bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beneficial effects of eculizumab regardless of prior transfusions or bone marrow disease: Results of the International Paroxysmal Nocturnal Hemoglobinuria Registry
Authors: Röth Alexander , Araten David J. , Larratt Loree , Kulasekararaj Austin G. , Maciejewski Jaroslaw P. , Wilson Amanda , Gustovic Philippe , Kanakura Yuzuru 
Published: July 2020

AbstractObjectivesTo evaluate the effects of eculizumab on transfusions and thrombotic events (TEs) in patients with and without prior history of transfusion in the International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry.MethodsRegistry patients enrolled on or before January 1, 2018, initiated on eculizumab no more than 12 months prior to enrollment, having known transfusion status for the 12 months before eculizumab initiation, and ≥12 months of Registry follow‐up after eculizumab initiation, were included.ResultsEculizumab treatment was associated with a 50% reduction in transfusions in patients with a transfusion history (10.6 units/patient‐year before eculizumab vs 5.4 after; P < .0001), with greater reduction observed in those with no history of bone marrow disease vs those with bone marrow disease. Mean lactate dehydrogenase levels decreased from a mean of 6.7 to 1.4 times the upper limit of normal (ULN) in patients with transfusion history and from 5.1 to 1.2 times ULN in those with no transfusion history. TE and major adverse vascular event rates also decreased by 70% in patients with and without history of transfusion.ConclusionsThe benefit of eculizumab therapy does not appear to be limited to any group defined by transfusion history or bone marrow disease history.
Receptor mechanisms mediating the anti‐neuroinflammatory effects of endocannabinoid system modulation in a rat model of migraine
Authors: Kilinc Erkan , Ankarali Seyit , Torun Ibrahim Ethem , Dagistan Yasar 
Published: July 2020

AbstractCalcitonin gene‐related peptide (CGRP), substance P and dural mast cells are main contributors in neurogenic inflammation underlying migraine pathophysiology. Modulation of endocannabinoid system attenuates migraine pain, but its mechanisms of action remain unclear. We investigated receptor mechanisms mediating anti‐neuroinflammatory effects of endocannabinoid system modulation in in vivo migraine model and ex vivo hemiskull preparations in rats. To induce acute model of migraine, a single dose of nitroglycerin was intraperitoneally administered to male rats. Moreover, isolated ex vivo rat hemiskulls were prepared to study CGRP and substance P release from meningeal trigeminal afferents. We used methanandamide (cannabinoid agonist), rimonabant (cannabinoid receptor‐1 CB1 antagonist), SR144528 (CB2 antagonist) and capsazepine (transient receptor potential vanilloid‐1 TRPV1 antagonist) to explore effects of endocannabinoid system modulation on the neurogenic inflammation, and possible involvement of CB1, CB2 and TRPV1 receptors during endocannabinoid effects. Methanandamide attenuated nitroglycerin‐induced CGRP increments in in vivo plasma, trigeminal ganglia and brainstem and also in ex vivo hemiskull preparations. Methanandamide also alleviated enhanced number and degranulation of dural mast cells induced by nitroglycerin. Rimonabant, but not capsazepine or SR144528, reversed the attenuating effects of methanandamide on CGRP release in both in vivo and ex vivo experiments. Additionally, SR144528, but not rimonabant or capsazepine, reversed the attenuating effects of methanandamide on dural mast cells. However, neither nitroglycerin nor methanandamide changed substance P levels in both in vivo and ex vivo experiments. Methanandamide modulates CGRP release in migraine‐related structures via CB1 receptors and inhibits the degranulation of dural mast cells through CB2 receptors. Selective ligands targeting CB1 and CB2 receptors may provide novel and effective treatment strategies against migraine.
Numerical determination and experimental verification of the optimum autofrettage pressure for a complex aluminium high‐pressure valve to foster crack closure
Authors: Repplinger Christian , Sellen Stephan , Kedziora Slawomir , Zürbes Arno , Cao Thanh Binh , Maas Stefan 
Published: July 2020

AbstractThe determination of the optimum autofrettage pressure enables a clear improvement of the fatigue life for an internally highly pressurized component. The autofrettage process induces residual compressive stress after the release of a single static overload pressure, leading to plastic deformation at the inner wall whereas the outer part is only elastically stressed. This autofrettage pressure is clearly above the subsequent pulsating operating pressure range. Due to the complex geometry of the aluminium valve body, a detailed elastic–plastic finite element analysis is used to determine the critical area and the optimum autofrettage pressure. Based on an experimental stress–strain curve, three important load steps are simulated in a non‐linear way. The FKM guideline is used to assess fatigue life and crack initiation with detailed subsequent experimental verification. Even if small cracks occur, residual compressive stresses prohibit crack growth (nonpropagating crack), which can be analytically verified by fracture mechanical considerations (crack closure effect).
Carbonic anhydrase IX (CA9) expression in multiple renal epithelial tumour subtypes
Authors: Baniak Nicholas , Flood Trevor A , Buchanan Mark , Dal Cin Paola , Hirsch Michelle S 
Published: July 2020

