tbuckley/cabot-search huggingface dataset:
The high burden of alcoholic cirrhosis in privately insured persons in the United States
Authors: Jessica L. Mellinger, Kerby Shedden, Gerald Scott Winder, Elliot Tapper, Megan Adams, Robert J Fontana, Michael L. Volk, Frederic C. Blow, Anna S.F. Lok
Journal: Hepatology (2018)

Alcoholic cirrhosis (AC) is a major cause of liver-related morbidity and mortality in the United States. Rising rates of alcohol use disorders in the United States will likely result in more alcoholic liver disease. Our aim was to determine the prevalence, health care use, and costs of AC among privately insured persons in the United States. We collected data from persons aged 18-64 with AC (identified by codes from the International Classification of Diseases, Ninth and Tenth Revisions) enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009-2015). We determined yearly prevalence, weighted to the national employer-sponsored, privately insured population. Using competing risk analysis, we estimated event rates for portal hypertensive complications and estimated the association between AC and costs as well as admissions and readmissions. In 2015, 294,215 people had cirrhosis and 105,871 (36%) had AC. Mean age at AC diagnosis was 53.5 years, and 32% were women. Over the 7 years queried, estimated national cirrhosis prevalence rose from 0.19% to 0.27% (P < 0.001) and for AC from 0.07% to 0.10% (P < 0.001). Compared to non-AC, AC enrollees were significantly more likely to have portal hypertensive complications at diagnosis and higher yearly cirrhosis and alcohol-related admissions (25 excess cirrhosis admissions and 6.3 excess alcohol-related admissions per 100 enrollees) as well as all-cause readmissions. Per-person costs in the first year after diagnosis nearly doubled for AC versus non-AC persons (US$ 44,835 versus 23,319).In a nationally representative cohort of privately insured persons, AC enrollees were disproportionately sicker at presentation, were admitted and readmitted more often, and incurred nearly double the per-person health care costs compared to those with non-AC. (Hepatology 2018).
MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis
Authors: Veeru Kasivisvanathan, Antti S. Rannikko, Marcelo Borghi, Valeria Panebianco, Lance A. Mynderse, Markku H. Vaarala, Alberto Briganti, Lars Budäus, Giles Hellawell, Richard G. Hindley, Monique J. Roobol, Scott Eggener, Maneesh Ghei, Arnauld Villers, Franck Bladou, Geert M. Villeirs, Jaspal Virdi, Silvan Boxler, Grégoire Robert, Paras B. Singh, Wulphert Venderink, Boris A. Hadaschik, Alain Ruffion, Jim C. Hu, Daniel Margolis, Sébastien Crouzet, Laurence Klotz, Samir S. Taneja, Peter Pinto, Inderbir Gill, Clare Allen, Francesco Giganti, Alex Freeman, Stephen Morris, Shonit Punwani, Norman R. Williams, Chris Brew-Graves, Jonathan Deeks, Yemisi Takwoingi, Mark Emberton, Caroline M. Moore
Journal: New England Journal of Medicine (2018)

Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited.In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer.A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001).The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .).
Maura Lynch: fistula fighter and nun
Authors: Joanna Lyall
Journal: BMJ (2018)

When Maura Lynch entered the order of the Medical Missionaries of Mary two days before her 18th birthday, she was hoping to spend her life serving poor populations in Africa. By the time of her death at the age of 79 in Kampala, Uganda, the surgeon-nun had spent 50 years on the continent, and the past three decades setting up and running an obstetric fistula clinic in Kitovu Hospital, Masaka. She rejoiced in restoring to health women who were often shunned by their families because of incontinence, and she was particularly fond of quoting the case of an 85 year old woman who underwent successful surgery after 40 years with incontinence. “Afterwards we danced,” said Lynch. “As a ministry, I think it beats all. It’s so worth while.”

Between 1993 and 2007 Lynch did more than 1000 repair operations. She was honoured by the Ugandan government, and on a state visit to Dublin in 2003 president Yoweri Museveni requested her presence at a reception to thank her for her contribution to medical services in Uganda.

