tbuckley/cabot-search huggingface dataset:
Abstract 16290: Racial and Ethnic Differences in Heart Failure Progression in Post-menopausal Women: The Women’s Health Initiative
Authors: Khadijah Breathett, Randi Foraker, William T Abraham, Laura Coker, Iris Leng, Keith Whitfield, Sally Shumaker, JoAnn Manson, Charles Eaton, Barbara V Howard, Nkechinyere Ijioma, Crystal Cene, Lisa Martin, Karen Johnson, Liviu Klein
Journal: Circulation (2015)

Background: Heart failure (HF), a leading cause of morbidity and mortality in women, continues to disproportionately affect African-American (AA) women compared to women of other races/ethnicities. In a large cohort of post-menopausal women, we investigated if AA women progress through HF stages and coronary heart disease (CHD) death more rapidly than Caucasian (Cau) or Hispanic/Latina (HL) women. Methods: We assessed the American College of Cardiology/American Heart Association (ACC/AHA) HF stage A upon enrollment into the Women’s Health Initiative (1993-1998) and the progression from Stage A to Stage C, Stage C to CHD death, up to the last date of follow-up (2010). Cox proportional hazard regressions models were used to assess disease progression risk. We adjusted for age, baseline comorbidities, duration of comorbidities, interval development of myocardial infarction, ejection fraction at HF diagnosis, socioeconomic factors, and sex specific variables. Results: At baseline, AA women were younger and had a higher percentage of Stage A HF (76%) than Cau (54%) and HL (55%) women. Overall, AA and HL women had significantly lower risk of progressing from Stage A to Stage C compared to Cau women [AA vs. Cau adjusted Hazard Ratio (HR) 0.77 (95% Confidence Interval (CI) 0.64 -0.93) p = 0.0055; HL vs. Cau HR 0.54 (95% CI 0.40 -0.71) p &lt; 0.0001]. After stratifying by age groups(&lt;65, 65-69, &gt;70 years), AA women had a similar risk of progression from stage A to C compared to Cau women. When compared to Cau women, AA had an insignificant increased risk of progressing from Stage C to CHD death [adjusted HR 1.29 (95% CI 0.72 -2.32) p = 0.3883)]. Conclusions: Cau women were at higher risk for HF progression from Stage A to Stage C compared to HL women, but at similar risk as AA women. AA women had an insignificant but increased risk of progression from Stage C to CHD death compared to Cau women.
Abstract LT016: Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance
Authors: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calò, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er
Journal: Cancer Research (2021)

Abstract Metastatic dissemination of cancer cells to vital secondary organs pose a lifelong lethal threat unless they can successfully be eliminated by the immune system. Interestingly, despite their ability to evade immunity at primary organs, the vast majority of disseminated cancer cells are killed at secondary organs, suggesting that the process of dissemination renders cancer cells sensitive to immunity. Understanding how dissemination renders cancer cells sensitive to immunity would therefore provide exciting new opportunities to target metastases, but the relationship between dissemination and the immune response is not clear. In our effort to study this relationship, we manipulated cancer cells’ expression of myocardin related transcription factors A and B (MRTFA/B), which are central in regulation of actin cytoskeleton and are indispensable for metastatic invasion, dissemination and colonization. Surprisingly, despite MRTFA/B’s established roles in promoting metastasis, we found that MRTFA/B expression in cancer cells downregulated metastatic colonization in fully immuno-competent mouse models. MRTFA/B mediated decrease in colonization was completely reversed upon immune cell depletion suggesting that the immune cells exploit MRTFA/B expression in cancer cells for cytotoxicity. Among various cancer cell parameters involved in immune cell activation, T- and NK cell activation most prominently correlated with MRTFA/B driven mechanical compliance of cancer cells. Mechanical compliance, also known as stiffness, of antigen presenting cells and synthetic substrates are well-known to activate T- and NK cells through biophysical and mechano-chemical signal transduction. As such, perturbing cancer cells’ stiffness downregulated the immune response and cytotoxicity. Thus, we termed this process mechanosurveillance. Our work on mechanosurveillance will help us understand how disseminated cancer cells are targeted by immunity and how they evade it at secondary organs. Importantly the concept of mechanosurveillance will help guide the use of existing therapeutics that alter tissue stiffness and immune boosting therapies to combat metastases. Citation Format: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calò, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er. Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT016.
Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer
Authors: Tracy L. Rose, Michael R. Harrison, Allison M. Deal, Sundhar Ramalingam, Young E. Whang, Blaine Brower, Mary Dunn, Chelsea K. Osterman, Hillary M. Heiling, Marc A. Bjurlin, Angela B. Smith, Matthew E. Nielsen, Hung-Jui Tan, Eric Wallen, Michael E. Woods, Daniel George, Tian Zhang, Anthony Drier, William Y. Kim, Matthew I. Milowsky
Journal: Journal of Clinical Oncology (2021)

