tbuckley/cabot-search huggingface dataset:
Abstract P5-11-03: Altered adipose-derived mesenchymal stem/stromal cells induced by obesity in the breast cancer microenvironment
Authors: Andreas Ritter, Susanne Roth, Alexandra Friemel, Nina-Naomi Kreis, Frank Louwen, Christine Solbach, Juping Yuan
Journal: Cancer Research (2022)

Abstract It is well documented that obesity, characterized by an increased body mass index (BMI≥30), is an important risk factor for the development of aggressive breast cancer (BC), which is associated with a reduced overall survival rate and decreased treatment response. The tumor microenvironment (TME), a cellular network majorly constructed by adipocytes, adipose-derived mesenchymal stem/stromal cells (bASCs) and immune cells, impacts progression of breast cancer and treatment response of patients. This study aims to examine how obesity influences the functional characteristics of bASCs in comparison to lean bASCs in the TME. To address this issue, various molecular, biological and cellular methods are applied including transcriptomic profiling and functional assays to characterize at first the features of bASCs in the TME (adjacent to tumor; -aT/distant to tumor; -dT) in obese (ob-) and lean (ln-) bASCs (n=5, for each group) patients with breast cancer. Second, based on the transcriptomic data, we investigated the interaction of bASCs with triple negative as well as triple positive BC cell lines in 3D-spheroids and in standard 2D-cell culture conditions.Indicated by the gene signature the TME shifts bASCs towards a cancer supporting phenotype with a significant deregulated protein expression, cytokine/chemokine secretion, and reduced differentiation capacity. These changes affect critically the cell-cell interaction of BC cells with bASCs. bASCs isolated adjacent to the tumor increase the malignancy of BCs by stimulating the proliferation, migration, invasion and chemoresistance of these cells significantly. These observed effects are further enhanced by ob-aT bASCs. In conclusion, this study identifies over 900 genes deregulated in bASCs adjacent to breast cancer. Many of these genes are associated with pathways known for the development of malignant cells. Moreover, it clarifies differences in obese versus lean bASCs and their impacts on progression of breast cancer cells. Citation Format: Andreas Ritter, Susanne Roth, Alexandra Friemel, Nina-Naomi Kreis, Frank Louwen, Christine Solbach, Juping Yuan. Altered adipose-derived mesenchymal stem/stromal cells induced by obesity in the breast cancer microenvironment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-11-03.
UTILIZATION OF SACUBITRIL-VALSARTAN FOR RIGHT VENTRICULAR FAILURE IN ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA
Authors: Theresa Maitz, Rahul Gupta, David Egeler, Thomas B. Weiss, Makoto Nagahama, Apurva Vijay Vyas, Deborah W. Sundlof
Journal: Journal of the American College of Cardiology (2022)
FAILURE OF THE SURGICAL ABLATION OF PAROXYSMAL ATRIAL FIBRILLATION: THE IMPORTANCE OF PREOPERATIVE LEFT ATRIAL AND RIGHT ATRIAL FUNCTION ESTIMATED BY CONVENTIONAL AND SPECKLE-TRACKING ECHOCARDIOGRAPHY
Authors: Olga N. Kislitsina, Vera H. Rigolin, James D. Thomas, Andrei Churyla, Bonnie Kane, Jane T. Kruse, Manyun Zhao, Adin-Cristian Andrei, James L. Cox, Patrick M. McCarthy
Journal: Journal of the American College of Cardiology (2022)
Exosomal CD73 from serum of patients with melanoma suppresses lymphocyte functions and is associated with therapy resistance to anti-PD-1 agents
Authors: Roberta Turiello, Mariaelena Capone, Elva Morretta, Maria Chiara Monti, Gabriele Madonna, Rosa Azzaro, Pasquale Del Gaudio, Ester Simeone, Antonio Sorrentino, Paolo A Ascierto, Silvana Morello
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background CD73 is an ectonucleotidase producing the immunosuppressor mediator adenosine. Elevated levels of circulating CD73 in patients with cancer have been associated with disease progression and poor response to immunotherapy. Immunosuppressive pathways associated with exosomes can affect T-cell function and the therapeutic efficacy of anti-programmed cell-death protein 1 (anti-PD-1) therapy. Here, we conducted a retrospective pilot study to evaluate levels of exosomal CD73 before and early during treatment with anti-PD-1 agents in patients with melanoma and its potential contribution to affect T-cell functions and to influence the clinical outcomes of anti-PD-1 monotherapy. Methods Exosomes were isolated