AimsRenal epithelial neoplasms (RENs) can be difficult to subclassify, owing to overlapping morphological features. Carbonic anhydrase 9 (CA9) is a common biomarker for clear cell renal cell carcinoma (CCRCC); however, the sensitivity and specificity across REN subtypes are less clear. The aim of this study was to investigate CA9 expression in RENs, especially those in the differential diagnosis with CCRCC and less common entities, to determine its reliability as a diagnostic biomarker.Methods and resultsCA9 immunostaining was performed on 262 RENs, including 119 CCRCCs and 143 non‐CCRCC. Immunostaining was evaluated as negative (0%), rare (1+, 1–10%), focal (2+, 11–50%), or diffuse (3+, >50%). CCRCCs were 3+ CA9‐positive in 93% of cases; 4% were CA9‐negative. Sixty‐seven percent of papillary renal cell carcinomas (RCCs) were 1+/2+ CA9‐positive, whereas 33% were CA9‐negative. Chromophobe RCCs were nearly always CA9‐negative (93%), with 7% showing rare cell reactivity. Clear cell tubulopapillary RCCs (CCTPRCCs) were consistently 3+ CA9‐positive, but with a cup‐like staining pattern. Fifty‐three percent of Xp11.2 RCCs were CA9‐negative; however, 6% were 3+ CA9‐positive and 12% were 2+ CA9‐positive. Two of eight fumarate hydratase‐deficient RCCs were 3+ CA9‐positive. A small subset of the remaining RCCs showed rare to focal CA9 expression. All oncocytomas and eosinophilic solid and cystic RCCs were CA9‐negative.ConclusionsOverall, diffuse CA9 expression was identified in nearly all CCRCCs and in all CCTPRCCs (high sensitivity); however, CA9 was not entirely specific. At least focal CA9 expression can been seen in a subset of many RCCs, and such findings should be taken into consideration with other morphological, immunophenotypic and clinical findings.
Gene fusion characterisation of rare aggressive prostate cancer variants—adenosquamous carcinoma, pleomorphic giant‐cell carcinoma, and sarcomatoid carcinoma: an analysis of 19 cases
Authors: Alhamar Mohamed , Tudor Vladislav I , Smith Steven C , Gao Yuan , Cheng Liang , Favazza Laura A , Alani Ali M , Ittmann Michael M , Riddle Nicole D , Whiteley Lisa J , Gupta Nilesh S , Carskadon Shannon , Gomez‐Gelvez Juan C , Chitale Dhananjay A , Palanisamy Nallasivam , Hes Ondrej , Trpkov Kiril , Williamson Sean R 
Published: July 2020

AimsTo evaluate the molecular underpinnings of the rare aggressive prostate cancer variants adenosquamous carcinoma, pleomorphic giant‐cell carcinoma, and sarcomatoid carcinoma.Methods and resultsWe retrieved 19 tumours with one or more variant(s), and performed ERG immunohistochemistry, a next‐generation sequencing assay targeting recurrent gene fusions, and fluorescencein‐situhybridisation (FISH) forERGandBRAF. Divergent differentiation included: sarcomatoid carcinoma (n = 10), adenosquamous carcinoma (n = 7), and pleomorphic giant‐cell carcinoma (n = 7). Five patients had more than one variant. Four had variants only in metastases.ERGrearrangement was detected in nine (47%, seven via sequencing, showingTMPRSS2–ERGfusions and oneGRHL2–ERGfusion, and two via FISH, showing rearrangement via deletion). ERG was immunohistochemically positive in the adenocarcinoma in eight of nine (89%) patients, but was immunohistochemically positive in the variant in only five of nine patients (56%, typically decreased). One patient had a false‐positive ERG immunohistochemical result in the sarcomatoid component despite a negative FISH result. Two (11%) harbouredBRAFfusions (FAM131A–BRAFandSND1–BRAF).ConclusionsERGfusions are present in these rare prostate cancer variants with a frequency close to that in conventional prostate cancer (9/19, 47%). ERG immunohistochemistry usually detects rearrangement in the adenocarcinoma, but is less sensitive for the variant histology, with weak to negative staining. Adenosquamous and sarcomatoid variants can, particularly, occur together. Molecular assessment may be an additional tool in selected cases to confirm the prostatic origin of unusual tumours. The presence of twoBRAFrearrangements suggests that this gene fusion may be enriched in this setting, as RAF kinase fusions have been previously reported in 1–2% of prostate cancers.
Performance of the Sysmex White Precursor Channel to discover circulating leukemic blast cells
Authors: Sejrup Jesper , Pedersen David M. , Phillipsen Jens P. , Nielsen Jesper Ø. , Koch Sheila P. R. , Smith Julie 
Published: July 2020

