tbuckley/cabot-search huggingface dataset:
Abstract P3-13-09: Increased mortality with repeat lumpectomy alone after ipsilateral breast tumor recurrence: A propensity-adjusted, population-based SEER analysis
Authors: Y Su, R Guo, J Xue, Y Chi, J Wu
Journal: Cancer Research (2019)

Abstract Background: The benefit of repeat lumpectomy for ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) is currently inconclusive. This issue has become even more important as small and isolated recurrent tumors were frequently diagnosed. Methods: IBTR patients with definitive surgery were identified in the Surveillance, Epidemiology, and End Results registry between 1973 and 2013. The effect of different IBTR surgeries on overall and cancer-specific mortality was assessed using risk-adjusted Cox proportional hazard regression modeling and stratified propensity score matching analysis (PSMA). Results: Based on the selection criteria, 5098 patients were recruited. Of those, 4048 (79.4%) women underwent mastectomy and 1050 (20.1%) underwent repeat lumpectomy after IBTR. Patients who received repeat lumpectomy had lower grade (23.7% vs 15% for well-differentiated) and smaller recurrent tumor (47% vs 36.2% for ≤ 1 cm) but earlier recurrence (23.9% vs 11.2% for interval times &amp;lt; 48 months) than those who underwent mastectomy. A minority of each group (24.7% of those undergoing repeat lumpectomy and 3% of the mastectomy group) underwent RT after surgery. In multivariable Cox regression analysis, repeat lumpectomy was associated with increased overall mortality (Hazard ratio (HR) = 1.58, 95% CI = 1.353 to 1.844, P &amp;lt; 0.001) and cancer-specific mortality (HR = 1.721, 95% CI = 1.345 to 2.202, P&amp;lt; 0.001). Similar HRs were derived from the PSMA cohort. However, we found no significant difference in overall mortality for women who underwent repeat lumpectomy followed by RT compared with that for those who underwent mastectomy (P= 0.411). Moreover, IBTR patients with small tumors (≤ 1 cm) who underwent repeat lumpectomy with RT rather than without had similar overall and cancer-specific survival rates to those who underwent mastectomy (P= 0.189 and P= 0.604, respectively). Conclusions: Our investigation suggests that compared with mastectomy, repeat lumpectomy for IBTR is associated with higher overall and cancer-specific mortality under real-world observational conditions. Furthermore, repeat lumpectomy with RT is equivalent to mastectomy with respect to overall mortality and may influence treatment decision making for patients with small IBTR. Citation Format: Su Y, Guo R, Xue J, Chi Y, Wu J. Increased mortality with repeat lumpectomy alone after ipsilateral breast tumor recurrence: A propensity-adjusted, population-based SEER analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-13-09.
Opium and the People. Opiate Use and Drug Control Policy in Nineteenth and Early Twentieth Century England
Authors: Amanda Taffinder
Journal: BMJ (1999)

At first glance and perhaps even for the first few chapters, Opium and the People may seem somewhat heavy going. A book so densely packed with facts and quotes does not make for light and easy reading. However, if you stopped at this point you would be deprived of a myriad of …
FRI-141-Rapid decrease in titer and breath of neutralizing anti-HCV antibodies in HIV/HCV-coinfected patients who achieved sustained virological response
Authors: Lorena Vigón, Sonia Vázquez-Morón, Juan Berenguer, Juan González-García, M Ángeles Jiménez-Sousa, Josep María Guardiola, Manuel Crespo, Ignacio De Los Santos, Miguel Von Wichmann, Ana Carrero, Salvador Resino, Isidoro Martínez
Journal: Journal of Hepatology (2019)
A multidrug resistant engineered CAR T cell for allogeneic combination immunotherapy.
Authors: Julien Valton
Journal: Journal of Clinical Oncology (2015)

