tbuckley/cabot-search huggingface dataset:
Starting Dose of Sorafenib for the Treatment of Hepatocellular Carcinoma: A Retrospective, Multi-Institutional Study
Authors: Kim A. Reiss, Shun Yu, Ronac Mamtani, Rajni Mehta, Kathryn D’Addeo, E. Paul Wileyto, Tamar H. Taddei, David E. Kaplan
Journal: Journal of Clinical Oncology (2017)

Purpose Sorafenib is currently the only Food and Drug Administration-approved first-line therapy for patients with advanced hepatocellular carcinoma. There are few data examining how sorafenib starting dose may influence patient outcomes and costs. Patients and Methods We retrospectively evaluated 4,903 patients from 128 Veterans Health Administration hospitals who were prescribed sorafenib for hepatocellular carcinoma between January 2006 and April 2015. After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HRs) were calculated using Cox regression and were tested against a noninferiority margin of HR = 1.1. A matched multivariate logistic regression was performed to adjust for potential confounders. The primary end point was overall survival (OS) of patients who were prescribed standard starting dosage sorafenib (800 mg/d per os) versus that of patients who were prescribed reduced starting dose sorafenib (< 800 mg/d per os). Results There were 3,094 standard dose sorafenib patients (63%) and 1,809 reduced starting dose sorafenib patients (37%). Reduced starting dose sorafenib patients had more Barcelona Clinic Liver Cancer stage D ( P < .001), higher Model for End-Stage Liver Disease Sodium scores ( P < .001), higher Child-Turcotte-Pugh scores ( P < .001), and higher Cirrhosis Comorbidity Index scores ( P = .01). Consequently, reduced starting dose sorafenib patients had lower OS (median, 200 v 233 days, HR = 1.10). After propensity score matching and adjusting for potential confounders, there was no longer a significant OS difference (adjusted hazard ratio [HRadj], 0.92; 95% CI, 0.83 to 1.01), and this fell significantly below the noninferiority margin ( P < .001). Reduced starting dose sorafenib patients experienced significantly lower total cumulative sorafenib cost and were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% v 10.8%; P = .047). Conclusion The initiation of sorafenib therapy at reduced dosages was associated with reduced pill burden, reduced treatment costs, and a trend toward a decreased rate of discontinuing sorafenib because of adverse events. Reduced dosing was not associated with inferior OS relative to standard dosing.
Differentially Culturable Tubercule Bacilli Are Generated during Nonpulmonary Tuberculosis Infection
Authors: Andrew Rosser, Manish Pareek, Obolbek Turapov, Martin J. Wiselka, Galina V. Mukamolova
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

PreDiCT-TB project funded by European Commission the Innovative Medicines Initiative (no. 115337), a joint undertaking of the European Union Seventh Framework Program and EFPIA (OT and GM); BBSRC, grant BB/K000330/1 (GM); the Dowager Countess Eleanor Peel Trust (AR and GM); the National Institute for
Health Research, PDF-2015-08-102 (MP).
GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes
Authors: Marcel H. A. Muskiet, Lennart Tonneijck, Mark M. Smits, Michaël J.B. van Baar, Mark H. H. Kramer, Ewout J. Hoorn, Jaap A. Joles, Daniël H. van Raalte
Journal: Nature Reviews Nephrology (2017)
PD-L1 expression and response to immunotherapy in patients with <i>MET</i> exon 14-altered non-small cell lung cancers (NSCLC).
Authors: Joshua K. Sabari, Joseph Montecalvo, Ruqin Chen, Jordan A. Dienstag, Chebli Mrad, Isabella Bergagnini, Wei-Chu Victoria Lai, Kathryn Cecilia Arbour, Catherine A. Shu, Matthew David Hellmann, Gregory J. Riely, Mark G. Kris, Charles M. Rudin, Natasha Rekhtman, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2017)

