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Bhat V.,Tata Memorial Center | Vira H.,Tata Memorial Center | Khattry N.,Bone Marrow Transplant Unit | Toshniwal M.,Bone Marrow Transplant Unit
Transplant Infectious Disease | Year: 2017

We report the recent isolation of Cryptococcus laurentii from the feces of a patient with Hodgkin's lymphoma who underwent autologous hematopoietic stem cell transplant (HSCT). The organism was identified using microscopic morphology, cultural characteristics, and biochemical tests including sugar assimilation. Minimum inhibitory concentration of various antifungals was determined by microbroth dilution method. The recovery of pure culture of C. laurentii from stool culture, and the patient's response to treatment with voriconazole support its potential etiological role. To the best of our knowledge, we report the first case of diarrhea caused by C. laurentii in an HSCT recipient. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd


Kaminitz A.,Center for Stem Cell Research | Mizrahi K.,Center for Stem Cell Research | Stein J.,Bone Marrow Transplant Unit | Askenasy N.,Center for Stem Cell Research
Journal of Autoimmunity | Year: 2010

Mounting evidence indicates that immunosuppressive therapy and autologous bone marrow transplantation are relatively inefficient approaches to treat autoimmune diabetes. In this study we assessed the impact of immunosuppression on inflammatory insulitis in NOD mice, and the effect of radiation on immunomodulation mediated by adoptive transfer of various cell subsets. Sublethal radiation of NOD females at the age of 14 weeks (onset of hyperglycemia) delayed the onset of hyperglycemia, however two thirds of the mice became diabetic. Adoptive transfer of splenocytes into irradiated NON and NOD mice precipitated disease onset despite increased contents of CD25+FoxP3+ T cells in the pancreas and regional lymphatics. Similar phenotypic changes were observed when CD25+ T cells were infused after radiation, which also delayed disease onset without affecting its incidence. Importantly, irradiation increased the susceptibility to diabetes in NOD and NON mice (71-84%) as compared to immunomodulation with splenocytes and CD25+ T cells in naïve recipients (44-50%). Although irradiation had significant and durable influence on pancreatic infiltrates and the fractions of functional CD25+FoxP3+ Treg cells were elevated by adoptive cell transfer, this approach conferred no protection from disease progression. Irradiation was ineffective both in debulking of pathogenic clones and in restoring immune homeostasis, and the consequent homeostatic expansion evolves as an unfavorable factor in attempts to restore self-tolerance and might even provoke uncontrolled proliferation of pathogenic clones. The obstacles imposed by immunosuppression on abrogation of autoimmune insulitis require replacement of non-specific immunosuppressive therapy by selective immunomodulation that does not cause lymphopenia. © 2010 Elsevier Ltd.


Askenasy N.,Center for Stem Cell Research | Mizrahi K.,Center for Stem Cell Research | Askenasy E.M.,Center for Stem Cell Research | Stein J.,Bone Marrow Transplant Unit
Biology of Blood and Marrow Transplantation | Year: 2013

Graft-versus-host disease (GVHD) can be prevented by Fas-mediated selective depletion of host-sensitized donor lymphocytes ex vivo. We tested the hypothesis that Fas-mediated depletion of lymphocytes in the absence of host-specific antigenic stimulation can alleviate GVHD. Brief exposure (24 hours) of unstimulated donor lymphocytes to Fas ligand (FasL) ex vivo results in balanced apoptosis of CD8+ and CD4+ subsets with preferential depletion of CD62L and CD69, increased T regulatory fractions, and sustained responses to stimulation. This procedure ameliorates weight loss and improves the clinical and histologic score of skin and gastrointestinal GVHD with and without concurrent transplantation of hematopoietic progenitors and irrespective of conditioning-induced tissue injury. Although FasL-resistant donor T cells are less potent effectors of GVHD, they facilitate hematopoietic progenitor engraftment when infused with or after the graft and retain the potential to elaborate graft-versus-tumor reactions. These findings in a preclinical model together with the known trophic effects of FasL on primitive hematopoietic progenitors suggest that brief ex vivo incubation of hematopoietic grafts with FasL may improve the outcome and safety of clinical T cell-replete allogeneic and haploidentical transplants. © 2013 American Society for Blood and Marrow Transplantation.