To evaluate the safety and efficacy of gemcitabine and cisplatin in combination with the immune checkpoint inhibitor pembrolizumab as neoadjuvant therapy before radical cystectomy (RC) in muscle-invasive bladder cancer.
Antibacterial mouthwash to prevent sexually transmitted infections in men who have sex with men taking HIV pre-exposure prophylaxis (PReGo): a randomised, placebo-controlled, crossover trial
Authors: Christophe Van Dijck, Achilleas Tsoumanis, Anke Rotsaert, Bea Vuylsteke, Dorien Van den Bossche, Elke Paeleman, Irith De Baetselier, Isabel Brosius, Jolein Laumen, Jozefien Buyze, Kristien Wouters, Lutgarde Lynen, Marjan Van Esbroeck, Natacha Herssens, Said Abdellati, Steven Declercq, Thijs Reyniers, Yven Van Herrewege, Eric Florence, Chris Kenyon
Journal: The Lancet Infectious Diseases (2021)
SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral spike vaccines
Authors: Xiaoying Shen, Haili Tang, Charlene McDanal, Kshitij Wagh, William Fischer, James Theiler, Hyejin Yoon, Dapeng Li, Barton F. Haynes, Kevin O. Sanders, Sandrasegaram Gnanakaran, Nick Hengartner, Rolando Pajon, Gale Smith, Gregory M. Glenn, Bette Korber, David C. Montefiori
Journal: Cell Host & Microbe (2021)
Patient research partner involvement in rheumatology clinical trials: analysis of journal articles 2016–2020
Authors: Huixin Wang, Sarah Stewart, Ben Darlow, Ben Horgan, Graham Hosie, Jane Clark, Nicola Dalbeth
Journal: Annals of the Rheumatic Diseases (2021)

In 2011, Ann Rheum Dis published the European League Against Rheumatism (EULAR) recommendations for the inclusion of patient representatives in scientific projects.1 Patient research partners were defined as ‘persons with a relevant disease who operate as active research team members’.1 The document strongly recommended participation of patient research partners in clinical research projects, and stated that ‘participation of patient research partners should be considered in all phases of the project’. Involvement of at least two patient research partners was recommended.1 It is unknown to what extent these recommendations have been integrated into the design and conduct of rheumatology clinical research since publication a decade ago. This study aimed to determine the involvement of patient research partners in rheumatology clinical trials published in the last 5 years.

We analysed all original articles reporting clinical trials published between January 2016 and December 2020 in rheumatology journals with Thomas Reuter’s Impact Factors >3.0 and rheumatology clinical trials in general medical journals with …
Connecting the dots: the role of connexins in the pulmonary vascular response to hypoxia
Authors: Martin Witzenrath, Wolfgang M. Kuebler
Journal: European Respiratory Journal (2021)

<b>Gap junctions, composed of connexins 37, 40 or 43, mediate the pulmonary vascular response to acute and chronic hypoxia as they propagate the hypoxic signal from the site of gas exchange retrogradely to the feeding arteri(ol)es</b>https://bit.ly/3orJKXM
Abstract PO-051: Development of web-based quality-assurance tool for radiotherapy target delineation for head and neck cancer: Quality evaluation of nasopharyngeal carcinoma
Authors: Jun Won Kim, Joseph Marsilla, Michal Kazmierski, Denis Tkachuk, Benjamin Haibe-Kains, Andrew Hope
Journal: Clinical Cancer Research (2021)

