tbuckley/cabot-search huggingface dataset:
Interventions to improve retention-in-care and treatment adherence among patients with drug-resistant tuberculosis: a systematic review
Authors: Stephanie Law, Amrita Daftary, Max O'Donnell, Nesri Padayatchi, Liviana Calzavara, Dick Menzies
Journal: European Respiratory Journal (2018)

The global loss to follow-up (LTFU) rate among drug-resistant tuberculosis (DR-TB) patients remains high at 15%. We conducted a systematic review to explore interventions to reduce LTFU during DR-TB treatment. We searched for studies published between January 2000 and December 2017 that provided any form of psychosocial or material support for patients with DR-TB. We estimated point estimates and 95% confidence intervals of the proportion LTFU. We performed subgroup analyses and pooled estimates using an exact binomial likelihood approach. We included 35 DR-TB cohorts from 25 studies, with a pooled proportion LTFU of 17 (12–23)%. Cohorts that received any form of psychosocial or material support had lower LTFU rates than those that received standard care. Psychosocial support throughout treatment, via counselling sessions or home visits, was associated with lower LTFU rates compared to when support was provided through a limited number of visits or not at all. Our review suggests that psychosocial support should be provided throughout DR-TB treatment in order to reduce treatment LTFU. Future studies should explore the potential of providing self-administered therapy complemented with psychosocial support during the continuation phase.
A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signalling and miRNA dysregulation
Authors: Martina Calore, Alessandra Lorenzon, Libero Vitiello, Giulia Poloni, Mohsin A F Khan, Giorgia Beffagna, Emanuela Dazzo, Claudia Sacchetto, Roman Polishchuk, Patrizia Sabatelli, Roberto Doliana, Daniela Carnevale, Giuseppe Lembo, Paolo Bonaldo, Leon De Windt, Paola Braghetta, Alessandra Rampazzo
Journal: Cardiovascular Research (2018)

Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern. We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/β-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease. Down-regulation of the canonical Wnt/β-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/β-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.
Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies
Authors: Greg P. Coffey, Jiajia Feng, Andreas Betz, Anjali Pandey, Matt Birrell, Janet M. Leeds, Kenneth Der, Sabah Kadri, Pin Lu, Jeremy Segal, Y. Lynn Wang, Glenn Michelson, John T. Curnutte, Pamela B. Conley
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Preclinical studies suggest SYK and JAK contribute to tumor-intrinsic and microenvironment-derived survival signals. The pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor, and associations with tumor response were investigated. Patients and Methods: In a phase I dose-escalation study in adults with relapsed/refractory B-cell malignancies, cerdulatinib was administered orally to sequential dose-escalation cohorts using once-daily or twice-daily schedules. The study enrolled 8 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 13 with follicular lymphoma, 16 with diffuse large B-cell lymphoma (DLBCL), and 6 with mantle cell lymphoma. Correlation of tumor response with pharmacodynamic markers was determined in patients with meaningful clinical responses. Results: Following cerdulatinib administration, complete SYK and JAK pathway inhibition was achieved in whole blood of patients at tolerated exposures. Target inhibition correlated with serum cerdulatinib concentration, and IC50 values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 μmol/L, depending on the phosphorylation event. Significant correlations were observed between SYK and JAK pathway inhibition and tumor response. Serum inflammation markers were reduced by cerdulatinib, and several significantly correlated with tumor response. Diminished expression of CD69 and CD86 (B-cell activation markers), CD5 (negative regulator of BCR signaling), and enhanced expression of CXCR4 were observed in 2 patients with CLL, consistent with BCR and IL4 suppression and loss of proliferative capacity. Conclusions: Cerdulatinib potently and selectively inhibited SYK/JAK signaling at tolerated exposures in patients with relapsed/refractory B-cell malignancies. The extent of target inhibition in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382).
CheckMate 592: A phase II exploratory study of biomarkers associated with the efficacy of first-line nivolumab (nivo) plus ipilimumab (ipi) in patients (pts) with stage IV or recurrent NSCLC
Authors: S. Gettinger, T. Beck, X. Yang, B. Telivala, D. Morgensztern, V. Velcheti, S.S. Ramalingam, K. Schalper, M. Dajee, A. Ranck, R. Yang, D.R. Spigel
Journal: Annals of Oncology (2018)
Near-Infrared Dye-Labeled Anti-Prostate Stem Cell Antigen Minibody Enables Real-Time Fluorescence Imaging and Targeted Surgery in Translational Mouse Models
Authors: Mo Zhang, Naoko Kobayashi, Kirstin A. Zettlitz, Evelyn A. Kono, Joyce M. Yamashiro, Wen-Ting K. Tsai, Ziyue K. Jiang, Chau P. Tran, Chung Wang, Johnny Guan, Anna M. Wu, Robert E. Reiter
Journal: Clinical Cancer Research (2018)