by mini size exclusion chromatography from serum of patients with melanoma (n=41) receiving nivolumab or pembrolizumab monotherapy. Expression of CD73 and programmed death-ligand 1 (PD-L1) were evaluated on exosomes enriched for CD63 by on-bead flow cytometry. The CD73 AMPase activity was evaluated by mass spectrometry, also in the presence of selective inhibitors of CD73. Interferon (IFN)-γ production and granzyme B expression were measured in CD3/28 activated T cells incubated with exosomes in presence of the CD73 substrate AMP. Levels of CD73 and PD-L1 on exosomes were correlated with therapy response. Exosomes isolated from healthy subjects were used as control. Results Isolated exosomes carried CD73 on their surface, which is enzymatically active in producing adenosine. Incubation of exosomes with CD3/28 activated T cells in the presence of AMP resulted in a significant reduction of IFN-γ release, which was reversed by the CD73 inhibitor APCP or by the selective A2A adenosine receptor antagonist ZM241385. Expression levels of exosomal CD73 from serum of patients with melanoma were not significantly different from those in healthy subjects. Early on-treatment, expression levels of both CD73 and PD-L1 on exosomes isolated from patients receiving pembrolizumab or nivolumab monotherapy were significantly increased compared with baseline. Early during therapy exosomal PD-L1 increased in responders, while exosomal CD73 resulted significantly increased in non-responders. Conclusions CD73 expressed on exosomes from serum of patients with melanoma produces adenosine and contributes to suppress T-cell functions. Early on-treatment, elevated expression levels of exosomal CD73 might affect the response to anti-PD-1 agents in patients with melanoma who failed to respond to therapy.
Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review
Authors: Sarah U. Morton, John Christodoulou, Gregory Costain, Francesco Muntoni, Emma Wakeling, Monica H. Wojcik, Courtney E. French, Anna Szuto, James J. Dowling, Ronald D. Cohn, F. Lucy Raymond, Basil T. Darras, David A. Williams, Sebastian Lunke, Zornitza Stark, David H. Rowitch, Pankaj B. Agrawal
Journal: JAMA Neurology (2022)

<h3>Importance</h3> Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease. <h3>Observations</h3> The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations. <h3>Conclusions and Relevance</h3> This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice.
The gut microbiota mediates protective immunity against tuberculosis <i>via</i> modulation of lncRNA
Authors: Fang Yang, Yi Yang, Lingming Chen, Zhiyi Zhang, Linna Liu, Chunmin Zhang, Qiongdan Mai, Yiwei Chen, Zixu Chen, Tao Lin, Liang Chen, Huixin Guo, Lin Zhou, Hongbo Shen, Xinchun Chen, Lei Liu, Guoliang Zhang, Hongying Liao, Lingchan Zeng, Gucheng Zeng
Journal: Gut Microbes (2022)

The gut-lung axis has been implicated as a potential therapeutic target in lung disorders. While increasing evidence suggests that gut microbiota plays a critical role in regulating host immunity and contributing to tuberculosis (TB) development and progression, the underlying mechanisms whereby gut microbiota may impact TB outcomes are not fully understood. Here, we found that broad-spectrum antibiotics treatment increased susceptibility to Mycobacterium tuberculosis (M. tuberculosis) infection and modulated pulmonary inflammatory responses in mouse M. tuberculosis infection model. We then identified a commensal gut bacteria-regulated lncRNA, termed lncRNA-CGB, which was down-regulated by dysbiosis of gut microbiota during TB infection. Furthermore, we found that Bacteroides fragilis (B. fragilis) was a direct regulator of lncRNA-CGB, and oral administration of B. fragilis enhanced expression of lncRNA-CGB and promoted anti-TB immunity. Genomic knock-out of lncRNA-CGB led to reduced IFN-γ expression and impaired anti-TB immunity, therefore leading to detrimental effects on M. tuberculosis infection. Mechanistically, lncRNA-CGB interacted with EZH2 and negatively regulated H3K27 tri-methylation (H3K27Me3) epigenetic programming, leading to enhanced IFN-γ expression. Thus, this work not only uncovered previously unrecognized importance of gut bacteria-lncRNA-EZH2-H3K27Me3 axis in conferring immune protection against TB but also identified a potential new paradigm to develop a microbiota-based treatment against TB and potentially other diseases.
SACUBITRIL/VALSARTAN IN THE TREATMENT OF SYSTEMIC RIGHT VENTRICULAR FAILURE: FOLLOW-UP.
