tbuckley/cabot-search huggingface dataset:
PTU-054 Peripheral blood and intrahepatic natural killer cells in chronic hepatitis C: relation to disease activity and hepatic fibrosis
Authors: H A El Aggan, F S Mohamed, N F El Deeb, M M El Sawy, M S Shater
Journal: Gut (2010)

<h3>Introduction</h3> Cellular immune responses are thought to play a key role in the pathogenesis of hepatitis C virus (HCV)-related liver damage. Recently, increasing attention has been drawn towards components of the innate immune system to HCV, including natural killer (NK) cells. The present work was designed to study peripheral blood and intrahepatic NK cells in patients with chronic hepatitis C in relation to disease activity and severity of hepatic fibrosis. <h3>Methods</h3> Fifteen patients with untreated chronic hepatitis C (CHC) and 12 healthy subjects were included in the current study. The NK and NKT cells in fresh whole blood samples were identified using two-colour flow cytometry as CD3-CD56+ and CD3+CD56 cells, respectively, and the results were expressed as percentages of the total lymphocyte count. Liver biopsies were taken from all patients and the specimens were evaluated as regards the histological activity grade and fibrosis stage according to METAVIR scoring system and for the presence and grade of steatosis. Immunohistochemical staining was done using antibodies against CD56 and smooth muscle actin (SMA) for detection of intrahepatic NK cells and activated hepatic stellate cells (HSCs), respectively. A semi-quantitative method was used to score the intensity of immunostaining. <h3>Results</h3> The percentages of CD3-CD56+ NK cells and CD3+CD56+ NKT cells in peripheral blood showed significant decreases in patients with CHC compared with healthy subjects (p&lt;0.01) and was positively correlated with the intensity of intrahepatic NK cells (p=0.001). The CD56+ NK cell infiltrate was found to be absent or minimal in about 70% of the liver biopsies of patients with CHC. Patients presented with chronic fatigue showed significantly lower percentages of circulating NK and NKT cells and intensity of intrahepatic NK cells than patients who were asymptomatic (p&lt;0.05). The percentages of peripheral blood NK cells and NKT cells and the intensity of intrahepatic NK cells showed significant inverse correlations with serum HCV RNA levels, steatosis grade, METAVIR fibrosis stage and intensity of activated HSCs (p&lt;0.05) and statistically insignificant correlations with serum levels of aminotransferases and the histological activity grade (p&gt;0.05). <h3>Conclusion</h3> The deficiency of peripheral blood and intrahepatic NK cells in patients with chronic hepatitis C may provide a mechanism for immune suppression resulting in viral persistence, disease chronicity and progression of hepatic fibrosis. Restoration of the NK cell population may be one of the potential manipulations for resolution of HCV infection and for therapeutic modulation of hepatofibrogenesis.
Epigenetic Reprogramming in Naive CD4+ T Cells Favoring T Cell Activation and Non‐Th1 Effector T Cell Immune Response as an Early Event in Lupus Flares
Authors: Patrick Coit, Mikhail G. Dozmorov, Joan T. Merrill, W. Joseph McCune, Kathleen Maksimowicz‐McKinnon, Jonathan D. Wren, Amr H. Sawalha
Journal: Arthritis & Rheumatology (2016)

Objective Systemic lupus erythematosus (SLE) is a relapsing autoimmune disease that affects multiple organ systems. T cells play an important role in the pathogenesis of lupus; however, early T cell events triggering disease flares are incompletely understood. This study was undertaken to examine DNA methylation in naive CD4+ T cells from lupus patients to determine if epigenetic remodeling in CD4+ T cells is an early event in lupus flares. Methods A total of 74 lupus patients with an SLE Disease Activity Index score of 0–18 were included. Naive CD4+ T cells were isolated from peripheral blood samples, and DNA was extracted for genome‐wide methylation assessment. RNA was also extracted from a subset of patients to determine the relationship between epigenetic changes and transcription activity using RNA sequencing and microRNA arrays. Results We demonstrated that naive CD4+ T cells in lupus undergo an epigenetic proinflammatory shift, implicating effector T cell responses in lupus flare. This epigenetic landscape change occurs without changes in expression of the corresponding genes, poises naive CD4+ T cells for Th2, Th17, and follicular helper T cell immune responses, and opposes inhibitory transforming growth factor β signaling. Bioinformatics analyses indicate that the epigenetic modulator EZH2 might play an important role in shifting the epigenetic landscape, with increased disease activity in lupus naive CD4+ T cells. Further, the expression of microRNA‐26a, which is sensitive to glucose availability and targets EZH2, was negatively correlated with disease activity in lupus patients. Conclusion An epigenetic landscape shift in naive CD4+ T cells that favors T cell activation and non‐Th1 immune responses predates transcription activity and correlates with lupus activity. A role for EZH2 dysregulation in triggering lupus flares warrants further investigation.
Jerome Gerald Lewis
Authors: Gerald Bevan
Journal: BMJ (2016)

