bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving Survival in Multiple Myeloma: Impact of Novel Therapies.
Authors: Kumar Shaji , Rajkumar S. Vincent , Dispenzieri Angela , Lacy Martha Q. , Hayman Suzanne R. , Buadi Francis K. , Zeldenrust Steven R. , Dingli David , Russell Stephen , Lust John A. , Greipp Philip R. , Kyle Robert A. , Gertz Morie A. 
Published: April 2020

Abstract
Background: Recent advances in the therapy of multiple myeloma (MM) have greatly increased the treatment options for this uniformly fatal plasma cell malignancy. It is not clear if introduction of novel therapies and the increased use of high dose therapy (HDT) in the past decade have translated into better outcome for patients (pts) with MM.
Methods: We examined the outcome of two cohorts of pts seen at our institution. The first cohort consisted of 387 pts who relapsed after HDT and was examined for potential improvement in survival following relapse after HDT. These pts were divided into two groups; those who relapsed before or after December 31, 2000. The second cohort consisted of 2981 patients with newly diagnosed MM seen between January 1971 and December 2006 and was used to examine the trends in overall survival (OS).
Results: Among those relapsing after HDT, there were 245 males (63%); median (range) age at HDT was 57 years (32.8–75.4) and the median time to HDT was 8.1 months (1–90 months) from diagnosis. The median time to relapse was 13.2 months (1.1 months-10.3 years) from HDT. In this cohort, a clear improvement in OS from time of relapse was seen over the past decade, with those relapsing after 2000 having a median OS of 23.9 months (95% CI; 19.8, 27.6) compared to 11.8 months (95% CI; 8.7, 14.9) for the rest (P &lt; 0.001) (Figure 1). In a multivariate analysis, the effect of the date of relapse on survival was independent of other prognostic factors such as relapse &lt;12 months after HDT, abnormal cytogenetics, and B2M &gt; 5.5 mg/dL. Pts who were treated with one or more of the newer drugs (thalidomide, lenalidomide, bortezomib) had longer survival from relapse (30.9 months (95% CI; 23.6, 38.2) compared to 14.8 months (95% CI; 11.3, 18.4); P &lt; 0.001) for others. Among the newly diagnosed MM cohort, the median age at diagnosis was 66 years (20.2 – 97 years), and 1,770 (59.4%) were males. The median follow up for the entire group was 27.4 months (0–29.4 years); and at the time of analysis 558 patients (18.7%) were alive with a median follow up of 32.7 months (0–29.4 years). Pts diagnosed in the last decade had an improved OS (44.8 months) compared to those diagnosed before this period (29.9 months; P &lt; 0.001) (Figure 2). The improvement in survival seen in the last decade among newly diagnosed patients was predominantly among those younger than 65 years (60.3 mos vs. 33.3 mos improvement in median survival); compared to those over 65 at diagnosis (26.5 mos vs. 32 mos).
Conclusion: In this study, for the first time, we demonstrate definite proof for improved outcome in patients with myeloma, both in the relapsed setting as well as at diagnosis, a change that is likely to continue with increased use of these drugs.
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The International Prognostic Scoring System for Waldestrom’s Macroglobulinemia (ISSWM) Is Applicable in Patients Treated with Rituximab-Based Regimens.
Authors: Dimopoulos Meletios Athanasios , Kastritis Efstathios , Gika Dimitra , Delimpassi Sossana , Zervas Konstantinos , Simeonidis Argiris , Eleftherakis-Papaiakovou Evangelos , Anagnostopoulos Nicolaos , Michali Evridiki , Kyrtsonis Marie Christine , Terpos Evangelos , Pangalis Gerassimos 
Published: April 2020