Mizrahi K.,Center for Stem Cell Research | Stein J.,Bone marrow Transplant Unit | Askenasy N.,Center for Stem Cell Research
Bone Marrow Transplantation | Year: 2014

Mobilized peripheral blood (mPB) is a prevalent source of hematopoietic progenitors for transplantation; however, allogeneic and haploidentical transplants are often accompanied by severe GVHD. Following the observation that murine GVHD is ameliorated by pretransplant donor cell exposure to Fas-ligand (FasL) without host-specific sensitization, we assessed the susceptibility of mPB cells to spontaneous and receptor-induced apoptosis as a possible approach to GVHD prophylaxis. Short incubation for 4 h resulted in spontaneous apoptosis of 50% of the T and B lymphocytes and 60% myeloid cells. Although expression of Fas and TNF-R1 was proportionate to fractional apoptosis, cell death was dominated by spontaneous apoptosis. Functional assays revealed that the death receptors modulated mPB graft composition as compared with incubation in medium, without detectable quantitative variations. Removal of dead cells increased the frequency of mPB myeloid progenitors (P<0.001 vs medium), and recipients of mPB exposed to death ligands displayed reduced GVHD (P<0.01 vs medium) and improved survival following lipopolysacharide stimulation. mPB grafts exposed to the apoptotic challenge retained SCID reconstituting potential and graft versus tumor activity. These data emphasize that short-term exposure of mPB grafts to an apoptotic challenge is effective in reduction of GVHD effector activity. © 2014 Macmillan Publishers Limited.


Mizrahi K.,Center for Stem Cell Research | Peled T.,Gamida Cell | Yaniv I.,Bone Marrow Transplant Unit | Askenasy N.,Center for Stem Cell Research
Bone Marrow Transplantation | Year: 2014

The influence of TNF-α and Fas-ligand (FasL) on viability and function was evaluated in fresh- and expanded-umbilical cord blood (UCB) cells. CD34 + progenitors and T cells display outstanding survival, whereas ∼30% and >50% B lymphocytes and myeloid cells undergo spontaneous apoptosis within 24 and 48 h, respectively. Although the impact of exposure to toxic doses of FasL and TNF-α was undetectable in measurements of apoptosis; removal of dead cells after 2 days of incubation with the ligands revealed a twofold increase in frequency of colony-forming cells (CFU). The sensitivity of progenitors to apoptosis was also unaffected by Fas cross-linking following TNF-induced upregulation of the receptor, increasing CFU frequency without impairing SCID repopulating cell (SRC) activity. Most significant enrichment in CD34 + progenitors and corresponding increase in CFU frequency were observed when FasL was applied during the final week of ex vivo expansion under the influence of nicotinamide, without impairing SRC activity. These data emphasize differential sensitivities of UCB progenitors and lineage-positive cells to apoptotic signaling mediated by the Fas and TNF receptors, which might be useful in improving the efficiency of ex vivo expansion and improving UCB cell engraftment. © 2014 Macmillan Publishers Limited.