Abstract Purpose: We developed Label-It, a new web-application for rapid review of radiotherapy (RT) target volumes, and used it to evaluate the relationship between target delineation compliance to the international guidelines and treatment outcomes of nasopharyngeal carcinoma (NPC) patients undergoing definitive RT. Methods and Materials: Our radiographic image database consists of anonymized simulation CT scans, RT structures, and treatment data of 3,211 head and neck cancer patients treated between July 2005 and August 2017. We used 332 patients treated with intensity-modulated RT for pathologically confirmed NPC as the study cohort and imported intermediate risk clinical target volumes of the primary tumor (IR-CTVp) receiving 56 Gy into Label-It. We determined inclusion of anatomic sites within IR-CTVp in accordance with 2018 International guideline for CTV delineation for NPC and correlated the results with time to local failure (TTLF) using Cox-regression. Results: At a median follow-up of 5.6 years, 5-year TTLF and overall survival rates were 93.1% and 85.9% respectively. The most frequently non-compliant anatomic sites were sphenoid sinus (n = 69, 20.8%), followed by cavernous sinus (n = 38, 11.4%), left and right petrous apices (n = 37 and 32, 11.1% and 9.6%), clivus (n = 14, 4.2%), and right and left foramen rotundum (n = 14 and 12, 4.2% and 3.6%). Among 23 patients with a local failure (6.9%), the number of non-compliant cases were 8 for sphenoid sinus, 7 cavernous sinus, 4 left and 3 right petrous apices, and 2 clivus. In Cox regression analysis, T4 disease (p = 0.003), RT alone (p = 0.007), cavernous sinus non-conformity (p = 0.020) were independent prognostic factors for TTLF. Conclusions: Label-It was an effective tool for rapid review of target volumes in a large patient cohort. Despite a high compliance to the international guidelines, inadequate coverage of cavernous sinus was correlated with decreased TTLF. Citation Format: Jun Won Kim, Joseph Marsilla, Michal Kazmierski, Denis Tkachuk, Benjamin Haibe-Kains, Andrew Hope. Development of web-based quality-assurance tool for radiotherapy target delineation for head and neck cancer: Quality evaluation of nasopharyngeal carcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-051.
Transcriptional mediators of treatment resistance in lethal prostate cancer
Authors: Meng Xiao He, Michael S. Cuoco, Jett Crowdis, Alice Bosma-Moody, Zhenwei Zhang, Kevin Bi, Abhay Kanodia, Mei-Ju Su, Sheng-Yu Ku, Maria Mica Garcia, Amalia R. Sweet, Christopher Rodman, Laura DelloStritto, Rebecca Silver, John Steinharter, Parin Shah, Benjamin Izar, Nathan C. Walk, Kelly P. Burke, Ziad Bakouny, Alok K. Tewari, David Liu, Sabrina Y. Camp, Natalie I. Vokes, Keyan Salari, Jihye Park, Sébastien Vigneau, Lawrence Fong, Joshua W. Russo, Xin Yuan, Steven P. Balk, Himisha Beltran, Orit Rozenblatt-Rosen, Aviv Regev, Asaf Rotem, Mary-Ellen Taplin, Eliezer M. Van Allen
Journal: Nature Medicine (2021)

Abstract Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors 1 . Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies 2,3 . Resistance to enzalutamide was associated with cancer cell–intrinsic epithelial–mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4–6 ). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8 + T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.
The Blanket Effect: How Turning the World Upside Down Reveals the Nature of Graphene Oxide Cytocompatibility
Authors: Brian D. Holt, Anne M. Arnold, Stefanie A. Sydlik
Journal: Advanced Healthcare Materials (2021)

Abstract Extensive cytocompatibility testing of 2D nanocarbon materials including graphene oxide (GO) has been performed, but results remain contradictory. Literature has yet to account for settling—although sedimentation is visible to the eye and physics suggests that even individual graphenic flakes will settle. To investigate settling, a series of functional graphenic materials (FGMs) with differing oxidation levels, functionalities, and physical dimensions are synthesized. Though zeta potential indicates colloidal stability, significant gravitational settling of the FGMs is theoretically and experimentally demonstrated. By creating a setup to culture cells in traditional and inverted orientations in the same well, a “blanket effect” is demonstrated in which FGMs settle out of solution and cover cells at the bottom of the well, ultimately reducing viability. Inverted cells protected from the blanket effect are unaffected. Therefore, these results demonstrate that settling is a crucial factor that must be considered for FGM cytocompatibility experiments.
Delineating the Impact of Mupirocin and Chlorhexidine Gluconate in Intensive Care Units—Models and Real-Life Considerations
Authors: Kyle J. Popovich
Journal: JAMA Network Open (2021)