AbstractIntroductionCirculating immature precursor cells indicate malignant diseases like acute myeloid or lymphoid leukemia, and blast cells are key finds for disease management. Automatized cell counters are an essential contemporary appliance for blast detection, but false‐positive samples remain challenging in terms of time and resources. To reduce this issue, the White Precursor Channel (WPC) was introduced to Sysmex XN series; however, sensitivity may reduce when accommodating low specificity. Therefore, our aim was to evaluate WPC blast alarm flag performance with regard to detecting blast cells.MethodsAt two major Danish hospitals, random blood samples were collected from the routine setting in a four‐week period and analyzed on WPC XN20 (Sysmex, Japan). Results were compared with manual differential white blood cell count (Manual WBCC) assisted by CellaVisionDM96.ResultsIn 117 samples, we found 0.2 to 34.4% blasts, WPC blast flag specificity = 82% and a low sensitivity = 40%. However, other XN alarm flags forwarded samples to Manual WBCC, so blast cells were detected despite missing a specific blast flag: With all alarm flags, combined sensitivity increased to 88%. Overall, the WPC application stopped 18% of the 117 samples going to Manual WBCC (three false negatives). Q values are arbitrary probability measurements for the blast flag, and in five samples (0.5 to 47.3% blasts) imprecision ranged from 5.3 to 122 CV%.ConclusionsWPC blast alarm flags are imprecise and inaccurate, especially when blast counts are low. However, the XN20 will alarm samples with other flags so that most samples containing blast cells will be manually reviewed after all. Hence, the presented flag types should not bias the decisions of manual reviewers.
A new approach for diagnosing hematological malignancies using monocytosis workflow optimization and abnormal lymphocyte/blast flag of Sysmex XN series of blood count analyzers
Authors: Kocaturk Evin , Kusku Kiraz Zeynep , Uskudar Teke Hava , Demir Sukru Saygin , Alatas Ibrahim Ozkan 
Published: July 2020

AbstractIntroductionMonocytosis Workflow Optimization rule set has been developed by using mono‐dysplasia‐score to determine reactive monocytosis and prevent unnecessary blood smear of these patients and for detection of chronic myelomonocytic leukemia cases during complete blood count. In our study, we aimed to examine the contribution of Monocytosis Workflow Optimization rule set.MethodsAdult patients with monocyte count ≥1.0 103/µL and monocyte percentage ≥10% were included in our study. Blood smears were made from the samples in our laboratory. These smears were examined and patients were divided into two groups as reactive monocytosis or hematological malignancy. The groups were compared in terms of Monocytosis Workflow Optimization rule set and device flags.ResultsTwenty‐one patients had hematological malignancies of 155 patients who were included in our study. Monocytosis Workflow Optimization rule set suggested performing blood smear in 19 of the patients with hematological malignancy, and evaluated two patients as reactive monocytosis with 90.5% sensitivity and 76.9% specificity. There was an “abnormal lymphocyte/ blast” flag in 90.5% of patients with hematological malignancies and in patients whose Monocytosis Workflow Optimization rule set defined as reactive monocytosis and it was found that sensitivity and negative predictive value reached 100%.ConclusionAutomated validation support systems and softwares developed especially for these systems make it possible to classify patients with their non‐specific findings, as a result both contributing to the reduction of laboratory workload and costs and assisting laboratory specialists and clinicians with adding value to laboratory results.
Lactic acid bacteria feeding reversed the malformed eye structures and ameliorated gut microbiota profiles of Drosophila melanogaster Alzheimer’s disease model
Authors: Liu G. , Tan F.H.-P. , Lau S.-Y.A. , Jaafar M.H. , Chung F.Y.-L. , Azzam G. , Liong M.-T. , Li Y. 
Published: July 2020

Abstract

Aims
To utilize transgenic GMR-Aβ42 Drosophila melanogaster as a model to evaluate potential Alzheimer’s disease (AD)-reversal effects via the administration of lactic acid bacteria (LAB) strains, and associations of LAB with changes in gut microbiota profiles.

