tbuckley/cabot-search huggingface dataset:
Accelerated Radiotherapy, Carbogen, and Nicotinamide in Glioblastoma Multiforme: Report of European Organization for Research and Treatment of Cancer Trial 22933
Authors: Raymond Miralbell, Françoise Mornex, Richard Greiner, Michel Bolla, Guy Storme, Maarten Hulshof, Jacques Bernier, Juliana Denekamp, Ana M. Rojas, Marianne Pierart, Martine van Glabbeke, René O. Mirimanoff
Journal: Journal of Clinical Oncology (1999)

PURPOSE: A three-step phase I/II trial associating accelerated radiotherapy with carbogen (step 1, ARCO), with nicotinamide (step 2, ARN), or with both (step 3, ARCON) was conducted, the aim of which was to overcome the effects of proliferation and hypoxia as potential causes of tumor radioresistance in glioblastoma multiforme. PATIENTS AND METHODS: Radiotherapy consisted of 60 Gy delivered over 4 weeks in 1.5-Gy fractions twice daily, 5 days a week. Carbogen breathing was started 5 minutes before each fraction and continued until the end of each treatment session. Nicotinamide was given daily as a single oral dose of 85 mg/kg. RESULTS: A total of 115 patients with a median age of 55 years were registered. Of 107 eligible patients, 23 were registered in step 1, 28 in step 2, and 56 in step 3. The planned treatment was administered without any interruption in 72% of patients (86% in ARCO but 68% in ARN and ARCON). The incidence and severity of acute skin and mucous membrane toxicity were higher in patients who received nicotinamide (ie, the ARN and ARCON groups). Grade 1 to 2 gastrointestinal toxicity was observed in 44% of patients in the ARN group and 32% of patients in the ARCON group, but only in 8% of patients in the ARCO group. Eight percent of evaluated patients presented with abnormal liver test results at treatment completion. The dose of corticosteroids had to be increased in 44% of patients. Late neurologic side effects were similar in all treatment steps and were observed mostly in patients with disease progression. Median survival times for patients treated with ARCO, ARN, and ARCON were 10.1, 9.7, and 11.1 months, respectively. CONCLUSION: Feasibility of ARCO treatment was good but that of ARN and ARCON was only fair. This probably reflected the higher acute toxicity rate, particularly gastrointestinal, for patients receiving nicotinamide. The dose of corticosteroids had to be increased frequently during treatment, suggesting a higher than expected acute neurologic toxicity. Overall survival was similar in the three treatment steps and not different when compared with results of other series that used radiotherapy alone.
PI3Kδ Inhibitors in Cancer: Rationale and Serendipity Merge in the Clinic
Authors: David A. Fruman, Christian Rommel
Journal: Cancer Discovery (2011)

Abstract Several phosphoinositide 3-kinase (PI3K) inhibitors are in the clinic and many more are in preclinical development. CAL-101, a selective inhibitor of the PI3Kδ isoform, has shown remarkable success in certain hematologic malignancies. Although PI3Kδ signaling plays a central role in lymphocyte biology, the degree of single-agent therapeutic activity of CAL-101 during early-phase development has been somewhat unexpected. CAL-101 works in part by blocking signals from the microenvironment that normally sustain leukemia and lymphoma cells in a protective niche. As PI3Ks enter the arena of molecular-targeted therapies, CAL-101 provides proof of principle that isoform-selective compounds can be effective in selected cancer types and patient populations. Significance: A key question is whether compounds targeting a single PI3K catalytic isoform can provide meaningful single agent efficacy in cancer cells that express multiple isoforms. Clinical studies of the drug CAL-101 have provided a significant advance by showing that selective targeting of PI3Kδ achieves efficacy in chronic lymphocytic leukemia, in part through targeting the tumor microenvironment. Cancer Discovery; 1(7); 562–72. ©2011 AACR.
Active TB case finding strategies in high-risk groups in low-incidence countries - A literature review
Authors: Dominik Zenner, Jo Southern, Rob van Hest, Gerard deVries, Helen R. Stagg, Delphine Antoine, Ibrahim Abubakar
Journal: European Respiratory Journal (2013)

Introduction

Most cases of Tuberculosis (TB) in low incidence countries arise in high-risk groups, such as migrants, or social risk groups. Increasingly, active case finding (ACF) initiatives amongst these groups are promoted in these settings. The aim of the review was to summarise the evidence for ACF interventions in low incidence countries.

