tbuckley/cabot-search huggingface dataset:
Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche
Authors: Zhiping Liu, Jiean Xu, Qian Ma, Xiaoyu Zhang, Qiuhua Yang, Lina Wang, Yapeng Cao, Zhimin Xu, Amany Tawfik, Ye Sun, Neal L. Weintraub, David J. Fulton, Mei Hong, Zheng Dong, Lois E. H. Smith, Ruth B. Caldwell, Akrit Sodhi, Yuqing Huo
Journal: Science Translational Medicine (2020)

Increased glycolysis facilitates reciprocal activation between myeloid cells and endothelial cells in pathological retinal angiogenesis.
Treatment of patients with inflammatory rheumatic diseases with rituximab should be carefully considered during the SARS-CoV-2/COVID-19 pandemic. Response to: ‘Persistence of rT-PCR-SARS-CoV-2 infection and delayed serological response, as a possible effect of rituximab according to the hypothesis of Schulze-Koops et al’ by Benucci<i>et al</i>
Authors: Hendrik Schulze-Koops, Klaus Krueger, Inka Vallbracht Vallbracht, Rebecca Hasseli, Alla Skapenko
Journal: Annals of the Rheumatic Diseases (2020)

<i>Dyrk1a</i> triplication in Down9s syndrome and its overexpression in Alzheimer9s disease suggest a role for increased DYRK1A activity in the abnormal metabolism of APP. Transport defects are early phenotypes in the progression of Alzheimer9s disease, which lead to APP processing impairments. However, whether DYRK1A regulates the intracellular transport and delivery of APP in human neurons remains unknown. From a proteomic dataset of human cerebral organoids treated with harmine, a DYRK1A inhibitor, we found expression changes in protein clusters associated with the control of microtubule-based transport and in close interaction with the APP vesicle. Live imaging of APP axonal transport in human-derived neurons treated with harmine or overexpressing a dominant negative DYRK1A revealed a reduction in APP vesicle density and enhanced the stochastic behavior of retrograde vesicle transport. Moreover, harmine increased the fraction of slow segmental velocities and changed speed transitions supporting a DYRK1A-mediated effect in the exchange of active motor configuration. Contrarily, the overexpression of DYRK1A in human polarized neurons increased the axonal density of APP vesicles and enhanced the processivity of retrograde APP. In addition, increased DYRK1A activity induced faster retrograde segmental velocities together with significant changes in slow to fast anterograde and retrograde speed transitions, suggesting the facilitation of the active motor configuration. Our results highlight DYRK1A as a modulator of the axonal transport machinery driving APP intracellular distribution in neurons, and stress DYRK1A inhibition as a putative therapeutic intervention to restore APP axonal transport in Down9s syndrome and Alzheimer9s disease. <b>SIGNIFICANCE STATEMENT</b> Axonal transport defects are early events in the progression of neurodegenerative diseases, such as Alzheimer9s disease. However, the molecular mechanisms underlying transport defects remain elusive. <i>Dyrk1a</i> kinase is triplicated in Down9s syndrome and overexpressed in Alzheimer9s disease, suggesting that DYRK1A dysfunction affects molecular pathways leading to early-onset neurodegeneration. Here, we show by live imaging of human-derived neurons that DYRK1A activity differentially regulates the intracellular trafficking of APP. Further, single-particle analysis revealed DYRK1A as a modulator of axonal transport and the configuration of active motors within the APP vesicle. Our work highlights DYRK1A as a regulator of APP axonal transport and metabolism, supporting DYRK1A inhibition as a therapeutic strategy to restore intracellular dynamics in Alzheimer9s disease.
