tbuckley/cabot-search huggingface dataset:
Immunotherapy for Merkel cell carcinoma: a turning point in patient care
Authors: Isaac S. Chan, Shailender Bhatia, Howard L. Kaufman, Evan J. Lipson
Journal: Journal for ImmunoTherapy of Cancer (2018)

Merkel Cell carcinoma (MCC) is a rare but aggressive cancer, with an estimated disease-associated mortality as high as 46%. MCC has proven to be an immunologically responsive disease and the advent of immune checkpoint inhibitors has changed the treatment landscape for patients with advanced MCC. In this review, we discuss the rationale for the use of immune checkpoint inhibition, review current single agent therapies tested in and approved for MCC, and discuss emerging immunotherapeutic options for these patients.
Bispecific antibody targeting of CD47/CD19 to promote enhanced phagocytosis of patient B lymphoma cells.
Authors: Zoe Johnson, Anne Papaioannou, Lucie Bernard, Emilio Cosimo, Bruno Daubeuf, Francoise Richard, Xavier Chauchet, Valery Moine, Lucile Broyer, Limin Shang, Maureen Deehan, Nicolas Fischer, Krzysztof Masternak, Marie Kosco-Vilbois, Alison Michie, Walter Ferlin
Journal: Journal of Clinical Oncology (2015)

e14016 Background: Many cancers up-regulate the expression of CD47 in order to evade immune surveillance and killing. This 'don't eat me' signal is a molecular means for healthy cells to limit their phagocytic elimination by macrophages and other innate immune cells. This cell purging mechanism is mediated by the interaction of CD47 on the target cell and Signal Regulatory Protein Alpha (SIRPα) on myeloid cells. Development of anti-CD47 monoclonal antibodies may be hindered due to the ubiquitous expression of CD47, leading to rapid drug elimination kinetics through target-mediated drug disposition, an unfavorable pharmacokinetic profile and target related toxicity including chronic anemia. Methods: To overcome these clinical liabilities, we have developed an anti-CD47 antibody arm paired with a high affinity anti-CD19 arm in a fully human bispecific format (kl-body) for targeted blockade of the CD47-SIRPα interaction on B cells. Results: Using human B cell lymphoma lines the kl-body demonstrated selective binding, targeted blockade of the CD47-SIRPα interaction and cell killing through Fc region-dependent effector functions such as ADCP (antibody-mediated cellular phagocytosis) and ADCC (antibody-dependent cellular cytotoxicity). Studies using PBMCs derived from CLL patient samples demonstrated a correlation between poor prognostic markers and expression of CD47, and efficient phagocytosis in the presence of the kl-body. Moreover, the kl-body demonstrated enhanced phagocytosis of primary acute lymphoblastic leukemia (ALL) B cells and bone marrow aspirates both unresponsive to anti-CD20 mediated ADCP by rituximab. kl-bodies demonstrated favorable elimination kinetics and no effects on hematological parameters (e.g., red blood cell and platelet counts) in non-human primates. Conclusions: Our lead kl-body, NI-1701, is in preclinical enabling studies with an anticipated entry into clinical trials in 2016.
Interest and Uptake of<i>MC1R</i>Testing for Melanoma Risk in a Diverse Primary Care Population
Authors: Jennifer L. Hay, Kate Zielaskowski, Kirsten Meyer White, Kimberly Kaphingst, Erika Robers, Dolores Guest, Andrew Sussman, Yvonne Talamantes, Matthew Schwartz, Vivian M. Rodríguez, Yuelin Li, Elizabeth Schofield, Jessica Bigney, Keith Hunley, David Buller, Marianne Berwick
Journal: JAMA Dermatology (2018)

