bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epicardial adipose tissue differentiates in patients with and without coronary microvascular dysfunction
Authors: Mahmoud Ihab , Dykun Iryna , Kärner Luisa , Hendricks Stefanie , Totzeck Matthias , Al-Rashid Fadi , Rassaf Tienush , Mahabadi Amir A. 
Published: June 2021

Abstract
Background/Objectives
Coronary microvascular dysfunction (CMD) is a common disorder, leading to symptoms similar to obstructive coronary artery disease and bears important prognostic implications. Local inflammation is suggested to promote development of CMD. Epicardial adipose tissue (EAT) is a local visceral fat depot surrounding the heart and the coronary arteries, modifying the inflammatory environment of the heart. We compared EAT in patients with and without CMD.

Methods
We retrospectively included consecutive patients undergoing diagnostic coronary angiography as well as transthoracic echocardiography between March and October 2016. EAT thickness was defined as space between the epicardial wall of the myocardium and the visceral layer of the pericardium and EAT index was calculated as EAT thickness/body surface area. Logistic regression analysis was used to determine the association of EAT index with the presence of CMD.

Results
Overall, 399 patients (mean age 60.2 ± 14.0 years, 46% male) were included. EAT thickness was significantly higher in patients with CMD compared to patients without CMD (EAT thickness 4.4 ± 1.8 vs. 4.9 ± 2.4 mm, p = 0,048 for patients without and with CMD, respectively). In univariate regression analysis, EAT index was associated with a 30% higher frequency of CMD (odds ratio [95% confidence interval]: 1.30 [1.001–1.69], p = 0.049). Effect sizes remained stable upon adjustment for body mass index (BMI, 1.30 [1.003–1.70], p = 0.048), but were attenuated when ancillary adjusting for age and gender (1.17 [0.90–1.54, p = 0.25). The effect was more pronounced in patients >65 years of age and independent of BMI and sex (1.85 [1.14–3.00], p = 0.013).

Conclusion
EAT thickness is independently associated with CMD and can differentiate between patients with and without CMD especially in older age groups. Our results support the hypothesis that modulation of local inflammation by epicardial fat is involved in the development of CMD.
Preclinical evaluation of eltrombopag in a PDX model of myelodysplastic syndromes
Authors: Schmitt Nanni , Jann Johann-Christoph , Altrock Eva , Flach Johanna , Danner Justine , Uhlig Stefanie , Streuer Alexander , Knaflic Antje , Riabov Vladimir , Xu Qingyu , Mehralivand Arwin , Palme Iris , Nowak Verena , Obländer Julia , Weimer Nadine , Haselmann Verena , Jawhar Ahmed , Darwich Ali , Weis Cleo-Aron , Marx Alexander , Steiner Laurenz , Jawhar Mohamad , Metzgeroth Georgia , Boch Tobias , Nolte Florian , Hofmann Wolf-Karsten , Nowak Daniel 
Published: June 2021

AbstractPreclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.
Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms
Authors: Steensma David P. , Wermke Martin , Klimek Virginia M. , Greenberg Peter L. , Font Patricia , Komrokji Rami S. , Yang Jay , Brunner Andrew M. , Carraway Hetty E. , Ades Lionel , Al-Kali Aref , Alonso-Dominguez Juan M. , Alfonso-Piérola Ana , Coombs Catherine C. , Deeg H. Joachim , Flinn Ian , Foran James M. , Garcia-Manero Guillermo , Maris Michael B. , McMasters Malgorzata , Micol Jean-Baptiste , De Oteyza Jaime Perez , Thol Felicitas , Wang Eunice S. , Watts Justin M. , Taylor Justin , Stone Richard , Gourineni Vikram , Marino Alyssa J. , Yao Huilan , Destenaves Benoit , Yuan Xiaobin , Yu Kun , Dar Sara , Ohanjanian Lernik , Kuida Keisuke , Xiao Jianjun , Scholz Catherine , Gualberto Antonio , Platzbecker Uwe 
Published: June 2021

AbstractWe conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
Neurexin 1 variants as risk factors for suicide death
Authors: William Nancy , Reissner Carsten , Sargent Robert , Darlington Todd M. , DiBlasi Emily , Li Qingqin S. , Keeshin Brooks , Callor William B. , Ferris Elliott , Jerominski Leslie , Smith Ken R. , Christensen Erik D. , Gray Douglas M. , Camp Nicola J. , Missler Markus , Williams Megan E. , Coon Hilary 
Published: June 2021

