tbuckley/cabot-search huggingface dataset:
Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer
Authors: Tejaswi Iyyanki, Baozhen Zhang, Qixuan Wang, Ye Hou, Qiushi Jin, Jie Xu, Hongbo Yang, Tingting Liu, Xiaotao Wang, Fan Song, Yu Luan, Hironobu Yamashita, Ruby Chien, Huijue Lyu, Lijun Zhang, Lu Wang, Joshua Warrick, Jay D. Raman, Joshua J. Meeks, David J. DeGraff, Feng Yue
Journal: Genome biology (2021)

Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown. RESULT: We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. CONCLUSION: In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.
Modulation of MRP1 activity reverses chemotherapy resistance in adult cancer cells
Authors: Kimberley M Hanssen, Christine C Gana, Madeleine S Wheatley, Denise M Yu, Claudia L Flemming, Richard Young, Gavin M Wright, Gwenaelle Conseil, Catherine J Kennedy, Anna deFazio, Ben Solomon, Susan P Cole, Murray D Norris, Michelle Haber, Jamie I Fletcher
Journal: Cancer Research (2019)
How COVID-19 has fundamentally changed clinical research in global health
Authors: Jay J H Park, Robin Mogg, Gerald E Smith, Etheldreda Nakimuli-Mpungu, Fyezah Jehan, Craig R Rayner, Jeanine Condo, Eric H Decloedt, Jean B Nachega, Gilmar Reis, Edward J Mills
Journal: The Lancet Global Health (2021)
Improved HIV-positive infant survival is correlated with high levels of HIV-specific ADCC activity in multiple cohorts
Authors: Zak A. Yaffe, Nicole E. Naiman, Jennifer Slyker, Bruce D. Wines, Barbra A. Richardson, P. Mark Hogarth, Rose Bosire, Carey Farquhar, Dorothy Mbori Ngacha, Ruth Nduati, Grace John-Stewart, Julie Overbaugh
Journal: Cell Reports Medicine (2021)

Defining immune responses that protect humans against diverse HIV strains has been elusive. Studying correlates of protection from mother-to-child transmission provides a benchmark for HIV vaccine protection because passively transferred HIV antibodies are present during infant exposure to HIV through breast milk. A previous study by our group illustrated that passively acquired antibody-dependent cellular cytotoxicity (ADCC) activity is associated with improved infant survival whereas neutralization is not. Here, we show, in another cohort and with two effector measures, that passively acquired ADCC antibodies correlate with infant survival. In combined analyses of data from both cohorts, there are highly statistically significant associations between higher infant survival and passively acquired ADCC levels (p = 0.029) as well as dimeric FcγRIIa (p = 0.002) or dimeric FcγRIIIa binding (p < 0.001). These results suggest that natural killer (NK) cell- and monocyte antibody-mediated effector functions may contribute to the observed survival benefit and support a role of pre-existing ADCC-mediating antibodies in clinical outcome.
Fitted Filtration Efficiency of Double Masking During the COVID-19 Pandemic
Authors: Emily E. Sickbert-Bennett, James M. Samet, Steven E. Prince, Hao Chen, Kirby L. Zeman, Haiyan Tong, William D. Bennett
Journal: JAMA Internal Medicine (2021)

This quality improvement study compares the fitted filtration efficiency of commonly available face masks worn singly, doubled, or in combinations.
Partha Kar: Changing the narrative around self-management
Authors: Partha Kar
Journal: BMJ (2021)

One of the biggest challenges for any healthcare system is how to support patients with chronic disease. While focusing on the availability of healthcare professionals is understandable, this may mean neglecting the basic tenets of chronic disease management and the greater challenge that lies elsewhere.

To me, managing chronic disease well is founded on three basic principles: self- management, peer support, and access to trained professionals. We do not spend enough time and effort on the first two.

