tbuckley/cabot-search huggingface dataset:
A Younger Man With Localized Prostate Cancer Asks, “Which Type of Radiation Is Right for Me?”
Authors: Justin E. Bekelman
Journal: Journal of Clinical Oncology (2018)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 61-year-old man presents with stage II prostate cancer after a period of active surveillance. Work-up reveals T1cN0M0 carcinoma, a prostate-specific antigen (PSA) level of 4.8 ng/mL, and Grade Group II (highest Gleason 3+4) in three cores of 12 taken, at the right mid-gland and right apex. The patient has been on active surveillance for the past 16 months. He was originally diagnosed after biopsy for an elevated PSA with stage I prostate cancer, T1cN0M0; PSA, 4.5 ng/mL; Grade Group 1 (Gleason 3+3) in one core of 12 taken, also at the right mid-gland. A multiparametric magnetic resonance imaging scan showed a heterogeneous peripheral zone without a dominant lesion and a calculated prostate volume of 28 mL. His medical history includes hypercholesterolemia, for which he takes atorvastatin. He is otherwise healthy and has no other significant medical or surgical history. His father had prostate cancer in his 70s and died of other causes at 89 years of age. The patient reports 2- to 3-hour urinary frequency and 0 to 1 nocturia, and has no difficulty obtaining or maintaining an erection. After meeting with his urologist, he sees a radiation oncologist.
Serotonergic Signaling Controls Input-Specific Synaptic Plasticity at Striatal Circuits
Authors: Anna Cavaccini, Marta Gritti, Andrea Giorgi, Andrea Locarno, Nicolas Heck, Sara Migliarini, Alice Bertero, Maddalena Mereu, Giulia Margiani, Massimo Trusel, Tiziano Catelani, Roberto Marotta, Maria Antonietta De Luca, Jocelyne Caboche, Alessandro Gozzi, Massimo Pasqualetti, Raffaella Tonini
Journal: Neuron (2018)
Inequalities in asthma mortality: a specific case of a general issue of health inequalities
Authors: Michael Marmot
Journal: Thorax (2018)

Respiratory disease was always the ‘British’ disease. Not the most common cause of death in Britain, but the cause that most marked Britain as being different from other countries. In the same way, liver disease was the French disease. In both cases, it is not difficult to think of reasons why. The French preoccupation with le foie had much to do with alcohol. French farmers were, in part, paid in wine: 1.5 L a day and for grape pickers 5 L a day, and for a time, France topped the league tables of per person annual alcohol consumption.

As for the British disease, it can be linked to foul air, polluted factories, crowded living conditions that promoted infection and exposure to moulds and other allergens, being early adopters of smoking. Dickens, in Hard Times, gave an account of Victorian living conditions:

> ‘ In the hardest working part of Coketown,…where Nature was as strongly bricked out as killing airs and gases were bricked in… where the chimneys, for want of air to make a draft, were built in an immense variety of stunted and crooked shapes ’.1 

Not that ‘Nature’, bricked out, was salubrious. The foul air of Britain’s industrial cities was justly infamous. Think of Monet’s—he of the luminous Water Lilies—1903 painting of ‘Waterloo Bridge in Fog’. It was hard to see, let alone breathe. Fog was the backdrop and sometimes the centre of Sherlock Holmes’s career. Here he is, for example, gazing out from his Baker Street window in 1895 as a dense yellow fog descends on London:

> ‘ we saw the greasy, heavy brown swirl still drifting past us and condensing in oily drops on the window panes ’ (quoted, p  229).2 

Victorians …
Association of Adjuvant Chemotherapy With Overall Survival in Patients With Rectal Cancer and Pathologic Complete Response Following Neoadjuvant Chemotherapy and Resection
Authors: Patricio M. Polanco, Ali A. Mokdad, Hong Zhu, Michael A. Choti, Sergio Huerta
Journal: JAMA Oncology (2018)

