tbuckley/cabot-search huggingface dataset:
Erratum: Eight Americas: Investigating mortality disparities across races, counties, and race-counties in the United States (PloS Medicine 3,9 DOI:10.1371/journal.pmed.0030260)
Authors: Christopher J.L. Murray, Sandeep C. Kulkarni, Catherine Michaud, Niels Tomijima, Maria T. Bulzacchelli, Terrell J. Iandiorio, Majid Ezzati
Journal: PLoS Medicine (2006)
Biochemical mechanisms implemented by human acute myeloid leukemia cells to suppress host immune surveillance
Authors: Inna M. Yasinska, Isabel Gonçalves Silva, Svetlana Sakhnevych, Bernhard F. Gibbs, Ulrike Raap, Elizaveta Fasler-Kan, Vadim V. Sumbayev
Journal: Cellular and Molecular Immunology (2018)
Suggested Paths to Fixing the Opioid Crisis
Authors: Jeffrey H. Samet, Stefan G. Kertesz
Journal: JAMA Network Open (2018)

Catherine S. Hwang, MSPH; Elizabeth M. Kang, MPH; Yulan Ding, MS; Josephine Ocran-Appiah, MD, MPH, MSc; Jana K. McAninch, MD, MPH, MS; Judy A. Staffa, PhD, RPh; Cynthia J. Kornegay, PhD; Tamra E. Meyer, PhD, MPH
Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity
Authors: Yves Deruyver, Emmanuel Weyne, Karel Dewulf, Roma Rietjens, Silvia Pinto, Nele Van Ranst, Jan Franken, Matthias Vanneste, Maarten Albersen, Thomas Gevaert, Rudi Vennekens, Dirk De Ridder, Thomas Voets, Wouter Everaerts
Journal: European Urology (2018)

Improvement of bladder emptying by modulating afferent nerve activity is an attractive therapeutic strategy for detrusor underactivity. Transient receptor potential vanilloid 4 (TRPV4) is a sensory ion channel in urothelial cells that contribute to the detection of bladder filling.To investigate the potential benefit of intravesical TRPV4 agonists in a pelvic nerve injury rat model for detrusor underactivity.Female wild-type and Trpv4 knockout rats underwent sham surgery or bilateral pelvic nerve injury (bPNI). Four weeks later, rats underwent cystometry with infusion of the TRPV4 agonist GSK1016790A. Bladders were harvested for in vitro pharmacological studies, quantitative reverse polymerase chain reaction and immunohistochemistry.Data are expressed as median ± interquartile range. Statistical comparisons were made using the Mann-Witney U test and Wilcoxon signed rank test as appropriate.Rats with bPNI showed a phenotype characteristic of detrusor underactivity with lower-amplitude voiding contractions, decreased voiding frequency, and increased postvoid residual. Intravesical application of GSK1016790A increased voiding frequency and reduced postvoid residual in wild-type, but not Trpv4-/-, rats. In isolated bladder strips, GSK1016790A did not induce relevant contractions, indicating that the observed improvements in bladder function are the result of increased afferent signalling through TRPV4 activation, rather than a local effect on the detrusor. The altered urinary phenotype of Trpv4-/- mice was not apparent in the Trpv4-/- rat model, suggesting species-related functional variations. Our results are limited to the preclinical setting in rodents.Intravesical activation of TRPV4 improves bladder dysfunction after bPNI by increasing afferent signalling.We demonstrate that the sensory protein transient receptor potential vanilloid 4 (TRPV4) can be targeted to improve bladder function in animals that have iatrogenic injury to the nerves innervating the bladder. Further research is required to determine whether these results can be translated to patients with an underactive bladder.
Rituximab treatment of pemphigus foliaceus: A retrospective study of 12 patients
Authors: Irene Palacios-Álvarez, Constanza Riquelme-Mc Loughlin, Laia Curto-Barredo, Pilar Iranzo, Irene García-Díez, Agustín España
Journal: Journal of the American Academy of Dermatology (2018)
Accelerometer-based predictive models of fall risk in older women: a pilot study
Authors: Andrew Hua, Zachary Quicksall, Chongzhi Di, Robert Motl, Andrea Z. LaCroix, Bruce Schatz, David M. Buchner
Journal: npj Digital Medicine (2018)