Jerome Gerald Lewis (“Jerry”) was evacuated to Cornwall during the second world war. On returning to St Clement Danes School in London he won a scholarship to the London Hospital Medical School. After national service in the Royal Air Force he worked in a series of junior hospital posts at the Hammersmith, Royal Free, and Brompton hospitals, culminating in a senior registrar position …
Persistent residual contamination in endoscope channels; a fluorescence epimicroscopy study
Authors: Rodolphe Hervé, Charles Keevil
Journal: Endoscopy (2016)

<b>Background and study aims:</b> The increasing demand for endoscopic procedures poses new contamination challenges, given developing antimicrobial resistance worldwide and potential viral or prion diseases in populations at risk. We examined working channels from reusable luminal endoscopes used in recent years. <b>Methods:</b> Very sensitive fluorescence epimicroscopy was used to examine working channels from 6 decommissioned and 6 factory-new channels, as received, or following spiking and washing in the laboratory. <b>Results:</b> After a single contamination and wash test cycle, new channels retained approximately 75 pg/mm<sup>2</sup> of proteins; through 7 subsequent cycles residual proteins fluctuated between 25 and 75 pg/mm<sup>2</sup>. Decommissioned channels harbored 1 – 4 µg of proteins each, except in one gastroscope (33 µg), including up to 2 % amyloid proteins except in one gastroscope and one sigmoidoscope (with over 80 %); lumens showed wearing with established abraded biofilms in 3 cases. After spiking with scrapie-infected blood components and washing, residual protein levels in new channels varied following standard (17.23 pg/mm<sup>2</sup>), duplicated (2.39 pg/mm<sup>2</sup>) or extended (11.3 pg/mm<sup>2</sup>) washing; no changes were measured among the long-established contamination in old channels. <b>Conclusions:</b> Our observations suggest that wear effects in endoscope lumens may contribute to the adsorption of proteins, thus facilitating retention and survival of bacteria. As demonstrated by recent outbreaks worldwide despite recommended reprocessing, the development of antimicrobial-resistant bacterial strains, and the estimated prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the UK particularly, combined with increasing demand for endoscopic procedures, call for sustained precautions and improved methods for the reprocessing of nonautoclavable, reusable surgical instruments.
Maps of the Auditory Cortex
Authors: Alyssa A. Brewer, Brian Barton
Journal: Annual Review of Neuroscience (2016)

One of the fundamental properties of the mammalian brain is that sensory regions of cortex are formed of multiple, functionally specialized cortical field maps (CFMs). Each CFM comprises two orthogonal topographical representations, reflecting two essential aspects of sensory space. In auditory cortex, auditory field maps (AFMs) are defined by the combination of tonotopic gradients, representing the spectral aspects of sound (i.e., tones), with orthogonal periodotopic gradients, representing the temporal aspects of sound (i.e., period or temporal envelope). Converging evidence from cytoarchitectural and neuroimaging measurements underlies the definition of 11 AFMs across core and belt regions of human auditory cortex, with likely homology to those of macaque. On a macrostructural level, AFMs are grouped into cloverleaf clusters, an organizational structure also seen in visual cortex. Future research can now use these AFMs to investigate specific stages of auditory processing, key for understanding behaviors such as speech perception and multimodal sensory integration.
Experts and activists discuss how to get “right care” for patients
Authors: Jeanne Lenzer
Journal: BMJ (2016)

Jeanne Lenzer reports on a growing movement aiming to overcome the medical and social barriers to appropriate care 

The fourth Lown Institute conference held in Chicago, Illinois, in April brought nearly 300 doctors, patients, policy makers, and activists together to discuss barriers to “right care.” The focus was on how to tackle the problems of bad science, undertreatment, and overtreatment—and how to build a movement for change, which several speakers likened to the civil rights movement.

A recurrent theme among speakers and participants was that fee-for-service medicine and profit driven testing and interventions are major obstacles to right care. Speakers emphasized that this could be achieved only if we simultaneously address issues such as the wealth gap, social disparities, and corporate control of politics.