Presence of antiphospholipid antibodies in COVID-19: a case series study
Authors: Luis M Amezcua-Guerra, Gustavo Rojas-Velasco, Malinalli Brianza-Padilla, Armando Vázquez-Rangel, Ricardo Márquez-Velasco, Francisco Baranda-Tovar, Rashidi Springall, Hector Gonzalez-Pacheco, Yaneli Juárez-Vicuña, Claudia Tavera-Alonso, Fausto Sanchez-Muñoz, Marisol Hernández-Salas
Journal: Annals of the Rheumatic Diseases (2020)

The outer membrane protein PorB is a conserved chlamydial protein that functions as a porin and is capable of eliciting neutralizing Abs. A topological antigenic map was developed using overlapping synthetic peptides representing the <i>Chlamydia trachomatis</i> PorB sequence and polyclonal immune sera. To identify which antigenic determinants were surface accessible, monospecific antisera were raised to the PorB peptides and were used in dot-blot and ELISA-based absorption studies with viable chlamydial elementary bodies (EBs). The ability of the surface-accessible antigenic determinants to direct neutralizing Ab responses was investigated using standardized in vitro neutralization assays. Four major antigenic clusters corresponding to Phe<sup>34</sup>-Leu<sup>59</sup> (B1-2 and B1-3), Asp<sup>112</sup> -Glu<sup>145</sup> (B2-3 and B2-4), Gly<sup>179</sup>-Ala<sup>225</sup> (B3-2 to B3-4), and Val<sup>261</sup>-Asn<sup>305</sup> (B4-4 to B5-2) were identified. Collectively, the EB absorption and dot-blot assays established that the immunoreactive PorB Ags were exposed on the surface of chlamydial EBs. Peptide-specific antisera raised to the surface-accessible Ags neutralized chlamydial infectivity and demonstrated cross-reactivity to synthetic peptides representing analogous <i>C. pneumoniae</i> PorB sequences. Furthermore, neutralization of chlamydial infectivity by <i>C. trachomatis</i> PorB antisera was inhibited by synthetic peptides representing the surface-exposed PorB antigenic determinants. These findings demonstrate that PorB Ags may be useful for development of chlamydial vaccines.
Defining gaps in pre-exposure prophylaxis delivery for pregnant and post-partum women in high-burden settings using an implementation science framework
Authors: Jillian Pintye, Dvora L Joseph Davey, Anjuli D Wagner, Grace John-Stewart, Rachel Baggaley, Linda-Gail Bekker, Connie Celum, Benjamin H Chi, Thomas J Coates, Allison K Groves, Jessica E Haberer, Renee Heffron, John Kinuthia, Lynn T Matthews, James A McIntyre, Dhayendre Moodley, Lynne M Mofenson, Nelly Mugo, Andrew Mujugira, Landon Myer, Steven Shoptaw, Lynda Stranix-Chibanda, Jared M Baeten
Journal: The Lancet HIV (2020)
Bidirectional Role of NLRP3 During Acute and Chronic Cholestatic Liver Injury
Authors: Mick Frissen, Lijun Liao, Kai Markus Schneider, Sonja Djudjaj, Johannes Haybaeck, Alexander Wree, Ulrike Rolle‐Kampczyk, Martin von Bergen, Eicke Latz, Peter Boor, Christian Trautwein
Journal: Hepatology (2020)

Background and Aims Cholestatic liver injury leads to cell death and subsequent inflammation and fibrosis. As shown for primary biliary cholangitis (PBC), the mechanisms and circuits between different cell death pathways leading to disease progression are incompletely defined. Common bile duct ligation (BDL) is a well‐established murine model to mimic cholestatic liver injury. Here, we hypothesized that pyroptotic cell death by the Nucleotide‐Binding Domain, Leucine‐Rich‐Containing Family, Pyrin Domain‐Containing‐3 (Nlrp3) inflammasome plays an essential role during human and murine cholestasis. Approach and Results NLRP3 activation was analyzed in humans with cholestatic liver injury. Wild‐type (WT) and Nlrp3−/− mice were subjected to BDL for 2 or 28 days. Chronic cholestasis in humans and mice is associated with NLRP3 activation and correlates with disease activity. Acute BDL in Nlrp3‐deficient mice triggered increased inflammation as well as liver injury, associated with stronger apoptotic and necroptotic cell death. In contrast, NLRP3 deletion led to decreased liver injury and inflammation in chronic cholestasis. Moreover, bridging fibrosis was observed in WT, but not in NLRP3 knockout, mice 28 days after BDL. In contrast, lack of NLRP3 expression attenuated kidney injury and fibrosis after acute and chronic BDL. Importantly, administration of MCC950, an NLRP3 small molecule inhibitor, reduced BDL‐induced disease progression in WT mice. Conclusions NLRP3 activation correlates with disease activity in patients with PBC. NLRP3 has a differential role during acute and chronic cholestatic liver injury in contrast to kidney injury. Disease progression during chronic cholestasis can be targeted through small molecules and thus suggests a potential clinical benefit for humans, attenuating liver and kidney injury.