Authors: Marieke Nederend, Monique R.M. Jongbloed, Philippine Kiès, Hubert W. Vliegen, Laurens Tops, Martin J. Schalij, Anastasia D. Egorova
Journal: Journal of the American College of Cardiology (2022)
PATIENT REPORTED VERSUS PHYSICIAN-ASSESSED HEALTH STATUS IN HEART FAILURE WITH REDUCED AND PRESERVED EJECTION FRACTION FROM ASIAN-HF REGISTRY
Authors: Kanako Teramoto, Wan Ting Tay, Jasper Tromp, Tiew-Hwa Katherine Teng, Chanchal Chandramouli, Wouter Ouwerkerk, Claire A. Lawson, Weiting Huang, Chung-Lieh Hung, Vijay Chopra, Inder Anand, Arthur Mark Richards, Carolyn S.P. Lam
Journal: Journal of the American College of Cardiology (2022)
Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India
Authors: Akash Khobragade, Suresh Bhate, Vijendra Ramaiah, Shrikant Deshpande, Krishna Giri, Himanshu Phophle, Pravin Supe, Inderjeet Godara, Ramesh Revanna, Rajnish Nagarkar, Jayesh Sanmukhani, Ayan Dey, T M Chozhavel Rajanathan, Kevinkumar Kansagra, Parshottam Koradia
Journal: The Lancet (2022)
Aberrant RNA Splicing Is a Primary Link between Genetic Variation and Pancreatic Cancer Risk
Authors: Jianbo Tian, Can Chen, Meilin Rao, Ming Zhang, Zequn Lu, Yimin Cai, Pingting Ying, Bin Li, Haoxue Wang, Lu Wang, Yao Li, Jinyu Huang, Linyun Fan, Xiaomin Cai, Caibo Ning, Yanmin Li, Fuwei Zhang, Wenzhuo Wang, Yuan Jiang, Yizhuo Liu, Min Wang, Heng Li, Chaoqun Huang, Zhiyong Yang, Jiang Chang, Ying Zhu, Xiaojun Yang, Xiaoping Miao
Journal: Cancer Research (2022)

Abstract Understanding the genetic variation underlying transcript splicing is essential for fully dissecting the molecular mechanisms of common diseases. The available evidence from splicing quantitative trait locus (sQTL) studies using pancreatic ductal adenocarcinoma (PDAC) tissues have been limited to small sample sizes. Here we present a genome-wide sQTL analysis to identify SNP that control mRNA splicing in 176 PDAC samples from TCGA. From this analysis, 16,175 sQTLs were found to be significantly enriched in RNA-binding protein (RBP) binding sites and chromatin regulatory elements and overlapped with known loci from PDAC genome-wide association studies (GWAS). sQTLs and expression quantitative trait loci (eQTL) showed mostly nonoverlapping patterns, suggesting sQTLs provide additional insights into the etiology of disease. Target genes affected by sQTLs were closely related to cancer signaling pathways, high mutational burden, immune infiltration, and pharmaceutical targets, which will be helpful for clinical applications. Integration of a large-scale population consisting of 2,782 patients with PDAC and 7,983 healthy controls identified an sQTL variant rs1785932-T allele that promotes alternative splicing of ELP2 exon 6 and leads to a lower level of the ELP2 full-length isoform (ELP2_V1) and a higher level of a truncated ELP2 isoform (ELP2_V2), resulting in decreased risk of PDAC [OR = 0.83; 95% confidence interval (CI), 0.77–0.89; P = 1.16 × 10−6]. The ELP2_V2 isoform functioned as a potential tumor suppressor gene, inhibiting PDAC cell proliferation by exhibiting stronger binding affinity to JAK1/STAT3 than ELP2_V1 and subsequently blocking the pathologic activation of the phosphorylated STAT3 (pSTAT3) pathway. Collectively, these findings provide an informative sQTL resource and insights into the regulatory mechanisms linking splicing variants to PDAC risk. Significance: In pancreatic cancer, splicing quantitative trait loci analysis identifies a rs1785932 variant that contributes to decreased risk of disease by influencing ELP2 mRNA splicing and blocking the STAT3 oncogenic pathway.