Shannon Brownlee, senior vice president of the Lown Institute, told The BMJ that the presence of a wide range of activists and organizations at the conference gives her hope that a genuine new social justice movement is emerging.

Rita Redberg, editor of JAMA Internal Medicine, said, “We spend $3tr, far more than other countries, yet we still have millions and millions of people without access to healthcare.” She added, “The Institute of Medicine estimated that $1tr a year is spent on waste or overuse.” Both physicians and patients imagine that if some care is good, more must be better, and that a test can’t hurt.

Insurance coverage of unnecessary tests, said Redberg, contributes to overtesting and overtreatment: “The United States Preventive Services Task Force gave a grade D recommendation to PSA [prostate specific antigen] testing but Medicare still covers it, so it means a lot of men are still getting a test that is costing not just money, but lives.”

From the audience, Jill Wruble related her own experience with the unintended consequences of medical testing. …
The Vast and Varied Global Burden of Norovirus: Prospects for Prevention and Control
Authors: Benjamin A. Lopman, Duncan Steele, Carl D. Kirkwood, Umesh D. Parashar
Journal: PLoS Medicine (2016)

Globally, norovirus is associated with approximately one-fifth of all diarrhea cases, with similar prevalence in both children and adults, and is estimated to cause over 200,000 deaths annually in developing countries. Norovirus is an important pathogen in a number of high-priority domains: it is the most common cause of diarrheal episodes globally, the principal cause of foodborne disease outbreaks in the United States, a key health care–acquired infection, a common cause of travel-associated diarrhea, and a bane for deployed military troops. Partly as a result of this ubiquity and burden across a range of different populations, identifying target groups and strategies for intervention has been challenging. And, on top of the breadth of this public health problem, there remain important gaps in scientific knowledge regarding norovirus, especially with respect to disease in low-income settings. Many pathogens can cause acute gastroenteritis. Historically, rotavirus was the most common cause of severe disease in young children globally. Now, vaccines are available for rotavirus and are universally recommended by the World Health Organization. In countries with effective rotavirus vaccination programs, disease due to that pathogen has decreased markedly, but norovirus persists and is now the most common cause of pediatric gastroenteritis requiring medical attention. However, the data supporting the precise role of norovirus in low- and middle-income settings are sparse. With vaccines in the pipeline, addressing these and other important knowledge gaps is increasingly pressing. We assembled an expert group to assess the evidence for the global burden of norovirus and to consider the prospects for norovirus vaccine development. The group assessed the evidence in the areas of burden of disease, epidemiology, diagnostics, disease attribution, acquired immunity, and innate susceptibility, and the group considered how to bring norovirus vaccines from their current state of development to a viable product that will benefit global health.
Reply to Kazutaka Saito's Words of Wisdom re: Nephron-sparing Techniques Independently Decrease the Risk of Cardiovascular Events Relative to Radical Nephrectomy in Patients with a T1a–T1b Renal Mass and Normal Preoperative Renal Function. Eur Urol. 2016;69:538
Authors: Umberto Capitanio, Paolo Dell’Oglio, Alessandro Larcher, Francesco Montorsi
Journal: European Urology (2016)
Role of MRI in Primary Brain Tumor Evaluation
Authors: Denise Leung, Xiaosi Han, Tom Mikkelsen, L Burt Nabors
Journal: Journal of the National Comprehensive Cancer Network (2014)

The NCCN Clinical Practice Guidelines in Oncology for Central Nervous System Cancers use radiologic presentation in the initial evaluation of patients with primary brain tumors and in the determination of response to therapy. The dominant modality use is MRI because of its superior image resolution, speed of acquisition, and high safety profile for patients. The interpretation of MRI is a critical aspect of patient care and evaluation. This article reviews the predominant aspects of MRI for brain tumors, the standard sequences, the criteria to consider in determining treatment response, and advanced aspects currently available. The proper integration of this essential imaging modality into patient care ensures timely disease evaluation and guides the use of therapeutic tools.
TCTAP C-234 Very Late Stent Thrombosis Caused by Obvious Very Late Acquired Stent Malapposition Assessed by Optical Coherence Tomography After Everolimus-eluting Stent Implantation into Sirolimus-eluting Stent
Authors: Yasunori Yamamoto, Yasushi Ino, Takashi Kubo, Yosuke Katayama, Hiroshi Aoki, Tsuyoshi Nishiguchi, Makoto Orii, Takeyoshi Kameyama, Takashi Yamano, Tomoyuki Yamaguchi, Yoshiki Matsuo, Hironori Kitabata, Atsushi Tanaka, Takeshi Hozumi, Takashi Akasaka
Journal: Journal of the American College of Cardiology (2016)
Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism
Authors: G P Soriano, L Besse, N Li, M Kraus, A Besse, N Meeuwenoord, J Bader, B Everts, H den Dulk, H S Overkleeft, B I Florea, C Driessen
Journal: Leukemia (2016)

