every week and fighting this disease just leaves me so tired. I can't sleep anymore. If I'm not thinking about the cancer, my thoughts turn to Nathan.

"I'm not coping very well. It's been a rollercoaster couple of years.

"I've then got all my money worries. I just don't know what more I can cope with.

"I was planning on having a 50th birthday in the new year but we've put the plans on hold because I don't know when I'll be in hospital. I wanted to something to say thank-you to all my friends and family but everything is still up in the air.

"I can't plan anything. My life has been on hold since the day that man attacked me."

Tania has monthly appointments at Christies in Manchester to check whether there is a match.

Urging people to join the register, she added: "It's just a simple test you do in your own home send off.

"I'm not doing this just for me but for everyone else who needs a donor. You never know, you could save someone's life. It's my last chance to see another Christmas."

Who can join?

Anyone aged 16 to 30 and in good health can join.

Younger donors provide better outcomes for patients, so our recruitment age range means we focus on recruiting the best possible donors.

How to join?

Fill in the online application form and Antony Nolan will send a swab pack in the post to complete and send back which will then be added to the stem cell register.

How long will I be on the register?

Those who join will remain on the register until the age of 61. If you ever come up as a match for a patient, Antony Nolan be in touch straightaway.

What happens if I'm a match?

Antony Nolan will organise everything including travel and accommodation.

How do you make a donation?

There are two ways you might be asked to donate:90% of people donate via their bloodstreamand10% have their stem cells collected via their bone marrowwhile under general anaesthetic.

See the article here:
Cancer-hit mum's plea for donor after her ex murdered son who could have been match - Mirror Online

Bone Marrow Stem Cells Comments Off on Cancer-hit mum’s plea for donor after her ex murdered son who could have been match – Mirror Online | December 29th, 2019

Edward Aschoff, a college football reporter for ESPN, died Tuesday on his 34th birthday, according to ESPN

When ESPN reporter Edward Aschoff died, he had been diagnosed with multifocal pneumonia and a rare disease known as HLH, his fiance tweeted.

Aschoff was first admitted to the hospital and diagnosed with pneumonia in many parts of his lungs but was brought back to the emergency room when antibiotic treatment failed and he got worse, Katy Berteau said.

"After many tests - bone marrow and lung biopsies - treatment was started for a presumed diagnosis of HLH," she tweeted. "Within 3 days of being moved into the ICU, he passed."

HLH, hemophagocytic lymphohistiocytosis, is a rare disease that affects the immune system.

She did not provide any further details about the manner of Aschoff's death, which occurred on his 34th birthday.

Other people, including Aschoff himself, expressed surprise about the seriousness of the illness in a young man in apparently good health.

"Anyone ever had multifocal (bilateral) pneumonia in their early 30s as some who never gets sick and has a very good immune system? Asking for two friends ... my lungs," he tweeted on December 5.

More questions have come up about his second diagnosis, HLH. It is unclear if Aschoff had HLH or pneumonia first, if one came from the other, and exactly how he died so quickly.

Here is what we know about the diseases Aschoff's had:

Pneumonia is when air sacs in the lungs fill with fluid or pus. It can be caused by a virus, bacteria or a fungus, causing a fever and respiratory problems.

It can occur in one or both lungs, and multifocal means the pneumonia occurs in multiple places.

Thousands of people die around the world each year of pneumonia, but most healthy people can fight it off, especially with antibiotics and antiviral medications. The people most at risk are the young, elderly, frail or immune-compromised.

HLH is a rare disease that affects the immune system, making certain white blood cells attack other blood cells and enlarging the spleen and liver, according to Johns Hopkins Medicine.

It can be inherited or acquired, Johns Hopkins said. About a quarter of cases are passed down through families, and the rest come from infections, a weakened immune system and cancer.

Symptoms can include coughing, difficulty breathing, fever, headaches, rashes, swollen lymph nodes, jaundice and digestive problems, according to Johns Hopkins.

There is treatment for HLH, and acquired forms may clear when properly treated, Johns Hopkins said. If familial HLH goes untreated, it is usually fatal.

Treatments include chemotherapy, immunotherapy, steroids, antibiotic drugs and antiviral drugs. Stem cell transplants can cure HLH in most cases if drug treatments don't work, Johns Hopkins said.

There is no way to prevent HLH, the medical center said.