The 28 bed unit and dedicated operating …
Mitotic Phosphorylation of SENP3 Regulates DeSUMOylation of Chromosome-Associated Proteins and Chromosome Stability
Authors: Bo Wei, Chao Huang, Bin Liu, Yang Wang, Nansong Xia, Qiuju Fan, Guo-Qiang Chen, Jinke Cheng
Journal: Cancer Research (2018)

Progression of mitotic cell cycle and chromosome condensation and segregation are controlled by posttranslational protein modifications such as phosphorylation and SUMOylation. However, how SUMO isopeptidases (SENP) regulate cell mitotic procession is largely unknown. Here, we demonstrate that precise phosphorylation of SENP3 during mitosis suppresses SENP3 deSUMOylation activity towards chromosome-associated proteins, including topoisomerase IIα (TopoIIα). Cyclin B-dependent kinases 1 and protein phosphatase 1α were identified as the kinase and phosphatase in control of mitotic SENP3 phosphorylation, respectively. SENP3 phosphorylation decreased its interaction with TopoIIα, resulting in reduced SENP3 deSUMOylation activity on TopoIIα. Furthermore, we observed mitotic arrest, increased chromosome instability, and promotion of tumorigenesis in cells expressing a nonphosphorylatable SENP3 mutant. These data show that SENP3 phosphorylation plays a crucial role in regulating the SUMOylation of chromosome-associated proteins and chromosome stability in mitosis.Significance: Phosphorylation of SENP3 regulates SUMOylation of chromosome-associated proteins to maintain genomic stability during mitosis. Cancer Res; 78(9); 2171-8. ©2018 AACR.
Kinetics of intratumoral T-cell activation during chemoradiation for cervical cancer.
Authors: Stephanie Dorta-Estremera, Krishna Nookala Sita Mahalakshmi, Ananta V Yanamandra, Lauren Elizabeth Colbert, Guojun Yang, Patricia J. Eifel, Anuja Jhingran, Lois M. Ramondetta, Amir A. Jazaeri, Michael M. Frumovitz, Ann Klopp, Jagannadha Sastry
Journal: Journal of Clinical Oncology (2018)

6 Background: Limited data in cancer patients have suggested that chemotherapy and radiation impact local and systemic immune cell populations. Radiation therapy (RT) is known to deplete circulating lymphocytes but is thought to increase local antigen presentation. The dynamics of these competing effects on the kinetics of intratumoral infiltration and expansion of activated and immunoregulatory T cells are unknown. Methods: We prospectively evaluated intratumoral immune infiltration during fractionated RT using multi-spectral flow cytometry. Cervical brushings were obtained from 14 patients before (baseline) and during RT (week 1, 3 and 5). Cells collected from the cervical brushings were stained with a 16-color panel of antibodies that included markers to identify T cell and dendritic cell subsets with activation and suppressor molecules. Changes in immune cell subsets at different time points were evaluated and calculated using matched-pair analysis with Wilcoxon rank sum test. Results: CD3+ T cells declined over the first week of treatment (28% of CD3 at baseline, vs. 14.8% at week 1, p = 0.0273). The percentage of CD3+ cells subsequently increased at 3 weeks (25.6%) and 5 weeks (37.8%). Both CD8+ and CD4+ T cells underwent a decline at week 1 followed by expansion at week 3 and 5. Percentages of regulatory T cells (CD4+Foxp3+) showed a similar trend of reduction and further expansion but did not reach significance. The percentage of CD8+ T cells expressing the T cell activation marker CD69 and the cytotoxic protease Granzyme B (GrzB) continuously increased over time (CD69+: 11.8%, 27.7%, 38.7%, 57.5%, and GrzB+: 23.9%, 53.2%, 48.1%, 58.2%). While the percentage of dendritic cells (CD11c+ CD11b+) was stable during treatment, the subset of activated dendritic cells expressing CD86 increased at week 1 and subsequently declined (week 1, 19.1% vs week 5, 9.8%, p = 0.0642). Conclusions: Activated CD8+ effector T cells expand in the cervix during radiation therapy. Moreover, in the first week of treatment, CD8+ T cells contract while dendritic cells undergo activation suggesting this may be a critical time to intervene to maximize anti-tumor immunity.
Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study
Authors: Elisabetta Patorno, Allison B Goldfine, Sebastian Schneeweiss, Brendan M Everett, Robert J Glynn, Jun Liu, Seoyoung C Kim
Journal: BMJ (2018)