Abstract
Introduction: An ISSWM was recently proposed (Morel et al, ASH 2006), which was based on a large number of patients treated primarily with alkylating agents and /or nucleoside analogues. The ISSWM based on 5 adverse covariates wich defined 3 risk groups: low, intermediate and high risk with 5-years survival rates of 87%, 68% and 36% respectively. In our current analysis, we assessed the impact of this system in patients with WM who received primary treatment with rituximab-based regimens.
Patients and methods: Ninety-three previously untreated, symptomatic patients who received treatment either with single agent rituximab (21 patients) or with the combination of dexamethasone, rituximab, and cyclophosphamide (72 patients) were classified according to the ISSWM, which is based on 5 adverse covariates: age&gt; 65 years, hemoglobin ≤11.5 g/dl, platelet count ≤ 100 x 109/L, β2- microglobulin &lt;3mg/L, serum monoclonal protein concentration &gt;70g/L. Low risk is defined by the presence of ≤ 1 adverse characteristics except age, high risk by the presence of &gt;2 adverse characteristics and intermediate risk by the presence of 2 adverse characteristics or age &gt;65 years.
Results: The disease features of the 93 patients were typical of symptomatic WM: age &gt; 65 years in 63%, males 65%, B-symptoms in 22%, splenomegaly in 29%, lymphadenopathy in 34%. 15% of patients were rated as low risk, 65% as intermediate risk and 20% as high risk. Criteria for initiation of therapy included cytopenia, hyperviscosity, constitutional symptoms, organomegaly or IgM-related disorders. Overall, 62% of patients were alive at 6 years. Median survival was not reached for low and intermediate risk and was 38 months for high risk patients (p=0.006). There was a clear separation of the survival curves in the three groups. At the time of last follow-up the percentage of patients alive was 100%, 82% and 58% for patients classified as low, intermediate and high-risk group respectively.
Conclusions: The recently proposed ISSWM is applicable in patients with WM who receive primary treatment with rituximab-based regimens and may serve as a basis to compare outcomes in different studies.
Suppression of Markers of Thrombin Generation and Inflammation in Patients Receiving Low Molecular Weight Heparin Compared to Unfractionated Heparin for TEE-Guided Cardioversion of Atrial Fibrillation.
Authors: Hoppensteadt Debra , Fareed Jawed , Klein Allan , Jasper Susan , Apperson-Hansen Carolyn , Lieber Elizabeth , Katz William , Malouf Joseph , Stoddard Marcus 
Published: April 2020

Abstract
Introduction: Atrial fibrillation (AF) represents a cardiovascular syndrome which can lead to embolic stroke. Several AF clinical trials have shown a decrease risk of stroke with anticoagulation using warfarin. Currently, there are two approaches for anticoagulation in AF patients. For outpatients, warfarin is used with an INR goal 2.0–3.0. For inpatients requiring cardioversion, unfractionated heparin (UFH, IV) is used as a bridge to therapeutic warfarin. More recently, anticoagulation with a low molecular weight heparin, enoxaparin, has been reported to give a more predictable anticoagulant response than UFH in TEEguided cardioversion. The present study compares the markers of inflammation and thrombin generation in patients included in the ACUTE II study.
Methods: This was a randomized multicenter trial of 155 patients from 17 clinical sites, the anticoagulant activity of LMWH (enoxaparin, 1 mg/kg sc bid, Sanofi-Aventis, n=76) was compared to that of UFH (APTT 1.5 – 2.5 x control, n=79). Blood samples were drawn at enrollment (baseline), day 2 (peri cardioversion) and day 4 in both groups. Day 2 and day 4 samples were taken 3–4 hours after the injection of LMWH in patients in the LMWH group. Blood samples were evaluated for inflammation: C-reactive protein (CRP), CD 40 ligand (CD 40L), monocyte chemotactic protein 1 (MCP-1) and anticoagulant effect: thrombin antithrombin complex (TAT) and prothrombin fragment (F 1.2).
Results: The APTT and anti-Xa levels indicated therapeutic anticoagulation was achieved (previously reported). In addition, both TAT and F1.2 levels were increased at baseline and were significantly decreased with LMWH (p&lt;0.01) in comparison to UFH. The CRP, CD40L, MCP-1 were decreased after treatment in both groups of patients. These results suggest that AF patients treated with LMWH demonstrate a stronger anticoagulant effect as measured by a significant reduction in the markers of thrombin generation. Furthermore, anticoagulation with either UFH of LMWH results in a decrease in inflammation which was not different between groups.
Conclusion: In the ACUTE II trial, anticoagulation with LMWH in AF patients may be a better alternate than UFH during TEE-guided cardioversion due to a a stronger anticoagulant.
Prothrombotic Platelet Signaling by the Scavenger Receptor, CD36.
Authors: Chen Kan , Febbraio Maria , Silverstein Roy 
Published: April 2020