News Article | November 14, 2016
Site: globenewswire.com

LEXINGTON, Mass., Nov. 14, 2016 (GLOBE NEWSWIRE) -- Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative and effective drug candidates for the treatment of human cancers, today announced the appointment of Lori A. Kunkel, M.D. to its Board of Directors. Dr. Kunkel currently serves on the Board of Directors at Loxo Oncology, where she was formerly Acting Chief Medical Officer.  Prior to Loxo Oncology, Dr. Kunkel served as Chief Medical Officer at Pharmacyclics, Inc. leading integrated clinical development highlighted by the approval of IMBRUVICA®. She has also served as Chief Medical Officer at Proteolix Inc. (acquired by Onyx), Syndax, and ACT Biotech. Prior to joining the biotechnology industry in 1995, Dr. Kunkel spent ten years in academic/clinical medicine and served as a faculty member in the Division of Hematology/Oncology’s Bone Marrow Transplant Unit at University of California, Los Angeles. She trained in internal medicine at Baylor College of Medicine, hematology at USC and oncology at UCLA, earning board certifications in these specialties. “We are delighted to welcome Lori to the Board of Curis and we will benefit tremendously from her depth of experience and instincts as we develop our drug candidates and place the company on a path for approval and commercialization of our products,” said CEO Ali Fattaey.  “Lori is well known and respected in the biotechnology community and we have benefited from her role as an advisor to the company in the past.” “I am pleased to join the Curis Board and look forward to working closely with the Board and management team as we collectively advance Curis as a leading oncology company,” said Dr. Kunkel. About Curis, Inc.  Curis is a biotechnology company focused on the development and commercialization of innovative and effective drug candidates for the treatment of human cancers. The Company's clinical drug candidates include CUDC-907, which is being investigated in a Phase 2 trial in patients with Diffuse Large B Cell Lymphoma, or DLBCL, and in a separate Phase 1 trial in patients with solid tumors. As part of a broad collaboration with Aurigene, Curis has an exclusive license to CA-170, an oral small molecule PD-L1/VISTA antagonist that is currently being investigated in a Phase 1 trial in patients with solid tumors or lymphoma. Curis also has an exclusive license to oral small molecule antagonists of the PD-1 and TIM-3 pathways, including PD-L1/TIM-3 antagonist CA-327, as well as to molecules designed to inhibit the IRAK4 kinase, including CA-4948.  Curis is also party to a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are commercializing Erivedge® for the treatment of advanced basal cell carcinoma, and are further developing Erivedge in other diseases including idiopathic pulmonary fibrosis and myelofibrosis. For more information, visit Curis's website at www.curis.com. Cautionary Statement This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including without limitation statements regarding the potential advantages and benefits of small molecule checkpoint inhibitors and the Company's plans and expectations for the collaboration with Aurigene, including its plans to discover and develop multiple first-in-class oral, small molecule checkpoint inhibitors for the treatment of patients with cancer. Forward-looking statements may contain the words "believes," "expects," "anticipates," "plans," "seeks," "estimates," "assumes," "will," "may," "could" or similar expressions. These forward-looking statements are not guarantees of future performance and involve risks, uncertainties, assumptions and other important factors that may cause actual results to be materially different from those indicated by such forward-looking statements. For example, Curis may experience adverse results, delays and/or failures in its drug development programs and may not be able to successfully advance the development of its drug candidates in the time frames it projects, if at all. Curis's drug candidates may cause unexpected toxicities, fail to demonstrate sufficient safety and efficacy in clinical studies and/or may never achieve the requisite regulatory approvals needed for commercialization. Favorable results seen in preclinical studies and early clinical trials of Curis's drug candidates may not be replicated in later trials. There can be no guarantee that the collaboration agreement with Aurigene will continue for its full term, that Curis or Aurigene will each maintain the financial and other resources necessary to continue financing its portion of the research, development and commercialization costs, or that the parties will successfully discover, develop or commercialize drug candidates under the collaboration. Regulatory authorities may determine to delay or restrict Genentech's and/or Roche's ability to continue to develop or commercialize Erivedge in BCC. Erivedge may not demonstrate sufficient or any activity to merit its further development in disease indications other than BCC. Competing drugs may be developed that are superior to Erivedge. Curis faces risks relating to its wholly-owned subsidiary's royalty-collateralized loan transaction, including the risk that it may not receive sufficient levels of royalty revenue from sales of Erivedge to satisfy the debt obligation or may otherwise lose its rights to royalties and royalty-related payments as a result of a foreclosure of the loan. Curis will require substantial additional capital to fund its business and such capital may not be available on reasonable terms, or at all. Curis faces substantial competition. Curis also faces risks relating to potential adverse decisions made by the FDA and other regulatory authorities, investigational review boards, and publication review bodies. Curis may not obtain or maintain necessary patent protection and could become involved in expensive and time-consuming patent litigation and interference proceedings. Unstable market and economic conditions and unplanned expenses may adversely affect Curis's financial conditions and its ability to access the substantial additional capital needed to fund the growth of its business. Important factors that may cause or contribute to such differences include the factors set forth under the caption “Risk Factors” in our in our most recent Form 10-K and Form 10-Q and the factors that are discussed in other filings that we periodically make with the Securities and Exchange Commission (“SEC”). In addition, any forward-looking statements represent the views of Curis only as of today and should not be relied upon as representing Curis's views as of any subsequent date. Curis disclaims any intention or obligation to update any of the forward-looking statements after the date of this press release whether as a result of new information, future events or otherwise, except as may be required by law.


Rhyasen G.W.,Cincinnati Childrens Hospital Medical Center | Rhyasen G.W.,University of Cincinnati | Bolanos L.,Cincinnati Childrens Hospital Medical Center | Bolanos L.,University of Cincinnati | And 18 more authors.
Cancer Cell | Year: 2013

Myelodysplastic syndromes (MDSs) arise from a defective hematopoietic stem/progenitor cell. Consequently, there is an urgent need to develop targeted therapies capable of eliminating the MDS-initiating clones. We identified that IRAK1, an immune-modulating kinase, is overexpressed and hyperactivated in MDSs. MDS clones treated with a small molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-κB inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is detrimental to MDS cells, while sparing normal CD34+ cells. Based on an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that cotreatment more effectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDSs. © 2013 Elsevier Inc.