Current clinical methods of screening older adults for fall risk have difficulties. We analyzed data on 67 women (mean age = 77.5 years) who participated in the Objective Physical Activity and Cardiovascular Health (OPACH) study within the Women's Health Initiative and in an accelerometer calibration substudy. Participants completed the short physical performance battery (SPPB), questions about falls in the past year, and a timed 400-m walk while wearing a hip triaxial accelerometer (30 Hz). Women with SPPB ≤ 9 and 1+reported falls (n = 19) were grouped as high fall risk; women with SPPB = 10-12 and 0 reported falls (n = 48) were grouped as low fall risk. Random Forests were trained to classify women into these groups, based upon traditional measures of gait and/or signal-based features extracted from accelerometer data. Eleven models investigated combined feature effects on classification accuracy, using 10-fold cross-validation. The models had an average 73.7% accuracy, 81.1% precision, and 0.706 AUC. The best performing model including triaxial data, cross-correlations, and traditional measures of gait had 78.9% accuracy, 84.4% precision, and 0.846 AUC. Mediolateral signal-based measures-coefficient of variance, cross-correlation with anteroposterior accelerations, and mean acceleration-ranked as the top 3 features. The classification accuracy is promising, given research on probabilistic models of falls indicates accuracies ≥80% are challenging to achieve. The results suggest accelerometer-based measures captured during walking are potentially useful in screening older women for fall risk. We are applying algorithms developed in this paper on an OPACH dataset of 5000 women with a 1-year prospective falls log and week-long, free-living accelerometer data.
Longitudinal follow-up of endothelial function in breast cancer survivors on aromatase inhibitors (AIs).
Authors: Anne Hudson Blaes, Heather Christine Beckwith, Robert P. Hebbel, Anna S. Solovey, David Potter, Douglas Yee, Ashley Petersen, Rachel Isaksson Vogel, Russell V Luepker, Daniel Duprez
Journal: Journal of Clinical Oncology (2018)

e12525 Background: AIs reduce breast cancer-related mortality however they may increase cardiovascular (CV) risk. We previously presented data demonstrating women on AIs have endothelial dysfunction, a measure of increased CV risk. Here, we present data of AIs on endothelial function over time. Methods: 19 healthy women (controls) and 18 women with locally advanced breast cancer and taking an AI (cases) underwent vascular testing at baseline and > 6 months (median follow up 7 months controls, 24 months cases). Subjects with tobacco use, hypertension or hyperlipidemia were excluded. Consented subjects underwent biomarker analysis and radial artery pulse wave analysis using the HDI/Pulse Wave CR-2000 CV Profiling System and pulse contour analysis using the Endo-PAT2000 system. Reductions in EndoPAT ratio, small artery elasticity (SAE) and large artery elasticity (LAE) are associated with worsening endothelial dysfunction. Functional test markers were compared between cases and controls using Wilcoxon Rank-Sum tests. Results: Mean baseline age (62 vs 59 years) and body mass index (26.3 vs 24.8 kg/m2) were similar between cases and controls, respectively. At baseline, mean systolic blood pressure (BP) was elevated in cases (126 mmHg vs 115 mmHg, p = 0.01). There were no differences in baseline cholesterol. Median estradiol levels were reduced in cases at baseline (2 vs 14 pg/mL, p < 0.0001). Baseline EndoPAT ratio (0.72 vs 2.63, p < 0.0001) and follow up (0.96 vs 2.14, p < 0.0001) were significantly reduced in cases on AIs vs controls (Table 1). LAE, SAE and EndoPAT ratio remain reduced in cases. Results remained significant after adjusting for BP. Conclusions: Breast cancer survivors on AIs have endothelial dysfunction, a predictor of adverse CV disease. These changes persist over time. Cases Controls Summary shown is median (minimum, maximum). Comparison of follow-up measurements between cases and controls. Baseline Follow-Up Baseline Follow-Up P-value EndoPAT Ratio 0.72 (0.36, 1.25) 0.96 (0.53, 1.40) 2.63 (1.29, 3.75) 2.14 (0.60, 3.07) < 0.0001 LAE Index 12.4 (7.4, 20.1) 10.1 (5.8, 19.0) 15.1 (9.4, 24.6) 14.2 (9.3, 19.3) 0.003 SAE Index 5.2 (1.8, 13.5) 4.4 (2.0, 10.3) 7.0 (3.3, 15.7) 7.8 (4.4, 15.8) 0.0005
Antitumor effect and mechanisms research of the PARP inhibition combination with platinum salts and PI3K inhibition on human triple negative breast cancer cell.
Authors: Jin Zhang
Journal: Journal of Clinical Oncology (2018)