8512 Background: MET exon 14 skipping alterations ( METΔ14) are present in 4% of NSCLCs. Response to MET inhibition has been observed in ongoing prospective trials (44% response rate, phase 1 trial of crizotinib; Drilon et al ASCO 2016), however responses to other types or therapy, such as immunotherapy, is unknown. We evaluated the immunophenotype of METΔ14 lung cancers and response to PD-(L)-1-based immunotherapy. Methods: Pts with recurrent/metastatic NSCLC were eligible. METΔ14 was identified by broad hybrid capture-based next-generation sequencing (MSK-IMPACT). PD-L1 expression was determined by immunohistochemistry. Response to immune therapy was evaluated by RECIST v1.1. Results: 63 pts with METΔ14-positive non-small cell lung cancers were identified; 41 (65%) had sufficient tissue for PD-L1 analysis. Patient characteristics: median age 71 years, 58% female, median pack year smoking 5.85 years, histology: 73% (30/41) adenocarcinoma, 20% (8/41) pleomorphic carcinoma, 7% (3/41) squamous cell. Tumor PD-L1 expression was ≥50% in 44% (18/41, 95% CI 30-59%), 1-49% in 17% (7/41, 95% CI 8-32%), and &lt; 1 in 39% (16/41, 95% CI 26-54%). The median age for patients with METΔ14 and PD-L1 positive (≥1%) tumors was 65 years (range 49-87); 60% (15/25) of patients were female; Histology: 72% (18/25) adenocarcinoma, 24% (6/25) sarcomatoid carcinoma, and 4% (1/25) squamous cell carcinoma. Immunotherapy was given to 15 pts: nivolumab (5), pembrolizumab (3), atezolizumab (2), durvalumab (1), and ipilimumab+nivolumab (4). The overall response rate to immunotherapy was 13% (2/15, 95% CI 3-39%). Overall response was 33% (1/3; 95% CI 6-80%) in patients with tumors PD-L1 ≥50%, and 20% (1/5, 95%CI 2-64%) in patients with tumors PD-L1 0%. Time on therapy ranged from 2 weeks to 9.6+ months. Conclusions: A substantial proportion of NSCLCs harboring METΔ14 alterations express PD-L1. Despite frequent PD-L1 expression, responses to immunotherapy were overall uncommon and lower than that observed with targeted therapy for this genomically defined subset of patients with lung cancers. Further exploration of this subset may reveal important mechanisms of immunotherapy resistance in PD-L1 expressing tumors.
Shifts in metabolism in the developing rat mammary gland: Potential mechanisms for the increased susceptibility to carcinogenesis elucidated by rigorous experimental design, analysis, and replication
Authors: Grier Page, Timothy Whitsett, Helen Kim, Mark Cope, Richie Herring, Michael Crowley, Dung-Tsa Chen, Hui-Chien Kuo, Coral Lamartiniere, Stephen Barnes
Journal: Cancer Research (2008)

2725   Initiation of chemical- and radiation-induced carcinogenesis in the rat mammary depends on the age of the animal. In this study we have examined the changes in gene expression in the mammary gland at two critical stages of mammary gland development, at the time of weaning at 21 days of age prior to onset of puberty and at 50 days of age, the time of maximum sensitivity to 7,12-dimethylbenz[a]anthracene (DMBA). The experiment and the analysis were carefully constructed to avoid unintended bias and yield reproducible results. Animals were fed a polyphenol-free, semi-purified AIN76A diet. The fourth right abdominal mammary gland was rapidly dissected from eight animals at days 21 and 50 and frozen in liquid N2. Rigorous quality control, normalization, and linear models analyses were conducted. The correlation (r 2 ) among the biological samples was over 0.98. Representative significantly changed genes were validated by quantitative RT-PCR. As a test of the veracity of the results obtained, the entire experiment was replicated in different animals raised and analyzed one year after the first experiment. Despite the time separation, the results of the two experiments were highly concordant.  RESULTS : Microarray data analyses demonstrated that progression to day 50 resulted in a significant shift in expression of 11616 genes with a p-value  2 = 0.76, p  90% of genes), fatty acid synthesis (>80% of genes), sterol/cholesterol biosynthesis (>70% of genes) and portions of glycolysis at 50 days of age. A number of these pathway and individual level changes were also observed in DIGE experiments in additional biologically distinct samples. These changes in expression lead to a marked shift in metabolism favoring the formation of fatty acids and sterols and a decrease in aerobic generation of ATP and critical intermediates needed for the synthesis and repair of macromolecules during a period of rapid cell proliferation.
Ministers must act “without delay” to solve GP indemnity crisis, defence bodies warn
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Medical defence unions have urged the government to reach an agreement to protect GPs against the damaging effects of government changes to personal injury discount rates.