See more here:
ESPN reporter Edward Aschoff was diagnosed with pneumonia and HLH before he died. What is HLH? - Q13 News Seattle

Bone Marrow Stem Cells Comments Off on ESPN reporter Edward Aschoff was diagnosed with pneumonia and HLH before he died. What is HLH? – Q13 News Seattle | December 28th, 2019

Victoria Gray's recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research -- gene therapy.

Picture: Supplied.

WASHINGTON, United States - In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering -- by editing her genome.

Victoria Gray's recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research -- gene therapy.

"I have hoped for a cure since I was about 11," the 34-year-old told AFP in an email.

"Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency."

Over several weeks, Gray's blood was drawn so doctors could get to the cause of her illness -- stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 -- pronounced "Crisper" -- a new tool informally known as molecular "scissors."

The genetically edited cells were transfused back into Gray's veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured.

"This is one patient. This is early results. We need to see how it works out in other patients," said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

"But these results are really exciting."

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta-thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified.

But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

"It's all developing very quickly," said French geneticist Emmanuelle Charpentier, one of Crispr's inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

CURES

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not -- such as making normal red blood cells, in Victoria's case, or making tumour-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies -- bringing the total to eight -- approved in recent years to treat certain cancers and inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

"Twenty-five, 30 years, that's the time it had to take," he told AFP from Paris.

"It took a generation for gene therapy to become a reality. Now, it's only going to go faster."

Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a "breakthrough period."

"We have hit an inflection point," said Carrie Wolinetz, NIH's associate director for science policy.

These therapies are exorbitantly expensive, however, costing up to $2 million -- meaning patients face gruelling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in the hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion -- and fighting a general infection.

"You cannot do this in a community hospital close to home," said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

**BIOTERRORISM **

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who don't necessarily share the medical ethics of Western medicine.

Last year in China, scientist He Jiankui triggered an international scandal -- and his ex-communication from the scientific community -- when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process.

"That technology is not safe," said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr "scissors" often cut next to the targeted gene, causing unexpected mutations.

"It's very easy to do if you don't care about the consequences," Musunuru added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species -- malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesn't believe in the more dystopian scenarios predicted for gene therapy, including American "biohackers" injecting themselves with Crispr technology bought online.

"Not everyone is a biologist or scientist," she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies' crops?

Charpentier thinks that technology generally tends to be used for the better.

"I'm a bacteriologist -- we've been talking about bioterrorism for years," she said. "Nothing has ever happened."

Visit link:
2019: The year gene therapy came of age - Eyewitness News

Bone Marrow Stem Cells Comments Off on 2019: The year gene therapy came of age – Eyewitness News | December 28th, 2019

WASHINGTON: In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering - by editing her genome.Victoria Gray's recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research - gene therapy.'; var randomNumber = Math.random(); var isIndia = (window.geoinfo && window.geoinfo.CountryCode === 'IN') && (window.location.href.indexOf('outsideindia') === -1 ); console.log(isIndia && randomNumber "I have hoped for a cure since I was about 11," the 34-year-old told AFP in an email.

"Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency."

Over several weeks, Gray's blood was drawn so doctors could get to the cause of her illness - stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 - pronounced "Crisper" -- a new tool informally known as molecular "scissors."

The genetically edited cells were transfused back into Gray's veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured.

"This is one patient. This is early results. We need to see how it works out in other patients," said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

"But these results are really exciting."

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified.

But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

"It's all developing very quickly," said French geneticist Emmanuelle Charpentier, one of Crispr's inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not -- such as making normal red blood cells, in Victoria's case, or making tumor-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies - bringing the total to eight - approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

"Twenty-five, 30 years, that's the time it had to take," he told AFP from Paris.

"It took a generation for gene therapy to become a reality. Now, it's only going to go faster."

Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a "breakthrough period."

"We have hit an inflection point," said Carrie Wolinetz, NIH's associate director for science policy.

These therapies are exorbitantly expensive, however, costing up to $2 million - meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion - and fighting a general infection.

"You cannot do this in a community hospital close to home," said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who don't necessarily share the medical ethics of Western medicine.

Last year in China, scientist He Jiankui triggered an international scandal - and his excommunication from the scientific community - when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process.

"That technology is not safe," said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr "scissors" often cut next to the targeted gene, causing unexpected mutations.

"It's very easy to do if you don't care about the consequences," Musunuru added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species - malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesn't believe in the more dystopian scenarios predicted for gene therapy, including American "biohackers" injecting themselves with Crispr technology bought online.