<h3>ABSTRACT</h3> <h3>Objective</h3> To evaluate the cardiovascular safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, in direct comparisons with DPP-4 inhibitors (DPP-4i), GLP-1 receptor agonists (GLP-1RA), or sulfonylureas, as used in routine practice. <h3>Design</h3> Population based retrospective cohort study. <h3>Setting</h3> Nationwide sample of patients with type 2 diabetes from a large de-identified US commercial healthcare database (Optum Clinformatics Datamart). <h3>Participants</h3> Three pairwise 1:1 propensity score matched cohorts of patients with type 2 diabetes 18 years and older who initiated canagliflozin or a comparator non-gliflozin antidiabetic agent (ie, a DPP-4i, a GLP-1RA, or a sulfonylurea) between April 2013 and September 2015. <h3>Main outcome measures</h3> The primary outcomes were heart failure admission to hospital and a composite cardiovascular endpoint (comprised of being admitted to hospital for acute myocardial infarction, ischemic stroke, or hemorrhagic stroke). Hazard ratios and 95% confidence intervals were estimated in each propensity score matched cohort controlling for more than 100 baseline characteristics. <h3>Results</h3> During a 30 month period, the hazard ratio for heart failure admission to hospital associated with canagliflozin was 0.70 (95% confidence interval 0.54 to 0.92) versus a DPP-4i (n=17 667 pairs), 0.61 (0.47 to 0.78) versus a GLP-1RA (20 539), and 0.51 (0.38 to 0.67) versus a sulfonylurea (17 354 ). The hazard ratio for the composite cardiovascular endpoint associated with canagliflozin was 0.89 (0.68 to 1.17) versus a DPP-4i, 1.03 (0.79 to 1.35) versus a GLP-1RA, and 0.86 (0.65 to 1.13) versus a sulfonylurea. Results were similar in sensitivity analyses further adjusting for baseline hemoglobin A1c levels and in subgroups of patients with and without prior cardiovascular disease or heart failure. <h3>Conclusions</h3> In this large cohort study, canagliflozin was associated with a lower risk of heart failure admission to hospital and with a similar risk of myocardial infarction or stroke in direct comparisons with three different classes of non-gliflozin diabetes treatment alternatives as used in routine care.
AGE AND OUTCOMES FOLLOWING GUIDED DE-ESCALATION OF ANTIPLATELET TREATMENT IN ACUTE CORONARY SYNDROME PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: RESULTS OF A RANDOMIZED MULTICENTRE TRIAL
Authors: Dirk Sibbing, Lisa Gross, Dietmar Trenk, Claudius Jacobshagen, Tobias Geisler, Martin Hadamitzky, Bela Merkely, Robert Kiss, András Komócsi, Radoslaw Parma, Tommaso Gori, Stephan Felix, Robert Schwinger, Franz-Josef Neumann, Joerg Hausleiter, Monika Baylacher, Lukasz Koltowski, Julinda Mehilli, Kurt Huber, Zenon Huczek, Daniel Aradi, Steffen Massberg
Journal: Journal of the American College of Cardiology (2018)
Abstract P3-05-07: Improving CAR T cell function by reversing the immunosuppressive tumor environment of breast cancer
Authors: P Bajgain, S Tawinwung, N Watanabe, S Sukumaran, U Anurathapan, HE Heslop, CM Rooney, M Brenner, AM Leen, JF Vera
Journal: Cancer Research (2018)

Abstract Adoptive transfer of T cells redirected to tumor-associated antigens (TAAs) by expression of chimeric antigen receptors (CARs) can produce tumor responses, even in patients with resistant malignancies. To target breast cancer, we generated T cells expressing a CAR directed to the TAA mucin-1 (MUC1). T cells expressing this CAR (86±1.9%, n=5) specifically killed MUC1-expressing cells (MDA-MB-468 – 45.9±7.3%, MCF-7 – 36.8±3.6) but not MUC1(-) 293T cells (3.7±1.6% specific lysis, 20:1 E:T, n=3). Although these CAR T cells had potent anti-tumor activity against breast cancer cells, when exposed to the Th2-polarizing cytokine IL4 [which is upregulated in tumor samples (Oncomine, p&amp;lt;0.05)] we observed a dramatic reduction in their cytolytic potential [IL2 - 45.9±7.3% vs IL4 - 11.3±3.7% specific lysis, 20:1 E:T ratio, n=4]. Thus, to protect our CAR.MUC1 T cells from the negative influences of IL4, we generated an inverted cytokine receptor (ICR) in which the IL4 receptor exodomain was fused to the IL7 receptor endodomain (4/7 ICR). Transgenic expression of this molecule in CAR.MUC1 T cells (55±4.8% double positive cells, n=5), restored the cytolytic function of CAR T cells (30.9±8.1% specific lysis, 20:1 E:T, n=3). Next, to determine the long term effects of this modification we co-cultured transgenic T cells with MUC1+ tumor cells and measured tumor and T cells numbers. In the presence of IL4, only double positive (CAR.MUC1-4/7) T cells expanded and eliminated the tumors in vitro and in vivo. However, upon tumor elimination, transgenic T cells rapidly contracted, demonstrating the antigen- and cytokine-dependence of the product. In conclusion, CAR.MUC1-4/7 T cells can effectively target breast cancer cells and retain their cytotoxic function even in the IL4-rich tumor microenvironment. Citation Format: Bajgain P, Tawinwung S, Watanabe N, Sukumaran S, Anurathapan U, Heslop HE, Rooney CM, Brenner M, Leen AM, Vera JF. Improving CAR T cell function by reversing the immunosuppressive tumor environment of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-07.
Organ Dysfunction After Surgery in Patients Treated With Individualized or Standard Blood Pressure Management
Authors: Kunal Karamchandani, Zyad J. Carr, Anthony Bonavia
Journal: JAMA (2018)