e12535 Background: TNBC is a heterogeneous group of tumors with more aggressive clinical features. Platinum salts have demonstrated sufficient efficacy and safety for consideration of their use for TNBC. Olaparib is an oral inhibitor of PARP that, blocks base-excision repair by trapping PARP at sites of DNA damage, leading to the collapse of DNA replication forks and the accumulation of DNA double-strand breaks. BKM120, a PI3K inhibitor has demonstrated anti-proliferative, pro-apoptotic, and anti-tumor activity in a variety of cell lines and xenograft models from cancers with and without aberrant PI3K pathway activation. However, the effects of combination of the three drugs on triple-negative breast cancer have not yet been elucidated. Methods: MTT assays and drug resistance clonogenic assays were performed to evaluate the cell viability in response to drug treatments alone and defined the combined measurements of three kinds of drugs. We used Flow cytometric analysis to evaluate cell cycle and cell apoptptic changes. The expression levels of γ-H2aX and PADPR were assessed by western blot to detection of DNA damage levels due to the three drug action. The expression levels of 53BP1, p-ATM, p-AKT and p53 were assessed by western blot to exam the proportion of DNA repair by non homologous terminal junction pathway. We also tested the level of p21 and p27 to exam whether drugs influence the cell cycle. Results: While combination of the three drugs in a very low dose was determined more effective than each one alone, strong synergistic antiproliferative effects were observed, meanwhile which was well tolerated when treated in MDA-10A cell line.Apoptotic assay, cell cycle assay and western blot proved that the combined killing effects of three drugs were performed on DNA damage, which Non-homologous end joining(NHEJ) repair was enhanced and HR repair was inhibited. Conclusions: This suggests a strong rationale to explore the therapeutic strategy of using carboplatin in combination of Olaparib and BKM120 for triple-negative breast cancer patients, and expand the olaparib drug population.
Combination of endoscopic treatment – septectomy and stricturotomy in the afferent ileal limb of the ileal pouch
Authors: Martin Lukas, Martin Bortlik, Bo Shen
Journal: Endoscopy (2018)

Endoscopic therapy of inflammatory bowel disease associated complications, such as stricture and fistula, has become an adjunct to medical and surgical treatment [1] [2]. Here we describe the case of a patient with ulcerative colitis and ileal pouch-anal anastomosis (IPAA) with complex stricture, which was successfully treated with a combined endoscopic stricturotomy and septectomy ([Video 1]).
IMpassion132: A double-blind randomized phase 3 trial evaluating chemotherapy (CT) ± atezolizumab (atezo) for early progressing locally advanced/metastatic triple-negative breast cancer (mTNBC).
Authors: Rebecca Dent, Fabrice Andre, Anthony Goncalves, Sherko Kummel, Miguel Martin, Peter Schmid, Florian Schuetz, Sandra M. Swain, Valerie Easton, Erika Pollex, Javier Cortés
Journal: Journal of Clinical Oncology (2018)