Evaluation of Pathologic Complete Response as a Surrogate for Long-Term Survival Outcomes in Triple-Negative Breast Cancer
Authors: Min Huang, Joyce O’Shaughnessy, Jing Zhao, Amin Haiderali, Javier Cortes, Scott Ramsey, Andrew Briggs, Vassiliki Karantza, Gursel Aktan, Cynthia Z. Qi, Chenyang Gu, Jipan Xie, Muhan Yuan, John Cook, Michael Untch, Peter Schmid, Peter A. Fasching
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: Pathologic complete response (pCR) is a common efficacy endpoint in neoadjuvant therapy trials for triple-negative breast cancer (TNBC). Previous studies have shown that pCR is strongly associated with improved long-term survival outcomes, including event-free survival (EFS) and overall survival (OS). However, the trial-level associations between treatment effect on pCR and long-term survival outcomes are not well established. This study sought to evaluate these associations by incorporating more recent clinical trials in TNBC. Methods: A literature review identified published randomized controlled trials (RCTs) of neoadjuvant therapy for TNBC that reported results for both pCR and EFS/OS. Meta-regression models were performed to evaluate the association of treatment effect on pCR and EFS/OS. Sensitivity analyses were conducted to assess the impact of divergent study designs. Results: Ten comparisons from 8 RCTs (N=2,478 patients) were identified from the literature review. The log (odds ratio) of pCR was a significant predictor of the log (hazard ratio) of EFS ( P =.003), with a coefficient of determination of 0.68 (95% CI, 0.41–0.95). There was a weaker association between pCR and OS ( P =.18), with a coefficient of determination of 0.24 (95% CI, 0.01–0.77). Consistent results were found in the exploratory analysis and sensitivity analyses. Conclusions: This is the first study that has shown a trial-level association between pCR and survival outcomes in TNBC. By incorporating the most up-to-date RCTs, this study showed a significant trial-level association between pCR and EFS. A positive association between pCR and OS was also recorded.
Association of Second-Generation Drug-Eluting Stent Length With 2-Year Adverse Clinical Outcomes Among Japanese Patients With Ischemic Heart Disease
Authors: Kentaro Ejiri, Mitsuaki Sawano, Yohei Numasawa, Shigetaka Noma, Hiroshi Ito, Keiichi Fukuda, Shun Kohsaka
Journal: JAMA Network Open (2020)

This cohort study examines the association between second-generation drug-eluting stent length and cardiovascular and bleeding events in Japanese patients with ischemic heart disease.
