tbuckley/cabot-search huggingface dataset:
Duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stent: systematic review and network meta-analysis
Authors: Shang-He-Lin Yin, Peng Xu, Bian Wang, Yao Lu, Qiao-Yu Wu, Meng-Li Zhou, Jun-Ru Wu, Jing-Jing Cai, Xin Sun, Hong Yuan
Journal: BMJ (2019)

Abstract Objective To evaluate the efficacy and safety of standard term (12 months) or long term (&gt;12 months) dual antiplatelet therapy (DAPT) versus short term (&lt;6 months) DAPT after percutaneous coronary intervention (PCI) with drug-eluting stent (DES). Design Systematic review and network meta-analysis. Data sources Relevant studies published between June 1983 and April 2018 from Medline, Embase, Cochrane Library for clinical trials, PubMed, Web of Science, ClinicalTrials.gov, and Clinicaltrialsregister.eu. Review methods Randomised controlled trials comparing two of the three durations of DAPT (short term, standard term, and long term) after PCI with DES were included. The primary study outcomes were cardiac or non-cardiac death, all cause mortality, myocardial infarction, stent thrombosis, and all bleeding events. Results 17 studies (n=46 864) were included. Compared with short term DAPT, network meta-analysis showed that long term DAPT resulted in higher rates of major bleeding (odds ratio 1.78, 95% confidence interval 1.27 to 2.49) and non-cardiac death (1.63, 1.03 to 2.59); standard term DAPT was associated with higher rates of any bleeding (1.39, 1.01 to 1.92). No noticeable difference was observed in other primary endpoints. The sensitivity analysis revealed that the risks of non-cardiac death and bleeding were further increased for ≥18 months of DAPT compared with short term or standard term DAPT. In the subgroup analysis, long term DAPT led to higher all cause mortality than short term DAPT in patients implanted with newer-generation DES (1.99, 1.04 to 3.81); short term DAPT presented similar efficacy and safety to standard term DAPT with acute coronary syndrome (ACS) presentation and newer-generation DES placement. The heterogeneity of pooled trials was low, providing more confidence in the interpretation of results. Conclusions In patients with all clinical presentations, compared with short term DAPT (clopidogrel), long term DAPT led to higher rates of major bleeding and non-cardiac death, and standard term DAPT was associated with an increased risk of any bleeding. For patients with ACS, short term DAPT presented similar efficacy and safety with standard term DAPT. For patients implanted with newer-generation DES, long term DAPT resulted in more all cause mortality than short term DAPT. Although the optimal duration of DAPT should take personal ischaemic and bleeding risks into account, this study suggested short term DAPT could be considered for most patients after PCI with DES, combining evidence from both direct and indirect comparisons. Systematic review registration PROSPERO CRD42018099519.
It is time for the world to take COPD seriously: a statement from the GOLD board of directors
Authors: David M.G. Halpin, Bartolome R. Celli, Gerard J. Criner, Peter Frith, M. Victorina López Varela, Sundeep Salvi, Claus F. Vogelmeier, Ronchang Chen, Kevin Mortimer, Maria Montes de Oca, Zaurbek Aisanov, Daniel Obaseki, Rebecca Decker, Alvar Agusti
Journal: European Respiratory Journal (2019)

<b>We must work together to prevent the development of COPD by reducing exposure to risk factors, to ensure the diagnosis is made as early as possible and to ensure all patients around the world receive effective therapy</b>http://bit.ly/2WDUPMp
Recycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling
Authors: Luca D'Agostino, Yingchao Nie, Sayantani Goswami, Kevin Tong, Shiyan Yu, Sheila Bandyopadhyay, Juan Flores, Xiao Zhang, Iyshwarya Balasubramanian, Ivor Joseph, Ryotaro Sakamori, Victoria Farrell, Qi Li, Chung S. Yang, Bin Gao, Ronaldo P. Ferraris, Ghassan Yehia, Edward M. Bonder, James R. Goldenring, Michael P. Verzi, Lanjing Zhang, Y. Tony Ip, Nan Gao
Journal: Cancer Research (2019)