7054 Background: the adoptive transfer of CAR T cell represents a highly promising strategy to fight against multiple cancers. The clinical outcome of such therapies is intimately linked to the ability of effector cells to engraft, proliferate and specifically kill tumor cells within patients. When allogeneic CAR T cell infusion is considered, host versus graft and graft versus host reactions must be avoided to prevent rejection of adoptively transferred cells, host tissue damages and to elicit significant antitumoral outcome. This work proposes to address these three requirements through the development of multidrug resistant TCRαβ-deficient CAR T cells. Methods: Primary T cells were successfully engineered using the TALEN technology Results: we demonstrate that these engineered T cells displayed efficient antitumor activity and proliferated in the presence of drugs, currently used in clinic as preconditioning lymphodepleting regimens. The absence of TCRαβ at their cell surface along with their drug-resistance properties could prevent their alloreactivity and enable them to resist to lymphodepleting regimens that may be required to avoid their ablation via HvG reaction. Conclusions: by providing a basic frame work to develop a universal T cell compatible with allogeneic adoptive transfer, this work is laying the foundation stone of the large scale utilization of CAR T cell immunotherapies.
Efficacy of tyrosine kinase inhibitors (TKIs) in advanced lung adenosquamous carcinoma
Authors: M. Hu, B. Zhang, S. Wang, Y. Shen, J. Qian, Y. Zhao, B.-H. Han
Journal: Annals of Oncology (2019)

Background: Adenosquamous carcinoma (ASC) is a rare type of lung cancers, with components of both squamous carcinoma and adenocarcinoma comprising to at least 10% of the tumor. EGFR-TKIs are playing an increasingly important role in the treatment of mutation-positive lung adenocarcinoma. However, the frequency and efficacy of multi-line EGFR-TKIs for ASC patients with sensitive EGFR mutations remain unclear. Methods: From January 2010 to January 2018, patients pathologically diagnosed as lung ASC in Shanghai Chest Hospital were screened. The effectiveness of EGFR-TKIs in advanced ASC patients with EGFR mutation is retrospectively analyzed. Results: A total of 268 ASC patients were screened and 189 patients were tested for the presence of EGFR mutation. 101 positive patients were identified (53.0%, 95% CI, 46.3-60.6%), of which there are 43 19del, 44 21L858R mutations, 6 compound mutations or rare mutations, the rest lack of specific information. A higher frequency of EGFR mutation was found in younger, female patients who were non-smokers. We retrospectively collected consecutive survival data of 67 advanced ACS patients with EGFR-TKI therapy of different generations. Forty-six (46/52, 88.5%) patients had disease progression after first-generation EGFR-TKI treatment, with a median progression free survival (PFS) of 10.7 months (95% CI, 8.6-12.8 months) and a median duration of treatment (MDT) of 13.1 months (95% CI, 8.4-17.8 months). Median PFS for 15 eligible patients received third-generation TKI treatment was 10.2 months (95% CI, 8.3-12.1 months). Median overall survival (OS) for 14 eligible patients with multi-line EGFR-TKIs treatment was 42.1 months (95% CI, 15.7-68.5 months), compared to median OS of patients without third-generation treatment (25.1 months, 95% CI, 10.7-39.4) months. Conclusions: Our data suggests the detection of EGFR mutations in patients with ASC, especially in young, female, non-smoking patients. The third-generation EGFR-TKI treatment could be a better choice to improve outcomes of advanced patients after progression of first-generation TKI. Legal entity responsible for the study: Minjuan Hu. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Optimal time between the last methotrexate administration and seasonal influenza vaccination in rheumatoid arthritis: post hoc analysis of a randomised clinical trial
Authors: Jin Kyun Park, Yunhee Choi, Kevin L Winthrop, Yeong Wook Song, Eun Bong Lee
Journal: Annals of the Rheumatic Diseases (2019)

Methotrexate (MTX), a mainstay treatment for rheumatoid arthritis (RA), suppresses immune responses to influenza vaccination by approximately 15%–20%.1 To improve responses, MTX can be stopped or a higher dose of influenza antigen can be administered. A pilot study showed that holding MTX for 2 weeks before and 2 weeks after vaccination, or for 4 weeks after vaccination reversed MTX-induced suppression of vaccine responses, but with a tendency to increasing RA flare.2 A subsequent randomised clinical trial (RCT) showed that discontinuing MTX temporarily for 2 weeks after vaccination improved vaccine responses to an extent similar to those after discontinuation of MTX for 4 weeks, with no increase in RA disease activity.3 In the latter trial, patients skipped two doses of MTX after vaccination. Since levels of MTX in blood fall after the last dose, the time between the last MTX dose and vaccination may influence vaccine responses. Here, we examined clinical factors associated with improved vaccine responses after MTX discontinuation.