Eric T. Lofgren, PhD; Matthew Mietchen, MPH; Kristen V. Dicks, MD; Rebekah Moehring, MD; Deverick Anderson, MD; Centers for Disease Control Modeling Infectious Diseases in Healthcare Program
Prosaposin mediates inflammation in atherosclerosis
Authors: Mandy M. T. van Leent, Thijs J. Beldman, Yohana C. Toner, Marnix A. Lameijer, Nils Rother, Siroon Bekkering, Abraham J. P. Teunissen, Xianxiao Zhou, Roy van der Meel, Joost Malkus, Sheqouia A. Nauta, Emma D. Klein, Francois Fay, Brenda L. Sanchez-Gaytan, Carlos Pérez-Medina, Ewelina Kluza, Yu-Xiang Ye, Gregory Wojtkiewicz, Edward A. Fisher, Filip K. Swirski, Matthias Nahrendorf, Bin Zhang, Yang Li, Bowen Zhang, Leo A. B. Joosten, Gerard Pasterkamp, Arjan Boltjes, Zahi A. Fayad, Esther Lutgens, Mihai G. Netea, Niels P. Riksen, Willem J. M. Mulder, Raphaël Duivenvoorden
Journal: Science Translational Medicine (2021)

Macrophages play a central role in the pathogenesis of atherosclerosis. The inflammatory properties of these cells are dictated by their metabolism, of which the mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator. Using myeloid cell-specific nanobiologics in apolipoprotein E-deficient (Apoe-/-) mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages' inflammatory activity. By investigating transcriptome modifications, we identified Psap, a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling. Subsequent in vitro experiments revealed that Psap inhibition suppressed both glycolysis and oxidative phosphorylation. Transplantation of Psap-/- bone marrow to low-density lipoprotein receptor knockout (Ldlr-/-) mice led to a reduction in atherosclerosis development and plaque inflammation. Last, we confirmed the relationship between PSAP expression and inflammation in human carotid atherosclerotic plaques. Our findings provide mechanistic insights into the development of atherosclerosis and identify prosaposin as a potential therapeutic target.
Gut microbiota-associated compounds increase lethal prostate cancer risk.
Authors: Bryan Douglas Naelitz, Chad A. Reichard, Zeneng Wang, Xun Jia, Jianbo Li, Meir J. Stampfer, Eric A. Klein, Stanley L. Hazen, Nima Sharifi
Journal: Journal of Clinical Oncology (2021)