Abstract The effects of polarized membrane trafficking in mature epithelial tissue on cell growth and cancer progression have not been fully explored in vivo. A majority of colorectal cancers have reduced and mislocalized Rab11, a small GTPase dedicated to trafficking of recycling endosomes. Patients with low Rab11 protein expression have poor survival rates. Using genetic models across species, we show that intact recycling endosome function restrains aberrant epithelial growth elicited by APC or RAS mutations. Loss of Rab11 protein led to epithelial dysplasia in early animal development and synergized with oncogenic pathways to accelerate tumor progression initiated by carcinogen, genetic mutation, or aging. Transcriptomic analysis uncovered an immediate expansion of the intestinal stem cell pool along with cell-autonomous Yki/Yap activation following disruption of Rab11a-mediated recycling endosomes. Intestinal tumors lacking Rab11a traffic exhibited marked elevation of nuclear Yap, upd3/IL6-Stat3, and amphiregulin-MAPK signaling, whereas suppression of Yki/Yap or upd3/IL6 reduced gut epithelial dysplasia and hyperplasia. Examination of Rab11a function in enteroids or cultured cell lines suggested that this endosome unit is required for suppression of the Yap pathway by Hippo kinases. Thus, recycling endosomes in mature epithelia constitute key tumor suppressors, loss of which accelerates carcinogenesis. Significance: Recycling endosome traffic in mature epithelia constitutes a novel tumor suppressing mechanism.
Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression
Authors: Cristina Segovia, Edurne San José-Enériz, Ester Munera-Maravilla, Mónica Martínez-Fernández, Leire Garate, Estíbaliz Miranda, Amaia Vilas-Zornoza, Iris Lodewijk, Carolina Rubio, Carmen Segrelles, Luis Vitores Valcárcel, Obdulia Rabal, Noelia Casares, Alejandra Bernardini, Cristian Suarez-Cabrera, Fernando F. López-Calderón, Puri Fortes, José A. Casado, Marta Dueñas, Felipe Villacampa, Juan José Lasarte, Félix Guerrero-Ramos, Guillermo de Velasco, Julen Oyarzabal, Daniel Castellano, Xabier Agirre, Felipe Prósper, Jesús M. Paramio
Journal: Nature Medicine (2019)
Abstract 14195: Diagnostic Value of MRI in Patients With Implanted Cardiac Devices: Does the Benefit Justify the Risk?
Authors: Huma Samar, June Yamrozik, Moneal Shah, Ronald B Williams, Mark Doyle, Christopher A Bonnet, Robert W Biederman
Journal: Circulation (2015)

Background: MRI is infrequently performed on patients with conventional pacemakers/ICD’s. Multiple recent studies and registries (MagnaSafe) have documented the safety of MRI in these patients, yet the diagnostic value of this approach has not been established remaining a critical issue to advance this field in an era of progressive MRI useage. Objective: 1) to examine a protocol to assess the diagnostic utility of thoracic and non-thoracic MRI in patients with implantable devices and 2) to determine if there is substantial benefit to the pt with regard to diagnosis and/or management. Methods: Over 8 years, 134 pts with PM/AICD’s underwent MRI (GE, 1.5T Milwaukee, WI) at a single institution. Specific criteria were followed for all pts to objectively define whether final diagnosis by MRI imaging enhanced patient care. A checklist of three questions was answered following scan interpretation by both the technologist and performing MRI physician(s):1) Did the primary diagnosis change? 2) Did the MRI provide additional information to the existing diagnosis? 3) Did patient management change? If ’Yes’ was answered to any of the above questions, it was considered that the MRI scan was of value to patient diagnosis and/or therapy. Results: All 134 pts underwent MRI/CMR without complications: avg scan time 24±9min including 42 pts with ICD’s, 5 pts with a retained lead and 87 non-MR conditional pacemakers. In 83% (n=112) MR added value to patient diagnosis and management. In 64% (n=86) MRI added additional valuable information to the primary diagnosis and in 19% (n=26) MRI was life-saving, changing the principal diagnosis and subsequent management of the pt. There were no deaths, arrhythmias or power-on-resets encountered and no adverse effects were noted in any pt. No post-procedure revisions or reimplantations of generator/lead were required. Conclusions: MR imaging in patients with implanted cardiac devices adds substantial value to patient diagnosis and management justifying the risk of the procedure. In this real-world patient population, we have shown that MR imaging retains its very high diagnostic yield. Risk-benefit ratios clearly justify the performance of MRI even in this higher risk population, that is, until such time as MR-conditional devices are universal.
Abstract 3779: Clonal tracing reveals different mechanisms of resistance to immune checkpoint blockade
Authors: Shengqing Gu, Xihao Hu, Xiaoqing Wang, Peng Jiang, Ziyi Li, Nicole Traugh, Xia Bu, Xiaofang Xing, Gordon J. Freeman, Myles Brown, Xiaole S. Liu
Journal: Cancer Research (2019)