TPS1115 Background: Atezo blocks the interaction of PD-L1 with receptors PD-1 and B7.1, restoring anti-tumor immunity. PD-L1 pathway inhibitors may be synergistic with CT. In a phase 1b study in mTNBC, atezo + nab-paclitaxel showed durable confirmed responses [Adams 2016]. The IMpassion130 and 131 randomized phase 3 trials are evaluating atezo combined with nab-paclitaxel and paclitaxel, respectively, as 1st-line therapy for mTNBC. Both exclude patients (pts) with disease progression (PD) within 12 mo of CT for early breast cancer (eBC). IMpassion132 (NCT03371017) compares atezo + CT vs placebo + CT in pts with PD ≤12 months after completing CT for eBC, and combines atezo with 2 commonly used non-taxane CT regimens. Methods: In this multinational placebo-controlled randomized phase 3 trial, pts with recurrent (inoperable locally advanced/metastatic) TNBC treated with standard (neo)adjuvant anthracycline and taxane CT and relapsing ≤12 months after the last treatment with curative intent for eBC are eligible if they have received no prior CT for advanced/metastatic TNBC. PD-L1 status (for stratification) and TNBC status are confirmed centrally before randomization. Investigators select CT (gemcitabine 1000 mg/m2 + carboplatin AUC 2, d1 & 8 q21d [GC] or capecitabine 1000 mg/m2 bid d1–14 q21d [X]) before randomization. All pts with prior platinum for eBC must receive X. At least 30% of ~350 planned pts will receive X. Stratification factors are: visceral (lung and/or liver) metastases (yes vs no); tumor PD-L1 status (IC 0 vs 1/2/3); and selected CT (GC vs X). Pts are randomized to either atezo or placebo 1200 mg q21d with the chosen CT, continued until PD, unacceptable toxicity or pt/physician decision. Tumors are assessed q8w for the 1st year and q12w thereafter until PD. The primary endpoint is overall survival (OS). Secondary endpoints include 12- and 18-mo OS rates, progression-free survival, objective response rate (RECIST v1.1), duration of response, clinical benefit rate, pt-reported outcomes (PROs; EORTC QLQ-C30) and safety. Exploratory endpoints include further PROs, pharmacokinetics and translational research. Clinical trial information: NCT03371017.
Abstract 17338: Development of a TIMI Risk Score for Stable Ischemic Heart Disease
Authors: Erin A Bohula, Marc P Bonaca, Philip E Aylward, Gaetano M De Ferrari, Ping He, Basil S Lewis, Piera Merlini, Sabina A Murphy, Marc S Sabatine, Benjamin M Scirica, Eugene Braunwald, David A Morrow
Journal: Circulation (2015)

Patients (pts) with stable ischemic heart disease (SIHD) who have had a prior myocardial infarction (MI) demonstrate a range of residual risk for recurrent CV events. A risk prediction tool may be useful to identify high risk pts who have the greatest potential for benefit from intensive treatment. Methods: The integer-based TIMI Risk Score for SIHD (Prior MI) was derived in 8,200 placebo-treated pts who were stable with a history of MI (2 wks to 12 mo) in the TRA 2°P-TIMI 50 trial. The score was developed to predict CV death, MI or ischemic stroke (CVD/MI/iCVA; n=676 events, median 2.5y follow-up). The score was validated in 8,274 vorapaxar-treated pts from the trial. Differential efficacy and safety (GUSTO severe bleeding) response to randomized treatment was assessed among pts with prior MI without a history of TIA or stroke for whom there is a clinical indication for vorapaxar. Results: The risk score predictors were age, CHF, smoking, diabetes mellitus, hypertension, prior stroke, peripheral arterial disease, family history of CAD, prior CABG, and eGFR (Fig 1a). The TIMI Risk Score showed a strong graded relationship with the rate of CVD/MI/iCVA as well as the individual components (p-trend&lt;0.001 for all), a pattern that was confirmed in the validation cohort (p&lt;0.001). In pts eligible for clinical use, those at intermediate (score 2-3) and high (score ≥4) risk had a 2.4% and 3.6% absolute risk reduction in CVD/MI/iCVA with vorapaxar, translating to a number needed to treat (NNT) of 41 and 28 in the intermediate and high risk groups (Fig 1b). Bleeding increased across risk groups (Fig 1b); however, net clinical outcome was increasingly favorable with vorapaxar with an increasing TIMI Risk Score. ICH was 0.5 vs 0.6% and fatal bleeding was 0.3 vs 0.5% with vorapaxar vs placebo in those with a score ≥4. Conclusions: The TIMI Risk Score for SIHD (Prior MI) identifies a strong gradient of increasing risk for recurrent CV events and may be useful as a basis for therapeutic decision-making.
Moving from the CLEOPATRA study to real life: Results from the G.O.N.O. SUPER trial.
Authors: Ornella Garrone, Tommaso Giarratano, Chiara Saggia, Ilaria Bertolini, Alessandra Beano, Eva Blondeaux, Francesca Riva, Loretta D'Onofrio, Laura Merlini, Luigi Coltelli, Nicla Maria La Verde, Anna Maria Vandone, Andrea Milani, Elena Collovà, Raffaele Ardito, Mario Airoldi, Enrico De Conciliis, Livio Blasi, Massimo Di Maio, Marco Carlo Merlano
Journal: Journal of Clinical Oncology (2018)