The inability to intraoperatively distinguish primary tumor, as well as lymphatic spread, increases the probability of positive surgical margins, tumor recurrence, and surgical toxicity. The goal of this study was to develop a tumor-specific optical probe for real-time fluorescence-guided surgery.A humanized antibody fragment against PSCA (A11 minibody, A11 Mb) was conjugated with a near-infrared fluorophore, IRDye800CW. The integrity and binding of the probe to PSCA were confirmed by gel electrophoresis, size-exclusion chromatography, and flow cytometry, respectively. The ability of the probe to detect tumor-infiltrated lymph nodes and metastatic lesions was evaluated in 2 xenograft models, as well as in transgenic mice expressing human PSCA (hPSCA). An invasive intramuscular model was utilized to evaluate the efficacy of the A11 Mb-IRDye800CW-guided surgery.A11 Mb was successfully conjugated with IRDye800CW and retained specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 48 hours. The A11 Mb-IRDye800CW specifically detected PSCA-positive primary tumors, tumor-infiltrated lymph nodes, and distant metastases with high contrast. Fluorescence guidance facilitated more complete tumor resection, reduced tumor recurrence, and improved overall survival, compared with conventional white light surgery. The probe successfully identified primary orthotopic tumors and metastatic lesions in hPSCA transgenic mice.Real-time fluorescence image-guided surgery with A11 Mb-IRDye800CW enabled detection of lymph node metastases and positive surgical margins, facilitated more complete tumor removal, and improved survival, compared with white light surgery. These results may be translatable into clinical practice to improve surgical and patient outcomes.
Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response—final results from GeparSixto
Authors: S. Loibl, K.E. Weber, K.M. Timms, E.P. Elkin, E. Hahnen, P.A. Fasching, B. Lederer, C. Denkert, A. Schneeweiss, S. Braun, C.T. Salat, M. Rezai, J.U. Blohmer, D.M. Zahm, C. Jackisch, B. Gerber, P. Klare, S. Kümmel, C. Schem, S. Paepke, R. Schmutzler, K. Rhiem, S. Penn, J. Reid, V. Nekljudova, A.-R. Hartman, G. von Minckwitz, M. Untch
Journal: Annals of Oncology (2018)

BackgroundIn the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD).Patients and methodsPatients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA).ResultsA significantly better DFS (hazard ratio 0.56, 95% CI 0.34–0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26–5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059).ConclusionsThe addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.
Cardiorespiratory Fitness, Coronary Artery Calcium, and Cardiovascular Disease Events in a Cohort of Generally Healthy Middle-Age Men
Authors: Nina B. Radford, Laura F. DeFina, David Leonard, Carolyn E. Barlow, Benjamin L. Willis, Larry W. Gibbons, Susan C. Gilchrist, Amit Khera, Benjamin D. Levine
Journal: Circulation (2018)