Abstract Immune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but its resistance presents a major clinical challenge. It remains unclear whether therapeutic resistance is driven predominantly by refractory clones of cancer cells or by immunosuppressive microenvironment. To address this, we utilized syngeneic transplantation model and performed clonal tracing of cancer cells to monitor the response to ICB. Different cancer clones displayed variable sensitivity to ICB treatment, reflecting intratumoral heterogeneity in therapy response. Furthermore, different recipients manifested distinct resistance mechanisms. ICB-responders developed resistance through selection and expansion of pre-existing ICB-resistant cancer clones, whereas non-responders presented with irresponsive microenvironment rather than dominance of resistant cancer clones. Extrapolation of the tumor-infiltrating immune repertoire revealed that higher IgG and lower IgA strongly correlated with better ICB response. This biomarker was further validated in multiple clinical cohorts. Our approach discriminates different sources of resistance to ICB, and identifies humoral immunity as biomarker of ICB response. Citation Format: Shengqing Gu, Xihao Hu, Xiaoqing Wang, Peng Jiang, Ziyi Li, Nicole Traugh, Xia Bu, Xiaofang Xing, Gordon J. Freeman, Myles Brown, Xiaole S. Liu. Clonal tracing reveals different mechanisms of resistance to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3779.
Abstract 16480: Characteristics and Outcomes of Patients With Papillary Muscle Ventricular Arrhythmias
Authors: Carola Gianni, Luigi Di Biase, Sanghamitra Mohanty, Chintan Trivedi, Yalçin Gökoglan, Mahmut F Günes, Rong Bai, Amin Al-Ahmad, J D Burkhardt, Joseph G Gallinghouse, Rodney Horton, Patrick M Hranitzky, Javier E Sanchez, Andrea Natale
Journal: Circulation (2015)

Introduction: We sought to investigate the characteristics and outcomes of patients who underwent RF ablation of PM ventricular arrhythmias (VA) in our center. Results: 26 patients were included, median age was 66 years (16 to 85), 46% female, all with normal LVEF. PM VAs were PVCs in 68% patients, and PVC + VT in 32%. Site of origin was the LV infero-septal PM in 73%, LV antero-lateral PM in 15% and right ventricular RV septal PM in 12%. 46% of patients showed other VAs in addition to the one originating from the PMs; in 33% of these patients, additional VAs were 2 or more. These VAs were mostly PVCs (92%), localized in the LVOT (64% - 56 % in the basal LV and 44% in the aortic cusps) and the septal RVOT (36%). The only additional VT was fascicular. All the PMs and mappable additional VAs were ablated with RF energy through an irrigated catheter and the aid of ICE; a remote magnetic navigation system (RMS) was used in half of the procedures. In one case, PVC suppression required additional epicardial ablation. Major complications occurred in 2 patients (8%): 1 pericardial effusion (the patient underwent ablation of a crista terminalis premature atrial complex in the same procedure) and 1 pseudoaneurysm. Acute success (PM VA suppression/non-inducibility) was achieved in 96% of patients (the patient with pericardial effusion could be anticoagulated further and the procedure was stopped). After a median follow-up period of 8 (4-14) months, long-term success (no PM VT recurrence or PVC burden reduced by 80% off antiarrhythmic drugs) was 92% after a single procedure, 96% after repeat procedures. When considering additional VAs, the only recurrence was a parahisian RVOT PVC. No difference in acute or overall long-term success was observed when comparing RMS-guided vs standard procedures (respectively 92% vs 100 % and 100% vs 92%; P = NS). Conclusion: PM VAs are most commonly PVCs originating from the LV infero-septal PM and are frequently (48%) associated with an additional ventricular focus (LVOT &gt; RVOT &gt;&gt; fascicular VT). RF ablation is safe and effective in eliminating or significantly reduce the burden of PM VAs, as well the extra-PM foci that are commonly encountered in this population. RMS guided ablation is not inferior to standard ablation in this subset of patients.
Abstract 808: Aggregation alters the metabolism of serous ovarian cancer cells
Authors: Stephanie Edwards, Emily Pyne, Lu Lui, Jack Guinan, Madlyn Frisard, Eva Schmelz
Journal: Cancer Research (2019)

