tbuckley/cabot-search huggingface dataset:
The state of latency in microbial pathogenesis
Authors: Liise-anne Pirofski, Arturo Casadevall
Journal: Journal of Clinical Investigation (2020)

The state of latency occurs when a microbe's persistence in a host produces host damage without perturbing homeostasis sufficiently to cause clinical symptoms or disease. The mechanisms contributing to latency are diverse and depend on the nature of both the microbe and the host. Latency has advantages for both host and microbe. The host avoids progressive damage caused by interaction with the microbe that may translate into disease, and the microbe secures a stable niche in which to survive. Latency is clinically important because some latent microbes can be transmitted to other hosts, and it is associated with a risk for recrudescent microbial growth and development of disease. In addition, it can predispose the host to other diseases, such as malignancies. Hence, latency is a temporally unstable state with an eventual outcome that mainly depends on host immunity. Latency is an integral part of the pathogenic strategies of microbes that require human (and/or mammalian) hosts, including herpesviruses, retroviruses, Mycobacterium tuberculosis, and Toxoplasma gondii. However, latency is also an outcome of infection with environmental organisms such as Cryptococcus neoformans, which require no host in their replicative cycles. For most microbes that achieve latency, there is a need for a better understanding and more investigation of host and microbial mechanisms that result in this state.
AB0152 LENABASUM, A CB2 AGONIST, INHIBITS INFLAMMASOME ACTIVATION
Authors: S. Chintalacharuvu, P. Zang, B. White, S. Atamas
Journal: Annals of the Rheumatic Diseases (2020)

Background: Upregulation of the innate immune response via the activity of Toll-like receptors and the NLRP3 inflammasome have been suggested as initiating events that can drive fibrosis in systemic sclerosis (SSc) (Pharmacol Ther. 2018;192:163). Lenabasum, a cannabinoid receptor type 2 agonist, is known to activate the resolution phase of acute human innate immune responses triggered through Toll-like receptor activation, favoring production of pro-resolving lipid mediators, reducing inflammatory infiltrates, and increasing bacterial clearance (Clin Pharmacol Ther. 2018;104:675). Given the potential importance of inflammasome activation in the pathogenesis of SSc, the question remained whether lenabasum inhibits inflammasome activation. Objectives: Assess effects of lenabasum on IL-1β and IL-18 production induced by inflammasome activation. Methods: Primary human macrophages were derived from monocytes, stimulated with LPS and ATP to active inflammasomes and cultured with lenabasum. Levels of IL-1β and IL-18 were measured in cell supernatants by ELISA. Separately, human PBMC were activated with 0.1 µg/ml LPS ± 10 µM lenabasum for 24 hours, and effects of lenabasum on the levels of IL-1β and other pro-inflammatory cytokines were measured. Results: Lenabasum significantly inhibited IL-1β and IL-18 secretion by monocyte-derived macrophages, with IC 50 = 66.73 ± 3.92 nM and 349.23 ± 21.27 nM, respectively. A control inflammasome activation inhibitor, MCC950, which showed IC 50 = 18.33 ± 1.22 nM for IL-1 β inhibition and IC 50 = 21.43 ± 0.81 nM for IL-8 inhibition. Conclusion: Lenabasum inhibits inflammasome activation, which could contribute to potential therapeutic efficacy in SSc and other autoimmune diseases. References: [1]Henderson, J., S. Bhattacharyya, J. Varga, and S. O’Reilly. 2018. ‘Targeting TLRs and the inflammasome in systemic sclerosis’, Pharmacol Ther, 192: 163-69. [2]Motwani, M. P., F. Bennett, P. C. Norris, A. A. Maini, M. J. George, J. Newson, A. Henderson, A. J. Hobbs, M. Tepper, B. White, C. N. Serhan, R. MacAllister, and D. W. Gilroy. 2018. ‘Potent Anti-Inflammatory and Pro-Resolving Effects of Anabasum in a Human Model of Self-Resolving Acute Inflammation’, Clin Pharmacol Ther, 104: 675-86. Disclosure of Interests: Subba Chintalacharuvu Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Ping Zang Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Sergei Atamas Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.
Factors Associated with Non-Melanoma Skin Cancer (NMSC) Among Chronic Lymphocytic Leukemia (CLL) Patients
Authors: Geffen Kleinstern, Abdul Rishi, Sara J Achenbach, Kari G Chaffee, Neil E. Kay, Tait D Shanafelt, Jacob Inda, Aaron Norman, Timothy G. Call, Christian L Baum, James R. Cerhan, Susan L Slager
Journal: Blood (2017)
Clinical Restaging and Tumor Sequencing are Inaccurate Indicators of Response to Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer
Authors: Russell E.N. Becker, Alexa R. Meyer, Aaron Brant, Adam C. Reese, Michael J. Biles, Kelly T. Harris, George Netto, Andres Matoso, Jean Hoffman-Censits, Noah M. Hahn, Woonyoung Choi, David McConkey, Phillip M. Pierorazio, Michael H. Johnson, Mark P. Schoenberg, Max R. Kates, Alex Baras, Trinity J. Bivalacqua
Journal: European Urology (2020)
Abstract PR09: Gene expression profiling in wild-type and mutant FGFR3 metastatic urothelial cancer treated with combination therapy with vofatamab and pembrolizumab
Authors: Woonyoung Choi, David McConkey, I-ling Lee, Graeme Currie, Steve Abella, William Kelly, Arlene Siefker-Radtke
Journal: Clinical Cancer Research (2020)