e13006 Background: Approximately 20% of breast cancers (BC) are HER-2+. Trastuzumab (T) has dramatically changed the outcome, both in early and in advanced settings in HER2+BC. Pertuzumab (P) plus T and docetaxel significantly prolonged PFS and OS in the phase III CLEOPATRA study. In order to describe the applicability of CLEOPATRA results in unselected pts, we performed a multicenter, retrospective-prospective, observational study, in HER-2+ metastatic BC (MBC) pts. Methods: We analyzed the outcome of all HER-2+ MBC pts treated with P+T and taxanes as first line therapy since the availability of P in Italy, at 18 general and university hospitals. Results: Until Jan 31st 2018 data from 300 HER-2+ MBC pts were recorded. Main pts characteristics were: median (m) age 55 y (28-80), m ECOG PS 0 (0-2), HR positive 203 pts (67%); 80/151 pts (53%) received neo/adjuvant CT + T and 107 pts (70%) adjuvant ET. Most common metastatic sites: bone 164 pts (54%), liver 122 pts (40%), lung 84 pts (28%), soft tissues 208 pts (69%); 12 pts had CNS involvement. 149 pts (49%) had metastatic disease on presentation. M number of metastatic sites was 2 (1-8). 188 pts (63%) and 112 pts (37%) received docetaxel (D) and paclitaxel (Pa) respectively. M number of CT cycles was 6 for both drugs (D range 1-13; Pa range 1-18). Up to now 27 pts are still on CT and 134 are on maintenance; ORR in 274 evaluable pts is 73% (CR and PR in 65 and 154 pts respectively), PD in 12 pts. 146 pts (48%) received ET concomitantly with P+T maintenance. With 121 events recorded (40%), M PFS is 24.5 months (95% CI 16.5 - 32.6). In 80 pts previously exposed to adjuvant T, with 40 events (50.0%), m PFS is 17.2 months (95% CI 11.8 - 22.7). Any grade leucopenia and neutropenia was recorded in 21% and 23% of pts respectively; febrile neutropenia 10 pts. 4 pts interrupted P maintenance, 23 stopped P and T due to drop in LVEF and refusal, 1 due to occurrence of ALL. Any grade non-hematological toxicities: diarrhea 131 pts (43%), asthenia 176 pts (58%), peripheral neuropathy 107 pts (35%). Stomatitis, nail changes, nausea, alopecia, rash and arthro-myalgia were reported. Conclusions: Our results highlight the activity and safety of the combination of CT plus P and T in unselected HER2+ MBC patients, also in pts previously exposed to adjuvant T.
Effect of breast tumor subtype and site of distant metastatic disease on prognostic outcome among patients with brain metastases and stage IV denovo breast cancer.
Authors: Shaheenah S. Dawood, Bhawna Sirohi, Paul Mainwaring, Rebecca Alexandra Dent
Journal: Journal of Clinical Oncology (2018)