Methods and Results
Wild-type flies (Oregon-R) were crossed with glass multimer reporter-GAL4 (GMR-GAL4) to produce GMR-OreR (Control), while UAS-Aβ42 (#33769) were crossed with GMR-GAL4 to produce transgenic Drosophila line that expressed Aβ42 (GMR-Aβ42). Feed containing seven different LAB strains (Lactobacillus paracasei 0291, Lactobacillus helveticus 1515, Lactobacillus reuteri 30242, L. reuteri 8513d, Lactobacillus fermentum 8312, Lactobacillus casei Y, Lactobacillus sakei Probio65) were given to GMR-Aβ42 respectively, while feed without LAB strains were given to control and transgenic GMR-Aβ42.nf Drosophila lines. The morphology of the eyes was viewed with scanning electron microscopy (SEM). The changes in gut microbiota profiles associated with LAB were analysed using 16s high throughput sequencing. Malformation of eye structures in transgenic GMR-Aβ42 Drosophila were reversed upon the administration of LAB strains, with more prevalent effects from L. sakei Probio65 and L. paracasei 0291. The GMR-Aβ42.nf group showed dominance of Wolbachia in the gut, a genus that was almost absent in the normal control group (P &lt; 0·05). The administration of L. sakei Probio65 and L. paracasei 0291 reduced the abundance of Wolbachia accompanied by increased abundance of Stenotrophomonas and Acetobacter (P &lt; 0·05), resembling the microbial profile of the control group.

Conclusions
Lactobacillus sakei Probio65 and Lactobacillus paracasei 0291 have more prominent effects in reversing malformed eye of transgenic GMR-Aβ42 Drosophila, and reducing the abundance of Wolbachia accompanied by an increased abundance of Stenotrophomonas and Acetobacter.

Significance and Impact of the Study
Potentials of LAB to prevent and/or alleviate the onset and pathogenesis of neurodegenerative diseases such as AD, supporting brain health strategies along the gut–brain axis.
From short‐term blood pressure variability to atherosclerosis: Relative roles of vascular stiffness and endothelial dysfunction
Authors: Tatasciore Alfonso , Di Nicola Marta , Tommasi Roberto , Santarelli Francesco , Palombo Carlo , Parati Gianfranco , De Caterina Raffaele 
Published: July 2020

AbstractBoth arterial blood pressure (BP) average levels and short‐term BP variability (BPV) relate to hypertension‐mediated organ damage, in particular increased carotid artery intima‐media thickness (IMT) and carotid‐femoral pulse wave velocity (PWV). Endothelial dysfunction possibly mediates such damage. The authors aimed at further investigating such role in hypertensive patients. In 189 recently diagnosed, untreated hypertensive patients the authors evaluated, in a cross‐sectional design, the relationships of BP average levels and short‐term systolic (S) BPV (standard deviation of awake SBP or of 24‐hour‐weighted SBP) with IMT and PWV, and how much these relationships are explained by endothelial function parameters—brachial artery flow‐mediated dilation (FMD) and digital reactive hyperemia index (RHI). Multivariable models assessed the strength of these relationships to derive a plausible pathogenetic sequence. Both average SBP values and our measures of SBPV were significantly related to IMT (24‐hour mean SBP: r = .156, P = .034; 24‐hour‐weighted SBPV: r = .157, P = .033) and to PWV (24‐hour mean SBP: r = .179, P = .015; 24‐hour‐weighted SBPV: r = .175; P = .018), but only poorly related to FMD or RHI (P > .05 for all). At univariable regression analysis, FMD and RHI were both related to IMT, (P < .001), but not to PWV. When FMD and RHI were added to average SBP and SBPV parameters in a multivariable model, both significantly (P < .005) contributed to predict IMT, but not PWV. Thus, endothelial dysfunction relates to IMT independently of BP parameters, but appears to play a minor role in the association between BP variability‐related variables and arterial stiffening.
A three‐tiered integrative analysis of transcriptional data reveals the shared pathways related to heart failure from different aetiologies
Authors: Jiang Zhenhong , Guo Ninghong , Hong Kui 
Published: July 2020

