tbuckley/cabot-search huggingface dataset:
Association of Clinical, Dermoscopic, and Histopathologic Findings With Gene Expression in Patients With Balloon Cell Melanoma
Authors: Ben J. Friedman, Rebecca Stoner, Joya Sahu, Jason B. Lee
Journal: JAMA Dermatology (2017)

Balloon cell melanoma is a rare subtype of melanoma that is underrecognized clinically and is challenging to diagnose on histologic studies.To further characterize the clinical, dermoscopic, and histopathologic features of balloon cell melanomas and their correlation to gene expression.Case series of 2 patients with balloon cell melanoma whose medical records were retrieved from the database of Thomas Jefferson University Dermatopathology Center in Philadelphia, Pennsylvania. Both cases had been referred to the institution's dermatopathology laboratory and provided complete data on clinical, dermoscopic, and histopathologic findings and gene-expression profiles.Dermoscopic findings, histopathologic findings, and results of gene expression tests.In the 2 patients included, translucent hypopigmented areas on gross examination and a translucent white-gray veil and dull yellow globules on dermoscopic examination correlated with the balloon cell melanocytic region demonstrated on histologic studies with hematoxylin-eosin stain. Specifically, dull yellow globules corresponded to the balloon cell melanocytic nests. Both lesions presented with a second, morphologically distinct population of melanocytes, common in balloon cell melanocytic neoplasms. In both cases, a prominent junctional component that consisted of cells demonstrating ample clear-to-granular cytoplasm and a central nucleus were present. Cytologic atypia was minimal to lacking in both cases, and architectural disorder served as a better clue to the diagnosis. Findings of a gene expression profiling test corroborated the diagnosis in both cases.Balloon cell melanomas may present with characteristic clinical and dermoscopic findings, and a gene expression profiling test may provide additional useful diagnostic information in cases that are difficult to interpret.
Randomised phase III study of alisertib or investigator's choice (selected singe agent) in patients with relapsed or refractory peripheral T-cell lymphoma
Authors: O O'connor, M Özcan, E Jacobsen, JM Roncero Vidal, J Trotman, J Demeter, T Masszi, J Pereira, R Ramchandren, A Beaven, D Caballero Barringon, S Horwitz, A Lennard, M Turgut, N Hamerschlak, Francesco Annibale d'Amore, F Foss, WS Kim, JP Leonard, PL Zinzani, CS Chiattone, ED His, H Liu, E Sheldon-Waniga, C Dansky Ullmann, EJ Leonard, A Shustov
Journal: The Lancet Oncology (2017)
Risk of second malignant neoplasm and mortality in patients with rheumatoid arthritis treated with biological DMARDs: a Danish population-based cohort study
Authors: Lene Dreyer, René L Cordtz, Inger Marie J Hansen, Lars Erik Kristensen, Merete L Hetland, Lene Mellemkjaer
Journal: Annals of the Rheumatic Diseases (2017)

To study the risk of a second malignant neoplasm (SMN) and mortality in patients with rheumatoid arthritis (RA) with a history of a primary cancer diagnosis and treated with biological disease-modifying antirheumatic drugs (bDMARD).Among patients with RA (n=15 286) registered in the DANBIO Register during 2000-2011, 1678 had a primary cancer according to the Danish Cancer Registry. HRs for SMN and death were calculated.During follow-up there were 279 patients with RA contributing person-years to the bDMARDs use before their primary cancer diagnosis, 220 to the only after, 92 to the both before and after, while 1203 patients with RA contributed to the non-use strata. Ever use of bDMARDs was associated with a HR of 1.11 (95% CI 0.74 to 1.67) for developing a SMN compared with non-use (cancer site adjusted). The HR for death associated with bDMARD use before the primary cancer diagnosis was increased 1.53 (95% CI 1.13 to 2.09). After further adjustment for extent of the primary cancer, the HR for death was 1.20 (95% CI 0.88 to 1.63) for bDMARDs use before cancer, 1.36 (95% CI 0.78 to 2.39) for bDMARD use only after cancer and 1.22 (95% CI 0.70 to 2.13) for use both before and after the cancer.Among patients with RA with a history of cancer, treatment with bDMARDs was not associated with increased risk of SMN. No clear conclusion can be drawn regarding mortality in bDMARD-treated patients with RA.
Scottish GPs back new contract making them “expert medical generalists”
Authors: Bryan Christie
Journal: BMJ (2017)