This is a post hoc analysis of the RCT that investigated the effect of MTX discontinuation for 2 weeks on responses to seasonal influenza vaccination.3 Briefly, 316 patients with RA …
Medicine, Religion, and Health
Journal: JAMA (2008)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Functional effects of the microbiota in chronic respiratory disease
Authors: Kurtis F Budden, Shakti D Shukla, Saima Firdous Rehman, Kate L Bowerman, Simon Keely, Philip Hugenholtz, Darius P H Armstrong-James, Ian M Adcock, Sanjay H Chotirmall, Kian Fan Chung, Philip M Hansbro
Journal: The Lancet Respiratory Medicine (2019)
p300 Acetyltransferase Is a Cytoplasm‐to‐Nucleus Shuttle for SMAD2/3 and TAZ Nuclear Transport in Transforming Growth Factor β–Stimulated Hepatic Stellate Cells
Authors: Yuanguo Wang, Kangsheng Tu, Donglian Liu, Luyang Guo, Yunru Chen, Qing Li, Jessica L. Maiers, Zhikui Liu, Vijay H. Shah, Changwei Dou, Daniel Tschumperlin, Luke Voneschen, Rendong Yang, Ningling Kang
Journal: Hepatology (2019)

Nuclear translocation of mothers against decapentaplegic homolog 2/3 (SMAD2/3), core transcription factors of transforming growth factor β (TGF‐β) signaling, is critical for hepatic stellate cell (HSC) differentiation into metastasis‐promoting myofibroblasts. SMAD2/3 have multiple coactivators, including WW domain‐containing transcription regulator protein 1 (WWTR1 or TAZ) and p300 acetyltransferase. In the nucleus, TAZ binds to SMAD2/3 to prevent SMAD2/3 nuclear export. However, how TAZ and SMAD2/3 enter the nucleus remains poorly understood because neither contains a nuclear localization signal (NLS), an amino acid sequence tagging proteins for nuclear transport. p300 is an NLS‐containing large scaffold protein, so we hypothesized that SMAD2/3 and TAZ may undergo nuclear import through complexing with p300. Coimmunoprecipitation, immunofluorescence, and nuclear fractionation assays revealed that TGF‐β1 promoted binding of SMAD2/3 and TAZ to p300 and that p300 inactivation disrupted TGF‐β1‐mediated SMAD2/3 and TAZ nuclear accumulation. Deleting the p300 NLS blocked TGF‐β1‐induced SMAD2/3 and TAZ nuclear transport. Consistently, p300 inactivation suppressed TGF‐β1‐mediated HSC activation and transcription of genes encoding tumor‐promoting factors, such as connective tissue growth factor, Tenascin C, Periostin, platelet‐derived growth factor C, and fibroblast growth factor 2, as revealed by microarray analysis. Chromatin immunoprecipitation‐real‐time quantitative PCR showed that canonical p300‐mediated acetylation of histones also facilitated transcription in response to TGF‐β1 stimulation. Interestingly, although both TGF‐β1‐mediated and stiffness‐mediated HSC activation require p300, comparison of gene expression data sets revealed that transcriptional targets of TGF‐β1 were distinct from those of stiffness‐p300 mechanosignaling. Lastly, in tumor/HSC coinjection and intrasplenic tumor injection models, targeting p300 of activated‐HSC/myofibroblasts by C646, short hairpin RNA, or cre ‐mediated gene disruption reduced tumor and liver metastatic growth in mice. Conclusion: p300 facilitates TGF‐β1‐stimulated HSC activation by both noncanonical (cytoplasm‐to‐nucleus shuttle for SMAD2/3 and TAZ) and canonical (histone acetylation) mechanisms. p300 is an attractive target for inhibiting HSC activation and the prometastatic liver microenvironment.
Direct assessment of skin epithelial barrier by electrical impedance spectroscopy
Authors: Arturo O. Rinaldi, Hideaki Morita, Paulina Wawrzyniak, Anita Dreher, Simon Grant, Per Svedenhag, Cezmi A. Akdis
Journal: Allergy (2019)