Background: A robust literature demonstrates that coronary artery calcification (CAC) and cardiorespiratory fitness (CRF) are independent predictors of cardiovascular disease (CVD) events. Much less is known about the joint associations of CRF and CAC with CVD risk. In the setting of high CAC, high versus low CRF has been associated with decreased CVD events. The goal of this study was to assess the effect of continuous levels of CRF on CVD risk in the setting of increasing CAC burden. Methods: We studied 8425 men without clinical CVD who underwent preventive medicine examinations that included an objective measurement of CRF and CAC between 1998 and 2007. There were 383 CVD events during an average follow-up of 8.4 years. Parametric proportional hazards regression models based on a Gompertz mortality rule were used to estimate total CVD incidence rates at 70 years of age as well as hazard ratios for the included covariates. Results: CVD events increased with increasing CAC and decreased with increasing CRF. Adjusting for CAC level (scores of 0, 1–99, 100–399, and ≥400), for each additional MET of fitness, there was an 11% lower risk for CVD events (hazard ratio, 0.89; 95% confidence interval, 0.84-0.94). When CAC and CRF were considered together, there was a strong association between continuous CRF and CVD incidence rates in all CAC groups. Conclusions: In a large cohort of generally healthy men, there is an attenuation of CVD risk at all CAC levels with higher CRF.
Genomics features (GF) and integration with MRI radiomics features (RF) to develop a prognostic model in oral cavity squamous cell carcinoma (OSCC)
Authors: S. Cavalieri, L. De Cecco, G. Calareso, M. Silva, S.E. Gazzani, M. Bologna, I. Nauta, F. Wesseling, L. Lopez Perez, R. Shefi, V. Tountopoulos, G. Fico, K. Scheckenbach, R.H. Brakenhoff, F. Hoebers, S. Canevari, T. Poli, L. Licitra, L. Mainardi
Journal: Annals of Oncology (2018)
The role of chemotherapy in the landscape of liposarcoma
Authors: A. De Vita, F. Recine, L. Mercatali, G. Miserocchi, C. Liverani, C. Spadazzi, R. Casadei, D. Cavaliere, A. Bongiovanni, F. Pieri, L. Medri, N. Riva, V. Fausti, T. Ibrahim
Journal: Annals of Oncology (2018)
BENEFIT RISK JUDGMENTS FOR PATIENTS RECEIVING RETINOIDS ON A SHORT-TERM AND LONG-TERM BASIS - PANEL DISCUSSION
Authors: Gd Weinstein, Hh Roenigk, Lc Harber, La Goldsmith, Tp Nigra, Js Strauss, Jh Epstein, Gg Krueger, Db Windhorst, Jj Voorhees, Wd Stewart, G Plewig, Jj Kamm, Ar Shalita, Gl Peck, Vj Derbes, Fl Meyskens, Cn Ellis, Ds Goodman, D West, Jg Marks, Aj Miller, Km Halprin
Journal: Journal of the American Academy of Dermatology (1982)
Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models
Authors: Marcus M. Ilg, Marta Mateus, William J. Stebbeds, Uros Milenkovic, Nim Christopher, Asif Muneer, Maarten Albersen, David J. Ralph, Selim Cellek
Journal: European Urology (2018)

Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option.To identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD.We have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD.The new assay was able to detect transforming growth factor-β1-induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy.This is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models.This report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase.
Polymer Thin Film–Induced Tumor Spheroids Acquire Cancer Stem Cell–like Properties
Authors: Minsuk Choi, Seung J. Yu, Yoonjung Choi, Hak R. Lee, Eunbeol Lee, Eunjung Lee, Yumi Lee, Junhyuk Song, Jin G. Son, Tae G. Lee, Jin Y. Kim, Sukmo Kang, Jieung Baek, Daeyoup Lee, Sung G. Im, Sangyong Jon
Journal: Cancer Research (2018)

Abstract Although cancer stem cells (CSC) are thought to be responsible for tumor recurrence and resistance to chemotherapy, CSC-related research and drug development have been hampered by the limited supply of diverse, patient-derived CSC. Here, we present a functional polymer thin film (PTF) platform that promotes conversion of cancer cells to highly tumorigenic three-dimensional (3D) spheroids without the use of biochemical or genetic manipulations. Culturing various human cancer cells on the specific PTF, poly(2,4,6,8-tetravinyl-2,4,6,8-tetramethyl cyclotetrasiloxane) (pV4D4), gave rise to numerous multicellular tumor spheroids within 24 hours with high efficiency and reproducibility. Cancer cells in the resulting spheroids showed a significant increase in the expression of CSC-associated genes and acquired increased drug resistance compared with two-dimensional monolayer-cultured controls. These spheroids also exhibited enhanced xenograft tumor-forming ability and metastatic capacity in nude mice. By enabling the generation of tumorigenic spheroids from diverse cancer cells, the surface platform described here harbors the potential to contribute to CSC-related basic research and drug development. Significance: A new cell culture technology enables highly tumorigenic 3D spheroids to be easily generated from various cancer cell sources in the common laboratory.
GW29-e1289 A novel Morphological Classification for left atrial appendage by transesophageal echocardiography and its impact in left atrial appendage closure
Authors: Zhiqing Qiao, Heng Ge, Lisheng Jiang, Zheng Li, Xinhua Wang, Xuedong Shen, Ben He
Journal: Journal of the American College of Cardiology (2018)
Association between patient outcomes and accreditation in US hospitals: observational study
Authors: Miranda B Lam, Jose F Figueroa, Yevgeniy Feyman, Kimberly E Reimold, E John Orav, Ashish K Jha
Journal: BMJ (2018)