New 3-Dimensional Volumetric Ultrasound Method for Accurate Quantification of Atherosclerotic Plaque Volume
Authors: Beatriz López-Melgar, Virgina Mass, Paula Nogales, Javier Sánchez-González, Robert Entrekin, Antoine Collet-Billon, Xavier Rossello, Leticia Fernández-Friera, Antonio Fernández-Ortiz, Javier Sanz, Jacob F. Bentzon, Héctor Bueno, Borja Ibáñez, Valentín Fuster
Journal: JACC. Cardiovascular imaging (2022)

Carotid and femoral plaque burden is a recognized biomarker of cardiovascular disease risk. A new electronic-sweep 3-dimensional (3D)-matrix transducer method can improve the functionality and image quality of vascular ultrasound atherosclerosis imaging.This study aimed to validate this method for plaque volume measurement in early and intermediate-advanced plaques in the carotid and femoral territories.Plaque volumes were measured ex vivo in pig carotid and femoral artery specimens by 3-dimensional vascular ultrasound (3DVUS) using a 3D-matrix (electronic-sweep) transducer and its associated 3D plaque quantification software, and were compared with gold-standard histology. To test the clinical feasibility and accuracy of the 3D-matrix transducer, an experiment was conducted in intermediate-high risk individuals with carotid and femoral atherosclerosis. The results were compared with those obtained using the previously validated mechanical-sweep 3D transducer and established 2-dimensional (2D)-based plaque quantification software.In the ex vivo study, the authors assessed 19 atherosclerotic plaques (plaque volume, 0.76 µL-56.30 μL), finding strong agreement between measurements with the 3D-matrix transducer and the histological gold-standard (intraclass correlation coefficient [ICC]: 0.992; [95% CI: 0.978-0.997]). In the clinical analysis of 20 patients (mean age 74.6 ± 4.45 years; 40% men), the authors found 64 (36 carotid and 28 femoral) of 80 scanned territories with atherosclerosis (measured atherosclerotic volume, 10 μL-859 μL). There was strong agreement between measurements made from electronic-sweep and mechanical-sweep 3DVUS transducers (ICC: 0.997 [95% CI: 0.995-0.998]). Agreement was also high between plaque volumes estimated by the 2D and 3D plaque quantification software applications (ICC: 0.999 [95% CI: 0.998-0.999]). Analysis time was significantly shorter with the 3D plaque quantification software than with the 2D multislice approach with a mean time reduction of 46%.3DVUS using new matrix transducer technology, together with improved 3D plaque quantification software, simplifies the accurate volume measurement of early (small) and intermediate-advanced plaques located in carotid and femoral arteries.
Changes in household food and drink purchases following restrictions on the advertisement of high fat, salt, and sugar products across the Transport for London network: A controlled interrupted time series analysis
Authors: Amy Yau, Nicolas Berger, Cherry Law, Laura Cornelsen, Robert Greener, Jean Adams, Emma J. Boyland, Thomas Burgoine, Frank de Vocht, Matt Egan, Vanessa Er, Amelia A. Lake, Karen Lock, Oliver Mytton, Mark Petticrew, Claire Thompson, Martin White, Steven Cummins
Journal: PLoS Medicine (2022)

Restricting the advertisement of products with high fat, salt, and sugar (HFSS) content has been recommended as a policy tool to improve diet and tackle obesity, but the impact on HFSS purchasing is unknown. This study aimed to evaluate the impact of HFSS advertising restrictions, implemented across the London (UK) transport network in February 2019, on HFSS purchases.Over 5 million take-home food and drink purchases were recorded by 1,970 households (London [intervention], n = 977; North of England [control], n = 993) randomly selected from the Kantar Fast Moving Consumer Goods panel. The intervention and control samples were similar in household characteristics but had small differences in main food shopper sex, socioeconomic position, and body mass index. Using a controlled interrupted time series design, we estimated average weekly household purchases of energy and nutrients from HFSS products in the post-intervention period (44 weeks) compared to a counterfactual constructed from the control and pre-intervention (36 weeks) series. Energy purchased from HFSS products was 6.7% (1,001.0 kcal, 95% CI 456.0 to 1,546.0) lower among intervention households compared to the counterfactual. Relative reductions in purchases of fat (57.9 g, 95% CI 22.1 to 93.7), saturated fat (26.4 g, 95% CI 12.4 to 40.4), and sugar (80.7 g, 95% CI 41.4 to 120.1) from HFSS products were also observed. Energy from chocolate and confectionery purchases was 19.4% (317.9 kcal, 95% CI 200.0 to 435.8) lower among intervention households than for the counterfactual, with corresponding relative reductions in fat (13.1 g, 95% CI 7.5 to 18.8), saturated fat (8.7 g, 95% CI 5.7 to 11.7), sugar (41.4 g, 95% CI 27.4 to 55.4), and salt (0.2 g, 95% CI 0.1 to 0.2) purchased from chocolate and confectionery. Relative reductions are in the context of secular increases in HFSS purchases in both the intervention and control areas, so the policy was associated with attenuated growth of HFSS purchases rather than absolute reduction in HFSS purchases. Study limitations include the lack of out-of-home purchases in our analyses and not being able to assess the sustainability of observed changes beyond 44 weeks.This study finds an association between the implementation of restrictions on outdoor HFSS advertising and relative reductions in energy, sugar, and fat purchased from HFSS products. These findings provide support for policies that restrict HFSS advertising as a tool to reduce purchases of HFSS products.
