1,532 results match your criteria Blood advances[Journal]


Specific patterns of H3K79 methylation influence genetic interaction of oncogenes in AML.

Blood Adv 2020 Jul;4(13):3109-3122

Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research and.

Understanding mechanisms of cooperation between oncogenes is critical for the development of novel therapies and rational combinations. Acute myeloid leukemia (AML) cells with KMT2A-fusions and KMT2A partial tandem duplications (KMT2APTD) are known to depend on the histone methyltransferase DOT1L, which methylates histone 3 lysine 79 (H3K79). About 30% of KMT2APTD AMLs carry mutations in IDH1/2 (mIDH1/2). Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001922DOI Listing

The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells.

Blood Adv 2020 Jul;4(13):3072-3084

Department of Malignant Hematology.

The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001800DOI Listing

HIF-1 directly induces TET3 expression to enhance 5-hmC density and induce erythroid gene expression in hypoxia.

Blood Adv 2020 Jul;4(13):3053-3062

Committee on Cancer Biology, Biological Sciences Division and.

In mammalian cells, cytosines found within cytosine guanine dinucleotides can be methylated to 5-methylcytosine (5-mC) by DNA methyltransferases and further oxidized by the Ten-eleven translocation dioxygenase (TET) enzymes to 5-hydroxymethylcytosine (5-hmC). We have previously shown that hematopoietic stem and progenitor cells (HSPCs) with TET2 mutations have aberrant 5-hmC distribution and less erythroid differentiation potential. However, these experiments were performed under standard tissue culture conditions with 21% oxygen (O2), whereas HSPCs in human bone marrow reside in ∼1% O2. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001535DOI Listing

Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders.

Blood Adv 2020 Jul;4(13):3041-3052

Division of Blood and Marrow Transplantation and Cellular Therapies and.

Children with many inherited nonmalignant disorders can be cured or their condition alleviated by hematopoietic stem cell transplantation (HSCT). Umbilical cord blood (UCB) units are a rapidly available stem cell source and offer great flexibility in HLA matching, allowing nearly uniform access to HSCT. Although reduced-intensity conditioning (RIC) regimens promise decreased treatment-related morbidity and mortality, graft failure and infections have limited their use in chemotherapy-naive patients. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001940DOI Listing

ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP.

Blood Adv 2020 Jul;4(13):3093-3101

Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001987DOI Listing

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura.

Blood Adv 2020 Jul;4(13):3085-3092

Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001973DOI Listing

Safety and efficacy of the combination of sonidegib and ruxolitinib in myelofibrosis: a phase 1b/2 dose-finding study.

Blood Adv 2020 Jul;4(13):3063-3071

Guy's and St Thomas' National Health Service Foundation Trust, Guy's Hospital, London, United Kingdom.

The sonidegib and ruxolitinib combination was assessed in an open-label study in JAK inhibitor-naive patients with myelofibrosis (MF). The primary objective of phase 1b was to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and phase 2 was to assess spleen volume reduction at weeks 24 and 48. Fifty patients were enrolled. Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001212DOI Listing

Platelet-derived extracellular vesicles infiltrate and modify the bone marrow during inflammation.

Blood Adv 2020 Jul;4(13):3011-3023

Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA.

During inflammation, steady-state hematopoiesis switches to emergency hematopoiesis to repopulate myeloid cells, with a bias toward the megakaryocytic lineage. Soluble inflammatory cues are thought to be largely responsible for these alterations. However, how these plasma factors rapidly alter the bone marrow (BM) is not understood. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001758DOI Listing

Inflammation-driven activation of JAK/STAT signaling reversibly accelerates acute myeloid leukemia in vitro.

Blood Adv 2020 Jul;4(13):3000-3010

Department of Hematology, University Hospital Essen, Essen, Germany.