Adaptive resistance of myeloma to proteasome inhibition represents a clinical challenge, whose biology is poorly understood. Proteasome mutations were implicated as underlying mechanism, while an alternative hypothesis based on low activation status of the unfolded protein response was recently suggested (IRE1/XBP1-low model). We generated bortezomib- and carfilzomib-adapted, highly resistant multiple myeloma cell clones (AMO-BTZ, AMO-CFZ), which we analyzed in a combined quantitative and functional proteomic approach. We demonstrate that proteasome inhibitor-adapted myeloma cells tolerate subtotal proteasome inhibition, irrespective of a proteasome mutation, and uniformly show an 'IRE1/XBP1-low' signature. Adaptation of myeloma cells to proteasome inhibitors involved quantitative changes in >600 protein species with similar patterns in AMO-BTZ and AMO-CFZ cells: proteins involved in metabolic regulation, redox homeostasis, and protein folding and destruction were upregulated, while apoptosis and transcription/translation were downregulated. The quantitatively most upregulated protein in AMO-CFZ cells was the multidrug resistance protein (MDR1) protein ABCB1, and carfilzomib resistance could be overcome by MDR1 inhibition. We propose a model where proteasome inhibitor-adapted myeloma cells tolerate subtotal proteasome inhibition owing to metabolic adaptations that favor the generation of reducing equivalents, such as NADPH, which is supported by oxidative glycolysis. Proteasome inhibitor resistance may thus be targeted by manipulating the energy and redox metabolism.
Extended follow-up results of phase Ib study (BRIM7) of vemurafenib (VEM) with cobimetinib (COBI) in <i>BRAF</i>-mutant melanoma.
Authors: Anna C. Pavlick, Antoni Ribas, Rene Gonzalez, Omid Hamid, Thomas Gajewski, Adil Daud, Igor Puzanov, Jessie J. Hsu, Nicholas W. Choong, Grant A. McArthur
Journal: Journal of Clinical Oncology (2015)

9020 Background: BRIM7 formed the basis for development of the VEM + COBI regimen, which, in a randomized phase III trial, confirmed the statistically significant and clinically meaningful progression-free survival (PFS) improvement of VEM + COBI over VEM. Results of BRIM7 with extended follow-up are presented. Methods: Eligible patients (pts) had advanced BRAFV600-mutated melanoma, ECOG PS 0-1, and could either have progressed on VEM (VEM-PD) or be BRAF inhibitor (BRAFi) naive. Dose escalation pts received VEM 720 mg or 960 mg twice daily (BID) continuously + COBI 60 mg, 80 mg, or 100 mg once daily (QD) 14 days on/14 days off (14/14); 21 days on/7 days off (21/7); or continuously. Two dose levels were expanded: VEM (720 mg and 960 mg BID) + COBI 60 mg QD 21/7. Results: Previously, we reported the 129 VEM + COBI treated pts with the following characteristics: BRAFi naive: 49%; stage M1c: 70% and 82%; LDH > ULN: 46% and 62%; and median follow-up: 13 months and 6 months, for BRAFi-naive and VEM-PD pts, respectively (Ribas A. Lancet Oncol 2014;15:954-965). In this update, the median follow-up in BRAFi-naive and VEM-PD pts was 21 months and 8 months, respectively. Adverse event (AE) frequency and severity remained stable with extended follow-up. The frequencies of symptomatic MEK inhibitor AEs (serous retinopathy and cardiomyopathy) and BRAFi AEs (skin squamous carcinoma) were also unchanged. Confirmed response rate in BRAFi-naive pts remained at 87%. Four additional pts attained complete response (CR) at Cycles 16-25, increasing CR rate from 10% (6 pts) to 16% (10 pts). Median PFS was unchanged at 13.8 months. With extended follow-up, median overall survival (OS) was reached at 28.5 months and 2-year OS was 61%. Confirmed response rate in VEM-PD pts remained at 15%, 1 pt attained CR at Cycle 22. CR was not observed previously in VEM-PD pts. Median PFS and OS were unchanged at 2.8 months and 8.4 months, respectively. The 2-year OS was 15% with extended follow-up. Conclusions: VEM + COBI continues to show robust efficacy in BRAFi-naive pts, with a manageable and tolerable safety profile without new safety signals. Median OS in BRAFi-naive pts was > 2 years. Late CR conversions indicate persistent activity with continued therapy. Clinical trial information: NCT01271803.
Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease
Authors: M Maier-Redelsperger, CT Noguchi, M de Montalembert, GP Rodgers, AN Schechter, A Gourbil, D Blanchard, JP Jais, R Ducrocq, JY Peltier
Journal: Blood (1994)
Clinical Dermatology
Authors: N. A. Soter, D. S. Wilkinson, T. B. Fitzpatrick
Journal: New England Journal of Medicine (1973)