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2019: the year gene therapy came of age - Times of India

Bone Marrow Stem Cells Comments Off on 2019: the year gene therapy came of age – Times of India | December 27th, 2019

Freeze thaw chambers are also called refrigerated humidity chambers. Freeze thaw chamber is used for applications which require temperature cycling down below freezing. Principle of freeze thaw cycle is used in cryopreservation technique. Cryopreservation is the process of preserving living cells and tissues at cryogenic temperature, which lead to suspended metabolic activity of cells in liquid nitrogen. Principle of freeze thaw cycle is nowadays used as treatment method for cancer, as freezing temperature is used in cryosurgery for local tissue destruction.

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Freezing and thawing cause cell death due to ice crystal formation, osmotic shock, and membrane damage. Advanced freeze thaw chambers are available in the market with new features, such as, epoxy coating to avoid corrosion, better condenser and evaporator, capillary tube system, CFC-free polyurethane foam for insulation, broad temperature range from -20 C to 60 C, and long service life designs.

Rise in understanding about the physical and chemical properties of freeze and thaw cycle, advancement in the field of mechanics, and flexibility to stimulate a broad range of conditions are some of the factors driving the growth of the freeze thaw chambers market. However, expensive maintenance and stringent regulatory standards are anticipated to hamper the growth of the market during the forecast period. Customized freeze thaw chambers are the ones which can be modified based on the requirement of the end-user. Introduction of customized freeze thaw instruments is likely to boost the growth of the freeze thaw chambers market during the forecast period.

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On the basis of application area, the global freeze thaw chambers market can be segmented into biopharmaceutical development, molecular biology and biochemistry, medical application, and others. Medical application can be further divided into cryopreserved products and others. Cryopreserved products can be further classified into blood transfusion, bone marrow transplantation, artificial insemination, in vitro fertilization (IVF), stem cell and organ, and others.

The biopharmaceutical development segment is propelling the growth of the freeze thaw chambers market as freezing is one of the processing steps in drug development that ensures the stability and quality of drugs, while freeze thaw chambers provide stability to drug substances. Freeze thaw chambers are also used for ASTM material testing. The cryopreserved products segment is expected to drive the growth of the freeze thaw chambers market during the forecast period due to increase in awareness about the importance and function of stem cell and tissue engineering. Advancement in organ transplantation technology is also another important factor contributing to the growth of stem cell and organ cryopreservation. Freeze thaw chambers are extensively used to transfer cryopreserved products to the end-user for applications, such as, blood transfusion, bone marrow transplantation, artificial insemination, and in vitro fertilization (IVF).

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Based on end-user, the global freeze thaw chambers market can be segmented into biopharmaceutical companies, pathology and research laboratories, hospitals, and stem cell and blood banks. The pathology and research laboratories segment is boosting the growth of the freeze thaw chambers market as these chambers are required for research applications which require very low freezing temperature. Biopharmaceutical companies is another growing segment of the freeze thaw chambers market. Freeze thaw chambers maximize productivity and reduce production cost by providing flexibility to drug substances.

In terms of region, the global freeze thaw chambers market can be categorized into North America, Europe, Asia Pacific, Lain America, and Middle East & Africa. North America is the leading market for freeze thaw chambers in the world due to extensive funding support from the government for research activities in the region. Europe is another leading market for freeze thaw chambers market owing to extensive research in the field of biochemistry and molecular biology in the region. The freeze thaw chambers market in Asia Pacific is expected to grow significantly during the forecast period due to rise in awareness in the region regarding medical applications involving cryopreservation process, such as, umbilical cord, stem cell, and blood sample.

Key players operating in the global freeze thaw chambers market are Darwin Chambers, Newtronic Lifecare Equipments Pvt. Ltd., Caron Products and Services, Inc, BIONICS SCIENTIFIC TECHNOLOGIES (P) LTD., Santorius, Feutron Klimasimulation GmBH., LR Environmental Equipment Co.Inc., and Dycometal.