A Circular RNA, Cholangiocarcinoma‐Associated Circular RNA 1, Contributes to Cholangiocarcinoma Progression, Induces Angiogenesis, and Disrupts Vascular Endothelial Barriers
Authors: Yi Xu, Kaiming Leng, Yue Yao, Pengcheng Kang, Guanqun Liao, Yi Han, Guangjun Shi, Daolin Ji, Peng Huang, Wangyang Zheng, Zhenglong Li, Jinglin Li, Lining Huang, Liang Yu, Yongxu Zhou, Xingming Jiang, Hao Wang, Chunlong Li, Zhilei Su, Sheng Tai, Xiangyu Zhong, Zhidong Wang, Yunfu Cui
Journal: Hepatology (2020)

Circular RNAs (circRNAs) and extracellular vesicles (EVs) are involved in various malignancies. We aimed to clarify the functions and mechanisms of dysregulated circRNAs in the cells and EVs of cholangiocarcinoma (CCA).CircRNA microarray was used to identify circRNA expression profiles in CCA tissues and bile-derived EVs (BEVs). CCA-associated circRNA 1 (circ-CCAC1) expression was measured by quantitative real-time PCR. The clinical importance of circ-CCAC1 was analyzed by receiver operating characteristic curves, Fisher's exact test, Kaplan-Meier plots, and Cox regression model. The functions of circ-CCAC1 and exosomal circ-CCAC1 were explored in CCA cells and human umbilical vein endothelial cells (HUVECs), respectively. Different animal models were used to verify the in vitro results. RNA sequencing, bioinformatics, RNA immunoprecipitation, RNA pulldown, chromatin immunoprecipitation followed by sequencing, and luciferase reporter assays were used to determine the regulatory networks of circ-CCAC1 in CCA cells and HUVECs. Circ-CCAC1 levels were increased in cancerous bile-resident EVs and tissues. The diagnostic and prognostic values of circ-CCAC1 were identified in patients with CCA. For CCA cells, circ-CCAC1 increased cell progression by sponging miR-514a-5p to up-regulate Yin Yang 1 (YY1). Meanwhile, YY1 directly bound to the promoter of calcium modulating ligand to activate its transcription. Moreover, circ-CCAC1 from CCA-derived EVs was transferred to endothelial monolayer cells, disrupting endothelial barrier integrity and inducing angiogenesis. Mechanistically, circ-CCAC1 increased cell leakiness by sequestering enhancer of zeste homolog 2 in the cytoplasm, thus elevating SH3 domain-containing GRB2-like protein 2 expression to reduce the levels of intercellular junction proteins. In vivo studies further showed that increased circ-CCAC1 levels in circulating EVs and cells accelerated both CCA tumorigenesis and metastasis.Circ-CCAC1 plays a vital role in CCA tumorigenesis and metastasis and may be an important biomarker/therapeutic target for CCA.
Abstract 12694: Use of Highly Sensitive Troponin T and N-Terminal Pro-Brain Natriuretic Peptide to Diagnose Acute Rejection in Pediatric Cardiac Transplant Recipients
Authors: Adrian K Dyer, Aliessa P Barnes, David E Fixler, Tejas K Shah, David L Sutcliffe, James A de Lemos
Journal: Circulation (2010)

Introduction: Biomarkers used in heart failure, including troponin T (cTnT) and brain natriuretic peptide (BNP), have been proposed to augment or replace endomyocardial biopsy (EMB) to diagnose acu...