Methods

We conducted a search on Medline (1966-2012), using a defined search strategy, to find ACF papers amongst social risk groups and migrants in low incidence countries and hand-searched reference lists of included papers and reviews.

Results

We included 27 of 578 papers for social risk groups, and 7 of 198 papers not included in a recent systematic review (Klinkenberg, 2008).

For social risk groups, the majority of studies (17 of 27) reported ACF in homeless persons, with a median of 726 (range 120-22,000) screenees, a median of 9.5 (range 0-313) detected cases and a yield of 0-6.0%. Other ACF settings included prisons (9 studies, median 11,576 screenees, yield 0.01-2.7%) and the drug user population (n=2). Among migrant studies, the overall median yield was 0.34% (a similar level to the 0.35% in the 2008 systematic review and 0.31% in the newer studies). Pre-entry screening had a significantly higher yield (1.21%).

Discussion

Despite the lack of randomised controlled trials, our review of observational studies demonstrated effectiveness of highly targeted interventions in high-risk groups. Further research to determine the best strategies for ACF in low incidence countries, and on the cost effectiveness of ACF, is needed.
DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus
Authors: Lucas TJ Kaaij, Marc van de Wetering, Fang Fang, Benjamin Decato, Antoine Molaro, Harmen JG van de Werken, Johan H van Es, Jurian Schuijers, Elzo de Wit, Wouter de Laat, Gregory J Hannon, Hans C Clevers, Andrew D Smith, René F Ketting
Journal: Genome biology (2013)

DNA methylation is of pivotal importance during development. Previous genome-wide studies identified numerous differentially methylated regions upon differentiation of stem cells, many of them associated with transcriptional start sites. We present the first genome-wide, single-base-resolution view into DNA methylation dynamics during differentiation of a mammalian epithelial stem cell: the mouse small intestinal Lgr5+ stem cell. Very little change was observed at transcriptional start sites and our data suggest that differentiation-related genes are already primed for expression in the stem cell. Genome-wide, only 50 differentially methylated regions were identified. Almost all of these loci represent enhancers driving gene expression in the differentiated part of the small intestine. Finally, we show that binding of the transcription factor Tcf4 correlates with hypo-methylation and demonstrate that Tcf4 is one of the factors contributing to formation of differentially methylated regions. Our results reveal limited DNA methylation dynamics during small intestine stem cell differentiation and an impact of transcription factor binding on shaping the DNA methylation landscape during differentiation of stem cells in vivo.
The pathology of butterfly densities in uraemia
Authors: R. T. Hughes
Journal: Thorax (1967)

Seven cases are presented which are considered to throw some light on the pathology of butterfly densities and their pathogenesis. It is shown that reversible butterfly densities may represent pulmonary vascular congestion and readily reabsorbed oedema fluid resulting from fluid retention and increased blood volume (fluid lung). Terminal butterfly densities associated with hypertensive heart failure in uraemia represent variable haemorrhagic and fibrinous pulmonary oedema with secondary cellular changes and organization (uraemic pneumonia). By means of whole lung sections haemorrhagic forms of uraemic pneumonia associated with hypertensive heart disease are shown to be localized to the lung `medulla9, and the relevance of secondary lobular boundaries to the pathological anatomy is demonstrated. It is considered probable that the butterfly distribution is not determined by uraemic factors but by a non-specific haemodynamic mechanism which is relevant to all forms of central pulmonary oedema.
Assembly of a phased diploid Candida albicans genome facilitates allele-specific measurements and provides a simple model for repeat and indel structure
Authors: Dale Muzzey, Katja Schwartz, Jonathan S Weissman, Gavin Sherlock
Journal: Genome biology (2013)