Abstract
The scavenger receptor CD36 binds a broad array of ligands, including oxidized low density lipoprotein (oxLDL), thrombospondin-1, fatty acids and apoptotic cells. CD36 was first isolated and characterized structurally from platelets, but the functional role of CD36 on platelets remains relatively obscure. We previously determined that treating platelets with oxLDL activated platelets and that activation was not seen in CD36-null platelets. Using a pharmacological inhibitor we now show that inhibition of JNK MAP kinase abrogated the activation of platelets by oxLDL. This effect was specific to oxLDL-mediated activation because this inhibitor had minimal effect on platelet activation by other classic agonists as exemplified by adenosine diphosphate (ADP). We demonstrated by immunoblotting that JNK2 and its upstream activator MKK4 were phosphorylated in the presence of oxLDL. We also found that the increase of JNK2 phosphorylation by oxLDL was diminished in CD36-null platelets. We showed that a src family kinase inhibitor (AG1879) blocked both platelet activation and JNK2 phosphorylation upon oxLDL treatment. By co-immunoprecipitation we demonstrated that CD36 recruited “active” fyn and lyn in platlets upon oxLDL treatment. These studies suggest that CD36 ligands can activate platelets through a signaling cascade involving src family tyrosine kinases and MAPK signaling molecules such as MKK4 and JNK2. OxLDL forms in the setting of hyperlipidemia and inflammation and plays an important role in atherosclerosis. A common characteristic of atherosclerosis is a prothrombotic state. Our results suggested that a specific signaling cascade activated by CD36 ligands generated in pathological states may contribute to a prothrombotic phenotype in vivo.
Overexpression of the Plasma Lysophospholipase D Autotaxin Reveals a Novel Pathway for Regulation of Hemostasis in Mice.
Authors: Federico Lorenzo , Pamuklar Zehra , Liu Sue , Mills Gordon , Morris Andrew , Smyth Susan 
Published: April 2020

Abstract
The cell-motility factor autotaxin (autotaxin/lysoPLD or Enpp2) is an enzyme with both lysophospholipase D (lysoPLD) and nucleotide pyrophosphatase/phosphodiesterase activities and has recently been identified as a critical component of the major pathway for generation of the bioactive lipid mediator lysophosphatidic acid (LPA) in the blood. Transgenic FVB mice overexpressing autotaxin/lysoPLD under the control of the alpha1-antitrypsin promoter (Enpp2-Tg mice) exhibited elevated plasma autotaxin/lysoPLD protein, lysoPLD activity and LPA levels, with no detectable alteration in plasma levels of ATP, ADP, and adenosine. Ennp2-Tg mice displayed a pronounced bleeding diathesis characterized by markedly prolonged tail bleeding time (&gt;10 min versus 3.2 ± 2.7 min in wild-type mice; p &lt;0.001) and variable protection from thrombosis. Ennp2-Tg mice did not form occlusive thrombus in the carotid artery within 30 min following application of ferric chloride (versus a time to thrombotic occlusion of 9 ± 2 min in wild-type mice; p&lt;0.001), and histologically, only mural thrombus was present along the ferric chloride-treated carotid arteries of the Ennp2-Tg mice. However, intravascular thrombosis in response to intravenous injection of collagen + epinephrine was normal in Ennp2-Tg mice. Enpp2-Tg mice exhibited normal platelet counts (928 ± 184 versus 808 ± 156 x 103/mm3), and normal platelet membrane protein expression, platelet aggregation, and coagulation parameters in ex vivo studies. Although LPA is a weak activator of platelets isolated from the majority of human donors, we found that treatment of isolated murine platelets with physiologically relevant levels of LPA (1μM) attenuated ADP (1μM)-induced and low-dose thrombin (0.01 – 0.05U/ml)-induced aggregation, but did not alter aggregation elicited by higher doses of thrombin or collagen. Treatment of murine platelets with LPA also elevated intraplatelet cAMP levels. Moreover, systemic administration of LPA to mice recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. These results confirm the importance of autotaxin/lysoPLD as the main determinant of circulating LPA levels and suggest a novel pathway for regulation of murine hemostasis and thrombosis involving the autotaxin/lysoPLD-LPA axis.
Lyn and Fyn Kinases Positively Regulate Thromboxane Generation in Platelets.
Authors: Bhavaraju Kamala , Kim Soochong , Kunapuli Satya P. 
Published: April 2020