GPs in England have already absorbed steep rises in indemnity costs in recent years, and the Ministry of Justice’s rule change in February 2017 has led to fears that cover will become unaffordable for many GPs. Last month, The BMJ reported that the rising cost of indemnity cover had left out-of-hours GP services in England struggling to fill shifts and was putting patient care at risk.1

The Department of Health has said that general practices could be reimbursed if indemnity providers substantially increase their prices. Medical defence organisations have so far held back from announcing fee increases while talks are ongoing, but defence bodies warned that a …
The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis
Authors: Maarten M J Wijnenga, Pim J French, Hendrikus J Dubbink, Winand N M Dinjens, Peggy N Atmodimedjo, Johan M Kros, Marion Smits, Renske Gahrmann, Geert-Jan Rutten, Jeroen B Verheul, Ruth Fleischeuer, Clemens M F Dirven, Arnaud J P E Vincent, Martin J van den Bent
Journal: Neuro-Oncology (2017)

Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes.We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model.Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1-5.0 cm3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002-1.02; P = 0.016) per cm3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1-5.0 cm) already negatively affected OS.Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.
Clinical screening of oropharyngeal dysphagia: standard of care
Authors: Ivan Caviedes, Sebastian Fernandez-Bussy, Gonzalo Labarca, Felix J.F. Herth
Journal: European Respiratory Journal (2017)

We read with interest the paper by Verin et al. [1] related to oropharyngeal dysphagia and its importance in institutionalised neurological and head and neck patients, between others. Furthermore, this is a very common problem in the critical and intermediate care settings, and a similar situation occurs with other acute neurological diseases, such as amyotrophic lateral sclerosis, cerebral trauma, post-neurosurgical procedures and toxic metabolic encephalopathies [2, 3]. The authors emphasised the necessity of identifying risks factors for aspiration early and suggested that clinical screening methods are needed to recognise patients with oropharyngeal dysphagia. However, swallowing clinical screening performed by speech therapists and nurses is a standard of care in critical care units. This concept is particularly relevant, considering that in stroke patients, the prognosis is closely related to the medical complications, and aspiration is responsible for >50% of these and increases mortality for up to 33% at 6 months. Even more, after the acute phase of a stroke, swallowing dysfunction has a recovery capacity of 87% at 6 months [4–6]. The three-ounce water test is a well-known and useful bedside screening tool for oropharyngeal dysphagia <http://ow.ly/9Krl30cW2HJ>
Interplay between cigarette smoking and pulmonary reverse lipid transport
Authors: Éric Jubinville, Maude Talbot, Jean-Christophe Bérubé, Mélanie Hamel-Auger, Michaël Maranda-Robitaille, Marie-Josée Beaulieu, Sophie Aubin, Marie-Ève Paré, David G. Kallend, Benoit Arsenault, Yohan Bossé, Mathieu C. Morissette
Journal: European Respiratory Journal (2017)

