bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted therapy with phosphodiesterase 5 inhibitors in patients with pulmonary hypertension due to heart failure and elevated pulmonary vascular resistance: a systematic review
Authors: Sanchez Palacios Galo M. , Schmidt Cindy , Wichman Tammy 
Published: October 2020

Pulmonary Hypertension due to left heart disease is the most common type of Pulmonary Hypertension. Morbidity and mortality significantly increase once Pulmonary Hypertension is present. Treatment is aimed toward optimizing the underlying condition. Targeted therapy has been evaluated in small studies with mixed results. The goal of this systematic review is to identify the possible benefit and safety of Phosphodiesterase 5 inhibitors in Pulmonary Hypertension due to left heart disease with elevated pulmonary vascular resistance, diagnosed by right heart catheterization. Electronic searches using MEDLINE/PREMEDLINE, EMBASE, and The Cochrane Library were searched on 21 October 2018. Randomized clinical trials comparing Phosphodiesterase 5 inhibitors versus placebo in patients with proven Pulmonary Hypertension by right heart catheterization secondary to left heart disease (both heart failure with reduced ejection fraction and with preserved ejection fraction) and reported pulmonary vascular resistance were included. We identified 436 potentially relevant studies. After reviewing the titles and abstracts to exclude irrelevant articles, five randomized clinical trials were considered for the study. Sildenafil was well tolerated among all studies. Sildenafil was found to improve hemodynamics, exercise capacity, and quality of life in patients with elevated pulmonary vascular resistance. Phosphodiesterase 5 inhibitors therapy in patients with proven Pulmonary Hypertension due to left heart disease and elevated pulmonary vascular resistance by right heart catheterization may improve the quality of life, exercise capacity, and pulmonary hemodynamics. Further prospective randomized controlled studies are needed to confirm.
Comparative effectiveness of endothelin receptor antagonists on mortality in patients with pulmonary arterial hypertension in a US Medicare population: a retrospective database analysis
Authors: Benza Raymond L. , Lickert Cassandra A. , Xie Lin , Drake William , Ogbomo Adesuwa , Yuce Huseyin , Cole Michele R. 
Published: October 2020

Limited evidence is available on outcomes associated with currently available medications from the endothelin receptor antagonist drug class (bosentan, ambrisentan, and macitentan) in elderly patients with pulmonary arterial hypertension. We evaluated mortality in predominantly elderly patients with pulmonary arterial hypertension in the US taking endothelin receptor antagonists. A retrospective administrative claims study was conducted using the Centers for Medicare and Medicaid Services national Medicare database. Patients with pulmonary arterial hypertension were identified using diagnostic codes. Cohort inclusion required age ≥18 years; ≥1 claim for macitentan, ambrisentan, or bosentan between 1 January 2014 and 31 December 2015 (index date and index endothelin receptor antagonist defined by first such claim); continuous enrollment for ≥12 months before and after the index date; and ≥80% of days covered for the index endothelin receptor antagonist. Follow‐up was from index date until the earliest of Medicare disenrollment, death, or 31 December 2016. Multivariable Cox proportional hazards regression models were used to estimate mortality hazard ratios with 95% confidence intervals for macitentan vs. ambrisentan or bosentan, adjusting for potential confounders. The study cohort included 1628 patients on index macitentan, 2852 on ambrisentan, and 1972 on bosentan. Overall, 69% of patients were aged ≥65 years and most were females (76%). Macitentan was associated with an 18% lower risk for mortality than ambrisentan (hazard ratio: 0.82, 95% confidence interval: 0.72–0.93; P = 0.0026) and a 39% lower risk than bosentan (hazard ratio: 0.61, 95% confidence interval: 0.53–0.71; P < 0.0001). Variables that independently increased the risk of mortality included higher comorbidity index, increasing age, and inpatient hospitalizations at baseline.
Tubo-ovarian abscess: Exploring optimal treatment options based on current evidence
Authors: Gkrozou Fani , Tsonis Orestis , Daniilidis Aggelos , Navrozoglou I , Paschopoulos Minas 
Published: October 2020