<h3>Importance</h3> Germline variants in the<i>MC1R</i>gene are common and confer moderate melanoma risk in those with varied skin types. Approaches to precision skin cancer prevention that include genetic information may promote risk awareness and risk reduction in the general population, including Hispanics. <h3>Objective</h3> To examine prevalence of interest in and uptake of<i>MC1R</i>testing in the general population and examine patterns across demographic and skin cancer risk factors. <h3>Design, Setting, and Participants</h3> A randomized clinical trial examined interest in and uptake of<i>MC1R</i>testing among patients at University of New Mexico General Internal Medicine clinics. Study participants were randomized to either a usual-care condition (National Cancer Institute skin cancer pamphlet for diverse skin types) or an<i>MC1R</i>test offer. Participants were registered clinic patients (≥6 months) and English or Spanish fluent. Of the 600 participants recruited to the overall trial, the present study included those 499 participants randomized to the<i>MC1R</i>test offer. <h3>Interventions</h3> Participants were presented with the option to log onto the study website to read 3 educational modules presenting the rationale, benefits, and drawbacks of<i>MC1R</i>testing. <h3>Main Outcomes and Measures</h3> Main outcomes include website log on (yes vs no), saliva test kit request (yes vs no), and saliva test kit return for<i>MC1R</i>testing (yes vs no). Demographic and skin cancer risk factors were examined as potential predictors of test interest and uptake. <h3>Results</h3> Of the 499 participants (220 [44%] non-Hispanic white, 242 [48%] Hispanic, 396 [79%] female; mean [SD] age, 54 [14.3] years), 232 (46%) elected to learn about<i>MC1R</i>testing by logging onto the website; 204 (88%) of those who logged on decided to request testing; and 167 (82%) of those who requested testing returned the kit. The strongest predictors of website log on were race/ethnicity and education (non-Hispanic whites were more likely to log on [odds ratio for Hispanics vs non-Hispanic whites, 0.5; 95% CI, 0.3-0.7], as were more highly educated individuals [odds ratio for more than high school vs high school or less, 2.7; 95% CI, 1.7-4.3]). The strongest predictor of ordering the test was sunburn history (odds ratio, 5.4; 95% CI, 2.3-12.9 vs no sunburn history). <h3>Conclusions and Relevance</h3> There were moderately high levels of<i>MC1R</i>test interest and uptake in this diverse sample. Addressing potential barriers to testing may be warranted as genomic information becomes integrated into general population approaches to the precision prevention of skin cancer. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT03130569
A microRNA screen uncovers O-Linked N-Acetylglucosamine transferase as a host factor involved in hepatitis C virus morphogenesis
Authors: S. Bandiera, S. Pernot, K. Herzog, C. Fauvelle, A. Weiss, S. Durand, W. Raffelsberger, L. Brino, T. Baumert, M. Zeisel
Journal: Journal of Hepatology (2018)
MutationalPatterns: comprehensive genome-wide analysis of mutational processes
Authors: Francis Blokzijl, Roel Janssen, Ruben van Boxtel, Edwin Cuppen
Journal: Genome Medicine (2018)

Base substitution catalogues represent historical records of mutational processes that have been active in a cell. Such processes can be distinguished by various characteristics, like mutation type, sequence context, transcriptional and replicative strand bias, genomic distribution and association with (epi)-genomic features. We have created MutationalPatterns, an R/Bioconductor package that allows researchers to characterize a broad range of patterns in base substitution catalogues to dissect the underlying molecular mechanisms. Furthermore, it offers an efficient method to quantify the contribution of known mutational signatures within single samples. This analysis can be used to determine whether certain DNA repair mechanisms are perturbed and to further characterize the processes underlying known mutational signatures. MutationalPatterns allows for easy characterization and visualization of mutational patterns. These analyses willsupport fundamental research into mutational mechanisms and may ultimately improve cancer diagnosis and treatment strategies. MutationalPatterns is freely available at http://bioconductor.org/packages/MutationalPatterns .
Sickle Cell Trait and Cognitive Function in African Americans: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort
Authors: Mary Cushman, Justin M Leach, Christina Cahill, Leslie A McClure, Marguerite Ryan Irvin, Neil A Zakai, Rakhi P. Naik, Frederick Unverzagt, Virginia Wadley, Hyacinth I Hyacinth, Suzanne E Judd, Jennifer Manly
Journal: Blood (2017)
Abstract 13069: Prescribed Flow Reserve as a Novel Method for Diagnosis of Coronary Artery Ischemia Under Physiologically-Realistic Conditions
Authors: Kranthi Kolli, Guanglei Xiong, Hilary Soohoo, James Min
Journal: Circulation (2015)