Abstract Background: FGFR3 mutations (mutFGFR3) are present in up to 20-35% of metastatic bladder (mUC) and upper tract urothelial cancer, respectively. Early data suggest that these tumors respond better to FGFR inhibition as compared with immunotherapy. Methods: Patients who failed prior treatment for mUC were treated with vofatamab, an antibody targeting both wild-type (wtFGFR3) and mutFGFR3. Patients were treated with a loading dose of vofatamab 25 mg/kg with a biopsy pre- and post-treatment, followed by combination therapy with pembrolizumab to cohorts of patients with and without mutFGFR3. We performed gene expression profiling on paired biopsies from patients enrolled to date. Results: We performed whole-transcriptome RNAseq on 17 matched tumors. The responses to the therapy were 7 partial responses (PR), 4 stable disease (SD), 5 progressed disease (PD), and 1 unknown. Surprisingly, we did not observe any relationships between FGFR3 mutation status and clinical response (ORR:1/3 mutant and 6/14 wild-type). Unsupervised cluster analysis of 17 matched tumors revealed the presence of two clusters: cluster 1 was enriched for responders (6 PR, 1 SD, and 1 PD), compared with cluster 2 (1 PD, 3 SD, and 4 PD). The significantly differentially expressed genes comparing cluster 1 and 2 were extracted and analyzed by Ingenuity Pathway Analysis (Sigma). Immune cell trafficking pathways, including migration of lymphocytes/T cells and phagocytes, were significantly upregulated in cluster 2 (p&amp;lt;0.001). We then used BASE47 (47 gene signature for basal and luminal subtypes) to assign 17 paired tumors to the molecular subtypes. Of the responding tumors, 6 were luminal and 1 was basal. To further explore sensitivity/resistance mechanisms, the differentially expressed genes between pre- and post-treated PR tumors were extracted and were used to perform IPA analysis. Upstream regulators (CEBPA and RXRA) that control luminal biology were significantly activated after treatment (p&amp;lt;0.001, Z score &amp;gt;2). Conclusions: Luminal biology may sensitize to combination of vofatamab with pembrolizumab regardless of presence of mutFGFR3, suggesting a role for this combination in wtFGFR3 mUC. Larger cohorts are needed to confirm these results. This abstract is also being presented as Poster B25. Citation Format: Woonyoung Choi, David McConkey, I-ling Lee, Graeme Currie, Steve Abella, William Kelly, Arlene Siefker-Radtke. Gene expression profiling in wild-type and mutant FGFR3 metastatic urothelial cancer treated with combination therapy with vofatamab and pembrolizumab [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR09.
Clinical Diagnosis—Is There Any Other Type?
Authors: Gurpreet Dhaliwal
Journal: JAMA Internal Medicine (2020)