For instance, in self-management much attention is given to what the healthcare system perceives to be the best way to deliver it instead of what is actually needed or even relevant today. A case in point is education programmes in diabetes care. Until the start of the covid-19 pandemic these programmes still …
Abstract 11478: Physical Activity and Biomarkers of Inflammation: The Genetic Epidemiology Network of Arteriopathy (GENOA) Study
Authors: Daisuke Kamimura, Seth T Lirette, B. Gwen Windham, Iftikhar J Kullo, Donald Clark, Takeki Suzuki, Adebamike A Oshunbade, Arsalan Hamid, Javed Butler, Kenneth R Butler, Thomas Mosley, Michael E Hall
Journal: Circulation (2019)

Background: Previous studies have shown the beneficial effects of physical activity (PA) on cardiovascular disease (CVD) mortality and morbidity, which may be mediated by decreased inflammation and...
Oncolytic viruses encoding bispecific T cell engagers: a blueprint for emerging immunovirotherapies
Authors: Johannes P. W. Heidbuechel, Christine E. Engeland
Journal: Journal of Hematology & Oncology (2021)

Bispecific T cell engagers (BiTEs) are an innovative class of immunotherapeutics that redirect T cells to tumor surface antigens. While efficacious against certain hematological malignancies, limited bioavailability and severe toxicities have so far hampered broader clinical application, especially against solid tumors. Another emerging cancer immunotherapy are oncolytic viruses (OVs) which selectively infect and replicate in malignant cells, thereby mediating tumor vaccination effects. These oncotropic viruses can serve as vectors for tumor-targeted immunomodulation and synergize with other immunotherapies. In this article, we discuss the use of OVs to overcome challenges in BiTE therapy. We review the current state of the field, covering published preclinical studies as well as ongoing clinical investigations. We systematically introduce OV-BiTE vector design and characteristics as well as evidence for immune-stimulating and anti-tumor effects. Moreover, we address additional combination regimens, including CAR T cells and immune checkpoint inhibitors, and further strategies to modulate the tumor microenvironment using OV-BiTEs. The inherent complexity of these novel therapeutics highlights the importance of translational research including correlative studies in early-phase clinical trials. More broadly, OV-BiTEs can serve as a blueprint for diverse OV-based cancer immunotherapies.
Myocardial Tissue Characterization in Arrhythmogenic Cardiomyopathy
Authors: Martina Perazzolo Marra, Alberto Cipriani, Stefania Rizzo, Manuel De Lazzari, Monica De Gaspari, Nicolò Akrami, Riccardo Bariani, Alessandro Zorzi, Federico Migliore, Ilaria Rigato, Carmelo Lacognata, Benedetta Giorgi, Raffaella Motta, Pietro Zucchetta, Giuseppe Tarantini, Kalliopi Pilichou, Gaetano Thiene, Barbara Bauce, Sabino Iliceto, Domenico Corrado, Cristina Basso
Journal: JACC. Cardiovascular imaging (2021)
Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability–High Gastric Cancer
Authors: Minsuk Kwon, Minae An, Samuel J. Klempner, Hyuk Lee, Kyoung-Mee Kim, Jason K. Sa, Hee Jin Cho, Jung Yong Hong, Taehyang Lee, Yang Won Min, Tae Jun Kim, Byung-Hoon Min, Woong-Yang Park, Won Ki Kang, Kyu-Tae Kim, Seung Tae Kim, Jeeyun Lee
Journal: Cancer Discovery (2021)

Abstract Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti–PD-1 antibodies. However, 50% of microsatellite instability–high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in patients with advanced MSI-H gastric cancer and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)–derived nonsynonymous mutations correlated with antitumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on-treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. In addition, an increase in PD-1+ CD8+ T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H gastric cancer and may inform development of strategies to enhance responsiveness. Significance: This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features. See related commentary by Fontana and Smyth, p. 2126. This article is highlighted in the In This Issue feature, p. 2113
Abstract PO-004: A phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma
Authors: Yaacov Lawrence, Keren Porper, Yael Shpatz, Uri Amit, Zvi Symon, Leor Zach
Journal: Clinical Cancer Research (2021)