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CDC Grand Rounds: Promoting Hearing Health Across the Lifespan
Authors: William J. Murphy, John Eichwald, Deanna K. Meinke, Shelly Chadha, John Iskander
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Globally, one in three adults has some level of measurable hearing loss, and 1.1 billion young persons are at risk for hearing loss attributable to noise exposure. Although noisy occupations such as construction, mining, and manufacturing are primary causes of hearing loss in adults, nonoccupational noise also can damage hearing. Loud noises can cause permanent hearing loss through metabolic exhaustion or mechanical destruction of the sensory cells within the cochlea. Some of the sounds of daily life, including those made by lawn mowers, recreational vehicles, power tools, and music, might play a role in the decline in hearing health. Hearing loss as a disability largely depends on a person's communication needs and how hearing loss affects the ability to function in a job. The loss of critical middle and high frequencies can significantly impair communication in hearing-critical jobs (e.g., law enforcement and air traffic control).
Oncological outcomes of neoadjuvant chemotherapy in patients with locally advanced upper tract urothelial carcinoma: A multicenter study.
Authors: Shingo Hatakeyama, Yuka Kubota, Hayato Yamamoto, Takahiro Yoneyama, Yasuhiro Hashimoto, Takuya Koie, Chikara Ohyama
Journal: Journal of Clinical Oncology (2018)

429 Background: The clinical impact of neoadjuvant chemotherapy (NAC) on oncological outcomes in patients with locally advanced upper tract urothelial carcinoma (UTUC) remains unclear. We investigated the oncological outcomes of platinum-based NAC for locally advanced UTUC. Methods: A total of 426 patients who underwent radical nephroureterectomy at five medical centers between January 1995 and April 2017 were examined retrospectively. Of the 426 patients, 234 were treated for a high-risk disease (stages cT3–4 or locally advanced [cN+] disease) with or without NAC. NAC regimens were selected based on eligibility of cisplatin. We retrospectively evaluated post-therapy pathological downstaging, lymphovascular invasion, and prognosis stratified by NAC use. Multivariate Cox regression analysis was performed for independent factors for prognosis. Results: Of 234 patients, 101 received NAC (NAC group) and 133 did not (Control [Ctrl] group). The regimens in the NAC group included gemcitabine and carboplatin (75%), and gemcitabine and cisplatin (21%). Pathological downstagings of the primary tumor and lymphovascular invasion were significantly improved in the NAC than in the Ctrl groups. NAC for locally advanced UTUC significantly prolonged recurrence-free and cancer-specific survival. Multivariate Cox regression analysis using an inverse probability of treatment weighted (IPTW) method showed that NAC was selected as an independent predictor for prolonged recurrence-free and cancer-specific survival. However, the influence of NAC on overall survival was not statistically significant. Conclusions: Platinum-based NAC for locally advanced UTUC potentially improves oncological outcomes. Further prospective studies are needed to clarify the clinical benefit of NAC for locally advanced UTUC.
Therapeutically targeting tumor microenvironment–mediated drug resistance in estrogen receptor–positive breast cancer
Authors: Kevin Shee, Wei Yang, John W. Hinds, Riley A. Hampsch, Frederick S. Varn, Nicole A. Traphagen, Kishan Patel, Chao Cheng, Nicole P. Jenkins, Arminja N. Kettenbach, Eugene Demidenko, Philip Owens, Anthony C. Faber, Todd R. Golub, Ravid Straussman, Todd W. Miller
Journal: The Journal of Experimental Medicine (2018)

Drug resistance to approved systemic therapies in estrogen receptor–positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance. FGF2-driven drug resistance in anti-estrogen–sensitive and –resistant models, including patient-derived xenografts, was reverted by neutralizing FGF2 or FGFRs. A transcriptomic signature of FGF2 signaling in primary tumors predicted shorter recurrence-free survival independently of age, grade, stage, and FGFR amplification status. These findings delineate FGF2 signaling as a ligand-based drug resistance mechanism and highlights an underdeveloped aspect of precision oncology: characterizing and treating patients according to their TME constitution.