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Association Between Bisphenol A Exposure and Risk of All-Cause and Cause-Specific Mortality in US Adults
Authors: Wei Bao, Buyun Liu, Shuang Rong, Susie Y. Dai, Leonardo Trasande, Hans-Joachim Lehmler
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Bisphenol A (BPA) is a major public health concern because of its high-volume industrial production, ubiquitous exposure to humans, and potential toxic effects on multiple organs and systems in humans. However, prospective studies regarding the association of BPA exposure with long-term health outcomes are sparse. <h3>Objective</h3> To examine the association of BPA exposure with all-cause mortality and cause-specific mortality among adults in the United States. <h3>Design, Setting, and Participants</h3> This nationally representative cohort study included 3883 adults aged 20 years or older who participated in the US National Health and Nutrition Examination Survey 2003-2008 and provided urine samples for BPA level measurements. Participants were linked to mortality data from survey date through December 31, 2015. Data analyses were conducted in July 2019. <h3>Exposures</h3> Urinary BPA levels were quantified using online solid-phase extraction coupled to high-performance liquid chromatography–isotope dilution tandem mass spectrometry. <h3>Main Outcomes and Measures</h3> Mortality from all causes, cardiovascular disease, and cancer. <h3>Results</h3> This cohort study included 3883 adults aged 20 years or older (weighted mean [SE] age, 43.6 [0.3] years; 2032 women [weighted, 51.4%]). During 36 514 person-years of follow-up (median, 9.6 years; maximum, 13.1 years), 344 deaths occurred, including 71 deaths from cardiovascular disease and 75 deaths from cancer. Participants with higher urinary BPA levels were at higher risk for death. After adjustment for age, sex, race/ethnicity, socioeconomic status, dietary and lifestyle factors, body mass index, and urinary creatinine levels, the hazard ratio comparing the highest vs lowest tertile of urinary BPA levels was 1.49 (95% CI, 1.01-2.19) for all-cause mortality, 1.46 (95% CI, 0.67-3.15) for cardiovascular disease mortality, and 0.98 (95% CI, 0.40-2.39) for cancer mortality. <h3>Conclusions and Relevance</h3> In this nationally representative cohort of US adults, higher BPA exposure was significantly associated with an increased risk of all-cause mortality. Further studies are needed to replicate these findings in other populations and determine the underlying mechanisms.
FRI0013 Open-label evaluation of the efficacy and safety of etanercept in common rheumatology usage (ecru)
Authors: M Herold, A Aytekin, G Klein, J Nowak, W Siegmeth, U Stuby
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Tumour Necrosis Factor-alpha (TNFα) plays an important role in the inflammatory processes of RA and the resulting joint pathology. Etanercept is a dimeric fusion protein consisting of two p75 TNFα receptors linked to the Fc portion of the human IgG1. This protein can bind and inactivate up to two free molecules of TNFα. The safety and efficacy of etanercept has been demonstrated in human clinical trials of early RA and active RA. <h3>Objectives</h3> The Primary efficacy variable was the proportion of patients achieving 20% improvement in symptoms according to American College of Rheumatology (ACR) response criteria at Week 16. Patients were evaluated clinically for adverse events at each visit. <h3>Methods</h3> This study was conducted in 55 Austrian outpatients with active RA who have failed at least one disease-modifying anti-rheumatic drug (DMARD). Each patient received twice-weekly subcutaneous injections of etanercept 25 mg administered over a treatment period of 16 weeks. Stable doses of methotrexate (MTX) and steroids were permitted. A clinical assessment of the patient’s response to therapy and safety assessments were performed at each regular visit. <h3>Results</h3> Efficacy: At week 16, 80% of the patients achieved an ACR 20 response (primary outcome measure). Moreover, 45,5% of patients achieved an ACR 50 response and 10,9% patients achieved an ACR 70 response at week 16. The mean number of swollen joints fell from 17 at baseline to 6,7 at week 16. The mean number of tender joints fell from 18,9 at baseline to 7,1 at week 16. The mean score of Patient’s Global assessment fell from 6,6 at baseline to 2,9 at week 16. The mean score of Physician’s Global Assessment score fell from 6,5 at baseline to 2,7 at week 16. Safety: Etanercept 25 mg twice weekly was well tolerated. Adverse Events were primarily mild injection site reactions. <h3>Conclusion</h3> This was an open-label, uncontrolled, 16 week study conducted in 55 Austrian RA patients for whom DMARD therapy was inappropriate or ineffective. Stable doses of MTX and steroids were allowed. The percentage of patients with an ACR 20 response in the present study (80%) is slightly greater than that reported in prior large multicentre studies (range 70‑75%). No unusual patterns of AEs were identified. The safety and efficacy of etanercept 25 mg s.c. twice weekly in a single European country in a naturalistic, “common usage” setting were similar to that observed in controlled clinical trials in the US and EU.
Abstract 6360: Development of a new substituted 1,3-dioxoisoindoline series that are RPS6K1 protein kinase inhibitors as potential cancer therapeutics
Authors: Jayalakshmi Sridhar, Rajesh Komati, Melyssa Bratton
Journal: Cancer Research (2020)