Acute myeloid leukemia (AML) is characterized by a high relapse rate and dismal long-term overall survival which is related to persistence of leukemia-initiating cells in their niche. Different animal models of myeloid malignancies reveal how neoplastic cells alter the structural and functional characteristics of the hematopoietic stem cell niche to reinforce malignancy. Understanding and disruption of the microenvironmental interactions with AML cells are a vital need. Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001292DOI Listing

DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality.

Blood Adv 2020 Jul;4(13):3024-3033

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Cytokine release syndrome (CRS) immune effector cell-associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell-mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001972DOI Listing

Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission.

Blood Adv 2020 Jul;4(13):3034-3040

Department of Molecular Biology, Centre Hospitalier de Versailles, Le Chesnay, France.

Treatment-free remission (TFR) is an opportunity for patients with chronic myeloid leukemia (CML). Reported cumulative incidence curves of molecular recurrence (MRec) arbor a 2-phase shape with mainly early events, but also some late events (late MRec [LMRec]). Having discontinued our first patient in 2004, we have access to a prolonged follow-up, enabling us to characterize these late events. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001772DOI Listing

Characterization of large in-frame von Willebrand factor deletions highlights differing pathogenic mechanisms.

Blood Adv 2020 Jul;4(13):2979-2990

Department of Biomedical Sciences, University of Hull, Hull, United Kingdom.

Copy number variation (CNV) is known to cause all von Willebrand disease (VWD) types, although the associated pathogenic mechanisms involved have not been extensively studied. Notably, in-frame CNV provides a unique opportunity to investigate how specific von Willebrand factor (VWF) domains influence the processing and packaging of the protein. Using multiplex ligation-dependent probe amplification, this study determined the extent to which CNV contributed to VWD in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease cohort, highlighting in-frame deletions of exons 3, 4-5, 32-34, and 33-34. Read More

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http://dx.doi.org/10.1182/bloodadvances.2018027813DOI Listing

Influenza-induced thrombocytopenia is dependent on the subtype and sialoglycan receptor and increases with virus pathogenicity.

Blood Adv 2020 07;4(13):2967-2978

Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001640DOI Listing

Dominant role of αIIbβ3 in platelet interactions with cross-linked fibrin fragment D-dimer.

Blood Adv 2020 Jul;4(13):2939-2949

Laboratory of Blood and Vascular Biology and.

Although much is known about the interaction of fibrinogen with αIIbβ3, much less is known about the interaction of platelets with cross-linked fibrin. Fibrinogen residue Lys406 plays a vital role in the interaction of fibrinogen with αIIbβ3, but because it participates in fibrin cross-linking, it is not available for interacting with αIIbβ3. We studied the adhesion of platelets and HEK cells expressing normal and constitutively active αIIbβ3 to both immobilized fibrinogen and D-dimer, a proteolytic fragment of cross-linked fibrin, as well as platelet-mediated clot retraction. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001545DOI Listing

Flow studies on human GPVI-deficient blood under coagulating and noncoagulating conditions.

Blood Adv 2020 Jul;4(13):2953-2961

Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

The role of glycoprotein VI (GPVI) in platelets was investigated in 3 families bearing an insertion within the GP6 gene that introduces a premature stop codon prior to the transmembrane domain, leading to expression of a truncated protein in the cytoplasm devoid of the transmembrane region. Western blotting and flow cytometry of GP6hom (homozygous) platelets confirmed loss of the full protein. The level of the Fc receptor γ-chain, which associates with GPVI in the membrane, was partially reduced, but expression of other receptors and signaling proteins was not altered. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001761DOI Listing

Platelet autoantibodies in the bone marrow of patients with immune thrombocytopenia.

Blood Adv 2020 Jul;4(13):2962-2966

Department of Medicine, Michael G. DeGroot School of Medicine and.