AbstractSuicide is a significant public health concern with complex etiology. Although the genetic component of suicide is well established, the scope of gene networks and biological mechanisms underlying suicide has yet to be defined. Previously, we reported genome-wide evidence that neurexin 1 (NRXN1), a key synapse organizing molecule, is associated with familial suicide risk. Here we present new evidence for two non-synonymous variants (rs78540316; P469S and rs199784139; H885Y) associated with increased familial risk of suicide death. We tested the impact of these variants on binding interactions with known partners and assessed functionality in a hemi-synapse formation assay. Although the formation of hemi-synapses was not altered with the P469S variant relative to wild-type, both variants increased binding to the postsynaptic binding partner, leucine-rich repeat transmembrane neuronal 2 (LRRTM2) in vitro. Our findings indicate that variants in NRXN1 and related synaptic genes warrant further study as risk factors for suicide death.
Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer
Authors: Qiu Yufan , Yang Yi , Yang Riyao , Liu Chunxiao , Hsu Jung-Mao , Jiang Zhou , Sun Linlin , Wei Yongkun , Li Chia-Wei , Yu Dihua , Zhang Jin , Hung Mien-Chie 
Published: June 2021

AbstractProgrammed cell death 1 (PD-1) is widely expressed in tumor-infiltrating lymphocytes (TILs) of triple-negative breast cancer (TNBC). As a dominant inhibitory immune checkpoint (ICP) receptor, cell surface PD-1 is well-known to transduce negative signaling of effector T cell activity during cell–cell contact. However, despite its well-documented inhibitory effects, higher PD-1 expression in TILs is significantly associated with longer survival in TNBC patients. This phenomenon raises an interesting question whether PD-1 harbors positive activity to enhance anti-tumor immunity. Here, we show that PD-1 is secreted in an exosomal form by activated T cells and can remotely interact with either cell surface or exosomal programmed death-ligand 1 (PD-L1), induce PD-L1 internalization via clathrin-mediated endocytosis, and thereby prevent subsequent cellular PD-L1: PD-1 interaction, restoring tumor surveillance through attenuating PD-L1-induced suppression of tumor-specific cytotoxic T cell activity. Our results, through revealing an anti-PD-L1 function of exosomal PD-1, provide a positive role to enhance cytotoxic T cell activity and a potential therapeutic strategy of modifying the exosome surface with membrane-bound inhibitory ICP receptors to attenuate the suppressive tumor immune microenvironment.
Kras activation in endometrial organoids drives cellular transformation and epithelial-mesenchymal transition
Authors: Maru Yoshiaki , Tanaka Naotake , Tatsumi Yasutoshi , Nakamura Yuki , Itami Makiko , Hippo Yoshitaka 
Published: June 2021

AbstractKRAS, an oncogene, is frequently activated by mutations in many cancers. Kras-driven adenocarcinoma development in the lung, pancreas, and biliary tract has been extensively studied using gene targeting in mice. By taking the organoid- and allograft-based genetic approach to these organs, essentially the same results as in vivo models were obtained in terms of tumor development. To verify the applicability of this approach to other organs, we investigated whether the combination of Kras activation and Pten inactivation, which gives rise to endometrial tumors in mice, could transform murine endometrial organoids in the subcutis of immunodeficient mice. We found that in KrasG12D-expressing endometrial organoids, Pten knockdown did not confer tumorigenicity, but Cdkn2a knockdown or Trp53 deletion led to the development of carcinosarcoma (CS), a rare, aggressive tumor comprising both carcinoma and sarcoma. Although they originated from epithelial cells, some CS cells expressed both epithelial and mesenchymal markers. Upon inoculation in immunodeficient mice, tumor-derived round organoids developed carcinoma or CS, whereas spindle-shaped organoids formed monophasic sarcoma only, suggesting an irreversible epithelial-mesenchymal transition during the transformation of endometrial cells and progression. As commonly observed in mutant Kras-driven tumors, the deletion of the wild-type Kras allele was identified in most induced tumors, whereas some epithelial cells in CS-derived organoids were unexpectedly negative for KrasG12D. Collectively, we showed that the oncogenic potential of KrasG12D and the histological features of derived tumors are context-dependent and varies according to the organ type and experimental settings. Our findings provide novel insights into the mechanisms underlying tissue-specific Kras-driven tumorigenesis.
New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin
Authors: Liu Xiaomin , Xu Hanshi , Xu Huaiqian , Geng Qingshan , Mak Wai-Ho , Ling Fei , Su Zheng , Yang Fang , Zhang Tao , Chen Jiyan , Yang Huanming , Wang Jian , Zhang Xiuqing , Xu Xun , Jia Huijue , Zhang Zhiwei , Liu Xiao , Zhong Shilong 
Published: June 2021