Abstract Background Candida albicans is a ubiquitous opportunistic fungal pathogen that afflicts immunocompromised human hosts. With rare and transient exceptions the yeast is diploid, yet despite its clinical relevance the respective sequences of its two homologous chromosomes have not been completely resolved. Results We construct a phased diploid genome assembly by deep sequencing a standard laboratory wild-type strain and a panel of strains homozygous for particular chromosomes. The assembly has 700-fold coverage on average, allowing extensive revision and expansion of the number of known SNPs and indels. This phased genome significantly enhances the sensitivity and specificity of allele-specific expression measurements by enabling pooling and cross-validation of signal across multiple polymorphic sites. Additionally, the diploid assembly reveals pervasive and unexpected patterns in allelic differences between homologous chromosomes. Firstly, we see striking clustering of indels, concentrated primarily in the repeat sequences in promoters. Secondly, both indels and their repeat-sequence substrate are enriched near replication origins. Finally, we reveal an intimate link between repeat sequences and indels, which argues that repeat length is under selective pressure for most eukaryotes. This connection is described by a concise one-parameter model that explains repeat-sequence abundance in C. albicans as a function of the indel rate, and provides a general framework to interpret repeat abundance in species ranging from bacteria to humans. Conclusions The phased genome assembly and insights into repeat plasticity will be valuable for better understanding allele-specific phenomena and genome evolution.
Chylothorax or leakage of total parenteral nutrition?
Authors: A Wolthuis, RB Landewe, PH Theunissen, LW Westerhuis
Journal: European Respiratory Journal (1998)

The diagnosis chylothorax is based on a chemical analysis of the pleural effusion. According to the literature, this analysis can be rather straightforward, comprising measurements of triglycerides, chylomicrons, and cholesterol. In this report we present an autopsy case that alerted us to interpret these results critically. Although the laboratory tests of the pleural effusion in this patient with parenteral nutrition suggested chylothorax, additional tests (potassium (11.3 mmol.L(-1)) and glucose (128 mmol.L(-1)) proved otherwise. Comparison of the pleural effusion analysis and the content of the parenteral nutrition led to the final conclusion that the effusion was due to a leakage of parenteral nutrition instead of chylothorax. We therefore suggest adding glucose and potassium measurements to the biochemical work-up of a patient under suspicion of chylothorax.
Lack of Serologic Association Between Human Herpesvirus-8 Infection and Multiple Myeloma and Monoclonal Gammopathies of Undetermined Significance
Authors: Roberta Santarelli, Antonio Angeloni, Antonella Farina, Roberta Gonnella, Giuseppe Gentile, Pietro Martino, Maria Teresa Petrucci, Franco Mandelli, Luigi Frati, Alberto Faggioni
Journal: JNCI Journal of the National Cancer Institute (1998)
Impact of centralising acute stroke services in English metropolitan areas on mortality and length of hospital stay: difference-in-differences analysis
Authors: S. Morris, R. M. Hunter, A. I. G. Ramsay, R. Boaden, C. McKevitt, C. Perry, N. Pursani, A. G. Rudd, L. H. Schwamm, S. J. Turner, P. J. Tyrrell, C. D. A. Wolfe, N. J. Fulop
Journal: BMJ (2014)

<b>Objective</b> To investigate whether centralisation of acute stroke services in two metropolitan areas of England was associated with changes in mortality and length of hospital stay. <b>Design</b> Analysis of difference-in-differences between regions with patient level data from the hospital episode statistics database linked to mortality data supplied by the Office for National Statistics. <b>Setting</b> Acute stroke services in Greater Manchester and London, England. <b>Participants</b> 258 915 patients with stroke living in urban areas and admitted to hospital in January 2008 to March 2012. <b>Interventions</b> "Hub and spoke" model for acute stroke care. In London hyperacute care was provided to all patients with stroke. In Greater Manchester hyperacute care was provided to patients presenting within four hours of developing symptoms of stroke. <b>Main outcome measures</b> Mortality from any cause and at any place at 3, 30, and 90 days after hospital admission; length of hospital stay. <b>Results</b> In London there was a significant decline in risk adjusted mortality at 3, 30, and 90 days after admission. At 90 days the absolute reduction was −1.1% (95% confidence interval −2.1 to −0.1; relative reduction 5%), indicating 168 fewer deaths (95% confidence interval 19 to 316) during the 21 month period after reconfiguration in London. In both areas there was a significant decline in risk adjusted length of hospital stay: −2.0 days in Greater Manchester (95% confidence interval −2.8 to −1.2; 9%) and −1.4 days in London (−2.3 to −0.5; 7%). Reductions in mortality and length of hospital stay were largely seen among patients with ischaemic stroke. <b>Conclusions</b> A centralised model of acute stroke care, in which hyperacute care is provided to all patients with stroke across an entire metropolitan area, can reduce mortality and length of hospital stay.
Diffuse interlobular septal thickening in a coal miner
Authors: S G Thrumurthy, S Kearney, M Sissons, Y Haider
Journal: Thorax (2009)