Autoantibodies cause platelet destruction in patients with immune thrombocytopenia (ITP); yet only 50% to 60% of patients have detectable platelet autoantibodies in peripheral blood. We hypothesized that in some ITP patients, platelet autoantibodies are sequestered in the bone marrow where pathological immune reactions target megakaryocytes or newly formed platelets. In this study, we modified the platelet glycoprotein-specific assay to test bone marrow aspiration samples for free platelet autoantibodies or antibodies bound to bone marrow cells in aspirate fluid from patients with ITP (n = 18), patients with nonimmune thrombocytopenia (n = 3), and healthy donors (n = 6). Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001846DOI Listing

First report of emicizumab use in a female patient with severe hemophilia A.

Blood Adv 2020 Jul;4(13):2950-2952

Haemostasis and Thrombosis Unit, Division of Haematology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

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http://dx.doi.org/10.1182/bloodadvances.2020002364DOI Listing

Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis.

Blood Adv 2020 Jul;4(13):2927-2938

Department of Lymphoma and Myeloma and.

Mantle cell lymphoma (MCL) is an incurable rare subtype of non-Hodgkin lymphoma and is subject to relapse and therapeutic resistance. Molecular aberrations in MCL affect pathogenesis, prognosis, and therapeutic response. In this systematic review, we searched 3 databases and selected 32 articles that described mutations in MCL patients. Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001350DOI Listing

Patterns of salivary microbiota injury and oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation.

Blood Adv 2020 Jul;4(13):2912-2917

Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.

Oral mucositis (OM) is a common debilitating dose-limiting toxicity of cancer treatment, including hematopoietic stem cell transplantation (HSCT). We hypothesized that the oral microbiome is disturbed during allogeneic HSCT, partially accounting for the variability in OM severity. Using 16S ribosomal RNA gene sequence analysis, metabolomic profiling, and computational methods, we characterized the behavior of the salivary microbiome and metabolome of 184 patients pre- and post-HSCT. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001827DOI Listing

Nationwide survey of systemic chronic active EBV infection in Japan in accordance with the new WHO classification.

Blood Adv 2020 Jul;4(13):2918-2926

Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.

Systemic chronic active Epstein-Barr virus infection (sCAEBV) was defined as a T- or NK-cell neoplasm in the 2017 World Health Organization (WHO) classification. To clarify the clinical features of sCAEBV under this classification and review the effects of chemotherapy, we performed a nationwide survey in Japan from 2016 through 2018 of patients with sCAEBV newly diagnosed from January 2003 through March 2016. One hundred cases were evaluated. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001451DOI Listing

Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma.

Blood Adv 2020 Jul;4(13):2886-2898

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.

Diffuse large B-cell lymphoma (DLBCL) patients are typically treated with immunochemotherapy containing rituximab (rituximab, cyclophosphamide, hydroxydaunorubicin-vincristine (Oncovin), and prednisone [R-CHOP]); however, prognosis is extremely poor if R-CHOP fails. To identify genetic mechanisms contributing to primary or acquired R-CHOP resistance, we performed target-panel sequencing of 135 relapsed/refractory DLBCLs (rrDLBCLs), primarily comprising circulating tumor DNA from patients on clinical trials. Comparison with a metacohort of 1670 diagnostic DLBCLs identified 6 genes significantly enriched for mutations upon relapse. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001696DOI Listing

CRISPR-based screens uncover determinants of immunotherapy response in multiple myeloma.

Blood Adv 2020 Jul;4(13):2899-2911

Institute for Neurodegenerative Diseases and.

Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference- and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell surface expression of the multiple myeloma immunotherapy antigen B-cell maturation antigen (BCMA). Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001346DOI Listing

Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma.

Blood Adv 2020 Jul;4(13):2871-2883

Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX.

The impact of bridging therapy (BT) administered between leukapheresis and chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is unclear. We evaluated the influence of BT (systemic therapy [ST], radiation therapy [RT], or combined-modality therapy [CMT]) on outcomes of 148 LBCL patients who underwent leukapheresis for planned axicabtagene ciloleucel (axi-cel) infusion. The 55% (n = 81) of patients who received BT were more likely to have international prognostic index (IPI) score ≥3 (P ≤ . Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001837DOI Listing

Navigating the narrow bridge to CAR T-cell therapy.