Abstract Background Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that metabolic stress (moderate hypoglycemia) would enhance the anti-tumor efficacy of concurrent DNA damage. We further hypothesized that concurrent metformin would decrease insulin resistance and consequently elevate ketone blood level. We performed a formal prospective phase I dose-escalation trial to assess the tolerability and feasibility of this approach. Methods A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin (850mg twice-daily) combined with dietary intervention and 3) high-dose metformin (850mg three-times daily) combined with dietary intervention. Statistics: The prediction of blood ketones levels was performed using a mixed-model univariate analysis methodology. Clinicaltrials.gov NCT02149459. Results A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4/5 adverse events. Median levels of β-hydroxybutyrate increased from 0.09 mmol/l at baseline to 0.59 mmol/l during the trial (p=0.006). Ketone levels were associated with dietary factors (ketogenic ratio, p &amp;lt; 0.001), use of metformin (p = 0.02) and low insulin levels (p = 0.002). Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease. Conclusions The intervention was fairly well tolerated. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a KD combined with 850mg metformin twice daily. The trial was supported by the EU FP7 Marie Curie program FP7-MC-CIG 303795, and the Rosetrees Trust. The MCT oil was provided by Nutricia, Netherlands. Citation Format: Yaacov Lawrence, Keren Porper, Yael Shpatz, Uri Amit, Zvi Symon, Leor Zach. A phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-004.
Seroprevalence of antibody to S1 spike protein following vaccination against COVID-19 in patients receiving hemodialysis: a call to arms
Authors: Roseanne E. Billany, Haresh Selvaskandan, Sherna F. Adenwalla, Katherine L. Hull, Daniel S. March, James O. Burton, Nicolette C. Bishop, Edward J. Carr, Rupert Beale, Julian W. Tang, Paul W. Bird, Chris W. Holmes, Richard Baines, Nigel J. Brunskill, Matthew P.M. Graham-Brown
Journal: Kidney International (2021)
Dioxin-induced transcriptional regulation of CYP1A1 and CYP1B1 by the aryl hydrocarbon receptor complex
Authors: Robert T. Taylor, Feng Wang, Ruixue Zhang, Oliver Hankinson
Journal: Cancer Research (2006)