Abstract Background Many skin and mucosal inflammatory disorders, such as atopic dermatitis, have been associated with an impaired epithelial barrier function, which allows allergens, pollutants, or microbes to enter the tissue and activate the immune response. The aim of this study was to establish a method to directly assess in vivo the epidermal barrier function by electrical impedance (EI) spectroscopy. Methods Mice epidermal barrier was damaged by epicutaneous application of proteases and cholera toxin and by tape stripping. EI and transepidermal water loss (TEWL) were measured before and after the application. Additionally, histological analysis, immunofluorescence staining, and RT‐PCR were performed on skin biopsies to evaluate the epithelial barrier. Results A few hours after papain application, a dose‐dependent reduction of EI was detected, reflecting the decreased barrier function. At the same time, an increase of TEWL was observed, with a significant negative correlation with EI, demonstrating that EI changes were directly linked to barrier defects. Twenty‐four and 48 hours after the treatment, EI starts to increase to background levels, indicating tissue healing and restoration of skin barrier. Barrier disruption was confirmed by histological analysis showing an impaired stratum corneum and higher cellular infiltration after papain application. In addition, immunofluorescence staining and RT‐PCR showed downregulation of molecules involved in the barrier function, such as filaggrin, occludin, and claudin‐1, and mRNA levels of filaggrin, loricrin, and involucrin. Comparable results were observed after tape stripping and cholera toxin treatment. Conclusion Electrical impedance spectroscopy is a rapid and reliable diagnostic tool to detect skin barrier defects.
Development of composite PLGA microspheres containing exenatide-encapsulated lecithin nanoparticles for sustained drug release
Authors: Ni Dong, Chune Zhu, Junhuang Jiang, Di Huang, Xing Li, Guilan Quan, Yang Liu, Wen Tan, Xin Pan, Chuanbin Wu
Journal: Asian Journal of Pharmaceutical Sciences (2019)

This study aimed to prepare poly (D, L-lactic-co-glycolic acid) microspheres (PLGA-Ms) by a modified solid-in-oil-in-water (S/O/W) multi-emulsion technique in order to achieve sustained release with reduced initial burst and maintain efficient drug concentration for a prolonged period of time. Composite PLGA microspheres containing exenatide-encapsulated lecithin nanoparticles (Ex-NPs-PLGA-Ms) were obtained by initial fabrication of exenatide-loaded lecithin nanoparticles (Ex-NPs) via the alcohol injection method, followed by encapsulation of Ex-NPs into PLGA microspheres. Compared to Ms prepared by the conventional water-in-oil-in-water (W/O/W) technique (Ex-PLGA-Ms), Ex-NPs-PLGA-Ms showed a more uniform particle size distribution, reduced initial burst release, and sustained release for over 60 d in vitro. Cytotoxicity studies showed that Ms prepared by both techniques had superior biocompatibility without causing any detectable cytotoxicity. In pharmacokinetic studies, the effective drug concentration was maintained for over 30 d following a single subcutaneous injection of two types of Ms formulation in rats, potentially prolonging the therapeutic action of Ex. In addition, administration of Ex-NPs-PLGA-Ms resulted in a more smooth plasma concentration-time profile with a higher area under the curve (AUC) compared to that of Ex-PLGA-Ms. Overall, Ex-NPs-PLGA-Ms prepared by the novel S/O/W method could be a promising sustained drug release system with reduced initial burst release and prolonged therapeutic efficacy.
PS-176-Hyperoxidized albumin promotes platelet dysregulation to induce systemic inflammation in severe alcoholic hepatitis
Authors: Adil Bhat, Sukanta Das, Gaurav Yadav, Sudrishiti Chaudhary, Mojahidul Islam, Ashish Kumar Vyas, Renu Goel, Meenu Bajpai, Rakhi Maiwall, Jaswinder Singh Maras, Shiv Kumar Sarin
Journal: Journal of Hepatology (2019)
Pretreatment T790M mutation detection by ultrasensitive PCR assay as predictor of efficacy in non-small lung cancer (NSCLC) patients treated with 1st or 2nd generation EGFR tyrosine kinase inhibitors (TKIs)
Authors: O.J. Juan Vidal, J. Simarro, D. Lorente Estelles, G. Pérez-Simó, N. Mancheno, R. Murria, J. Gomez Codina, B. Laiz, S. Palanca
Journal: Annals of Oncology (2019)