Blood Adv 2020 Jul;4(13):2884-2885

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1182/bloodadvances.2020002346DOI Listing

Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria.

Blood Adv 2020 Jul;4(13):2851-2864

Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.

Microvascular thrombosis and blood-brain barrier (BBB) breakdown are key components of cerebral malaria (CM) pathogenesis in African children and are implicated in fatal brain swelling. How Plasmodium falciparum infection causes this endothelial disruption and why this occurs, particularly in the brain, is not fully understood. In this study, we have demonstrated that circulating extracellular histones, equally of host and parasite origin, are significantly elevated in CM patients. Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001258DOI Listing

COVID-19 coagulopathy vs disseminated intravascular coagulation.

Authors:
Marcel Levi

Blood Adv 2020 06;4(12):2850

Department of Medicine, University College London Hospitals (UCLH) NHS Foundation Trust, London, United Kingdom; and Cardiometabolic Programme, Biomedical Research Centre, National Institute for Health Research, UCLH/University College London, London, United Kingdom.

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http://dx.doi.org/10.1182/bloodadvances.2020002197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322961PMC

Hurdles in treating Hurler disease: potential routes to achieve a "real" cure.

Blood Adv 2020 Jun;4(12):2837-2849

Sylvia Toth Center for Multidisciplinary Follow-up after Hematopoietic Cell Transplantation.

Mucopolysaccharidoses (MPSs) are multiorgan devastating diseases for which hematopoietic cell transplantation (HCT) and, to a lesser extent, enzyme replacement therapy have substantially altered the course of the disease. Furthermore, they have resulted in increased overall survival, especially for Hurler disease (MPS-1). However, despite the identification of clinical predictors and harmonized transplantation protocols, disease progression still poses a significant burden to patients, although at a slower pace. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322951PMC

Pharmacologic thromboprophylaxis in adult patients undergoing neurosurgical interventions for preventing venous thromboembolism.

Blood Adv 2020 Jun;4(12):2798-2809

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

The impact of pharmacologic prophylaxis for venous thromboembolism in patients undergoing neurosurgical intervention remains uncertain. We reviewed the efficacy and safety of pharmacologic compared with nonpharmacologic thromboprophylaxis in neurosurgical patients. Three databases were searched through April 2018, including those for randomized controlled trials (RCTs) and for nonrandomized controlled studies (NRSs). Read More

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http://dx.doi.org/10.1182/bloodadvances.2020002195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322965PMC

TLR-mediated activation of Waldenström macroglobulinemia B cells reveals an uncoupling from plasma cell differentiation.

Blood Adv 2020 Jun;4(12):2821-2836

Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; and.

Waldenström macroglobulinemia (WM) is a rare malignancy in which clonal B cells infiltrate the bone marrow and give rise to a smaller compartment of neoplastic plasma cells that secrete monoclonal immunoglobulin M paraprotein. Recent studies into underlying mutations in WM have enabled a much greater insight into the pathogenesis of this lymphoma. However, there is considerably less characterization of the way in which WM B cells differentiate and how they respond to immune stimuli. Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322944PMC

Geriatric assessment in older alloHCT recipients: association of functional and cognitive impairment with outcomes.

Blood Adv 2020 Jun;4(12):2810-2820

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA.

Use of allogeneic hematopoietic cell transplantation (alloHCT) is increasing in older patients with hematologic malignancies. Studies suggest that geriatric assessment (GA), incorporating functional measures such as instrumental activities of daily living (IADL), delineates subtle age-related impairments that enhance risk-stratification. The objective of this multi-institutional retrospective study was to evaluate the prognostic utility of GA metrics collected pre-alloHCT. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322958PMC

Cotargeting BCL-2 and MCL-1 in high-risk B-ALL.

Blood Adv 2020 Jun;4(12):2762-2767

Centre for Cancer Research, University of Melbourne, Parkville, Melbourne, Australia.

Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322969PMC

Ex vivo drug screening defines novel drug sensitivity patterns for informing personalized therapy in myeloid neoplasms.