The proposed new contract for family doctors in Scotland has been backed at a special conference of local medical committees where the Scottish government announced plans to recruit an additional 800 GPs over the next 10 years.

LMC leaders were asked for their views on the potential of the new contract to reduce workloads, make the service more sustainable and attractive; and reduce the risks to GPs associated with owning premises and employing staff. In each case there was a majority in agreement, with the conference registering votes of between 79% and 85% in favour of the new contract.

The new deal, which has been agreed between the BMA and the Scottish government, seeks to establish GPs as “expert medical …
Temporal trajectories of novel object recognition performance in mice exposed to intermittent hypoxia
Authors: David Gozal, Abdelnaby Khalyfa, Zhuanghong Qiao, Isaac Almendros, Ramon Farré
Journal: European Respiratory Journal (2017)

Intermittent hypoxia is one of the major perturbations of sleep-disordered breathing and has been causally implicated in neurocognitive deficits. However, the reversibility of such deficits is unclear. Male C57BL/6J mice were exposed to either intermittent hypoxia or room air for 3–240 days, and then half were randomly selected and allowed to recover in normoxic conditions for the same duration of the previous exposure. A novel object recognition (NOR) test was performed. NOR performance was stable over time in room air. Intermittent hypoxia induced significant reductions in recognition index that progressed over the first 45 days and stabilised thereafter. Normoxic recovery of recognition index was essentially complete and indistinguishable from room air in mice exposed to shorter intermittent hypoxia times (&lt;90 days). However, significant residual deficits emerged after normoxic recovery following prolonged intermittent hypoxia exposures (p&lt;0.01). In addition, gradual attenuation of the magnitude of recovery in recognition index occurred with increasingly longer intermittent hypoxia exposures (MANOVA p&lt;0.0001). Intermittent hypoxia during the resting period reduces NOR performance in a time-dependent fashion. Reversal of NOR performance deficits is unlikely after prolonged intermittent hypoxia duration. These findings suggest that early recognition of sleep apnoea and effective treatment are critical for restoration of the adverse cognitive effects of the disease.
<i>CDKN2A/p16</i>Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition
Authors: Mayur A. Gadhikar, Jiexin Zhang, Li Shen, Xiayu Rao, Jing Wang, Mei Zhao, Nene N. Kalu, Faye M. Johnson, Lauren A. Byers, John Heymach, Walter N. Hittelman, Durga Udayakumar, Raj K. Pandita, Tej K. Pandita, Curtis R. Pickering, Abena B. Redwood, Helen Piwnica-Worms, Katharina Schlacher, Mitchell J. Frederick, Jeffrey N. Myers
Journal: Cancer Research (2017)

Checkpoint kinase inhibitors (CHKi) exhibit striking single-agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of CHK1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity. To explore genomic underpinnings of CHKi hypersensitivity, comparative genomic analysis was performed between hypersensitive cells and cells categorized as least sensitive because they showed drug IC50 value greater than the cell panel median and lacked early S-phase arrest. Novel association between CDKN2A/p16 copy number loss, CDK2 activation, replication stress, and hypersensitivity of HNSCC cells to CHKi monotherapy was found. Restoring p16 in cell lines harboring CDKN2A/p16 genomic deletions alleviated CDK2 activation and replication stress, attenuating CHKi hypersensitivity. Taken together, our results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from CHKi therapy.Significance: These results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from therapy with CHK inhibitors. Cancer Res; 78(3); 781-97. ©2017 AACR.
Letter by Chi and Marszalek Regarding Article, “Composite End Points in Clinical Research: A Time for Reappraisal”
Authors: Gerald Chi, Jolanta Marszalek
Journal: Circulation (2017)