急性心筋梗塞患者における心筋酵素のウォッシュアウトとBMIPP/Tl SPECT画像上のミスマッチとの間の関係性
Authors: Mori Hiroaki, Isobe Satoshi, Aoki Toshijirou, Miki Yusuke, Tsuda Takuma, Mitsuda Takayuki, Kawamiya Toshiki, Mihara Hirotsugu, Watanabe Junji, Kanashiro Masaaki, Ichimiya Satoshi, Miura Manabu, Sakai Shinichi
Journal: Circulation (2013)
Prognostic Value of Stress CMR Perfusion Imaging in Patients With Reduced Left Ventricular Function
Authors: Yin Ge, Panagiotis Antiochos, Kevin Steel, Scott Bingham, Shuaib Abdullah, Yi-Yun Chen, J Ronald Mikolich, Andrew E. Arai, W. Patricia Bandettini, Sujata M. Shanbhag, Amit R. Patel, Afshin Farzaneh-Far, John F. Heitner, Chetan Shenoy, Steve W. Leung, Jorge A. Gonzalez, Dipan J. Shah, Subha V. Raman, Victor A. Ferrari, Jeanette Schulz-Menger, Matthias Stuber, Orlando P. Simonetti, Raymond Y. Kwong
Journal: JACC. Cardiovascular imaging (2020)
Risk Factors Predicting Graft-Versus-Host Disease and Relapse-Free Survival (GRFS) after Allogeneic Hematopoietic Stem Cell Transplantation in Relapse/Refractory Non-Hodgkin Lymphomas
Authors: Young-Woo Jeon, Sung-Soo Park, Jae-Ho Yoon, Sung-Eun Lee, Ki-Seong Eom, Yoo-Jin Kim, Hee-Je Kim, Seok Lee, Jong-Wook Lee, Seok-Goo Cho
Journal: Blood (2017)
AB0645 PREDICTORS OF THE EFFECTIVENESS OF INTRA-ARTICULAR GLUCOCORTICOID INJECTIONS IN RHEUMATIC HIP INVOLVEMENT
Authors: H. Ferjani, L. Ben Ammar, K. Maatallah, D. Ben Nessib, D. Kaffel, W. Hamdi
Journal: Annals of the Rheumatic Diseases (2020)

Background: Hip involvement in chronic inflammatory rheumatic diseases is a turning point in the course of the disease because of disability and functional impairment. Total joint replacement surgery rate in spondyloarthritis increased 40% despite the use of Disease-modifying anti-rheumatic drugs (DMARD) and biologic treatment. Intra-articular glucocorticoid injection may help prevent hip joint replacement surgery and radiographic progression. Objectives: This study aimed to determine predictive factors of the steroid injections’ efficiency in chronic inflammatory rheumatic diseases with hip involvement. Methods: This is a retrospective study over a 13-years (2006-2019) that included patients followed for chronic inflammatory rheumatic diseases complicated by hip involvement and underwent intra-articular glucocorticoid injection. Results: Forty-two patients were enrolled: 32 male (76,2%) and 10 women (23,8%). The average age was 27 years [6-73] at the time of the steroid injection. Ankylosing spondylitis (AS) was present in 73,8% of cases (radiographic axial spondylarthritis 90,3%, Psoriatic spondylitis 6,5% and peripheral enthesitis 3.2%) and juvenile idiopathic arthritis (JIA) in 26.2% of cases (enthesitis-related arthritis 63,6%, oligoarticular JIA 18,2%, seronegative polyarticular JIA 9,1% and juvenile psoriatic arthritis 9,1%). Active smoking was found in 47.6% of cases. All patients were on DMARD: NSAIDs (19%), methotrexate (42.9%), salazopyrin (23.8%), combination of methotrexate and salazopyrin (2.4%) and anti-TNF alpha (7.1%). Hip involvement was bilateral in 81% of patients. Examination revealed pain and limited hip mobility in all cases. Radiographic forms in AS were: early coxitis (17,2%), condensing form (17,2%), destructive form (58,6%), synostosante (3,4%) et combined (3,4%). During JIA, hip involvement was destructive in 45.4% of cases and minimal to moderate in the remaining cases. Lequesne algofunctional index averaged 11 (3-18). An improvement was reported in 63.4% of cases. Statistically significant decrease was found in the BASDAI score, visual analogue scale (VAS) for general health status as estimated by the patient and C-reactive Protein (CRP) (p=0.001; p=0.01 and p=0.03; respectively). There was no statistically significant difference between the efficacy of intra-articular glucocorticoid injection and sex, age, smoking, diagnosis and whether the hip involvement was bilateral or not (p=0.5; p=0.2; p=0.8 and p=0.1; p=0.6; respectively). Steroid injections were less effective in patients treated with biologics (p=0.04). However, it was more effective in AS with early hip involvement (p=0.03). Conclusion: Hip involvement is a negative prognostic factor in chronic inflammatory rheumatic diseases. Therefore, early diagnosis and management is essential in order to slow down the structural progression and the need for prosthetic surgery. Disclosure of Interests: None declared
