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In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps.
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In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps.

Blood. 2016 Dec 05;:

Authors: Noubouossie DF, Whelihan MF, Yu YB, Sparkenbaugh E, Pawlinski R, Monroe DM, Key NS

Abstract
NETosis is a physiological process in which neutrophils release their nuclear material in the form of neutrophil extracellular traps (NETs). NETs have been reported to directly promote thrombosis in animal models. Although the effects of purified NET components including DNA, histone proteins and neutrophil enzymes on coagulation have been characterized, the mechanism by which intact NETs promote thrombosis is largely unknown. In this study, human neutrophils were stimulated to produce NETs in platelet-free plasma (PFP) or in buffer using PMA or calcium ionophore. DNA and histone proteins were also separately purified from normal human neutrophils, and used to reconstitute chromatin using a salt-gradient dialysis method. Neutrophil stimulation resulted in robust NET release. In re-calcified PFP, purified DNA triggered contact-dependent thrombin generation and amplified thrombin generation initiated by low concentrations of tissue factor. Similarly, in a buffer milieu, DNA initiated the contact pathway and amplified thrombin-dependent factor XI activation. Recombinant human histones H3 and H4 triggered thrombin generation in re-calcified human plasma in a platelet-dependent manner. In contrast, neither intact NETs, reconstituted chromatin, individual nucleosome particles nor octameric core histones reproduced any of these procoagulant effects. We conclude that unlike DNA or individual histone proteins, human intact NETs do not directly initiate or amplify coagulation in vitro. This difference is likely explained by the complex histone-histone and histone-DNA interactions within the nucleosome unit and higher order supercoiled chromatin leading to neutralization of the negative charges on polyanionic DNA and modification of the binding properties of individual histone proteins.

PMID: 27919911 [PubMed - as supplied by publisher]




Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
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Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.

Blood. 2016 Dec 05;:

Authors: Jain N, Roberts KG, Jabbour E, Patel K, Eterovic AK, Chen K, Zweidler-McKay P, Lu X, Fawcett G, Wang SA, Konoplev S, Harvey RC, Chen IM, Payne-Turner D, Valentine M, Thomas D, Garcia-Manero G, Ravandi F, Cortes J, Kornblau S, O'Brien S, Pierce S, Jorgensen J, Shaw KR, Willman CL, Mullighan CG, Kantarjian H, Konopleva M

Abstract
Ph-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of ALL in children. There are limited and conflicted data on the incidence and prognosis of Ph-like ALL in adults. Patients with newly-diagnosed B-ALL who received frontline chemotherapy at MD Anderson Cancer Center underwent gene expression profiling of leukemic cells to identify Ph-like ALL. Patients received hyper-CVAD (80%) or augmented-BFM (20%) regimen. Of 148 patients, 33.1% had Ph-like, 31.1% had Ph+, and 35.8% had other B-ALL subtypes (B-other). Within the Ph-like ALL cohort, 61% had CRLF2 overexpression. Patients with Ph-like ALL had significantly worse overall survival (OS), event-free survival, and remission duration compared to B-other with a 5-year survival of 23% (vs. 59% for B-other, p=0.006). Sixty-eight percent of patients with Ph-like ALL were of Hispanic ethnicity (78% among the CRLF2+ group). The following were independently associated with inferior OS on multivariable analysis: age (hazard ratio [HR] 3.299, p<0.001); WBC count (HR 1.910, p=0.017); platelet count (HR 7.437, p=0.005) and Ph-like ALL (HR 1.818, p=0.03). Next-generation sequencing of the CRLF2+ group identified mutations in JAK-STAT and Ras pathway in 85% of patients, and 20% had a mutation of CRLF2 Within the CRLF2+ group, JAK2 mutation was associated with inferior outcomes. Our findings show high frequency of Ph-like ALL in adults; an increased frequency of Ph-like ALL in adults of Hispanic ethnicity; significantly inferior outcomes of adult patients with Ph-like ALL; and significantly worse outcomes in CRLF2+ subset of Ph-like ALL. Novel strategies are needed to improve the outcome of these patients.

PMID: 27919910 [PubMed - as supplied by publisher]




Severe anemia early in life as a risk factor for sickle cell kidney disease.
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Severe anemia early in life as a risk factor for sickle cell kidney disease.

Blood. 2016 Dec 05;:

Authors: Aban I, Baddam S, Hilliard LM, Howard TH, Feig D, Lebensburger JD

PMID: 27919909 [PubMed - as supplied by publisher]




Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality.
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Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality.

Blood. 2016 Dec 05;:

Authors: Rosenblatt J, Avigan D

Abstract
PD-1/PD-L1 pathway is a negative regulator of immune activation that is up-regulated in multiple myeloma and is a critical component of the immunosuppressive tumor microenvironment. Expression is increased in advanced disease and in the presence of bone marrow stromal cells. PD-1/PD-L1 blockade is associated with tumor regression in several malignancies but single agent activity is limited in myeloma patients. Combination therapy involving strategies to expand myeloma specific T cells and T cell activation via PD-1/PD-L1 blockade are currently being explored.

PMID: 27919908 [PubMed - as supplied by publisher]