Reverse lipid transport is critical to maintain homeostasis. Smoking causes lipid accumulation in macrophages, therefore suggesting suboptimal reverse lipid transport mechanisms. In this study, we investigated the interplay between smoking and reverse lipid transport and the consequences on smoking-induced lung and peripheral alterations. To investigate the relationship between smoking and reverse lipid transport, we used a clinical lung gene expression dataset and a mouse model of cigarette smoke exposure. We also used ApoA-1 −/− mice, with reduced reverse lipid transport capacity, and a recombinant ApoA-1 Milano/phospholipid complex (MDCO-216) to boost reverse lipid transport. Cellular and functional analyses were performed on the lungs and impact on body composition was also assessed. Smoking affects pulmonary expression of abca1 , abcg1 , apoe and scarb1 in both mice and humans, key genes involved in reverse lipid transport. In mice, the capacity of bronchoalveolar lavage fluid and serum to stimulate cholesterol efflux in macrophages was increased after a single exposure to cigarette smoke. ApoA-1 −/− mice showed increased lung neutrophilia, larger macrophages and greater loss in lean mass in response to smoking, whereas treatment with MDCO-216 reduced the size of macrophages and increased the lean mass of mice exposed to cigarette smoke. Altogether, this study shows a functional interaction between smoking and reverse lipid transport, and opens new avenues for better understanding the link between metabolic and pulmonary diseases related to smoking.
Violence Against Women
Authors: I. Heath
Journal: BMJ (1998)

Ed Susan Bewley, John Friend, Gillian Mezey

RCOG Press, £35, pp 355

ISBN 1 900364 03 4

The family is consistently presented as the moral foundation of our society, and yet, apart from the police and the military, the family is society's most violent grouping and the home its most violent setting. At some time in their lives, as many as one in four women suffer violence at the hands of the men with whom they have intimate relationships. The 1992 British crime survey showed that violence against women by partners, former partners, and relatives is the most common form of physical interpersonal crime. The total number of …
Inflammatory Bowel Disease. Diagnosis and Treatment
Authors: E J Israel, R E Kleinman
Journal: Annals of Internal Medicine (1991)

The primary feature of IBD which distinguishes pediatric from adult patients is the presence of or potential for significant growth failure. Recognizing this complication before permanent stunting occurs is critically important. The onset of these disorders during childhood also means that many of these children will have a lifetime of disease and therapy, during both growing as well as reproductive years. The impact of this lifelong process on the psychosocial development of the child and adolescent also needs to be recognized and addressed. Treatments must be carefully considered for their chronic adverse consequences (side effects) as well as immediate benefits. This includes the risks of early, and likely repeated, bowel resections as well as potentially mutagenic or teratogenic medications. The resurgence of tuberculosis and other chronic intestinal infections, particularly in certain high-risk pediatric populations, requires a careful consideration of the differential diagnosis of IBD in children. Finally, promising therapies must be tested in children as well as adults to develop the most effective approach to controlling IBD in pediatric patients by taking advantage of potential age-related differences in intestinal immune barrier function.
Effect of Nucleates on Dehydrogenase Systems&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;
Authors: Harold W. Chalkley, Jesse P. Greenstein
Journal: JNCI Journal of the National Cancer Institute (1945)

Journal Article Effect of Nucleates on Dehydrogenase Systems Get access Harold W. Chalkley, Harold W. Chalkley senior physiologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Jesse P. Greenstein Jesse P. Greenstein principal biochemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 6, Issue 2, October 1945, Pages 119–141, https://doi.org/10.1093/jnci/6.2.119 Published: 01 October 1945
Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia
Authors: Diana Passaro, Alessandro Di Tullio, Ander Abarrategi, Kevin Rouault-Pierre, Katie Foster, Linda Ariza-McNaughton, Beatriz Montaner, Probir Chakravarty, Leena Bhaw, Giovanni Diana, François Lassailly, John Gribben, Dominique Bonnet
Journal: Cancer Cell (2017)

The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient-derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX.
Early intervention in Crohn’s disease: towards disease modification trials
Authors: Silvio Danese, Gionata Fiorino, Laurent Peyrin-Biroulet
Journal: Gut (2017)