Abstract A64: Functional genomics of metastatic Ewing sarcoma
Authors: Wajih Jawhar, Paul Waterhouse, Rama Khokha, Takeaki Ishii, Robert Turcotte, Nada Jabado, Livia Garzia
Journal: Cancer Research (2020)

Abstract Ewing sarcoma (ES) is a poorly differentiated bone and soft tissue tumor of high metastatic potential. ES mainly affects children, adolescents, and young adults (AYAs) at a frequency of ~1.5 cases per million globally. Ewing neoplasms strikingly converge on a single recurrent initiating event, which is a chromosomal translocation that generates a fusion transcript between the EWSR1 gene and a gene of the ETS family of transcription factors, most commonly FLi1 (85%). After 20 years since the discovery of the EWS-FLi1 fusion, ES remains a clinical challenge with unacceptably low survival rates, primarily due to metastasis. The bulk of research conducted to date (&amp;gt;95%) being focused on the primary tumor has resulted in a critical knowledge gap. To address this issue and unravel the dysregulated pathways in ES tumor evolution and metastatic dissemination, we harnessed the genome-wide insertional mechanism of transposons and the transduction efficiency of lentiviruses to engineer ES cell models. Human mesenchymal stem cells (hMSC), the putative cells of origin of ES, were engineered to constitutively express EWS-Fli1 accompanied by the inducible expression of a highly active transposase. Upon activation of the former, transposon-mediated mutagenesis will activate oncogenes and inactivate tumor suppressor genes, to mediate transformation of the transduced that can now engraft when implanted in recipient mice. Xenografted tumors are resected and the mice observed for development of distant metastases. Matching primary and metastatic tumors are sequenced to uncover the genes commonly affected by transposition in the two compartments. Pathway-oriented bioinformatic analysis will further reveal candidate metastatic driver genes. Matching of the targeted pathways with drugs will be used to validate the candidates by in vitro and in vivo metastasis assays. Citation Format: Wajih Jawhar, Paul Waterhouse, Rama Khokha, Takeaki Ishii, Robert Turcotte, Nada Jabado, Livia Garzia. Functional genomics of metastatic Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A64.
Computed Tomography–based Airway Surface Area–to-Volume Ratio for Phenotyping Airway Remodeling in Chronic Obstructive Pulmonary Disease
Authors: Sandeep Bodduluri, Abhilash Kizhakke Puliyakote, Arie Nakhmani, Jean-Paul Charbonnier, Joseph M. Reinhardt, Surya P. Bhatt
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Airway remodeling in chronic obstructive pulmonary disease (COPD) is due to luminal narrowing and/or loss of airways. Existing computed tomographic metrics of airway disease reflect only components of these processes. With progressive airway narrowing, the ratio of the airway luminal surface area to volume (SA/V) should increase, and with predominant airway loss, SA/V should decrease.
Designing Evolutionary-based Interception Strategies to Block the Transition from Precursor Phases to Multiple Myeloma
Authors: Francesco Maura, Ola Landgren, Gareth J. Morgan
Journal: Clinical Cancer Research (2020)

Abstract The development of next-generation sequencing technology has dramatically improved our understanding of the genetic landscape of multiple myeloma. Several new drivers and recurrent events have been reported and linked to a potential driver role. This complex landscape is enhanced by intraclonal mutational heterogeneity and variability introduced through the dimensions of time and space. The evolutionary history of multiple myeloma is driven by both the accumulation of different genomic drivers and by the activity of different mutational processes active overtime. In this review, we describe how these new findings and sequencing technologies have been progressively allowed to understand and reshape our knowledge of the complexity of multiple myeloma at each of its developmental stages: premalignant, at diagnosis, and in relapsed/refractory states. We discuss how these evolutionary concepts can be utilized in the clinic to alter evolutionary trajectories providing a framework for therapeutic intervention at early-disease stages.