Diffuse interlobular septal thickening (DIST) is an abnormality seen on high-resolution CT (HRCT) scanning of the thorax. While DIST may be present to variable extents in a number of lung conditions, it is uncommon as a predominant finding except in a few entities. This report features an ex-coal miner, thought to have coal workers’ pneumoconiosis (CWP), in whom the HRCT scan showed no evidence of CWP and instead showed DIST. The patient’s condition progressed incessantly towards death from severe secondary pulmonary hypertension. The case links fatal pulmonary hypertension to DIST, a pattern not previously described in coal workers.
Increased Levels of Elastase and α<sub>1</sub>-Antitrypsin in Sputum of Asthmatic Patients
Authors: ANTONIO M. VIGNOLA, ANNA BONANNO, ANGELA MIRABELLA, LOREDANA RICCOBONO, FRANCO MIRABELLA, MIRELLA PROFITA, VINCENZO BELLIA, JEAN BOUSQUET, GIOVANNI BONSIGNORE
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Asthma and chronic bronchitis are inflammatory diseases associated with remodeling of the extracellular matrix (ECM). Elastin, a major component of the ECM in the airways, has been previously found to be disrupted in asthma and chronic bronchitis. This study was aimed at evaluating whether elastin disruption might be associated with an imbalance between elastase (active and total) and α1-proteinase inhibitor ( α1-PI), the main inhibitor of elastase. We measured elastase and α1-PI in induced sputum obtained from 16 control subjects, 10 healthy smokers, 19 asthmatic patients, and 10 chronic bronchitis patients. We also assessed the possible origin of elastase, evaluating its levels in sputum with reference to differential cell counts. We found that in induced sputum obtained from asthmatic and chronic bronchitis patients, the levels of both total and active elastase were significantly increased as compared with those of control subjects and healthy smokers and were significantly correlated with the percentage of neutrophils. In addition, in asthma and chronic bronchitis patients, the levels of active and total elastase were inversely correlated with the degree of airway obstruction as assessed from FEV1 values. This study shows that airway inflammation in asthma and chronic bronchitis is associated with high levels of active elastase, which may play a role in the pathogenesis of airway remodeling.
Doctors and managers: radical thinking required
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2010)

Amid the slashing sound of treasury cuts, Her Majesty's Government has raised the whisper of clinician leadership. Pragmatic medics may view this as a cynical attempt to subdue the profession in troubled times for the health service. Others will view it as an opportunity to restore rightful leadership to the NHS and banish the 20-year plague of managers. A middle road that marries the most clinically savvy managers with the most managerially skilled clinicians is probably the wisest.

Invariably, the future reality of the NHS is tricky to decipher from present government rhetoric but the preparations for clinician leadership are gathering pace. Aidan Halligan believes that the financial crisis will impact on the duty of care to patients although instead of being a disaster for patient care, the emergence of a new cadre of clinical leaders could result in the NHS’ finest hour. To that end, Halligan and colleagues at University College London Hospitals have set up an NHS staff college to establish a new global standard in the development of healthcare leaders (JRSM 2010;103:387–91).

Four themes of leadership will be at the heart of the NHS staff college curriculum: self-awareness, self-management, leading the team, and big leadership. But most leaders could devise their own themes within moments. The success of the NHS staff college, and other leadership initiatives, will not be in the use of terminology. It will be dependent on bridging the distance between doctors and managers, restoring a sense of vocation for healthcare professionals, and removing a culture of fear and slavish compliance.