Mizrahi K.,Center for Stem Cell Research | Stein J.,Center for Stem Cell Research | Stein J.,Bone Marrow Transplant Unit | Pearl-Yafe M.,Center for Stem Cell Research | And 4 more authors.
Leukemia | Year: 2010

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway has selective toxicity to malignant cells. The TRAIL receptors DR4 and DR5 are expressed at low levels in human umbilical cord blood cells (3-15%) and are upregulated by incubation with the cognate ligand, triggering apoptosis in 70-80% of receptor-positive cells (P0.001). Apoptosis is not induced in hematopoietic progenitors, as determined from sustained severe combined immunodeficiency reconstituting potential and clonogenic activity. Furthermore, elimination of dead cells after incubation with TRAIL for 72 h results in a threefold enrichment in myeloid progenitors. Exposure to TRAIL in semisolid cultures showed synergistic activity of DR4 and granulocyte/macrophage colony-stimulating factor in recruiting lineage-negative (lin ) and CD34 progenitors and in promoting the formation of large colonies. In murine bone marrow, 30% of lin cells express TRAIL-R2 (the only murine receptor), and the receptor is upregulated after transplantation in cycling and differentiating donor cells that home to the host marrow. However, this receptor is almost ubiquitously expressed in the most primitive (lin SCA-1 c-kit ) progenitors, and stimulates the clonogenic activity of lin cells (P0.001), suggesting a tropic function after transplantation. It is concluded that TRAIL does not trigger apoptosis in hematopoietic progenitors, and upregulation of its cognate receptors under stress conditions mediates tropic signaling that supports recovery from hypoplasia. © 2010 Macmillan Publishers Limited All rights reserved.


Mizrahi K.,Center for Stem Cell Research | Mizrahi K.,Weizmann Institute of Science | Kagan S.,Weizmann Institute of Science | Stein J.,Bone Marrow Transplant Unit | And 3 more authors.
Stem Cells and Development | Year: 2014

Umbilical cord blood (UCB) is a good source of hematopoietic progenitors with increasing implementation in the clinical transplant setting. This study evaluates the molecular mechanisms of progenitor resistance to apoptosis triggered by Fas cross-linking. CD34+ and lineage-negative progenitors survive short-term ex vivo incubation and are not induced into apoptosis by Fas cross-linking. Furthermore, brief exposure of UCB cells to Fas-ligand for 24-48 h does not impair quantitative severe combine immune deficiency (SCID) reconstitution activity and appears to foster myelomonocyte reconstitution. The transcriptome of Fas receptor-positive CD34+ cells that survived an apoptotic challenge showed significant transcriptional upregulation of caspase-8, mucosa-associated lymphoid tissue lymphoma translocation gene-1 (MALT1), HtrA2, and GSK3β in addition to higher levels of c-FLICE inhibitory protein (FLIP), Bcl-2, and cytosolic inhibitor of apoptosis protein (cIAP) in all Fas-positive cells. Most prominent is the transcriptional upregulation of several key components the NFκB1 pathway including the membrane receptors TGF-β, interleukin-1 (IL-1), and TCR, the associated factor TNF receptor-associated factor-6 (TRAF6), and the converting enzymes TGF-β-activated kinase-1 (TAK1), double-stranded RNA-activated protein kinase (PKR), and α-catalytic subunit of IκB kinase (IKKα), that promote activation and nuclear translocation of this transcription factor. These data indicate that hematopoietic progenitors are not insensitive to apoptosis but are actively shielded from the extrinsic and intrinsic apoptotic pathways. This may occur through inherent transcriptional upregulation of the entire NFκB pathway in the presence of competent apoptotic signaling. © Mary Ann Liebert, Inc. 2014.


Mizrahi K.,Center for Stem Cell Research | Mizrahi K.,Tel Aviv University | Stein J.,Bone Marrow Transplant Unit | Yaniv I.,Tel Aviv University | And 2 more authors.
Stem Cells | Year: 2013

Tumor necrosis factor-α (TNF-α) has been suggested to exert detrimental effects on hematopoietic progenitor function that might limit the success of transplants. In this study, we assessed the influences of TNF-α and its two cognate receptors on the function of fresh umbilical cord blood (UCB) and cryopreserved mobilized peripheral blood (mPB). CD34+ progenitors from both sources are less susceptible to spontaneous apoptosis than lineage-committed cells and are not induced into apoptosis by TNF-α. Consequently, the activity of UCB-derived severe combined immune deficiency (SCID) reconstituting cells and long-term culture-initiating cells is unaffected by this cytokine. On the contrary, transient exposure of cells from both sources to TNF-α stimulates the activity of myeloid progenitors, which persists in vivo in UCB cell transplants. Progenitor stimulation is selectively mediated by TNF-R1 and involves activation of caspase-8, without redundant activity of TNF-R2. Despite significant differences between fresh UCB cells and cryopreserved mPB cells in susceptibility to apoptosis and time to activation, TNF-α is primarily involved in tropic signaling in hematopoietic progenitors from both sources. Cytokine-mediated tropism cautions against TNF-α neutralization under conditions of stress hematopoiesis and may be particularly beneficial in overcoming the limitations of UCB cell transplants. © AlphaMed Press.

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