Background. Failure to achieve maximal hyperemia in coronary arteries during fractional flow reserve (FFR) may result in under-estimation of pressure drop (ΔP) and over-estimation of FFR, and possibly lead to misdiagnosis of hemodynamically-significant lesions. Further, induction of hyperemia does not allow for precise determination of ischemic thresholds for physiologically-realistic conditions, such as for increasing levels of exercise. We investigated the influence of prescribed flow rates on the pressure ratio (P d /P a ) of coronary artery stenoses of varying severities. Methods. Prescribed flow reserves (PFR) were evaluated using an in vitro experimental flow loop with a pump circulating water at steady-state flow (Figure 1A). Three stenoses of 30%, 50% and 70% diameter stenosis (DS) severity with smooth Gaussian shapes were fabricated using VeroClear rigid material in an Objet260 Connex printer. Mean proximal pressure (P a ) was maintained at 90 and 140 mm Hg using a linear flow needle valve that allowed for adjustment of physiologically-realistic microcirculatory resistance. P d /P a at differing prescribed flow rates (Q), titrated by a flow meter, applied to each of the stenosis, were assessed for the 2 levels of P a . A PFR of P d /P a ≤0.80 was considered diagnostic of coronary ischemia. Results. The ΔP-Q characteristics demonstrated a quadratic relationship. The P d /P a -Q curve (Figure 1B and 1C) followed a similar trend, with decreasing slope. Further, the average slope of the P d /P a -Q decreased with increasing DS at either levels of the P a . When compared amongst lesions of increasing severity (Figure 1C and 1B), P d /P a -Q curve slopes at the 0.80 ischemic threshold increased by 9%, 20% and 25%, respectively, for 30%, 50% and 70% DS. Conclusions. Coronary artery ischemia, as determined by P d /P a , differs under increasing flow rates. PFR may be a potential alternative to FFR for determination of coronary ischemia under precise physiologically-realistic conditions.
Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP
Authors: Luke Piggott, Andreia Silva, Timothy Robinson, Angelica Santiago-Gómez, Bruno M. Simões, Michael Becker, Iduna Fichtner, Ladislav Andera, Philippa Young, Christine Morris, Peter Barrett-Lee, Fouad Alchami, Marco Piva, Maria dM. Vivanco, Robert B. Clarke, Julia Gee, Richard Clarkson
Journal: Clinical Cancer Research (2018)

Abstract Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer. Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors. Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP. Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452–63. ©2018 AACR.
ERS/ECDC Statement: European Union standards for tuberculosis care, 2017 update
Authors: Giovanni Battista Migliori, Giovanni Sotgiu, Senia Rosales-Klintz, Rosella Centis, Lia D'Ambrosio, Ibrahim Abubakar, Graham Bothamley, Jose Antonio Caminero, Daniela Maria Cirillo, Masoud Dara, Gerard de Vries, Stefano Aliberti, Anh Tuan Dinh-Xuan, Raquel Duarte, Fabio Midulla, Ivan Solovic, Dragan R. Subotic, Massimo Amicosante, Ana Maria Correia, Andra Cirule, Gina Gualano, Heinke Kunst, Fabrizio Palmieri, Vija Riekstina, Simon Tiberi, Remi Verduin, Marieke J. van der Werf
Journal: European Respiratory Journal (2018)

The International Standards for Tuberculosis Care define the essential level of care for managing patients who have or are presumed to have tuberculosis, or are at increased risk of developing the disease. The resources and capacity in the European Union (EU) and the European Economic Area permit higher standards of care to secure quality and timely TB diagnosis, prevention and treatment. On this basis, the European Union Standards for Tuberculosis Care (ESTC) were published in 2012 as standards specifically tailored to the EU setting. Since the publication of the ESTC, new scientific evidence has become available and, therefore, the standards were reviewed and updated. A panel of international experts, led by a writing group from the European Respiratory Society (ERS) and the European Centre for Disease Prevention and Control (ECDC), updated the ESTC on the basis of new published evidence. The underlying principles of these patient-centred standards remain unchanged. The second edition of the ESTC includes 21 standards in the areas of diagnosis, treatment, HIV and comorbidities, and public health and prevention. The ESTC target clinicians and public health workers, provide an easy-to-use resource and act as a guide through all the required activities to ensure optimal diagnosis, treatment and prevention of TB.
Kerry Fiona Watt
Authors: Roger Watt
Journal: BMJ (2018)

Born in south Manchester, Kerry Fiona Watt was educated at Canon Slade School in Bolton and entered Birmingham University Medical School with A levels gained at Blackburn College. At school she completed the Duke of Edinburgh silver award.