‘If we always do what we always did,’ writes Halligan, ‘we will always get what we always got.’ And it is this challenge I wish to throw open to JRSM readers. If we accept the survey results of the Institute for Health Improvement, the American Joint Commission and the Rand Corporation that point to a rift between doctors and managers, how do we bring these protagonists closer together? What do we need to do now to improve the relationship between doctors and managers?

We might need radical thinking, and I invite JRSM readers to submit their 50–100 word contributions by the end of October, the best of which will be published in the December issue of the journal. ‘Only one man in a thousand is a leader of men,’ said the management guru Groucho Marx, ‘the other nine hundred and ninety-nine follow women.’ He might have solved the crisis of the NHS with such original thinking. Now it's your turn.
Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell–dependent inflammation
Authors: Jian Wang, Fengqi Li, Haiming Wei, Zhe-Xiong Lian, Rui Sun, Zhigang Tian
Journal: The Journal of Experimental Medicine (2014)

Influenza in humans is often accompanied by gastroenteritis-like symptoms such as diarrhea, but the underlying mechanism is not yet understood. We explored the occurrence of gastroenteritis-like symptoms using a mouse model of respiratory influenza infection. We found that respiratory influenza infection caused intestinal injury when lung injury occurred, which was not due to direct intestinal viral infection. Influenza infection altered the intestinal microbiota composition, which was mediated by IFN-γ produced by lung-derived CCR9+CD4+ T cells recruited into the small intestine. Th17 cells markedly increased in the small intestine after PR8 infection, and neutralizing IL-17A reduced intestinal injury. Moreover, antibiotic depletion of intestinal microbiota reduced IL-17A production and attenuated influenza-caused intestinal injury. Further study showed that the alteration of intestinal microbiota significantly stimulated IL-15 production from intestinal epithelial cells, which subsequently promoted Th17 cell polarization in the small intestine in situ. Thus, our findings provide new insights into an undescribed mechanism by which respiratory influenza infection causes intestinal disease.
Unexpected Abundance of HLA Class II Presented Peptides in Primary Renal Cell Carcinomas
Authors: Jörn Dengjel, Maria-Dorothea Nastke, Cécile Gouttefangeas, Gitsios Gitsioudis, Oliver Schoor, Florian Altenberend, Margret Müller, Björn Krämer, Anna Missiou, Martina Sauter, Jörg Hennenlotter, Dorothee Wernet, Arnulf Stenzl, Hans-Georg Rammensee, Karin Klingel, Stefan Stevanović
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To elicit a long-lasting antitumor immune response, CD8+ and CD4+ T cells should be activated. We attempted to isolate HLA-DR–presented peptides directly from dissected solid tumors, in particular from renal cell carcinoma, to identify MHC class II ligands from tumor-associated antigens (TAA) for their use in peptide-based immunotherapy. Experimental Design: Tumor specimens were analyzed by immunohistochemical staining for their HLA class II expression. HLA class II peptides were subsequently isolated and identified by mass spectrometry. Gene expression analysis was done to detect genes overexpressed in tumor tissue. Peptides from identified TAAs were used to induce peptide-specific CD4+ T-cell responses in healthy donors and in tumor patients. Results: In the absence of inflammation, expression of MHC class II molecules is mainly restricted to cells of the immune system. To our surprise, we were able to isolate and characterize hundreds of class II peptides directly from primary dissected solid tumors, especially from renal cell carcinomas, and from colorectal carcinomas and transitional cell carcinomas. Infiltrating leukocytes expressed MHC class II molecules and tumor cells, very likely under the influence of IFNγ. Our list of identified peptides contains ligands from several TAAs, including insulin-like growth factor binding protein 3 and matrix metalloproteinase 7. The latter bound promiscuously to HLA-DR molecules and were able to elicit CD4+ T-cell responses. Conclusions: Thus, our direct approach will rapidly expand the limited number of T-helper epitopes from TAAs for their use in clinical vaccination protocols.
Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial
Authors: PL Shah, D-J Slebos, PFG Cardoso, E Cetti, K Voelker, B Levine, ME Russell, J Goldin, M Brown, JD Cooper, GW Sybrecht
Journal: The Lancet (2011)