Abstract The 40S ribosomal S6 kinase 1 (S6K1), a conserved serine/threonine protein kinase, is the principal kinase effector downstream of the PI3K/mTOR regulatory signaling pathway. Over-expression of RPS6K1 has been associated with cell transformation and elevated proliferation rates in tumors, poor prognosis and an increased risk of local recurrence. RPS6K1 has been found to play an important role in the progression of ER-positive breast cancer, HER2 positive breast cancer and node-negative premenopausal breast cancer. Overexpression of RPS6K1 is closely correlated with aggressive progression and poor prognosis in prostate cancer patients. Inhibition of this kinase can prove to be beneficial for the treatment of several types of cancer including breast cancer, prostate cancer, non-small cell lung cancer, etc. Our laboratory has identified 7-amino-5-amido-1,3-dioxoisoindolines as S6K1 inhibitors with low micromolar IC50 values (2-5 μM). These compounds also inhibited the growth of prostate cancer cells DU-145 and breast cancer cells MCF-7 (ER-positive) and SKBR3 (HER2-positive). The IC50 values of growth inhibition of SKBR3 breast cancer cell lines by the compounds RJ19, RJ22 and RJ28 are 3.3, 1.9 and 4.7 μM, respectively. The core structure 5,7-diamino-1,3-dioxoisoindoline was found to selectively inhibit RPS6K1 over 99 other oncologic protein kinases. This series of compounds have the potential to become viable therapeutics for many types of cancer. The results from the synthesis of 7-amino-5-amido-1,3-dioxoisoindoline derivatives, the structure activity studies, and their efficacy studies will be presented. Citation Format: Jayalakshmi Sridhar, Rajesh Komati, Melyssa Bratton. Development of a new substituted 1,3-dioxoisoindoline series that are RPS6K1 protein kinase inhibitors as potential cancer therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6360.
Outcomes in Patients with Enteropathy-Associated T-Cell Lymphoma (EATL) and Hepatosplenic T-Cell Lymphoma (HSTCL): A Population Based Analysis Using the SEER Data
Authors: Mukhija Dhruvika, Tomas Radivoyevitch, Brian T. Hill, Robert M. Dean, Brad Pohlman, Deepa Jagadeesh
Journal: Blood (2017)
The Association Between Physician Gender and Career Advancement Among Academic Rheumatologists in the United States
Authors: April Jorge, Marcy Bolster, Xiaoqing Fu, Daniel M. Blumenthal, Nate Gross, Kimberly G. Blumenthal, Zachary Wallace
Journal: Arthritis & Rheumatology (2020)