Adjuvant chemotherapy (AC) in patients with rectal cancer with pathologic complete response following neoadjuvant chemoradiotherapy (nCRT) and resection is recommended by treatment guidelines. However, its role in this setting is equivocal because data supporting benefits are lacking.To compare the overall survival (OS) between AC and postoperative observation (OB) in patients with rectal cancer with pathologic complete response following nCRT and resection.We identified a cohort of patients with rectal cancer and a complete pathological response (ypT0N0) after nCRT in the National Cancer Database between 2006 and 2012. Patients who received AC were compared with OB patients by propensity score matching. Overall survival was compared using the stratified log-rank test and stratified Cox regression model. The outcomes after AC vs OB were also evaluated in patient subgroups. The data analysis was completed in June 2017.Adjuvant chemotherapy and OB.Overall survival.We identified 2764 patients (mean [SD] age, 60.0 [12.3] years; 40% female) with clinical stage II or III resected adenocarcinoma of the rectum who had received nCRT and were complete responders (ypT0N0M0). Of this cohort, 741 patients in the AC group were matched by propensity score to 741 patients who underwent OB. The AC cohort had better OS compared with the OB cohort (hazard ratio, 0.50; 95% CI, 0.32-0.79). The 1-, 3-, and 5-year OS rates were 99.7%, 97.1%, and 94.7% for the AC group and 99.2%, 93.6%, and 88.4% for the OB group (P = .005). In subgroup analysis, patients with clinical stage T3/T4 and node-positive disease benefited most from AC (hazard ratio, 0.47; 95% CI, 0.25-0.91).Adjuvant chemotherapy was associated with improved OS in patients with pathologic complete response after nCRT for resected locally advanced rectal cancer. This study supports the use of AC in this setting where there is currently paucity of data.
43Molecular characterisation of fibro-fatty infiltrations in the ventricular myocardium of obese sheep
Authors: T A Agbaedeng, R Mahajan, S Thanigaimani, E Mclennan, D J Twomey, D H Lau, P Sanders
Journal: Cardiovascular Research (2018)

Background: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia.Beta (b)adrenergic stimulation is a well-known trigger of AF.Excessive epicardial adipose tissue (EAT) around the heart is also a risk factor for AF.However, whether b-adrenergic activation stimulates EAT to promote AF in human myocardium remains unknown.Purpose: To determine if human EAT enhances AF induced by b-adrenergic stimulation in human atrial muscles.Methods: After informed consent, human right atrial appendages were obtained from patients that underwent open chest surgery (n ¼ 20).From the tissue isolated muscles (trabeculae) were mounted in a bath, and the susceptibility of AF was measured based on the development of spontaneous contractions during one-minute rest period that followed one-minute stimulation at 1Hz (60 bpm) (automaticity protocol).The automaticity protocol was then repeated following 30 minutes of b-adrenergic stimulation (isoproterenol (ISO), 10-5M).In a separate group of patients (n ¼ 10), trabeculae and a piece of human EAT (average weight ¼ 53 6 8 mg) was obtained.The EAT was situated upstream of the muscle in an adjacent bath, so the superfusion fluid of the EAT flows over the trabecula, and the automaticity protocol was performed during b-adrenergic stimulation (ISO, 10-5M) in the absence and presence of EAT in the adjacent bath.Results: b-adrenergic stimulation increased the percentage of muscles with spontaneous contractions (No ISO: 0%, with ISO: 55%, p < 0.001, Chi-square test) and also the numbers of spontaneous contraction (No ISO: 0 vs. with ISO: 2267 number of spontaneous contractions, p¼0.001,Wilcoxon signed-rank test).In the second group, superfusion of the muscles with EAT alone did not induce spontaneous contractions in the muscles.Interestingly, when the EAT was triggered by b-adrenergic stimulation, 70% of the muscles superfused with EAT developed spontaneous contractions compared to 20% of the muscles without EAT superfusion (p¼0.02,Chi-square test).However, there was no significant difference in the numbers of spontaneous contractions between the muscles superfused with or without EAT after b-adrenergic stimulation (No EAT: 12610 vs. with EAT 1468, number of spontaneous contractions, p¼0.2, Wilcoxon signed-rank test). Conclusion:The b-adrenergic stimulation-induced increases in the susceptibility for developing spontaneous contractions in human cardiac muscles was enhanced in the presence of human EAT.Thus, human EAT has a functional interaction with the human myocardium that affects the susceptibility for AF, specifically through modulation of the b-adrenergic arrhythmogenic trigger.
Topical Lyophilized Targeted Lipid Nanoparticles in the Restoration of Skin Barrier Function following Burn Wound
Authors: Jilong Li, Subhadip Ghatak, Mohamed S. El Masry, Amitava Das, Yang Liu, Sashwati Roy, Robert J. Lee, Chandan K. Sen
Journal: Molecular Therapy (2018)