Background: T790M mutation detection previos to 1st/2nd generation EGFR TKIs treatmentis rare by conventional methods (1-8%), although PCR ultrasensitive methods increase their prevalence to 34-80%. The aim of the study is to evaluate the presence of T790M mutations by 2 different ultrasensitive assays and their impact efficacy. Methods: 127 patients (pts) with NSCLC and EGFR mutations were analyzed. 73 of them had sufficient pretreatment tissue for T790M testing. The T790M mutation was screened by PNA Clamp TaqMan Assay (Applied Biosystems) and by ddPCR (BioRad). Results: The limit of detection (LOD) of variant allele frequency was 0.081% and 0.136% for PNA Clamp and ddPCR, respectively. Prevalence of T790M mutations pretreatment was 23% (17/73) and 32% (23/71), respectively. A total of 71 samples gave a certain result in both methodologies (71/73; 95.89%). Agreement between the results of both techniques was 91.55%. Finally, 31 pts who met the eligibility criteria: diagnoses of advanced NSCLC, treated with 1st/2on generation TKIs, have pre-treatment tissue for the analysis and the result of the T790M ultrasensitive analysis was conclusive; were selected to assess the relationship between the results of T790M determined by ultrasensitive methods and the prognosis. Nine (29%) of them had pretreatment T790M+ mutation by both ultrasensitive methods. Median PFS and OS were superior for patients with T790M detected by ultrasensitive PCR assay pre-treatment with TKIs: 24,9 vs. 19,6 m (p = 0.107) and 47,3 vs. 19,9 m (p = 0.76), respectively. To evaluate the association between T790M pretreatment and in the moment of progression we selected 16 pts with T790M mutation analyzed at progression (8 T790M+ and 8 T790M-). T790M at the time of progression was detected in 7 (63,6%) of 11 T790M- diagnosis patients, whilst only 1 (20%) of 5 T790M+ diagnosis patients were positive at the time of progression. Conclusions: Both methods were highly effective for detection of EGFR T790M mutation. The detection of T790M mutation pretreatment of 1st/2ndgeneration EGFR TKIs by ultrasensitive PCR assay was associated with better PFS and OS. Legal entity responsible for the study: Precision Medicine and Biomarkers Unit. IISLAFE. Funding: AstraZeneca. Disclosure: O.J. Juan Vidal: Honoraria, advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche/Genetech, AstraZeneca, Pfizer, Eli Lilly, AbbVie; Institutional research funding: Bristol-Myers Squibb, AstraZeneca. All other authors have declared no conflicts of interest.
High throughput therapeutic screening of malignant pleural mesothelioma (MPM) to identify correlation of sensitivity to FGFR inhibitors with BAP1 inactivation.
Authors: Constantine Alifrangis, Josine Quispel Janssen, Jitendra Badhai, Francesco Iorio, Laurel Schunselaar, Krishna Kolluri, Paul Baas, Mathew Garnett, Ultan McDermott
Journal: Journal of Clinical Oncology (2015)

7563 Background: Small molecule inhibitors have failed to find a role in the treatment of MPM patients. We utilised a high throughput therapeutic screen to identify novel compounds with efficacy in MPM, and performed comprehensive molecular characterisation to identify clinically relevant subgroups within a panel of MPM cell lines. Methods: 26 MPM cell lines including immortalised and primary early passage lines underwent Illumina whole exome sequencing, copy number analysis and Affymetrix array transcriptome profiling. In parallel a high throughput drug screen was performed utilising a panel of targeted therapeutic agents. Results: From a drug screen of 896 cancer cell lines across all tumour types, MPM lines featured amongst the most sensitive 5% to FGFR inhibitors. We validated this sensitivity in a panel of early passage MPM cultures and with multiple FGFR inhibitors and also siRNA silencing of FGFR family members. We did not detect FGFR mutations or amplifications in the MPM. However we identified BAP1 loss, either through truncating mutations or promoter methylation-induced silencing, in those MPM lines with enhanced responses to FGFR inhibition. This association was further confirmed using BAP1 overexpression constructs and BAP1 shRNA knockdown, which modulated response to FGFR inhibition in mesothelioma cell lines. Baseline gene expression pathway analysis shows significant activation of MAPK pathway signalling in BAP1 mutant compared to wild type MPM. Furthermore, we observe significantly increased levels of both FGFR1 and FGFR3 receptor transcripts and of FGF9 and FGF18 in BAP1mutant versus wild type MPM cell lines. We validated this observation in a panel of 54 human MPM tumours. Conclusions: We show that a subgroup of mesotheliomas demonstrate exquisite sensitivity to FGFR inhibition when compared to other tumour types. We identify BAP1 loss as a potential biomarker for FGFR inhibitor efficacy to define this subgroup and furthermore describe activation of FGFR signalling in BAP1 inactivated MPM. This data would suggest a clinically relevant MPM subgroup against which FGFR inhibition could be directed in future clinical studies.
FRI-433-Bevacizumab for the treatment of liver involvement in patients with hereditary hemorrhagic telangiectasia
Authors: Assaf Issachar, Michal Cohen-Naftaly, Orly Sneh Arbib, Ran Tur-Kaspa, Amir Shlomai, Marius Braun, Meir Mei-Zahav
Journal: Journal of Hepatology (2019)