147 Background: Gut-microbiota-mediated metabolism of trimethylamine-associated nutrients and amino acids has been linked to altered cholesterol metabolism and endothelial inflammation. However, the association between these compounds and lethal prostate cancer (PCa) remains unknown. Methods: A nested case-control study was performed using samples from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to evaluate the association between baseline serum levels of target metabolites (choline, carnitine, betaine, γ-butyrobetaine, crotonobetaine, trimethylamine N-oxide, phenylacetylglutamine, hippuric acid, and p-cresol sulfate) and lethal PCa risk. Lethal cases were randomly matched to controls at a 1:3 ratio on the basis of age, race, and enrollment date. Multivariable logistic regression, conditioned on case status and adjusted for PSA and BMI, was performed to assess the association between analyte quartile (Q) with lethal PCa. Trend of increasing odd ratios (OR) was evaluated using the Cochran-Armitage test. Results: 173 lethal PCa cases and 519 controls were analyzed. Relative to those in Q1, cases with baseline levels of choline and betaine above the median exhibited increased odds of developing lethal PCa after adjusting for BMI and PSA (Table). Lethal PCa risk increased across quartiles of choline in a dose-dependent fashion ( P-trend: 0.005), but not for betaine (P-trend: 0.08). Higher serum levels of other trimethylamine-associated compounds including γ-butyrobetaine, crotonobetaine, trimethylamine N-oxide were not consistently associated with PCa mortality. Baseline serum levels of phenylacetylglutamine, a gut-microbiota metabolite of phenylalanine, were associated with incident lethal PCa, with risk increasing across quantiles (P-trend: 0.003). Elevations in hippuric acid and p-cresol sulfate levels were not consistently associated with greater lethal PCa risk. Conclusions: Serum levels choline, betaine, and phenylacetylglutamine are associated with PCa mortality, underscoring the potential role of gut-microbiota-mediated metabolism in the biology of lethal PCa. Clinical trial information: NCT00002540. [Table: see text]
PI3K/AKT pathway biomarkers analysis from the phase III IPATential150 trial of ipatasertib plus abiraterone in metastatic castration-resistant prostate cancer.
Authors: Johann S. De Bono, Christopher Sweeney, Sergio Bracarda, Cora N. Sternberg, Kim N. Chi, David Olmos, Shahneen Kaur Sandhu, Christophe Massard, Nobuaki Matsubara, Josep Garcia, Malgorzata Nowicka, Matthew Wongchenko, Zhen Shi
Journal: Journal of Clinical Oncology (2021)

13 Background: In IPATential150 (NCT03072238), ipatasertib (ipat) + abiraterone (abi) as first-line treatment for metastatic castration-resistant prostate cancer (mCRPC) significantly reduced the risk for disease worsening or death vs placebo (pbo) + abi in patients (pts) with tumors with PTEN loss by immunohistochemistry (IHC; HR, 0.77 [95% CI: 0.61, 0.98]; P = 0.0335) but not in the intention-to-treat population (de Bono, ESMO 2020). In patients with PTEN loss tumors by IHC, median radiographic progression-free survival (rPFS) was 16.5 mo (95% CI: 13.9, 17.0) with pbo + abi and 18.5 mo (95% CI: 16.3, 22.1) with ipat + abi. Here, we present exploratory analyses evaluating putative biomarker associations with rPFS. Methods: Before randomization, tumor samples ( &gt; 90% archival) were tested for PTEN loss by VENTANA PTEN (SP218) IHC assay (N = 1101). PTEN loss was pre-defined as ≥ 50% of tumor cells with no specific cytoplasmic IHC staining. Exploratory analysis evaluated different IHC staining cutoffs. Tumor genomic alterations were profiled with next-generation sequencing (NGS) using the Foundation Medicine FoundationOne CDx NGS assay (Shi, ASGO-GU 2020; n = 743 evaluable by NGS, of which n = 518 were PTEN evaluable). rPFS was determined by the investigator. Results: Consistent benefit with the combination arm vs pbo + abi was observed when PTEN loss by IHC was defined more stringently (rPFS at ≥ 60% tumor cells with PTEN loss: HR, 0.72 [95% CI, 0.56, 0.92]; ≥ 70%: HR, 0.72 [95% CI, 0.56, 0.93]; ≥ 80%: HR, 0.71 [95% CI, 0.54, 0.92]; ≥ 90%: HR, 0.72 [95% CI, 0.53, 0.97]; 100%: HR, 0.65 [95% CI, 0.39, 1.08]). In contrast, ipat + abi was not associated with improved rPFS in pts with PTEN intact by IHC tumors ( &lt; 50% no staining; stratified HR, 0.91 [95% CI: 0.72, 1.16]); the median rPFS was 19.1 mo (95% CI: 16.4, 21.9) with pbo + abi and 19.7 mo (95% CI: 16.4, 26.3) with ipat + abi. By NGS assessment, pts with tumors with PTEN loss and with genomic alterations in PIK3CA/AKT1/PTEN had a larger magnitude of rPFS benefit with ipat + abi than pts with no detectable alterations (Table). Conclusions: Analyses of more-stringent biomarkers associated with activation of the PI3K/AKT pathway further support ipat + abi as a treatment option for first-line mCRPC with PI3K/AKT pathway alterations, a mCRPC subtype with a worse prognosis. Clinical trial information: NCT03072238. [Table: see text]