Abstract
Src family Kinases (SFKs) are important tyrosine kinases in platelets. The family consists of 9 members (viz., Blk, Fgr, Fyn, Hck, Lck, Lyn, Src, Yes and Yrk) and many of the isoforms are expressed in platelets. SFKs are key kinases in glycoprotein (GPVI) mediated platelet activation and we have shown that these kinases play an important role in thromboxane generation. Until now, the role of specific SFKs downstream of G protein signaling in platelets is not well understood. In the present study we characterized functional roles of specific SFK members Fyn, Lyn, Lck and Src Kinases downstream of ADP receptors. Src, Lyn and Fyn are activated downstream of ADP receptors (P2Y) receptors in a time and concentration dependent manner. The presence of fibrinogen receptor antagonist, GR144053, did not affect the activation of Src and Fyn; however, Lyn is not activated in the presence of GR144053, suggesting that Lyn requires outside-in signaling for it’s activation. On the other hand, Lck kinase is not activated downstream of ADP receptors. ADP activates P2Y1 and P2Y12 receptors which in turn couple to Gq and Gi, respectively. In order to further delineate the Src activation pathways we used P2Y1 and P2Y12 receptor antagonists MRS 2179 and AR-C69931MX respectively. Src activation is not inhibited by either P2Y1 or P2Y12 receptor antagonists, suggesting that both receptors independently contribute to the activation of Src kinase. Platelets from mice deficient in Src, Fyn or Lyn were analyzed for thromboxane generation upon stimulation with ADP. Lyn and Fyn KO mice had reduced levels of thromboxane A2 compared to wild type littermates. However, thromboxane generation from platelets lacking Src was unaffected. Hence, we conclude Lyn and Fyn kinases, but not Src, positively regulate thromboxane generation downstream of ADP receptors. We also conclude that Lyn requires outside-in signaling for its activation.
LPS Stimulates Platelet Secretion and Promotes Platelet Aggregation Via TLR4/MyD88 and the cGMP-Dependent Protein Kinase Pathway.
Authors: Zhang Guoying , Welch Emily , Malik Asrar B. , Du Xiaoping , Li Zhenyu 
Published: April 2020

Abstract
Bacterial lipopolysaccharide (LPS) induces rapid thrombocytopenia, hypotension and sepsis. Although growing evidence suggests that platelet activation plays a critical role in LPS-induced thrombocytopenia and tissue damage, the mechanism of LPS-mediated platelet activation is unclear. Here we show that LPS stimulated platelet secretion of dense and alpha granules as indicated by ATP release and P-selectin expression, and thus enhanced platelet activation induced by low concentrations of platelet agonists. Platelets express components of the LPS receptor-signaling complex, including Toll-like receptor (TLR4), CD14, MD2, and MyD88. The effect of LPS on platelet activation was abolished by an anti-TLR4 blocking antibody or TLR4 knockout. Furthermore, LPS-induced potentiation of platelet aggregation and FeCl3-induced thrombus formation were abolished in MyD88 knockout mice. Importantly, TLR4 mediates LPS-induced cGMP elevation and the stimulatory effect of LPS on platelet aggregation was also abolished by inhibitors of nitric oxide synthase (NOS) and the cGMP-dependent protein kinase (PKG). Thus, LPS promotes platelet secretion and aggregation through a TLR4/MyD88 and cGMP/PKG-dependent pathway.
Donor-Cell Derived Aplastic Anemia (AA) with a Small Population of CD55−CD59− Blood Cells after Allogeneic Stem Cell Transplantation: Evidence for the Immune System Attack Against Normal Hematopoietic Stem Cells in AA.
Authors: Sugimori Chiharu , Mochizuki Kanako , Yamazaki Hirohito , Nakao Shinji 
Published: April 2020