Lyophilized keratinocyte-targeted nanocarriers (TLNκ) loaded with locked nucleic acid (LNA) modified anti-miR were developed for topical application to full thickness burn injury. TLNκ were designed to selectively deliver LNA-anti-miR-107 to keratinocytes using the peptide sequence ASKAIQVFLLAG. TLNκ employed DOTAP/DODAP combination pH-responsive lipid components to improve endosomal escape. To minimize interference of clearance by non-targeted cells, especially immune cells in the acute wound microenvironment, surface charge was neutralized. Lyophilization was performed to extend the shelf life of the lipid nanoparticles (LNPs). Encapsulation efficiency of anti-miR in lyophilized TLNκ was estimated to be 96.54%. Cargo stability of lyophilized TLNκ was tested. After 9 days of loading with anti-miR-210, TLNκ was effective in lowering abundance of the hypoxamiR miR-210 in keratinocytes challenged with hypoxia. Keratinocyte uptake of DiD-labeled TLNκ was selective and exceeded 90% within 4 hr. Topical application of hydrogel-dispersed lyophilized TLNκ encapsulating LNA anti-miR-107 twice a week significantly accelerated wound closure and restoration of skin barrier function. TLNκ/anti-miR-107 application depleted miR-107 and upregulated dicer expression, which accelerated differentiation of keratinocytes. Expression of junctional proteins such as claudin-1, loricrin, filaggrin, ZO-1, and ZO-2 were significantly upregulated following TLNκ/anti-miR-107 treatment. These LNPs are promising as topical therapeutic agents in the management of burn injury.
Cenicriviroc treatment for adults with non-alcoholic steatohepatitis: Year 2 analysis of the Phase 2b CENTAUR study
Authors: V. Ratziu, A. Sanyal, S. Francque, W. Sun, V. Wong, R. Loomba, Z. Goodman, E. Lefebvre, G. Aithal, S. Harrison, M. Abdelmalek, S. Friedman, F. Tacke
Journal: Journal of Hepatology (2018)
Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial
Authors: Andrew Tutt, Holly Tovey, Maggie Chon U. Cheang, Sarah Kernaghan, Lucy Kilburn, Patrycja Gazinska, Julie Owen, Jacinta Abraham, Sophie Barrett, Peter Barrett-Lee, Robert Brown, Stephen Chan, Mitchell Dowsett, James M Flanagan, Lisa Fox, Anita Grigoriadis, Alexander Gutin, Catherine Harper-Wynne, Matthew Q. Hatton, Katherine A. Hoadley, Jyoti Parikh, Peter Parker, Charles M. Perou, Rebecca Roylance, Vandna Shah, Adam Shaw, Ian E. Smith, Kirsten M. Timms, Andrew M. Wardley, Gregory Wilson, Cheryl Gillett, Jerry S. Lanchbury, Alan Ashworth, Nazneen Rahman, Mark Harries, Paul Ellis, Sarah E. Pinder, Judith M. Bliss
Journal: Nature Medicine (2018)
Intralesional Deoxycholic Acid Treatment for Fibrofatty Residua of Involuted Infantile Hemangiomas
Authors: Michael A. Cardis, Cynthia Marie Carver DeKlotz
Journal: JAMA Dermatology (2018)

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An easy-to-use nomogram to predict overall survival (OS) at 6 months after initiation of FOLFIRINOX first-line chemotherapy in patients (pts) with metastatic pancreatic cancer (mPC).
Authors: Lorenzo Fornaro, Francesco Leone, Angelique Vienot, Andrea Casadei Gardini, Caterina Vivaldi, Pasquale Lombardi, Aurelia Meurisse, Alessandro Passardi, Enrico Vasile, Emmanuele De Luca, Julien Edeline, Gianna Musettini, Maria Antonietta Satolli, Cindy Neuzillet, Rosella Spadi, Dewi Vernerey, Alfredo Falcone, Mario Clerico, Astrid Lievre, Francesco Montagnani
Journal: Journal of Clinical Oncology (2018)