Objective To determine the potential association between physician gender and academic advancement among US rheumatologists. Methods We performed a nationwide, cross‐sectional study of all rheumatologists practicing in the US in 2014 using a comprehensive database of all licensed physicians. Among academic rheumatologists, we estimated gender differences in faculty rank, adjusting for differences in physician age, years since residency graduation, publications, National Institutes of Health (NIH) grants, registered clinical trials, and appointment at a top 20 medical school using a multivariate logistic regression model. We also estimated gender differences in leadership positions (i.e., division director and fellowship program director). Results Among 6,125 total practicing rheumatologists, 941 (15%) had academic faculty appointments in 2014. Women academic rheumatologists (41.4%) were younger and had completed residency more recently than men. Women had fewer total publications, publications on which they were the first or last author, and NIH grants. In fully adjusted analyses, women were less likely to be full or associate professors than men, with an adjusted odds ratio (OR) of 0.78 (95% confidence interval [95% CI] 0.62–0.99]). Women in rheumatology had similar odds as men of being a fellowship program director or division director (adjusted OR 0.99 [95% CI 0.69–1.43] and adjusted OR 0.96 [95% CI 0.66–1.41], respectively). Conclusion Among academic rheumatologists, women are less likely than men to be full or associate professors but have similar odds of being fellowship program directors or division directors, when adjusting for several factors known to influence faculty promotion. These differences suggest barriers to academic promotion despite representation in leadership positions within rheumatology divisions.
Making everyone’s job easier. How do data scientists fit as a critical member of integrated support teams?
Authors: Johann Windt, David Taylor, Dean Little, Ben C Sporer
Journal: British Journal of Sports Medicine (2020)

As technological advances abound and a tidal wave of data hits the sporting world’s shore, the demand for organisations to hire professionals who can reliably collect, integrate and analyse these data continues to rise.1 Sports biostatisticians have recently been promoted as integral members within sport science and sport medicine teams.1 Although data-focused professionals may work as a ‘sports biostatistician’, ‘data analyst’, ‘sport scientist’, ‘performance analyst’ or more,1 2 we will use ‘data scientist’ for consistency. Regardless of their specific title, common responsibilities for these professionals may include applying data management and analysis skillsets to athlete monitoring, building efficient data collection tools, analysing data for scouting/recruitment, performance analysis, epidemiological reporting and more.1 As a foundation, data scientists may build or maintain a data infrastructure to support these processes. As an end-product, they provide decision-support systems that inform and audit decisions made across departments.3–5 The benefits that such decision-support systems provide and their ability to outperform single humans’ decision-making in many realms has been reviewed elsewhere,4 5 underscoring the value of data scientists within sport. What remains to be clearly outlined in the literature is how these individuals fit within integrated support teams.

No universally accepted integrated support team structure exists. Sporting demands, organisational resources and other contextual factors all dictate the number, role and responsibilities of physicians, physiotherapists, strength and conditioning coaches, coaching staff, athletic trainers exist within a given integrated support team. However, most integrated support teams are athlete-centred, with complementary disciplines providing support for athletes’ performance and health-related needs.6

Each discipline brings its respective skillset to the table and ideally enables a collaborative conversation to guide health and performance-related decisions.7 Logically, a well-structured, collaborative and multidisciplinary integrated support team would be improved if one adds a data scientist as another voice …
SARS-CoV-2 renal tropism associates with acute kidney injury
Authors: Fabian Braun, Marc Lütgehetmann, Susanne Pfefferle, Milagros N Wong, Alexander Carsten, Maja T Lindenmeyer, Dominik Nörz, Fabian Heinrich, Kira Meißner, Dominic Wichmann, Stefan Kluge, Oliver Gross, Klaus Pueschel, Ann S Schröder, Carolin Edler, Martin Aepfelbacher, Victor G Puelles, Tobias B Huber
Journal: The Lancet (2020)