Abstract
Acquired aplastic anemia (AA) is thought to be caused by the immune system attack against hematopoietic stem cells. However, there is no direct evidence that an immune system attack against normal hematopoietic stem cells leads to development of AA. The immune system attack may be directed toward abnormal stem cells given the fact that some patients with myelodysplastic syndrome respond to immunosuppressive therapy. Although the presence of a small population of CD55−CD59− blood cells represents a reliable marker for the immune pathophysiology of AA, little is known regarding when and how such paroxysmal nocturnal hemoglobinuria (PNH)-type cells appear in patients with AA. The development of AA with a small population of PNH-type cells was recently observed in an allogeneic stem cell transplant (SCT) recipient. This patient, a 59-year-old male, who had been treated with allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-compatible sibling for treatment of very severe AA in March 2002, developed severe pancytopenia in December 2005. Late graft failure (LGF) without residual recipient cells was diagnosed based on the results of a chimerism analysis. Sensitive flow cytometry failed to reveal any increase in the proportion of CD55−CD59− PNH-type blood cells. The patient underwent a second PBSCT from the original donor without preconditioning in February 2006. Although his pancytopenia was completely resolved by day 20, his blood counts gradually decreased from day 60 without any apparent complications. Flow cytometry revealed small populations of PNH-type granulocytes in his peripheral blood (Figure 1). Both the PNH-type and normal phenotype granulocytes were of donor origin. PIG-A gene analyses showed the PNH-type granulocytes in the patient to be a clonal stem cell with an insertion of thymine at position 593 (codon 198). Similar results were obtained from the sorted PNH-type granulocytes obtained 6 months later. The patient was treated with horse antithymocyte globulin and cyclosporine. The patient required no further transfusions after 88 days of the therapy and remains well as of August, 2007. The small population of PNH-type cells was not detectable in any of 50 SCT recipients showing stable engraftment or in an AA patient suffering graft rejection after a SCT. These findings suggest that some factors expressed by the patient induced an immune system attack against autologous hematopoietic cells, leading to de novo development of donor-cell derived AA. This is the first evidence that an immune system attack against normal hematopoietic stem cells results in AA associated with a clonal expansion of a PIG-A mutant which may originally be present in the donor bone marrow.
Figure Figure
Disease-Related Symptoms Reported across a Broad Population of Patients with Paroxysmal Nocturnal Hemoglobinuria.
Authors: Meyers Gabrielle , Weitz Ilene , Lamy Thierry , Cahn Jean-Yves , Kroon Henk-André , Severino Beth , Uranga Maria Teresa , Alonso Miguel Sanz , Vela José Antonio García , Hill Anita 
Published: April 2020

Abstract
In paroxysmal nocturnal hemoglobinuria (PNH), lack of the GPI-anchored terminal complement inhibitor CD59 from erythrocytes renders them susceptible to chronic hemolysis, which is central to the signs and symptoms of PNH. Patients are at elevated risk for thrombosis, experience anemia that may require transfusion support, and suffer from fatigue that can be severe. Patients often have a poor quality of life resulting from PNH related symptoms including pain, dyspnea, dysphagia and erectile dysfunction, which negatively impact quality of life. The prevalence and severity of symptoms were explored in the context of a multi-national content validation study, of patients not receiving eculizumab therapy, employing the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30) instruments. Symptom questions were asked of 29 PNH patients (19 men, 10 women, mean age 41.2±13.2 years) from the United Kingdom, United States, France and Spain. More than half (52%) had PNH for over 5 years. Most (76%) reported never having had a blood clot, 31% reported not receiving any medication for their PNH, and 59% reported either that they had never been transfused or had not received transfusion within the last year for PNH. Patients viewed overall quality of life, global health, functioning, fatigue, pain, and shortness of breath as important PNH-related signs/symptoms. Both the FACIT-Fatigue and EORTC instruments were relevant and adequate in assessing the level of fatigue and other quality of life measures in PNH. The burden of disease in this multicultural and diverse cohort of patients was significant: 76% were forced to modify their daily activities to manage their PNH and 17% were unemployed due to PNH. Nearly all (96%) complained of fatigue and more than half reported abdominal pain, headache and shortness of breath (Table). Patients also commonly reported dysphagia (41%) and erectile dysfunction (47% in males). Most patients reported these PNH-related symptoms as moderate to very severe, and a substantial majority reported distress associated with the symptoms. Significant disease burden was identified in a diverse population of PNH patients, most of which had minimal or no transfusion requirements and a low incidence of thrombosis. Therapy that controls hemolysis and thereby improves fatigue, pain, shortness of breath, dysphagia and erectile dysfunction may prove beneficial for PNH patients with these disease characteristics.