394 Background: FOLFIRINOX achieved a significant step forward in the treatment of mPC. However, patient prognosis remains dismal, and better discrimination of outcomes could be useful to guide clinical decision-making and patient stratification. We aimed at developing and validating a prognostic model and nomogram able to predict the risk of early death (within 6 months post-treatment initiation) in mPC pts treated with first-line FOLFIRINOX. Methods: Data from 137 mPC treated with the GONO FOLFOXIRI schedule at a single institution were used as developing set. Univariate associations with death in the first 6 months after treatment initiation were investigated. Based on the multivariate model, a nomogram was developed assigning points equal to its weighted relevance to each significant variable. The nomogram was externally validated on an independent, parallel cohort of 206 mPC pts treated with FOLFIRINOX at different Italian and French centers. Predictive ability was assessed with the concordance index (C-index) and visual inspection of the calibration plot. Results: 4 out of the 27 considered variables were retained in the multivariable model: ECOG performance status (PS), neutrophils-to-lymphocytes ratio (NLR), liver metastases, and basal serum CA19.9. The nomogram demonstrated adequate discriminative ability in the validation set with a C-index of 0.754. When grouped in different prognostic categories (according to none, 1, 2, or &gt; 2 risk factors), pts included in our study showed significantly different outcomes with median OS ranging from 6.2 ( &gt; 2 risk factors) to 19.5 months (no risk factors, P &lt; 0.05). Conclusions: PS, NLR, liver metastasis, and CA19.9 were the major determinants of 6-month OS. Our nomogram may help clinicians in discussing with pts the benefits and risks of therapy, and in designing future clinical trials. A visual format of the nomogram will be presented. [Table: see text]
Lung cancer staging: a concise update
Authors: Ramón Rami-Porta, Sergi Call, Christophe Dooms, Carme Obiols, Marcelo Sánchez, William D. Travis, Ivan Vollmer
Journal: European Respiratory Journal (2018)

Diagnosis and clinical staging of lung cancer are fundamental to planning therapy. The techniques for clinical staging, i.e . anatomic and metabolic imaging, endoscopies and minimally invasive surgical procedures, should be performed sequentially and with an increasing degree of invasiveness. Intraoperative staging, assessing the magnitude of the primary tumour, the involved structures, and the loco-regional lymphatic spread by means of systematic nodal dissection, is essential in order to achieve a complete resection. In resected tumours, pathological staging, with the systematic study of the resected specimens, is the strongest prognostic indicator and is essential to make further decisions on therapy. In the present decade, the guidelines on lung cancer staging of the American College of Chest Physicians and the European Society of Thoracic Surgeons are based on the best available evidence and are widely followed. Recent advances in the classification of the adenocarcinoma of the lung, with the definition of adenocarcinoma in situ , minimally invasive adenocarcinoma and lepidic predominant adenocarcinoma, and the publication of the eighth edition of the tumour, node and metastasis classification of lung cancer, have to be integrated into the staging process. The present review complements the latest guidelines on lung cancer staging by providing an update of all these issues.
Assessment of Community Awareness and Practices Concerning Indoor Air Pollutants — Madison County, Alabama, June 2017
Authors: Charlene Siza, Melissa Morrison, Scott Harris, Timothy Hatch, Michael Tyler
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

The Alabama Department of Public Health (ADPH) conducts an annual community assessment to evaluate household preparedness and local public health concerns. In June 2017, ADPH conducted a Community Assessment for Public Health Emergency Response (CASPER), focusing on indoor air pollutants in seven neighborhoods in Madison County, Alabama, where a large percentage of homes were built before 1980. Local health partners had concerns about indoor air quality and environmental risks such as radon; however, limited information was available regarding community awareness, prevention, and mitigation measures related to potential exposures. Weighted response frequencies were calculated from assessment responses. Among 192 household interview respondents, 78.4% were aware of potential indoor lead exposures, but only 12.6% of respondents living in houses built before 1978 reported that the house had been tested for lead. Similarly, respondents in 70.2% of households had heard of radon; however, only 7.3% of houses had been tested for radon. Smoking was reported by residents of 45.7% of households; among those, 48.4% reported that smoking occurred inside the house. Identified gaps in exposure prevention and mitigation, including low lead and radon testing rates and a high prevalence of indoor smoking, were shared with the local health department, and recommendations for timely interventions and policy guidance (e.g., targeted education campaigns and smoking cessation programs) were presented. Results of this CASPER demonstrated its usefulness and efficiency in gathering community-level data to help guide public health policies and timely interventions.
SVR is the strongest predictor of occurrence and recurrence of hepatocellular carcinoma in HCV cirrhotic patients after treatment with DAAs: a prospective multi-centric Italian study
Authors: A. Lleo, A. Aglitti, A. Ciancio, V. Di Marco, A. Aghemo, P. Lampertico, M. Brunetto, M.G. Zuin, P. Andreone, E. Villa, G. Troshina, V. Calvaruso, E. Degasperi, B. Coco, A. Giorgini, F. Conti, A. DI Leo, L. Marzi, V. Boccaccio, S. Bollani, P. Maisonneuve, M.G. Rendina, M. Persico, S. Bruno
Journal: Journal of Hepatology (2018)
HIV infection adversely influences the natural history of untreated hepatocellular carcinoma (HCC)
Authors: D.J. Pinato, T.-Y. Chen, E. Allara, F. Trevisani, B. Minguez, M. Zoli, M. Harris, A.D. Pria, N. Merchante, H. Platt, M. Jain, E. Caturelli, L. Kikuchi, J. Pineda, M. Nelson, F. Farinati, G. Ludovico Rapaccini, A. Aytaman, M. Yin, M. Bower, E. Giovanni Giannini, N. Brau
Journal: Journal of Hepatology (2018)
CD2‐Associated Protein Contributes to Hepatitis C, Virus Propagation and Steatosis by Disrupting Insulin Signaling
Authors: Huixia Zhang, Chao Zhang, Hong Tang, Shanshan Gao, Fang Sun, Yuan Yang, Weiping Zhou, Yu Hu, Changshu Ke, Yu Wu, Zeyang Ding, Lin Guo, Rongjuan Pei, Xinwen Chen, Man‐Sun Sy, Bixiang Zhang, Chaoyang Li
Journal: Hepatology (2018)