Purpose: Tubo-ovarian abscess (TOA) and pelvic abscess are characterized by an inflammatory pelvic mass. In the majority of cases, this condition involves the ovaries, the fallopian tubes and/or any other adjacent tissue. TOA is considered a severe complication of PID and can cause severe sepsis. The main risk factors for women’s health are the size of the abscess, the initial amount of white blood cells (WBC), patients’ age as well as, any co-existing comorbidities. Methods: This study provides a review of the current literature regarding the management of TOA and the different criteria used in order to establish the optimal therapeutic approach or to predict outcome by individualizing cases. Four major search engines, MEDLINE, Google Scholar, PubMed and EMBASE, up to February 2020 were explored, focusing in epidemiology and risk factors, pathogenesis, diagnosis and treatment. Results: Our review suggests that there are no clear guidelines for best practice, in case of TOA, but it appears that intravenous antibiotics combined with interventional radiology have good results for TOA <5 cm. When TOA is >5 cm, laparoscopic approach is indicated. Further studies are needed in order to evaluate the best treatment for women with TOA. Conclusions: More prospective studies on large-series of patients are in need, in order to determine a clear pathway and to suggest specific criteria, which can guide clinicians to choose optimal approach in a timely manner.
Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice
Authors: Raboso-Gallego Javier , Casado-García Ana , Jiang Xiaoyu , Isidro-Hernández Marta , Gentles Andrew J. , Zhao Shuchun , Natkunam Yaso , Blanco Oscar , Domínguez Verónica , Pintado Belén , Alonso-López Diego , De Las Rivas Javier , Vicente-Dueñas Carolina , Lossos Izidore S. , Sanchez-Garcia Isidro 
Published: October 2020

AbstractDiffuse large B-cell lymphomas (DLBCLs) are clinically and genetically heterogeneous tumors. Deregulation of diverse biological processes specific to B cells, such as B-cell receptor (BCR) signaling and motility regulation, contribute to lymphomagenesis. Human germinal center associated lymphoma (HGAL) is a B-cell–specific adaptor protein controlling BCR signaling and B lymphocyte motility. In normal B cells, it is expressed in germinal center (GC) B lymphocytes and promptly downregulated upon further differentiation. The majority of DLBCL tumors, primarily GC B-cell types, but also activated types, express HGAL. To investigate the consequences of constitutive expression of HGAL in vivo, we generated mice that conditionally express human HGAL at different stages of hematopoietic development using 3 restricted Cre-mediated approaches to initiate expression of HGAL in hematopoietic stem cells, pro-B cells, or GC B cells. Following immune stimulation, we observed larger GCs in mice in which HGAL expression was initiated in GC B cells. All 3 mouse strains developed DLBCL at a frequency of 12% to 30% starting at age 13 months, leading to shorter survival. Immunohistochemical studies showed that all analyzed tumors were of the GC B-cell type. Exon sequencing revealed mutations reported in human DLBCL. Our data demonstrate that constitutive enforced expression of HGAL leads to DLBCL development.
A wave of bipotent T/ILC-restricted progenitors shapes the embryonic thymus microenvironment in a time-dependent manner
Authors: Elsaid Ramy , Meunier Sylvain , Burlen-Defranoux Odile , Soares-da-Silva Francisca , Perchet Thibaut , Iturri Lorea , Freyer Laina , Vieira Paulo , Pereira Pablo , Golub Rachel , Bandeira Antonio , Perdiguero Elisa Gomez , Cumano Ana 
Published: October 2020