Kerry was a sporting soul and enjoyed skiing, climbing, swimming, and hockey. She took up an army cadetship in 2003, which facilitated her love of skiing and travel, enabling her to visit six continents. She completed officer training at Sandhurst College, passing out in 2008.

After initial training …
Prevalence of EGFR mutations in non-small cell lung cancer (NSCLC) smoker patients.
Authors: Yann Izarzugaza, Manuel Domine, Federico Rojo, Victoria Casado, Ana Leon, Maria Jesus Fernandez-Acenero, Gustavo Rubio, Sharon Cordova, Juan Madoz, Jose Ignacio Martin-Valades, Juan Luis Arranz, Gloria Serrano, Cristina Carames, Sandra Zazo, Raul Rincon, Carmen Canadas, Nuria Perez-Gonzalez, Angel Campos, Francisco Lobo, Jesus Garcia-Foncillas
Journal: Journal of Clinical Oncology (2012)

e21015 Background: Mutations in the Epidermal Growth Factor Receptor (EGFR) predict a better response to tyrosine kinase inhibitors compared to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Previous studies in caucasian population have reported a frequency of EGFR mutation of 10-15%. The aim of this study is to analyze the prevalence of EGFR mutations in caucasian smoker patients with NSCLC. Methods: Prospective mutation testing in NSCLC patients included in our institution since October 2010 to January 2012 was performed on DNA obtained from available tumor tissue and cytologic samples, using ARMS-scorpion TheraScreen EGFR 29 Mutation Test Kit (Qiagen). Results: From 218 consecutive NSCLC diagnoses, 18 (8.25%) patients showed EGFR mutations: 6 (33.3%) exon 19 deletions, 9 (50%) exon 21 mutations (7 cases L858R and 2 cases L861Q) and 3 (16.6%) exon 20 insertions. In the EGFR-mutated patients, 13 (72.25%) were never-smoker and 5 (27.7%) were smoker (3 current-smoker and 2 former-smoker). The EGFR-mutated smoker population showed the following characteristics: 3 female, 2 male; 4 adenocarcinoma, one squamous cell carcinoma; 3 stage IV, 2 stage IA at diagnosis; 1 (20%) case EGFR deletion exon 19, 1 (20%) case insertion exon 20 and 3 patients (60%) mutation exon 21 (2, L858R and 1, L861Q). Conclusions: The EGFR mutation rate in NSCLC smoking patients in our referral area is superior (27.7%) than previously reported, reinforcing the importance of including EGFR mutation testing in NSCLC smoking population for the correct management of these patients.
Circulating exosomal non-coding RNAs as prognostic biomarkers in human hepatocellular carcinoma
Authors: Y.R. Lee, S.Y. Park, K. Hur, G. Kim, S.Y. Jang, W.Y. Tak, Y.O. Kweon, B. Jeong, G.-E. Kang, S. Seo, J.G. Park, H.W. Lee
Journal: Journal of Hepatology (2018)
Home treatment of COPD exacerbation selected by DECAF score: a non-inferiority, randomised controlled trial and economic evaluation
Authors: Carlos Echevarria, Joanne Gray, Tom Hartley, John Steer, Jonathan Miller, A John Simpson, G John Gibson, Stephen C Bourke
Journal: Thorax (2018)

Previous models of Hospital at Home (HAH) for COPD exacerbation (ECOPD) were limited by the lack of a reliable prognostic score to guide patient selection. Approximately 50% of hospitalised patients have a low mortality risk by DECAF, thus are potentially suitable.In a non-inferiority randomised controlled trial, 118 patients admitted with a low-risk ECOPD (DECAF 0 or 1) were recruited to HAH or usual care (UC). The primary outcome was health and social costs at 90 days.Mean 90-day costs were £1016 lower in HAH, but the one-sided 95% CI crossed the non-inferiority limit of £150 (CI -2343 to 312). Savings were primarily due to reduced hospital bed days: HAH=1 (IQR 1-7), UC=5 (IQR 2-12) (P=0.001). Length of stay during the index admission in UC was only 3 days, which was 2 days shorter than expected. Based on quality-adjusted life years, the probability of HAH being cost-effective was 90%. There was one death within 90 days in each arm, readmission rates were similar and 90% of patients preferred HAH for subsequent ECOPD.HAH selected by low-risk DECAF score was safe, clinically effective, cost-effective, and preferred by most patients. Compared with earlier models, selection is simpler and approximately twice as many patients are eligible. The introduction of DECAF was associated with a fall in UC length of stay without adverse outcome, supporting use of DECAF to direct early discharge.Registered prospectively ISRCTN29082260.
P76The minor contribution of sarcolemmal calcium currents and "Ca2+ clock" in generation of pacemaking in the 10-day-old chick embryo auricle cells
Authors: V Golovko, E Lebedeva, M Gonotkov
Journal: Cardiovascular Research (2018)