Abstract Ovarian cancer is typically diagnosed at late stages with a poor prognosis due to high recurrence. Exfoliation from the primary tumor results in aggregation of ovarian cancer cells into spheroids in the peritoneal cavity, which may increase survival of cancer and metastasis to other tissues. We have previously reported metabolic changes in adherent ovarian cancer cells to rely more heavily on glycolysis. However, metabolic changes in cancer cell aggregates are poorly understood. In this study, we investigated differences in spheroid metabolism in normoxic and hypoxic conditions as compared to adherent cells. We examined late-stage and tumor-initiating murine ovarian cancer monolayers and spheroids. Using a Seahorse XF extracellular flux analyzer, we investigated changes in metabolism over time in the presence of mitochondrial inhibitors (oligomycin and rotenone) or uncouplers (FCCP). Data show a reduction in basal respiration, maximal oxygen consumption rate, and spare respiratory capacity of spheroids compared to adherent monolayers. This suggests a reduction in energetic demand and metabolic flexibility in spheroids, which may confer increased survival capabilities. The identification of these metabolic changes that may increase survival and metastasis of spheroids provide targets for treatment to control the ability of spheroids to survive in the peritoneal cavity. Citation Format: Stephanie Edwards, Emily Pyne, Lu Lui, Jack Guinan, Madlyn Frisard, Eva Schmelz. Aggregation alters the metabolism of serous ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 808.
Assisted dying: MPs call for inquiry into ban’s effects
Authors: Adrian O’Dowd
Journal: BMJ (2019)

The government should launch a wide ranging investigation or inquiry to gather evidence on the effects of the current laws on assisted dying, in anticipation of possible new laws to change the approach.

This call came during a passionate debate on assisted dying held on Thursday 4 July in the House of Commons, during which many MPs argued for and against a change in the current law, many citing personal experiences.

A debate on the motion that “this House has considered the functioning of the existing law relating to assisted dying” was the first major Commons debate on assisted dying since 2015 and was prompted by the case of Ann and Geoffrey Whaley.

Geoffrey Whaley, aged 80, who had motor neurone disease, died at Dignitas in Switzerland on 7 February this year. He and his wife were reported to local authorities and investigated by police and social …
Abstract 2228: Comparison of the Epic CTC HRD assay vs. tumor DDR mutations in metastatic castration-resistant prostate cancer (mCRPC) patients (pts)
Authors: Joseph Schonhoft, Adam Jendrisak, Jerry Lee, Angel Rodriguez, Ramsay Sutton, Yipeng Wang, Ryan Dittamore, Mark Landers
Journal: Cancer Research (2019)