875  2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) is mediated by the Aryl Hydrocarbon Receptor complex (AHRC). The AHRC consists of a heterodimer formed between the Aryl Hydrocarbon Receptor (AHR) and the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT). The aim of this study was to investigate the kinetics of AHR and coactivator recruitment to two AHRC target genes CYP1A1 and CYP1B1 by TCDD in the human breast carcinoma cell line MCF-7. We also seek to identify coactivator proteins that are essential for CYP1A1 and/ or CYP1B1 induction. We hypothesize that the differences in TCDD-induction of CYP1A1 and CYP1B1 in these cells are based on the differences in promoter/enhancer structure of the two genes and the coactivator proteins that are recruited to each gene. The chromatin immunoprecipitation assay was employed to determine the kinetics of TCDD-induced protein recruitment to the CYP1A1 and CYP1B1 promoter and enhancer regions. We found that TCDD treatment leads to rapid recruitment of AHR to the enhancer region of both genes. As opposed to other published reports, we observed no “cycling” of the AHR on and off of the enhancer region of either gene up to 105 minutes of TCDD treatment. Nor did we observe binding of the AHR to the promoter region of either gene. Conversely, RNA polymerase II is recruited to the promoter region of both genes and not to the enhancer. RNA interference was utilized to identify coactivator proteins that are essential for cytochrome P450 induction by TCDD. We found the coactivator proteins p300 and Steroid Receptor Interacting Protein-2 (SRC-2) to be essential for both CYP1A1 and CYP1B1 maximal TCDD-induction. While the nucleosome remodeling factors Brahma/SWI2 Related Gene 1 (BRG-1) and Brahma (BRM) appear to be required for CYP1A1 induction and not CYP1B1. These results indicate that the promoter regions of CYP1A1 and CYP1B1 require a different set of transcriptional coactivators and thus may explain their different induction levels in these MCF-7 breast carcinomas.
Valve Academic Research Consortium 3: Updated Endpoint Definitions for Aortic Valve Clinical Research
Authors: Philippe Généreux, Nicolo Piazza, Maria C. Alu, Tamim Nazif, Rebecca T. Hahn, Philippe Pibarot, Jeroen J. Bax, Jonathon A. Leipsic, Philipp Blanke, Eugene H. Blackstone, Matthew T. Finn, Samir Kapadia, Axel Linke, Michael J. Mack, Raj Makkar, Roxana Mehran, Jeffrey J. Popma, Michael Reardon, Josep Rodes-Cabau, Nicolas M. Van Mieghem, John G. Webb, David J. Cohen, Martin B. Leon
Journal: Journal of the American College of Cardiology (2021)
Reply to Francesco Montorsi, Nicola Fossati, Carlo A. Bravi, Giorgio Gandaglia, Nazareno Suardi, and Alberto Briganti’s Letter to the Editor re: Sophie Knipper, Luigi Ascalone, Benjamin Ziegler, et al. Salvage Surgery in Patients with Local Recurrence After Radical Prostatectomy. Eur Urol 2021;79:537–44. Surgical Treatment of Local Recurrence Following Radical Prostatectomy: Reality or Illusion?
Authors: Sophie Knipper, Tobias Maurer
Journal: European Urology (2021)
Autoantibodies Against Methylglyoxal-Modified Apolipoprotein B100 and ApoB100 Peptide Are Associated With Less Coronary Artery Atherosclerosis and Retinopathy in Long-Term Type 1 Diabetes
Authors: Kari Anne Sveen, Kristine Bech Holte, Mona Svanteson, Kristian F. Hanssen, Jan Nilsson, Eva Bengtsson, Tore Julsrud Berg
Journal: Diabetes Care (2021)

Methylglyoxal (MGO), a reactive aldehyde forming advanced glycation end products (AGEs), is increased in diabetes and recognized by the immune system, resulting in anti-AGE-specific autoantibodies. The association of these immune responses with macro- and microvascular complications in type 1 diabetes remains unclarified. We investigated associations between MGO-modified apolipoprotein B100 (apoB100) and apoB100 peptide 5 (MGO-p5) autoantibodies and coronary atherosclerosis and retinopathy in type 1 diabetes.IgM and IgG against MGO-apoB100 and MGO-p5 were measured by ELISA in plasma from 103 subjects with type 1 diabetes and 63 control subjects (Dialong study) and in a replication cohort of 27 subjects with type 1 diabetes (Oslo study). Coronary atherosclerosis was assessed by computed tomography coronary angiography or intravascular ultrasound. Retinopathy was classified by retinal photos.MGO-apoB100 IgM and MGO-p5 IgM levels were higher in subjects with diabetes with no coronary artery stenosis compared with subjects with significant stenosis (median [interquartile range]: 96.2 arbitrary units [AU] [71-126.8] vs. 54 AU [36.1-85.4], P= 0.003 for MGO-apoB100; and 77.4 AU [58-106] vs. 36.9 AU [28.9-57.4], P= 0.005 for MGO-p5). MGO-apoB100 IgM and MGO-p5 IgM were associated with less severe coronary stenosis after adjusting for confounders (odds ratio 0.2 [95% CI 0.05-0.6], P= 0.01; and 0.22 [0.06-0.75], P= 0.02). The inverse association of MGO-p5 IgM and coronary stenosis was confirmed in the replication cohort. Subjects with proliferative retinopathy had significantly lower MGO-apoB100 IgM and MGO-p5 IgM than those with background retinopathy.Autoantibodies against AGE-modified apoB100 are inversely associated with coronary atherosclerosis and proliferative retinopathy, suggesting vascular protective effects of these autoantibodies in type 1 diabetes.
Correction: Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2+ Breast Cancer
Authors: Ariella B. Hanker, Mónica Valeria Estrada, Giampaolo Bianchini, Preston D. Moore, Junfei Zhao, Feixiong Cheng, James P. Koch, Luca Gianni, Darren R. Tyson, Violeta Sánchez, Brent N. Rexer, Melinda E. Sanders, Zhongming Zhao, Thomas P. Stricker, Carlos L. Arteaga
Journal: Cancer Research (2019)