Chronic hepatitis C virus (HCV) infection can result in steatosis, a condition displaying aberrant accumulation of neutral lipid vesicles, the component of lipid droplets (LDs), which are essential for HCV assembly. However, the interplay between HCV infection and steatosis remains unclear. Here, we show that HCV-infected cells have higher levels of CD2-associated protein (CD2AP), which plays two distinct, yet tightly linked, roles in HCV pathogenesis: Elevated CD2AP binds to nonstructural protein 5A (NS5A) and participates in the transport of NS5A to LDs to facilitate viral assembly; Up-regulated CD2AP also interacts with casitas B-lineage lymphoma (b) (Cbl/Cbl-b) E3 ligases to degrade insulin receptor substrate 1 (IRS1), which, in turn, disrupts insulin signaling and increases LD accumulation through the IRS1/protein kinase B (Akt)/adenosine monophosphate-activated protein kinase (AMPK)/hormone-sensitive lipase (HSL) signaling axis to accommodate viral assembly. In the HCV-infected mouse model, CD2AP expression is up-regulated during the chronic infection stage and this up-regulation correlates well with liver steatosis. Importantly, CD2AP up-regulation was also detected in HCV-infected human liver biopsies showing steatosis compared to non-HCV-infected controls. Conclusion: CD2AP is indicated as a protein up-regulated by HCV infection, which, in turn, stimulates HCV propagation and steatosis by disrupting insulin signaling; targeting CD2AP may offer an opportunity for alleviating HCV infection and its associated liver pathology. (Hepatology 2018;XX:XXX-XXX.).
Letter by Clerkin et al Regarding Article, “Importance of Routine Antihuman/Leukocyte Antibody Monitoring: De Novo Donor Specific Antibodies Are Associated With Rejection and Allograft Vasculopathy After Heart Transplantation”
Authors: Kevin J. Clerkin, Maryjane A. Farr, Donna M. Mancini
Journal: Circulation (2018)

3][4] We recently reported our experience with a prospective cohort of 221 patients who underwent routine standardized screening for DSA.Of these 221 patients, 52 developed dnDSA during a median of 3.5 years of follow-up. 5AMR occurred 74 times in 38 unique patients, and dnDSA were associated with a 3-fold increased risk of AMR.However, there was no increased risk of AMR for patients (n=11) who developed only de novo Class I DSA.We concur with the authors' conclusion regarding the importance of routine screening for DSA following heart transplantation.A concern we have about the report by Wong et al is the association of de novo Class I DSA and AMR.The authors found a nearly 28-fold increased risk of AMR (without report of the confidence interval) for patients who developed de novo Class I DSA.Only 7 patients in the study developed de novo Class I DSA, and of these, 3 patients also developed de novo Class II DSA.The association with AMR is based on 5 patients with Class I DSA, of which ≥1 had both Class I and Class II DSA.Additionally, ≈80% of patients (Figure 1C) with Class I dnDSA developed AMR in the immediate period following transplantation; an incidence that far exceeds anything previously reported.Lastly, the reported association is generated from a multivariable model with 16 rejection events and at least 4 covariates, a ratio that increases the risk of a Type I error.This report adds to the literature on dnDSA following heart transplantation and we thank the authors for sharing the experience at their institution, though we caution against strong conclusions regarding the association between AMR and de novo Class I DSA based on 5 patients.