AbstractAlthough a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events (MACE) in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI), these genotypes account for only a small fraction of the variation and evidence is insufficient. This study aims to identify new genetic variants associated with MACE end point during the 18-month follow-up period by a two-stage large-scale sequencing data, including high-depth whole exome sequencing of 168 patients in the discovery cohort and high-depth targeted sequencing of 1793 patients in the replication cohort. We discovered eight new genotypes and their genes associated with MACE in patients with ACS, including MYOM2 (rs17064642), WDR24 (rs11640115), NECAB1 (rs74569896), EFR3A (rs4736529), AGAP3 (rs75750968), ZDHHC3 (rs3749187), ECHS1 (rs140410716), and KRTAP10-4 (rs201441480). Notably, the expressions of MYOM2 and ECHS1 are downregulated in both animal models and patients with phenotypes related to MACE. Importantly, we developed the first superior classifier for predicting 18-month MACE and achieved high predictive performance (AUC ranged between 0.92 and 0.94 for three machine-learning methods). Our findings shed light on the pathogenesis of cardiovascular outcomes and may help the clinician to make a decision on the therapeutic intervention for ACS patients.
TNF-α induces endothelial–mesenchymal transition promoting stromal development of pancreatic adenocarcinoma
Authors: Adjuto-Saccone Marjorie , Soubeyran Philippe , Garcia Julie , Audebert Stéphane , Camoin Luc , Rubis Marion , Roques Julie , Binétruy Bernard , Iovanna Juan Lucio , Tournaire Roselyne 
Published: June 2021

AbstractEndothelial–mesenchymal transition (EndMT) is an important source of cancer-associated fibroblasts (CAFs), which facilitates tumour progression. PDAC is characterised by abundant CAFs and tumour necrosis factor-α (TNF-α). Here, we show that TNF-α strongly induces human endothelial cells to undergo EndMT. Interestingly, TNF-α strongly downregulates the expression of the endothelial receptor TIE1, and reciprocally TIE1 overexpression partially prevents TNF-α-induced EndMT, suggesting that TNF-α acts, at least partially, through TIE1 regulation in this process. We also show that TNF-α-induced EndMT is reversible. Furthermore, TNF-α treatment of orthotopic mice resulted in an important increase in the stroma, including CAFs. Finally, secretome analysis identified TNFSF12, as a regulator that is also present in PDAC patients. With the aim of restoring normal angiogenesis and better access to drugs, our results support the development of therapies targeting CAFs or inducing the EndMT reversion process in PDAC.
CT45A1 promotes the metastasis of osteosarcoma cells in vitro and in vivo through β-catenin
Authors: Wen Mingxin , Ren Hui , Zhang Shouqiang , Li Tao , Zhang Jiefeng , Ren Peng 
Published: June 2021

AbstractIncreased expression of cancer/testis antigens (CTAs) is reported in various tumors. However, the unique role of CTAs in tumor genesis has not yet been verified. Here, we first report the functional role of CT45A1 in the carcinogenesis of osteosarcoma. RNA sequencing and immunohistochemistry confirmed that elevated expression of CT45A1 was detected in osteosarcoma, especially in metastatic tissues of osteosarcoma. Furthermore, osteosarcoma patients with poorer prognosis showed high expression of CT45A1. In cell tests, CT45A1 overexpression was shown to strengthen the proliferation, migration, and invasion abilities of osteosarcoma cells, while silencing CT45A1 markedly elicited the opposite effects in these tests by disrupting the activation of β-catenin. In summary, we identify a novel role of CT45A1 in osteosarcoma. Furthermore, our results suggested that CT45A1 may contribute to the development of osteosarcoma and could be a possible therapeutic target for osteosarcoma patients.
Crystalline chirality and interlocked double hourglass Weyl fermion in polyhedra-intercalated transition metal dichalcogenides
Authors: Huang Pu , Chen Xinbo , Zhang Peng , Sun Hongyi , Xu Shaogang , Xiong Wen , Wang Rui , Zhang Han , Liu Qihang , Zhang Xiuwen 
Published: June 2021