To determine whether patients admitted to US hospitals that are accredited have better outcomes than those admitted to hospitals reviewed through state surveys, and whether accreditation by The Joint Commission (the largest and most well known accrediting body with an international presence) confers any additional benefits for patients compared with other independent accrediting organizations.Observational study.4400 hospitals in the United States, of which 3337 were accredited (2847 by The Joint Commission) and 1063 underwent state based review between 2014 and 2017.4 242 684 patients aged 65 years and older admitted for 15 common medical and six common surgical conditions and survey respondents of the Hospital Consumer Assessment of Healthcare Provider and Systems (HCAHPS).Risk adjusted mortality and readmission rates at 30 days and HCAHPS patient experience scores. Hospital admissions were identified from Medicare inpatient files for 2014, and accreditation information was obtained from the Centers for Medicare and Medicaid Services and The Joint Commission.Patients treated at accredited hospitals had lower 30 day mortality rates (although not statistically significant lower rates, based on the prespecified P value threshold) than those at hospitals that were reviewed by a state survey agency (10.2% v 10.6%, difference 0.4% (95% confidence interval 0.1% to 0.8%), P=0.03), but nearly identical rates of mortality for the six surgical conditions (2.4% v 2.4%, 0.0% (-0.3% to 0.3%), P=0.99). Readmissions for the 15 medical conditions at 30 days were significantly lower at accredited hospitals than at state survey hospitals (22.4% v 23.2%, 0.8% (0.4% to 1.3%), P<0.001) but did not differ for the surgical conditions (15.9% v 15.6%, 0.3% (-1.2% to 1.6%), P=0.75). No statistically significant differences were seen in 30 day mortality or readmission rates (for both the medical or surgical conditions) between hospitals accredited by The Joint Commission and those accredited by other independent organizations. Patient experience scores were modestly better at state survey hospitals than at accredited hospitals (summary star rating 3.4 v 3.2, 0.2 (0.1 to 0.3), P<0.001). Among accredited hospitals, The Joint Commission did not have significantly different patient experience scores compared to other independent organizations (3.1 v 3.2, 0.1 (-0.003 to 0.2), P=0.06).US hospital accreditation by independent organizations is not associated with lower mortality, and is only slightly associated with reduced readmission rates for the 15 common medical conditions selected in this study. There was no evidence in this study to indicate that patients choosing a hospital accredited by The Joint Commission confer any healthcare benefits over choosing a hospital accredited by another independent accrediting organization.
Abstract 15752: Incidence of Silent Myocardial Infarction in a Major Cardiovascular Clinical Trial: Insights From the PRECISION Trial
Authors: Nyal Borges, A. M Lincoff, Steven E Nissen, Katherine Wolski, Lisa Wisniewski, Kimberly Brown, Venu Menon
Journal: Circulation (2017)

Introduction: Although clinically meaningful, adjudication of silent MI in the setting of a cardiovascular (CV) outcome trial is logistically challenging and expensive. The PRECISION trial evaluate...
Intensified 14-day rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP14) compared to RCHOP21 in patients with newly diagnosed diffuse large B cell lymphoma (DLBCL): A systematic review and meta-analysis of randomized controlled trials
Authors: J.D. Sandoval-Sus, S. Dalia, R.S. Mhaskar, J.C. Chavez, A. Ausekar, K. Purnapatre, J. Scheiber, L. Sokol
Journal: Annals of Oncology (2018)
A comparative study of 18F-FDG PET/CT with bilateral bone marrow trephine biopsy for assessment of bone marrow infiltration by lymphoma
Authors: D. Arjunan, G. Prakash, P. Malhotra, N. Varma, S.C. Varma, A. Das, B.R. Mittal, R. Basher, D. Lad, S. Kumari, A.R. Khadwal, S. Vikas, S. Naseem, A. Bal
Journal: Annals of Oncology (2018)
Abstract 13875: Risk Classification of Post-Cardiac Arrest Syndrome Based on the CAST: Is Targeted Temperature Management at 34°C Recommended in the Moderate-Risk Group?
Authors: Mitsuaki Nishikimi, Takayuki Ogura, Kazuki Nishida, Keibun Liu, Mitsunobu Nakamura, Tetsuya Sakamoto, Naoyuki Matsuda
Journal: Circulation (2017)

Introduction: There are few studies on the risk classification of post-cardiac arrest syndrome (PCAS) patients and on the optimal core temperature setting in targeted temperature management (TTM) b...
A phase 1b study of S-1 combined with trastuzumab emtansine (T-DM1) for HER2 positive metastatic breast cancer
Authors: Yasuyuki Kojima, Reiko Yoshie, Hisanori Kawamoto, Arata Shimo, Tomoko Uejima, Tsuguo Iwatani, Ai Motoyoshi, Ei Haku, Yoshihide Kanemaki, Koichiro Tsugawa
Journal: Annals of Oncology (2018)