Skin Disorders Associated with Increased Epidermal-Cell Proliferation Psoriasis. Increased epidermal-cell proliferation occurs in some of the ichthyosiform dermatoses (lamellar ichthyosis and epidermolytic hyperkeratosis) and in psoriasis. Only psoriasis will be reviewed here, since the major types of ichthyosis and their treatment have recently been the topic of a report in the Journal.220aDespite the vast amount of continuing work in psoriasis and its therapy, we still do not know the cause or the ideal method of treatment. The prevalence of the disease is itself still unknown in most parts of the world. Two large-scale but localized population surveys . . .
Use of Diethylstilbestrol to Prevent Fetal Loss from Complications of Late Pregnancy
Authors: O. Watkins Smith, George Van S. Smith
Journal: New England Journal of Medicine (1949)

THE present communication deals with further progress in a clinical evaluation of our concept concerning the action of diethylstilbestrol in human pregnancy. Analyses of results in 632 pregnancies during which this drug was given in the manner recommended by us have been reported.1 In 491 of these cases stilbestrol was administered for the prevention or treatment of abortion. A preliminary report was included, however, upon its use in 95 patients for the purpose of preventing complications of late pregnancy. These 95 cases are included in the present study of a total of 180 women in whom the indication for therapy . . .
Development and Clinical Validation of a Blood Test Based on 29-Gene Expression for Early Detection of Colorectal Cancer
Authors: Laura Ciarloni, Sahar Hosseinian Ehrensberger, Natsuko Imaizumi, Sylvain Monnier-Benoit, Cristina Nichita, Seung-Jae Myung, Joo Sung Kim, Si Young Song, Tae Il Kim, Boudewijn van der Weg, Rémy Meier, Jan Borovicka, Christoph Beglinger, Cédric Vallet, Philippe Maerten, Curzio Rüegg, Gian Dorta
Journal: Clinical Cancer Research (2016)

Abstract Purpose: A blood test for early detection of colorectal cancer is a valuable tool for testing asymptomatic individuals and reducing colorectal cancer–related mortality. The objective of this study was to develop and validate a novel blood test able to differentiate patients with colorectal cancer and adenomatous polyps (AP) from individuals with a negative colonoscopy. Experimental Design: A case–control, multicenter clinical study was designed to collect blood samples from patients referred for colonoscopy or surgery. Predictive algorithms were developed on 75 controls, 61 large AP (LAP) ≥1 cm, and 45 colorectal cancer cases and independently validated on 74 controls, 42 LAP, and 52 colorectal cancer cases (23 stages I–II) as well as on 245 cases including other colorectal findings and diseases other than colorectal cancer. The test is based on a 29-gene panel expressed in peripheral blood mononuclear cells alone or in combination with established plasma tumor markers. Results: The 29-gene algorithm detected colorectal cancer and LAP with a sensitivity of 79.5% and 55.4%, respectively, with 90.0% specificity. Combination with the protein tumor markers carcinoembryonic antigen (CEA) and CYFRA21-2 resulted in a specificity increase (92.2%) with a sensitivity for colorectal cancer and LAP detection of 78.1% and 52.3%, respectively. Conclusions: We report the validation of a novel blood test, Colox®, for the detection of colorectal cancer and LAP based on a 29-gene panel and the CEA and CYFRA21-1 plasma biomarkers. The performance and convenience of this routine blood test provide physicians a useful tool to test average-risk individuals unwilling to undergo upfront colonoscopy. Clin Cancer Res; 22(18); 4604–11. ©2016 AACR.
Interleukin 1 induces human marrow stromal cells in long-term culture to produce granulocyte colony-stimulating factor and macrophage colony- stimulating factor
Authors: WE Fibbe, J van Damme, A Billiau, HM Goselink, PJ Voogt, G van Eeden, P Ralph, BW Altrock, JH Falkenburg
Journal: Blood (1988)