Crohn's disease (CD) is a chronic progressive destructive inflammatory bowel disease. As in rheumatoid arthritis, there is increasing evidence that early treatment initiation with disease-modifying agents, such as biological drugs, may lead to complete disease control, prevention of disease progression thus protecting against irreversible damage and restoration of normal quality of life. Data from randomised clinical trials with immunosuppressants and biologics suggest that treating patients with a disease duration of <2 years and an absence of complications may significantly reduce the risk for complications and increase time in remission in patients with CD. Moreover, rapid disease control may effectively prevent disease progression and allow dose reduction or even withdrawal of treatment, reducing the risk of long-term adverse events and healthcare costs. However, prospective disease modification trials are needed to confirm these initial results. Here we review the literature regarding early intervention in adult patients with CD and propose criteria for future disease modification trials.
Impact of alpha 1-antitrypsin deficiency and prior augmentation therapy on patients' survival after lung transplantation
Authors: Anton Conrad, Sabina Janciauskiene, Thomas Köhnlein, Jan Fuge, Philipp Ivanyi, Igor Tudorache, Jens Gottlieb, Tobias Welte, Thomas Fuehner
Journal: European Respiratory Journal (2017)

Alpha 1-antitrypsin (AAT) deficiency (AATD) is a genetic condition characterised by low serum levels of AAT and is associated with a high risk of developing early-onset pulmonary emphysema, especially in cigarette smokers [1]. The most common deficiency alleles among Caucasians are Pi*Z (Glu342Lys) and Pi*S (Glu264Val), and the majority of individuals with severe AATD are Pi type ZZ. According to available literature, PiZZ AATD comprises about 1–5% of all chronic obstructive pulmonary disease (COPD) cases [2]. Given the importance of the protease/anti-protease imbalance in causing Pi*Z-related emphysema [3], intravenous infusions of exogenous AAT are used as a specific augmentation therapy. Data from large interventional and observational studies suggest that decline in lung function and overall mortality decelerates in augmented compared to non-augmented patients [4]. Despite this therapy, it is impossible to halt the progression of emphysema in many patients and for those who develop end-stage lung disease, lung transplantation (LTx) remains the only option [5]. AATD is the fourth-most common reason for LTx, accounting for about 6% of all adult lung transplants [6]; however, there are only a few studies of post-LTx outcomes of patients with AATD [7, 8]. Evidence for the use of augmentation therapy after LTx is insufficient, and there is no consensus whether LTx recipients with AATD should receive augmentation therapy. According to the data, only 13–19% of AATD patients receive augmentation therapy after LTx [7]. Furthermore, the putative influence of previous augmentation therapy on lung recipients who discontinued this therapy following transplantation is entirely unknown. AATD patients who received augmentation therapy prior to LTx show worse survival rates <http://ow.ly/tfgX30e5cVW>
先駆的な例としての乳癌におけるシアル酸の代謝糖鎖工学を用いたセラノスティック応用のための利用性のある癌細胞代謝【Powered by NICT】
Authors: A Badr Haitham, M M AlSadek Dina, E El-Houseini Motawa, T Saeui Christopher, P Mathew Mohit, J Yarema Kevin, Ahmed Hafiz
Journal: Biomaterials (2017)
改良されたドラッグデリバリーのための単一鎖Fc二量体ヒト成長ホルモン融合蛋白質【Powered by NICT】
Authors: Zhou Li, Wang Hsuan-Yao, Tong Shanshan, T Okamoto Curtis, Shen Wei-Chiang, L Zaro Jennica
Journal: Biomaterials (2017)
18F-FDG PET/CT Imaging of Tracheal Mucoepidermoid Carcinoma
Authors: Lei Jiang, Yan Huang, Shanshan Huang, Qiang Li, Huoqiang Wang
Journal: Clinical Nuclear Medicine (2017)

A 54-year-old woman presented with dry cough for 3 months. An FDG PET/CT was performed to evaluate a tracheal nodule, which was revealed by chest CT. The PET/CT images showed increased FDG uptake with SUVmax of 3.3 in the known tracheal lesion. The results of pathological examination from the specimen of bronchoscopy were consistent with tracheal mucoepidermoid carcinoma.
Carpal Tunnel Biopsy Identifying Transthyretin Amyloidosis
Authors: Taryn Youngstein, Janet A. Gilbertson, David F. Hutt, Mark R. E. Coyne, Tamer Rezk, Richa Manwani, Candida C. Quarta, Helen J. Lachmann, Julian D. Gillmore, Huw Beynon, Nicholas Goddard, Philip N. Hawkins
Journal: Arthritis & Rheumatology (2017)