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Freeze Thaw Chambers Market Poised to Expand at a Robust Pace by 2026 - Market Research Sheets

Bone Marrow Stem Cells Comments Off on Freeze Thaw Chambers Market Poised to Expand at a Robust Pace by 2026 – Market Research Sheets | December 27th, 2019

Global Hematopoietic Stem Cell Transplantation (HSCT) Market 2019 by key players, regions, type, and application, forecast to 2025. The Report contains a forecast of 2019 and ending 2025 with a host of metrics like supply-demand ratio, Hematopoietic Stem Cell Transplantation (HSCT) market frequency, dominant players of Hematopoietic Stem Cell Transplantation (HSCT) market, driving factors, restraints, and challenges. The report also contains market revenue, sales, Hematopoietic Stem Cell Transplantation (HSCT) production and manufacturing cost that could help you get a better view of the market. The report focuses on the key global Hematopoietic Stem Cell Transplantation (HSCT) manufacturers, to define, describe and analyze the sales volume, value, market competition landscape, market share, SWOT analysis and development plans in future years.

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Major Players included in this report are as follows Regen Biopharma IncChina Cord Blood CorpCBR Systems IncEscape Therapeutics IncCryo-Save AGLonza Group LtdPluristem Therapeutics IncViaCord I

Hematopoietic Stem Cell Transplantation (HSCT) Market can be segmented into Product Types as AllogeneicAutologous

Hematopoietic Stem Cell Transplantation (HSCT) Market can be segmented into Applications as Peripheral Blood Stem Cells Transplant (PBSCT)Bone Marrow Transplant (BMT)Cord Blood Transplant (CBT)

Hematopoietic Stem Cell Transplantation (HSCT) Market: Regional analysis includes:Asia-Pacific (Vietnam, China, Malaysia, Japan, Philippines, Korea, Thailand, India, Indonesia, and Australia)Europe (Turkey, Germany, Russia UK, Italy, France, etc.)North America (United States, Mexico, and Canada.)South America (Brazil etc.)The Middle East and Africa (GCC Countries and Egypt.)

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Influence of the Hematopoietic Stem Cell Transplantation (HSCT) market report: Comprehensive assessment of all opportunities and risk in the Hematopoietic Stem Cell Transplantation (HSCT) market. The Hematopoietic Stem Cell Transplantation (HSCT) market recent innovations and major events. A detailed study of business strategies for growth of the Hematopoietic Stem Cell Transplantation (HSCT) market-leading players. Conclusive study about the growth plot of Hematopoietic Stem Cell Transplantation (HSCT) market for forthcoming years. In-depth understanding of Hematopoietic Stem Cell Transplantation (HSCT) market-particular drivers, constraints and major micro markets. Favourable impression inside vital technological and market latest trends striking the Hematopoietic Stem Cell Transplantation (HSCT) market.

Objective of Studies: 1. To provide detailed analysis of the market structure along with forecast of the various segments and sub-segments of the global Hematopoietic Stem Cell Transplantation (HSCT) market. 2. To provide insights about factors affecting the market growth. To analyse the Hematopoietic Stem Cell Transplantation (HSCT) market based on various factors- price analysis, supply chain analysis, Porte five force analysis etc. 3. To provide historical and forecast revenue of the market segments and sub-segments with respect to four main geographies and their countries- North America, Europe, Asia, Latin America and Rest of the World. 4. To provide country level analysis of the market with respect to the current market size and future prospective. 5. To provide country level analysis of the market for segment by application, product type and sub-segments. 6. To provide strategic profiling of key players in the market, comprehensively analysing their core competencies, and drawing a competitive landscape for the market. 7. To track and analyse competitive developments such as joint ventures, strategic alliances, mergers and acquisitions, new product developments, and research and developments in the global Hematopoietic Stem Cell Transplantation (HSCT) market.

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The huge assortment of tables, graphs, diagrams, and charts obtained in this market research report generates a strong niche for an in-depth analysis of the ongoing trends in the Hematopoietic Stem Cell Transplantation (HSCT) market. Further, the report revises the market share held by the key players and forecast their development in the upcoming years. The report also looks at the latest developments and advancement among the key players in the market such as mergers, partnerships, and achievements.

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Global Hematopoietic Stem Cell Transplantation (HSCT) Market 2019 Industry Key Players, Trends, Sales, Supply, Demand, Analysis & Forecast to 2025...

Bone Marrow Stem Cells Comments Off on Global Hematopoietic Stem Cell Transplantation (HSCT) Market 2019 Industry Key Players, Trends, Sales, Supply, Demand, Analysis & Forecast to 2025… | December 27th, 2019

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

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

Bone Marrow Stem Cells Comments Off on Sickle cell patient is pain free after geneediting trial altered her DNA – The Times | December 25th, 2019