AbstractDuring embryonic development, multiple waves of hematopoietic progenitors with distinct lineage potential are differentially regulated in time and space. Two different waves of thymic progenitors colonize the fetal thymus where they contribute to thymic organogenesis and homeostasis. The origin, the lineage differentiation potential of the first wave, and their relative contribution in shaping the thymus architecture, remained, however, unclear. Here, we show that the first wave of thymic progenitors comprises a unique population of bipotent T and innatel lymphoid cells (T/ILC), generating a lymphoid tissue inducer cells (LTi's), in addition to invariant Vγ5+ T cells. Transcriptional analysis revealed that innate lymphoid gene signatures and, more precisely, the LTi-associated transcripts were expressed in the first, but not in the second, wave of thymic progenitors. Depletion of early thymic progenitors in a temporally controlled manner showed that the progeny of the first wave is indispensable for the differentiation of autoimmune regulator–expressing medullary thymic epithelial cells (mTECs). We further show that these progenitors are of strict hematopoietic stem cell origin, despite the overlap between lymphopoiesis initiation and the transient expression of lymphoid-associated transcripts in yolk sac (YS) erythromyeloid-restricted precursors. Our work highlights the relevance of the developmental timing on the emergence of different lymphoid subsets, required for the establishment of a functionally diverse immune system.
The metabolic enzyme pyruvate kinase M2 regulates platelet function and arterial thrombosis
Authors: Nayak Manasa K. , Ghatge Madankumar , Flora Gagan D. , Dhanesha Nirav , Jain Manish , Markan Kathleen R. , Potthoff Matthew J. , Lentz Steven R. , Chauhan Anil K. 
Published: October 2020

Abstract
Very little is known about the role of metabolic regulatory mechanisms in platelet activation and thrombosis. Dimeric pyruvate kinase M2 (PKM2) is a crucial regulator of aerobic glycolysis that facilitates the production of lactate and metabolic reprogramming. Herein, we report that limiting PKM2 dimer formation, using the small molecule inhibitor ML265, negatively regulates lactate production and glucose uptake in human and murine stimulated platelets. Furthermore, limiting PKM2 dimer formation reduced agonist-induced platelet activation, aggregation, clot retraction, and thrombus formation under arterial shear stress in vitro in both human and murine platelets. Mechanistically, limiting PKM2 dimerization downregulated phosphatidylinositol 3-kinase (PI3K)-mediated protein kinase B or serine/threonine-specific protein kinase (Akt)/glycogen synthase kinase 3 (GSK3) signaling in human and murine platelets. To provide further evidence for the role of PKM2 in platelet function, we generated a megakaryocyte or platelet-specific PKM2−/− mutant strain (PKM2fl/flPF4Cre+). Platelet-specific PKM2-deficient mice exhibited impaired agonist-induced platelet activation, aggregation, clot retraction, and PI3K-mediated Akt/GSK3 signaling and were less susceptible to arterial thrombosis in FeCl3 injury–induced carotid- and laser injury–induced mesenteric artery thrombosis models, without altering hemostasis. Wild-type mice treated with ML265 were less susceptible to arterial thrombosis with unaltered tail bleeding times. These findings reveal a major role for PKM2 in coordinating multiple aspects of platelet function, from metabolism to cellular signaling to thrombosis, and implicate PKM2 as a potential target for antithrombotic therapeutic intervention.
Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study
Authors: Stein Eytan M. , DiNardo Courtney D. , Fathi Amir T. , Mims Alice S. , Pratz Keith W. , Savona Michael R. , Stein Anthony S. , Stone Richard M. , Winer Eric S. , Seet Christopher S. , Döhner Hartmut , Pollyea Daniel A. , McCloskey James K. , Odenike Olatoyosi , Löwenberg Bob , Ossenkoppele Gert J. , Patel Prapti A. , Roshal Mikhail , Frattini Mark G. , Lersch Frederik , Franovic Aleksandra , Nabhan Salah , Fan Bin , Choe Sung , Wang Hongfang , Wu Bin , Hua Lei , Almon Caroline , Cooper Michael , Kantarjian Hagop M. , Tallman Martin S. 
Published: October 2020