Abstract Background: PARPi have recently demonstrated clinical activity in a subset of mCRPC pts with defects in homologous recombination (HRD). Predicting PARPi response with HRD gene mutations have struggled to show clinical specificity. Previously, we described a novel circulating tumor cell (CTC) based method (CTC-HRD) that identifies a specific cell morphology associated with genomic scarring [e.g. large scale transitions (LST)] and demonstrated CTC-HRD’s clinical utility in identifying pts likely to respond to PARPi and likely to resist to standard of care (SOC) therapies (Tx), including AR signaling inhibitors. We also observed some discordance between CTC-HRD and DNA damage response (DDR) mutational status from tissue sequencing. Here we compare the prevalence of CTCs, # LSTs/CTC and the % of CTCs with BRCA2 loss in mCRPC patient samples with matched tumor sequencing DDR status. Materials and methods: 302 CTCs from 26 mCRPC pts collected prior to Tx were collected from pts with matched tissue biopsy sequencing. CTCs were identified, assayed for CTC-HRD status, and low pass whole genome sequenced for LSTs and gene copy number alterations (CNA). We compared the prevalence of CTCs, HRD properties of each identified cell including BRCA2 copy loss, # of LSTs/CTC and their prevalence in cells derived from pts vs. CTC-HRD score and tissue DDR mutational status. Results: CTC-HRDDDR Tumor# PtsMedian CTC/mLMedian LST/CTCMedian % CTC BRCA2 Loss per Pt++913.83259.00%+-1010.42347.20%-+72.430.00% CTC-HRD positive pts, independent of tissue DDR status had higher CTC/mL, higher median # LST/CTC and higher percentages of BRCA2 loss in their CTCs vs. those pts who were CTC-HRD negative. Notably, we identified 10 pts that were negative for tissue DDR mutation but were CTC-HRD+ with a high frequency of CTC BRCA2 loss. Conclusions: These results highlight the concordance of the Epic CTC-HRD assay with known markers of HRD and demonstrate differences in CTC-HRD status from tissue DDR mutations which have struggled to achieve the required clinical specificity required for PARPi patient selection. Citation Format: Joseph Schonhoft, Adam Jendrisak, Jerry Lee, Angel Rodriguez, Ramsay Sutton, Yipeng Wang, Ryan Dittamore, Mark Landers. Comparison of the Epic CTC HRD assay vs. tumor DDR mutations in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2228.
Ribonuclease 7 Shields the Kidney and Bladder from Invasive Uropathogenic Escherichia coli Infection
Authors: Tad Eichler, Kristin Bender, Matthew J. Murtha, Laura Schwartz, Jackie Metheny, Lindsey Solden, Robert M. Jaggers, Michael T. Bailey, Sudipti Gupta, Claudia Mosquera, Christina Ching, Krista La Perle, Birong Li, Brian Becknell, John David Spencer
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement In 80% of urinary tract infections (UTIs), uropathogenic Escherichia coli is the causative pathogen. Evidence suggests that antimicrobial peptides protect the kidneys and bladder from bacterial challenge. The authors previously identified ribonuclease 7 (RNase 7) as an antibacterial peptide produced by human kidneys and bladder. In this study, they found significantly lower urinary RNase 7 concentrations in girls and female adolescents with a UTI history compared with controls. They also demonstrated that silencing RNase 7 expression in human urothelial cultures increased uropathogen susceptibility, whereas its overexpression conferred protection. In vivo , humanized RNase 7–expressing transgenic mice showed protection against uropathogenic E. coli challenge compared with controls. These findings suggest that RNase 7 has potential as a UTI prognostic marker or a therapeutic target for protection against bacterial infection. Background Evidence suggests that antimicrobial peptides, components of the innate immune response, protect the kidneys and bladder from bacterial challenge. We previously identified ribonuclease 7 (RNase 7) as a human antimicrobial peptide that has bactericidal activity against uropathogenic Escherichia coli (UPEC). Functional studies assessing RNase 7’s contributions to urinary tract defense are limited. Methods To investigate RNase 7’s role in preventing urinary tract infection (UTI), we quantified urinary RNase 7 concentrations in 29 girls and adolescents with a UTI history and 29 healthy female human controls. To assess RNase 7’s antimicrobial activity in vitro in human urothelial cells, we used siRNA to silence urothelial RNase 7 production and retroviral constructs to stably overexpress RNase 7; we then evaluated UPEC’s ability to bind and invade these cells. For RNase 7 in vivo studies, we developed humanized RNase 7 transgenic mice, subjected them to experimental UTI, and enumerated UPEC burden in the urine, bladder, and kidneys. Results Compared with controls, study participants with a UTI history had 1.5-fold lower urinary RNase 7 concentrations. When RNase 7 was silenced in vitro , the percentage of UPEC binding or invading human urothelial cells increased; when cells overexpressed RNase 7, UPEC attachment and invasion decreased. In the transgenic mice, we detected RNase 7 expression in the kidney’s intercalated cells and bladder urothelium. RNase 7 humanized mice exhibited marked protection from UPEC. Conclusions These findings provide evidence that RNase 7 has a role in kidney and bladder host defense against UPEC and establish a foundation for investigating RNase 7 as a UTI prognostic marker or nonantibiotic-based therapy.