1034 Background: The objective of this study was to examine the impact of breast tumor subtype and site of distant metastatic disease on prognostic outcome among patients with stage IV denovo breast cancer who have brain metastases at diagnosis. Methods: We searched the SEER registry to identify 1025 patients(pts) with stage IV denovo breast cancer and upfront brain metastases diagnosed between 2010 and 2014. Pts were divided into four groups depending on the breast tumor subtype: a) triple negative (TNBC), b) HER2-ve/HR+ve, c) HER2+/HR-ve, d) HER2+/HR+ve. The presence of distant metastatic disease (DM) other than the brain was defined as disease in the lung, liver or bone. Overall survival (OS) was computed using the Kaplan Meier product limit method. Multivariable cox models were then fit to look at the association of breast tumor subtype and OS adjusted for various pt and tumor characteristics. Results: Median age at diagnosis was 60 years and median OS was 9m. 225 (21.5%), 480 (46.8%), 138(13.4%) and 186(18.15%) pts had TNBC, HER2-ve/HR+ve, HER2+/HR-ve and HER2+/HR+ve disease respectively. Median OS was 5m(TNBC), 13m(HER2-ve/HR+ve), 9m(HER2+/HR-ve), and 21m(HER2+/HR+ve) across the subtypes(p < 0.0001) respectively. Median OS among those who did and did not have surgery of their primary tumor was 14m and 7m respectively (p < 0.0001). Median OS among those with lung , liver , bone only or no distant metastases was 8m, 6m, 15m and 10m respectively (p < 0.0001). In the multivariable cox model compared to pts who had TNBC pts who had HER2-ve/HR+ve (HR0.59, CI 0.48-0.73, p < 0.001), HER2+/HR-ve (HR0.79, CI 0.60-1.04, p = 0.09) and HER2+/HR+ve (HR0.35, CI 0.27-0.47, p < 0.001) had a lower risk of death. 250 (24%)pts did not have DM at presentation. Median OS in this cohort was 5m(TNBC), 10m(HER2-ve/HRve+), 14m(HER2+/HR-ve) and 34m (HER2+/HR+ve) across the subtypes respectively(p = 0.0003). Conclusions: Among pts with stage IV denovo breast cancer and brain metastases at diagnosis factors such as bone only or no distant metastatic disease and HER2+v/HR+ve subtype was associated with the best prognostic.
Effect of anticoagulants and NSAIDs on accuracy of faecal immunochemical tests (FITs) in colorectal cancer screening: a systematic review and meta-analysis
Authors: Stella A V Nieuwenburg, Fanny E R Vuik, Marieke J H A Kruip, Ernst J Kuipers, Manon C W Spaander
Journal: Gut (2018)

Objective Most colorectal cancer (CRC) screening programmes are nowadays based on faecal immunochemical testing (FIT). Eligible subjects often use oral anticoagulants (OACs) or non-steroidal anti-inflammatory drugs (NSAIDs), which could possibly stimulate bleeding from both benign and premalignant lesions in the colon. The aim of this meta-analysis was to study the effect of OACs and NSAIDs use on FIT performance. Design A systematic search was conducted until June 2017 to retrieve studies from PubMed, Embase, MEDLINE, Web of science, Cochrane Central and Google Scholar. Studies were included when reporting on FIT results in users versus non-users of OACs and/or NSAIDs in average risk CRC screening populations. Primary outcome was positive predictive value for advanced neoplasia (PPV AN ) of FIT in relation to OACs/NSAIDs use. Values were obtained by conducting random-effect forest plots. Results Our literature search identified 2022 records, of which 8 studies were included. A total of 3563 participants with a positive FIT were included. Use of OACs was associated with a PPV AN of 37.6% (95% CI 33.9 to 41.4) compared with 40.3% (95% CI 38.5 to 42.1) for non-users (p=0.75). Pooled PPV AN in aspirin/NSAID users was 38.2% (95% CI 33.8 to 42.9) compared with 39.4% (95% CI 37.5 to 41.3) for non-users (p=0.59). Conclusion FIT accuracy is not affected by OACs and aspirin/NSAIDs use. Based on the current literature, withdrawal of OACs or NSAIDs before FIT screening is not recommended. Future studies should focus on duration of use, dosage and classes of drugs in association with accuracy of FIT to conduct more specific guideline recommendations.