AbstractIntroducing crystalline chirality into transition metal dichalcogenides (TMDs) has attracted much attention due to its modulation effect on optical properties and the potential to reveal new forms of electronic states. Here, we predict a number of chiral materials by intercalating polyhedra into TMD lattices, finding a type of double hourglass Weyl fermion interlocked with crystalline chirality. The best candidate RhV3S6 (P6322) possesses the largest hourglass energy window of ~380 meV, as well as strong optical circular dichroism (CD) in the infrared regime, both of which are tunable by external strains. The chirality is originally induced by the configuration of intercalated polyhedra and then reduced by the rotational atomic displacements triggered by intercalation, as indicated by CD calculations. Our study opens the way of designing chiral materials with spin-split double hourglass Weyl fermions via structural unit intercalation in achiral crystals for future chiral-functionalized optoelectronic and spintronic devices.
Intravitreal injections: past trends and future projections within a UK tertiary hospital
Authors: Chopra Reena , Preston Gabriella C. , Keenan Tiarnan D. L. , Mulholland Pádraig , Patel Praveen J. , Balaskas Konstantinos , Hamilton Robin D. , Keane Pearse A. 
Published: June 2021

Abstract
Aims
To describe past trends and future projections for the number of intravitreal injections being administered at a large tertiary hospital in London, United Kingdom.

Methods
Retrospective data from Moorfields Eye Hospital were collected using the electronic medical record system. Descriptive statistics were used to visualise overall trends. Time series forecasting was used to predict the number of injections that will be administered up to and including the year 2029.

Results
The number of injections has increased nearly 11-fold from 2009 to 2019, with a total of 44,924 injections delivered in 2019. The majority of injections were given for the treatment of neovascular age-related macular degeneration. Aflibercept formed 87% of injections administered in 2019. The number of injections is predicted to continue to increase every year, with nearly 83,000 injections forecasted in the year 2029.

Conclusion
The demand for intravitreal injections has increased substantially over the last decade and is predicted to further increase. Healthcare systems will need to adapt to accommodate the high demand. Other solutions may include longer-acting therapies to reduce the treatment burden.
Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function
Authors: Palanikumar L. , Karpauskaite Laura , Al-Sayegh Mohamed , Chehade Ibrahim , Alam Maheen , Hassan Sarah , Maity Debabrata , Ali Liaqat , Kalmouni Mona , Hunashal Yamanappa , Ahmed Jemil , Houhou Tatiana , Karapetyan Shake , Falls Zackary , Samudrala Ram , Pasricha Renu , Esposito Gennaro , Afzal Ahmed J. , Hamilton Andrew D. , Kumar Sunil , Magzoub Mazin 
Published: June 2021

AbstractMissense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer’s disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent.
Post-myocardial infarction heart failure dysregulates the bone vascular niche
Authors: Hoffmann Jedrzej , Luxán Guillermo , Abplanalp Wesley Tyler , Glaser Simone-Franziska , Rasper Tina , Fischer Ariane , Muhly-Reinholz Marion , Potente Michael , Assmus Birgit , John David , Zeiher Andreas Michael , Dimmeler Stefanie 
Published: June 2021

AbstractThe regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the bone vascular cell composition. We demonstrate an age-independent loss of type H endothelium in heart failure after myocardial infarction in both mice and humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium, showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1β production partially prevented the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of bone vascular function in ischemic heart disease.
Temporal trends of SARS-CoV-2 seroprevalence during the first wave of the COVID-19 epidemic in Kenya
Authors: Adetifa Ifedayo M. O. , Uyoga Sophie , Gitonga John N. , Mugo Daisy , Otiende Mark , Nyagwange James , Karanja Henry K. , Tuju James , Wanjiku Perpetual , Aman Rashid , Mwangangi Mercy , Amoth Patrick , Kasera Kadondi , Ng’ang’a Wangari , Rombo Charles , Yegon Christine , Kithi Khamisi , Odhiambo Elizabeth , Rotich Thomas , Orgut Irene , Kihara Sammy , Bottomley Christian , Kagucia Eunice W. , Gallagher Katherine E. , Etyang Anthony , Voller Shirine , Lambe Teresa , Wright Daniel , Barasa Edwine , Tsofa Benjamin , Bejon Philip , Ochola-Oyier Lynette I. , Agweyu Ambrose , Scott J. Anthony G. , Warimwe George M. 
Published: June 2021

AbstractObserved SARS-CoV-2 infections and deaths are low in tropical Africa raising questions about the extent of transmission. We measured SARS-CoV-2 IgG by ELISA in 9,922 blood donors across Kenya and adjusted for sampling bias and test performance. By 1st September 2020, 577 COVID-19 deaths were observed nationwide and seroprevalence was 9.1% (95%CI 7.6-10.8%). Seroprevalence in Nairobi was 22.7% (18.0-27.7%). Although most people remained susceptible, SARS-CoV-2 had spread widely in Kenya with apparently low associated mortality.