Abstract
Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor’s known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
TNFR2 is required for RIP1-dependent cell death in human leukemia
Authors: Aguadé-Gorgorió Júlia , McComb Scott , Eckert Cornelia , Guinot Anna , Marovca Blerim , Mezzatesta Caterina , Jenni Silvia , Abduli Liridon , Schrappe Martin , Dobay Maria Pamela , Stanulla Martin , von Stackelberg Arend , Cario Gunnar , Bourquin Jean-Pierre , Bornhauser Beat C. 
Published: October 2020

AbstractDespite major advances in the treatment of patients with acute lymphoblastic leukemia in the last decades, refractory and/or relapsed disease remains a clinical challenge, and relapsed leukemia patients have an exceedingly dismal prognosis. Dysregulation of apoptotic cell death pathways is a leading cause of drug resistance; thus, alternative cell death mechanisms, such as necroptosis, represent an appealing target for the treatment of high-risk malignancies. We and other investigators have shown that activation of receptor interacting protein kinase 1 (RIP1)–dependent apoptosis and necroptosis by second mitochondria derived activator of caspase mimetics (SMs) is an attractive antileukemic strategy not currently exploited by standard chemotherapy. However, the underlying molecular mechanisms that determine sensitivity to SMs have remained elusive. We show that tumor necrosis factor receptor 2 (TNFR2) messenger RNA expression correlates with sensitivity to SMs in primary human leukemia. Functional genetic experiments using clustered regularly interspaced short palindromic repeats/Cas9 demonstrate that TNFR2 and TNFR1, but not the ligand TNF-α, are essential for the response to SMs, revealing a ligand-independent interplay between TNFR1 and TNFR2 in the induction of RIP1-dependent cell death. Further potential TNFR ligands, such as lymphotoxins, were not required for SM sensitivity. Instead, TNFR2 promotes the formation of a RIP1/TNFR1-containing death signaling complex that induces RIP1 phosphorylation and RIP1-dependent apoptosis and necroptosis. Our data reveal an alternative paradigm for TNFR2 function in cell death signaling and provide a rationale to develop strategies for the identification of leukemias with vulnerability to RIP1-dependent cell death for tailored therapeutic interventions.
DNA methylation microarrays identify epigenetically regulated lipid related genes in obese patients with hypercholesterolemia
Authors: Płatek Teresa , Polus Anna , Góralska Joanna , Raźny Urszula , Gruca Anna , Kieć-Wilk Beata , Zabielski Piotr , Kapusta Maria , Słowińska-Solnica Krystyna , Solnica Bogdan , Malczewska-Malec Małgorzata , Dembińska-Kieć Aldona 
Published: October 2020

Abstract
Background
Epigenetics can contribute to lipid disorders in obesity. The DNA methylation pattern can be the cause or consequence of high blood lipids. The aim of the study was to investigate the DNA methylation profile in peripheral leukocytes associated with elevated LDL-cholesterol level in overweight and obese individuals.

Methods
To identify the differentially methylated genes, genome-wide DNA methylation microarray analysis was performed in leukocytes of obese individuals with high LDL-cholesterol (LDL-CH, ≥ 3.4 mmol/L) versus control obese individuals with LDL-CH, < 3.4 mmol/L. Biochemical tests such as serum glucose, total cholesterol, HDL cholesterol, triglycerides, insulin, leptin, adiponectin, FGF19, FGF21, GIP and total plasma fatty acids content have been determined. Oral glucose and lipid tolerance tests were also performed. Human DNA Methylation Microarray (from Agilent Technologies) containing 27,627 probes for CpG islands was used for screening of DNA methylation status in 10 selected samples. Unpaired t-test and Mann–Whitney U-test were used for biochemical and anthropometric parameters statistics. For microarrays analysis, fold of change was calculated comparing hypercholesterolemic vs control group. The q-value threshold was calculated using moderated Student’s t-test followed by Benjamini–Hochberg multiple test correction FDR.