In the original version of this article (1), the stated disclosure of the author Carlos L. Arteaga is incorrect. The error has been corrected in the latest online HTML and PDF versions of the article. The authors regret this error.
Postvaccination SARS-CoV-2 Infections Among Skilled Nursing Facility Residents and Staff Members — Chicago, Illinois, December 2020–March 2021
Authors: Richard A. Teran, Kelly A. Walblay, Elizabeth L. Shane, Shannon Xydis, Stephanie Gretsch, Alexandra Gagner, Usha Samala, Hyeree Choi, Christy Zelinski, Stephanie R. Black
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Twenty-two possible breakthrough SARS-CoV-2 infections occurred among fully vaccinated persons ≥14 days after their second dose of COVID-19 vaccine. Two thirds of persons were asymptomatic. A minority of persons with breakthrough infection experienced mild to moderate COVID-19–like symptoms; two COVID-19–related hospitalizations and one death occurred. No facility-associated secondary transmission was identified.
Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment
Authors: Sophie M. Poznanski, Kanwaldeep Singh, Tyrah M. Ritchie, Jennifer A. Aguiar, Isabella Y. Fan, Ana L. Portillo, Eduardo A. Rojas, Fatemeh Vahedi, Abdullah El-Sayes, Sansi Xing, Martin Butcher, Yu Lu, Andrew C. Doxey, Jonathan D. Schertzer, Hal W. Hirte, Ali A. Ashkar
Journal: Cell Metabolism (2021)
COVID-19 pneumonia and the pulmonary vasculature: a marriage made in hell
Authors: Peter M. George, Sujal R. Desai
Journal: European Respiratory Journal (2021)

Automated analysis of medical images is not new [1–3]. Researchers in the respiratory sciences and, particularly, the field of interstitial lung diseases, have long enthused about the potential for computers to analyse medical images thereby revealing "signals" hitherto invisible to the human eye: an enthusiasm only enhanced by recent developments in machine learning and artificial intelligence [4–6]. By leveraging the central importance of computed tomography (CT) scanning for diagnosis, treatment decisions and prognostication, a key aim is to identify imaging biomarkers to more accurately phenotype disease and, in so doing, move a step closer to truly patient-centric medicine. Another goal is to apply novel imaging analyses to pathogenesis, disease "behaviour" and prognostication in the hope that this might unlock new therapeutic approaches. Given the digital nature of the data and the potentially myriad imaging patterns, frequently compounded by patient, therapeutic and disease-based factors, lung imaging is ideally suited to more sophisticated analytic approaches. Quantitative CT of the pulmonary vasculature is potentially important in COVID-19 associated pneumonia <https://bit.ly/3vUTTRM>
Not all melanomas are created equal: a review and call for more research into nodular melanoma
Authors: C. Dessinioti, A.C. Geller, D.C. Whiteman, C. Garbe, J.J. Grob, J.W. Kelly, R.A. Scolyer, R.V. Rawson, A. Lallas, G. Pellacani, A.J. Stratigos
Journal: British Journal of Dermatology (2021)

Among the histogenic subtypes of melanoma, nodular melanoma (NM) is the major contributor for thicker and fatal melanomas and it has been associated with melanoma-specific death in thin tumours, highlighting an important subgroup of 'aggressive thin' melanomas. This review provides a synthesis of the distinct characteristics of NM, with respect to epidemiology and risk factors, clinical presentation, histopathology, molecular and dermoscopic aspects, and screening practices. The real challenges are to find better biomarkers of aggressiveness and to know whether the control of such aggressive melanomas can be influenced by targeted interventions such as early detection, drug interventions and preventive strategies.