AbstractHeart failure (HF) is the end stage of most heart disease cases and can be initiated from multiple aetiologies. However, whether the molecular basis of HF has a commonality between different aetiologies has not been elucidated. To address this lack, we performed a three‐tiered analysis by integrating transcriptional data and pathway information to explore the commonalities of HF from different aetiologies. First, through differential expression analysis, we obtained 111 genes that were frequently differentially expressed in HF from 11 different aetiologies. Several genes, such as NPPA and NPPB, are early and accurate biomarkers for HF. We also provided candidates for further experimental verification, such as SERPINA3 and STAT4. Then, using gene set enrichment analysis, we successfully identified 19 frequently dysregulated pathways. In particular, we found that pathways related to immune system signalling, the extracellular matrix and metabolism were critical in the development of HF. Finally, we successfully acquired 241 regulatory relationships between 64 transcriptional factors (TFs) and 17 frequently dysregulated pathways by integrating a regulatory network, and some of the identified TFs have already been proven to play important roles in HF. Taken together, the three‐tiered analysis of HF provided a systems biology perspective on HF and emphasized the molecular commonality of HF from different aetiologies.
Effect of icosapent ethyl on susceptibility to ventricular arrhythmias in postinfarcted rat hearts: Role of GPR120‐mediated connexin43 phosphorylation
Authors: Chen Wei‐Ting , Chen Syue‐yi , Wu De‐Wei , Lee Cheng‐Che , Lee Tsung‐Ming 
Published: July 2020

AbstractThe ω‐3 fatty acids exert as an antioxidant via the G protein‐coupled receptor 120 (GPR120). Icosapent ethyl, a purified eicosapentaenoic acid, showed a marked reduction in sudden cardiac death. Connexin43 is sensitive to redox status. We assessed whether icosapent ethyl attenuates fatal arrhythmias after myocardial infarction, a status of high oxidative stress, through increased connexin43 expression and whether the GPR120 signalling is involved in the protection. Male Wistar rats after ligating coronary artery were assigned to either vehicle or icosapent ethyl for 4 weeks. The postinfarction period was associated with increased oxidative‐nitrosative stress. In concert, myocardial connexin43 levels revealed a significant decrease in vehicle‐treated infarcted rats compared with sham. These changes of oxidative‐nitrosative stress and connexin43 levels were blunted after icosapent ethyl administration. Provocative arrhythmias in the infarcted rats treated with icosapent ethyl were significantly improved than vehicle. Icosapent ethyl significantly increased GPR120 compared to vehicle after infarction. The effects of icosapent ethyl on superoxide and connexin43 were similar to GPR120 agonist GW9508. Besides, the effects of icosapent ethyl on oxidative‐nitrosative stress and connexin43 phosphorylation were abolished by administering AH‐7614, an inhibitor of GPR120. SIN‐1 abolished the Cx43 phosphorylation of icosapent ethyl without affecting GPR120 levels. Taken together, chronic use of icosapent ethyl after infarction is associated with up‐regulation of connexin43 phosphorylation through a GPR120‐dependent antioxidant pathway and thus plays a beneficial effect on arrhythmogenic response to programmed electrical stimulation.
PD‐1 mRNA expression in peripheral blood mononuclear cells as a biomarker for different stages of primary gouty arthritis
Authors: Su Jing , Zhang Xuefang , Zhao Qing , Guo Zhaodi , Wu Jianxiong , Chen Guoqiang , Liang Qianxin , Chen Zhixiang , He Zhiliang , Cai Xiuping , Xie Manlin , Zheng Lei , Zhao Kewei 
Published: July 2020

AbstractThere is currently a lack of biomarkers to assist the diagnosis and prediction of primary gouty arthritis (PG). Therefore, we evaluated the clinical value of programmed cell death protein 1 (PD‐1) mRNA expression in peripheral blood mononuclear cells (PBMCs) of patients with PG. This study included 36 patients with acute phase PG (APPG), 48 with non‐acute phase PG (NAPPG), 42 with asymptomatic hyperuricemia (AH) and 79 normal controls (NCs). PD‐1 mRNA expression levels were detected by qRT‐PCR. PD‐1 mRNA expression was statistically analysed by ANOVA or t tests, while correlations between PD‐1 mRNA and clinical variables were assessed using Pearson correlation tests. Receiver operator characteristic (ROC) curve analysis was used to evaluate the diagnostic value of PD‐1 in different PG stages. PD‐1 mRNA expression was significantly lower in patients with APPG than that in NAPPG, AH and NCs (P < 0.01). Correlation analysis revealed that PD‐1 mRNA levels correlated negatively with T‐score (r = −0.209, P < 0.01). ROC curve analysis showed that serum uric acid (SUA), PD‐1 mRNA and both combined displayed higher diagnostic value in patients with PG, NAPPG and APPG compared to that in NCs and patients with non‐PG arthritis (NPG). Moreover, ROC curve analysis showed that SUA and PD‐1 mRNA had good diagnostic value in APPG, with the greatest diagnostic power when combined. PD‐1 mRNA could be a clinical auxiliary diagnostic biomarker for APPG, and the combined use of PD‐1 mRNA and SUA is better than that of SUA alone.