Results
In this preliminary study we identified 190 lipid related CpG loci differentially methylated in hypercholesterolemic versus control individuals. Analysis of DNA methylation profiles revealed several loci engaged in plasma lipoprotein formation and metabolism, cholesterol efflux and reverse transport, triglycerides degradation and fatty acids transport and β-oxidation. Hypermethylation of CpG loci located in promoters of genes regulating cholesterol metabolism: PCSK9, LRP1, ABCG1, ANGPTL4, SREBF1 and NR1H2 in hypercholesterolemic patients has been found. Novel epigenetically regulated CpG sites include ABCG4, ANGPTL4, AP2A2, AP2M1, AP2S1, CLTC, FGF19, FGF1R, HDLBP, LIPA, LMF1, LRP5, LSR, NR1H2 and ZDHHC8 genes.

Conclusions
Our results indicate that obese individuals with hypercholesterolemia present specific DNA methylation profile in genes related to lipids transport and metabolism. Detailed knowledge of epigenetic regulation of genes, important for lipid disorders in obesity, underlies the possibility to influence target genes by changing diet and lifestyle, as DNA methylation is reversible and depends on environmental factors. These findings give rise for further studies on factors that targets methylation of revealed genes.
TRPM7 silencing attenuates Mg2+ influx in cardiac myoblasts, H9c2 cells
Authors: Tashiro Michiko , Konishi Masato , Kobayashi Ryo , Inoue Hana , Yokoyama Utako 
Published: October 2020

AbstractTRPM7, a member of the melastatin subfamily of transient receptor potential channels, is suggested to be a potential candidate for a physiological Mg2+ channel. However, there is no direct evidence of Mg2+ permeation through endogenous TRPM7. To determine the physiological roles of TRPM7 in intracellular Mg2+ homeostasis, we measured the cytoplasmic free Mg2+ concentration ([Mg2+]i) in TRPM7-silenced H9c2 cells. [Mg2+]i was measured in a cluster of 8–10 cells using the fluorescent indicator, furaptra. TRPM7 silencing did not change [Mg2+]i in Ca2+-free Tyrode’s solution containing 1 mM Mg2+. Increasing the extracellular Mg2+ to 92.5 mM raised [Mg2+]i in control cells (1.56 ± 0.19 mM) at 30 min, while this effect was significantly attenuated in TRPM7-silenced cells (1.12 ± 0.07 mM). The Mg2+ efflux driven by Na+ gradient was unaffected by TRPM7 silencing. These results suggest that TRPM7 regulates the rate of Mg2+ influx in H9c2 cells, although cytoplasmic Mg2+ homeostasis at basal conditions is unaffected by TRPM7 silencing.
Masakari: visualization supported statistical analysis of genome segmentations
Authors: Zeckzer Dirk , Hausdorf Alrik , Hinzmann Nicole , Müller Lydia , Wiegreffe Daniel 
Published: October 2020

Abstract
Background
In epigenetics, the change of the combination of histone modifications at the same genomic location during cell differentiation is of great interest for understanding the function of these modifications and their combinations. Besides analyzing them locally for individual genomic locations or globally using correlations between different cells types, intermediate level analyses of these changes are of interest. More specifically, the different distributions of these combinations for different cell types, respectively, are compared to gain new insights.

Results and discussion
We propose a new tool called ‘Masakari’ that allows segmenting genomes based on lists of ranges having a certain property, e.g., peaks describing histone modifications. It provides a graphical user interface allowing to select all data sets and setting all parameters needed for the segmentation process. Moreover, the graphical user interface provides statistical graphics allowing to assess the quality and suitability of the segmentation and the selected data.

Conclusion
Masakari provides statistics based visualizations and thus fosters insights into the combination of histone modification marks on genome ranges, and the differences of the distribution of these combinations between different cell types.