Short-term, intermediate-term and long-term risks of acute coronary syndrome in cohorts of patients with RA starting biologic DMARDs: results from four Nordic countries
Authors: Benedicte Delcoigne, Lotta Ljung, Sella A Provan, Bente Glintborg, Merete Lund Hetland, Kathrine Lederballe Grøn, Ritva Peltomaa, Heikki Relas, Carl Turesson, Bjorn Gudbjornsson, Brigitte Michelsen, Johan Askling
Journal: Annals of the Rheumatic Diseases (2022)

To compare the 1-year, 2-year and 5-year incidences of acute coronary syndrome (ACS) in patients with rheumatoid arthritis (RA) starting any of the biologic disease-modifying antirheumatic drugs (bDMARDs) currently available in clinical practice and to anchor these results with a general population comparator.Observational cohort study, with patients from Denmark, Finland, Norway and Sweden starting a bDMARD during 2008-2017. Time to first ACS was identified through register linkages. We calculated the 1-year, 2-year and 5-year incidence rates (IR) (on drug and ever since treatment start) and used Cox regression (HRs) to compare ACS incidences across treatments taking ACS risk factors into account. Analyses were further performed separately in subgroups defined by age, number of previous bDMARDs and history of cardiovascular disease. We also compared ACS incidences to an individually matched general population cohort.24 083 patients (75% women, mean age 56 years) contributing 40 850 treatment courses were included. During the maximum (5 years) follow-up (141 257 person-years (pyrs)), 780 ACS events occurred (crude IR 5.5 per 1000 pyrs). Overall, the incidence of ACS in RA was 80% higher than that in the general population. For all bDMARDs and follow-up definitions, HRs were close to 1 (etanercept as reference) with the exception of the 5-year risk window, where signals for abatacept, infliximab and rituximab were noted.The rate of ACS among patients with RA initiating bDMARDs remains elevated compared with the general population. As used in routine care, the short-term, intermediate-term and longer-term risks of ACS vary little across individual bDMARDs.
Integrating melt electrowriting and inkjet bioprinting for engineering structurally organized articular cartilage
Authors: A. Dufour, X. Barceló Gallostra, C. O'Keeffe, K. Eichholz, S. Von Euw, O. Garcia, D.J. Kelly
Journal: Biomaterials (2022)

Successful cartilage engineering requires the generation of biological grafts mimicking the structure, composition and mechanical behaviour of the native tissue. Here melt electrowriting (MEW) was used to produce arrays of polymeric structures whose function was to orient the growth of cellular aggregates spontaneously generated within these structures, and to provide tensile reinforcement to the resulting tissues. Inkjet printing was used to deposit defined numbers of cells into MEW structures, which self-assembled into an organized array of spheroids within hours, ultimately generating a hybrid tissue that was hyaline-like in composition. Structurally, the engineered cartilage mimicked the histotypical organization observed in skeletally immature synovial joints. This biofabrication framework was then used to generate scaled-up (50 mm × 50 mm) cartilage implants containing over 3,500 cellular aggregates in under 15 min. After 8 weeks in culture, a 50-fold increase in the compressive stiffness of these MEW reinforced tissues were observed, while the tensile properties were still dominated by the polymer network, resulting in a composite construct demonstrating tension-compression nonlinearity mimetic of the native tissue. Helium ion microscopy further demonstrated the development of an arcading collagen network within the engineered tissue. This hybrid bioprinting strategy provides a versatile and scalable approach to engineer cartilage biomimetic grafts for biological joint resurfacing.
PREVALENCE, CHARACTERISTICS, AND OUTCOMES OF PATIENTS WITH AMYLOIDOSIS AND RENAL INSUFFICIENCY: A NATIONAL INPATIENT SAMPLE ANALYSIS
Authors: Alejandro Sarabia Gonzalez, Jennifer Ma, Tayana Rodriguez, Sarah Ream, Luis Alvarado, Alok Dwivedi, Debabrata Mukherjee
Journal: Journal of the American College of Cardiology (2022)