Purpose: We aimed to study the expression of circulating miRNAs in plasma of patients with an acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).We sought to correlate the level of these miRNAs with the consequent adverse cardiac remodeling observed in some patients.Methods: Taqman-array was used to analyze the expression of 384 miRNAs in blood samples collected from 12 patients.The expression of miRNAs was further validated, using qRT-PCR, in blood samples of patients with STEMI, before PPCI (time 0) and after revascularization (at 3, 12 and 24 hours).As control we took blood samples from patients who, after a pain chest, underwent coronary angiogram and finally they did not present any coronary lesions.Results: The analysis of miRNAs' expression shows a time-dependent release of miRNAs in the blood of patients with maximum expression at 12 hours after PPCI.We found significant changes in the expression of some miRNAs, previously related to different cardiovascular diseases, such as miR-133a, miR-133b, miR-499 and miR-423-5p.In addition, we found that the expression level of new miRNAs, miR-193b, miR-324 and miR-339-5p was significantly increased 12 hours after PPCI, whereas miR-519a, miR-522 and miR-545 levels were significantly reduced.Next, we analyzed the correlation between cardiac remodeling, indicated by echocardiography hemodynamic parameters, and miRNAs levels changes.Importantly, the increment in some miRNA levels correlated with the appearance of left ventricular remodeling in 20% of the patients 6 months after the ischemic event. Conclusion:We determined the time course of new circulating miRNAs release in patients with AMI treated with PPCI.Our data suggest, for the first time, that some miRNAs might be an early and sensitive marker predicting left ventricular remodeling in patients undergoing PPCI.
Profound consequences of hidradenitis suppurativa: a review
Authors: Ł. Matusiak
Journal: British Journal of Dermatology (2018)

Hidradenitis suppurativa (HS) influences patients’ lives in many ways. The most troublesome symptom of HS is chronic pain, of mild‐to‐moderate intensity, which is reported by almost all patients. With reference to psychosocial evaluation, HS appears to be a highly debilitating disease. The major factors influencing patients’ well‐being are disease severity, the number of flares or affected skin areas, and the lesion location. The mean Dermatology Life Quality Index scores of 8·3–12·7 points obtained among patients with HS are typical for severe dermatoses, which have a large impact on patients’ quality of life (QoL). HS not only affects skin‐related QoL issues, but also has a profound impact on general QoL measures – it causes substantial deterioration of both physical and mental health. Considering the impaired QoL due to HS and HS‐associated, nonpsychiatric comorbidities, it is not surprising that patients with HS experience psychological disturbances. In both observational and registry studies, depression and anxiety were significantly related to HS. The prevalences were estimated as 1·6–42·9% and 0·8–3·9%, respectively. HS was also linked to feelings of loneliness and stigmatization. Moreover, these patients have a significantly increased suicide risk (hazard ratio 2·42). HS, with its frequent involvement of the genital area, causes a pronounced impairment of sex life (66·7% of patients with HS reported sexual difficulties). Finally, HS causes significant financial burden, not only through the costs of healthcare, but also due to a substantial impact on patients’ professional careers. This is a reason for absenteeism from work for approximately half of patients, and a relatively high unemployment rate.
UK will explore net zero carbon emissions policy by 2050, says minister
Authors: Susan Mayor
Journal: BMJ (2018)

The UK government is asking the Committee on Climate Change, an independent advisory body, to give advice on working towards a net zero carbon emissions economy by 2050.

The announcement was made by Claire Perry, minister for energy and clean growth, during a parliamentary debate on 24 April. “We are the first developed country to ask for advice on what a zero emissions economy would look like in 2050,” said Perry.

Perry told the Commonwealth heads of government meeting on 17 April that the UK government will review its long term target …