Blood Adv 2020 Jun;4(12):2768-2778

Division of Hematology, Department of Medicine, Stanford University Medical Center, Stanford, CA; and.

Precision medicine approaches such as ex vivo drug sensitivity screening (DSS) are appealing to inform rational drug selection in myelodysplastic syndromes (MDSs) and acute myeloid leukemia, given their marked biologic heterogeneity. We evaluated a novel, fully automated ex vivo DSS platform that uses high-throughput flow cytometry in 54 patients with newly diagnosed or treatment-refractory myeloid neoplasms to evaluate sensitivity (blast cytotoxicity and differentiation) to 74 US Food and Drug Administration-approved or investigational drugs and 36 drug combinations. After piloting the platform in 33 patients, we conducted a prospective feasibility study enrolling 21 patients refractory to hypomethylating agents (HMAs) to determine whether this assay could be performed within a clinically actionable time frame and could accurately predict clinical responses in vivo. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322964PMC

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

Blood Adv 2020 Jun;4(12):2789-2797

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322948PMC

Systematic review and meta-analysis of outcomes in patients with suspected deep vein thrombosis.

Blood Adv 2020 Jun;4(12):2779-2788

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

After deep vein thrombosis (DVT) is diagnosed, prompt evaluation and therapeutic intervention are of paramount importance for improvement in patient-important outcomes. We systematically reviewed patient-important outcomes in patients with suspected DVT, including mortality, incidence of pulmonary embolism (PE) and DVT, major bleeding, intracranial hemorrhage, and postthrombotic sequelae. We searched the Cochrane Central Register of Controlled Trials, Ovid Medline, Embase for eligible studies, references lists of relevant reviews, registered trials, and relevant conference proceedings. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322950PMC

First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis.

Blood Adv 2020 Jun;4(12):2723-2735

Analytical Epidemiology and Health Impact Unit, Department of Research, National Tumour Institute of Milan, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Milan, Italy.

Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of the optimal first-line TKI for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322957PMC

American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.

Blood Adv 2020 Jun;4(12):2656-2701

Department of Emergency Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Background: The management of acute and chronic pain for individuals living with sickle cell disease (SCD) is a clinical challenge. This reflects the paucity of clinical SCD pain research and limited understanding of the complex biological differences between acute and chronic pain. These issues collectively create barriers to effective, targeted interventions. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322963PMC

Line-selective macrophage activation with an anti-CD40 antibody drives a hemophagocytic syndrome in mice.

Blood Adv 2020 Jun;4(12):2751-2761

Division of Internal Medicine and.

Hemophagocytic syndromes comprise a cluster of hyperinflammatory disorders, including hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Overwhelming macrophage activation has long been considered a final common pathway in the pathophysiology of hemophagocytic syndromes leading to the characteristic cytokine storm, laboratory abnormalities, and organ injuries that define the clinical spectrum of the disease. So far, it is unknown whether primary macrophage activation alone can induce the disease phenotype. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322947PMC

Apohemoglobin-haptoglobin complexes attenuate the hypertensive response to low-molecular-weight polymerized hemoglobin.

Blood Adv 2020 Jun;4(12):2739-2750

William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH; and.

Polymerized hemoglobin (PolyHb) is a promising hemoglobin (Hb)-based oxygen carrier currently undergoing development as a red blood cell substitute. Unfortunately, commercially developed products are composed of low-molecular-weight (LMW) PolyHb molecules, which extravasate, scavenge nitric oxide, and result in vasoconstriction and hypertension. The naturally occurring Hb-scavenging species haptoglobin (Hp), combined with the purified heme-scavenging species apohemoglobin (apoHb), is a potential candidate to alleviate the pressor effect of PolyHb. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020002045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322967PMC

Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita.

Blood Adv 2020 Jun;4(12):2717-2722

Department of Medicine and.

Dyskeratosis congenita (DC) is a pediatric bone marrow failure syndrome caused by germline mutations in telomere biology genes. Mutations in DKC1 (the most commonly mutated gene in DC), the 3' region of TERC, and poly(A)-specific ribonuclease (PARN) cause reduced levels of the telomerase RNA component (TERC) by reducing its stability and accelerating TERC degradation. We have previously shown that depleting wild-type DKC1 levels by RNA interference or expression of the disease-associated A353V mutation in the DKC1 gene leads to decay of TERC, modulated by 3'-end oligoadenylation by noncanonical poly(A) polymerase 5 (PAPD5) followed by 3' to 5' degradation by EXOSC10. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322949PMC

A report of clustered COVID-19 in a hematology ward.

Blood Adv 2020 06;4(12):2736-2738

Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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http://dx.doi.org/10.1182/bloodadvances.2020001982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322968PMC

Sequencing of RNA in single cells reveals a distinct transcriptome signature of hematopoiesis in GATA2 deficiency.

Blood Adv 2020 Jun;4(12):2656-2670

Hematology Branch, National Heart, Lung, and Blood Institute.

Constitutional GATA2 deficiency caused by heterozygous germline GATA2 mutations has a broad spectrum of clinical phenotypes, including systemic infections, lymphedema, cytopenias, and myeloid neoplasms. Genotype-phenotype correlation is not well understood mechanistically in GATA2 deficiency. We performed whole transcriptome sequencing of single hematopoietic stem and progenitor cells from 8 patients, who had pathogenic GATA2 mutations and myelodysplasia. Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322959PMC

Gut dysbiosis modulates the immune response to factor VIII in murine hemophilia A.

Blood Adv 2020 Jun;4(12):2644-2655

Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen's University, Kingston, ON, Canada.

The development of neutralizing FVIII antibodies is the most serious complication of hemophilia A treatment. The currently known patient- and treatment-related risk factors for inhibitor development do not accurately predict this adverse event in all patients. The composition of the gut microbiota has been shown to influence immune-mediated diseases at distant anatomical sites (eg, lungs, brain, and joints). Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322952PMC

A case of thrombomodulin mutation causing defective thrombin binding with absence of protein C and TAFI activation.

Blood Adv 2020 Jun;4(12):2631-2639

Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.

Thrombomodulin functions as an anticoagulant through thrombin binding and protein C activation. We herein report the first case of hereditary functional thrombomodulin deficiency presenting with recurrent subcutaneous hemorrhage and old cerebral infarction. The patient had a homozygous substitution of glycine by aspartate at amino acid residue 412 (Gly412Asp) in the thrombin-binding domain of the thrombomodulin gene (designated thrombomodulin-Nagasaki). Read More

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http://dx.doi.org/10.1182/bloodadvances.2019001155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322956PMC

Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia.

Blood Adv 2020 Jun;4(12):2611-2616

Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.

The study of early T-cell development in humans is challenging because of limited availability of thymic samples and the limitations of in vitro T-cell differentiation assays. We used an artificial thymic organoid (ATO) platform generated by aggregating a DLL4-expressing stromal cell line (MS5-hDLL4) with CD34+ cells isolated from bone marrow or mobilized peripheral blood to study T-cell development from CD34+ cells of patients carrying hematopoietic intrinsic or thymic defects that cause T-cell lymphopenia. We found that AK2 deficiency is associated with decreased cell viability and an early block in T-cell development. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322962PMC

Loss of GPVI and GPIbα contributes to trauma-induced platelet dysfunction in severely injured patients.

Blood Adv 2020 Jun;4(12):2623-2630

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

Trauma-induced coagulopathy (TIC) is a complex, multifactorial failure of hemostasis that occurs in 25% of severely injured patients and results in a fourfold higher mortality. However, the role of platelets in this state remains poorly understood. We set out to identify molecular changes that may underpin platelet dysfunction after major injury and to determine how they relate to coagulopathy and outcome. Read More

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http://dx.doi.org/10.1182/bloodadvances.2020001776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322946PMC