Thus far, there is no consensus on the best practice for simultaneously analyzing multiple disparate end points to arrive at NCB.The bivariate analysis allows for a collective assessment of efficacy and safety outcomes while integrating customizable noninferiority margins.This novel approach could be a valuable addition to the conventional methods to assist clinical decision making.
Research on HIV cure: Mapping the ethics landscape
Authors: Karine Dubé, Laurie Sylla, Lynda Dee, Jeff Taylor, David Evans, Carl Dean Bruton, Adam Gilberston, Lisa Gralinski, Brandon Brown, Asheley Skinner, Bryan J. Weiner, Sandra B. Greene, Amy Corneli, Adaora A. Adimora, Joseph D. Tucker, Stuart Rennie
Journal: PLoS Medicine (2017)

According to current estimates, 36.7 million people are infected with HIV worldwide.Despite large-scale and growing programs to prevent and treat HIV infection, possible approaches to achieve a cure for HIV infection are of strong interest.• In the development of candidate approaches to achieve an HIV cure, issues of future translation to human study participants, evidence-based practice, clinical care, diverse populations, and populations in low-and middle-income countries should all be considered.• An HIV cure should be effective, safe, simple, affordable, and scalable.• Acceptability research is a critical adjunct to ongoing biomedical HIV cure research efforts.• Anticipating some of the ethical and implementation challenges related to HIV cure strategies is necessary before the availability of effective interventions.• Ongoing engagement of stakeholders is needed to resolve ethical, logistical, social, cultural, policy, regulatory, and implementation challenges at all stages of the HIV cure research development process.
European Society for Medical Oncology (ESMO) position paper on supportive and palliative care
Authors: K. Jordan, M. Aapro, S. Kaasa, C.I. Ripamonti, F. Scotté, F. Strasser, A. Young, E. Bruera, J. Herrstedt, D. Keefe, B. Laird, D. Walsh, J.Y. Douillard, A. Cervantes
Journal: Annals of Oncology (2017)

Oncology has come a long way in addressing patients' quality of life, together with developing surgical, radio-oncological and medical anticancer therapies. However, the multiple and varying needs of patients are still not being met adequately as part of routine cancer care. Supportive and palliative care interventions should be integrated, dynamic, personalised and based on best evidence. They should start at the time of diagnosis and continue through to end-of-life or survivorship. ESMO is committed to excellence in all aspects of oncological care during the continuum of the cancer experience. Following the 2003 ESMO stand on supportive and palliative care (Cherny N, Catane R, Kosmidis P. ESMO takes a stand on supportive and palliative care. Ann Oncol 2003; 14(9): 1335–1337), this position paper highlights the evolving and growing gap between the needs of cancer patients and the actual provision of care. The concept of patient-centred cancer care is presented along with key requisites and areas for further work.
Overcoming sunitinib-induced resistance by dose escalation in renal cell carcinoma: Evidence in animal models and patients.
Authors: Roberto Pili, Remi Adelaiye, Kiersten Marie Miles, Eric Ciamporcero, Paula Sotomayor, Georg A. Bjarnason
Journal: Journal of Clinical Oncology (2013)

4582 Background: Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). However, despite the clinical efficacy, eventually tumors develop resistance and progress. Thus, we have tested the hypothesis whether sunitinib dose-escalation could overcome initial drug resistance. Methods: Human patient-derived ccRCC xenografts were implanted in SCID mice and were randomly assigned into two groups (sunitinib and vehicle). Mice were treated with sunitinib 5 days/week with a dose-escalation schema starting from 40 mg/kg to 60 mg/kg and 80 mg/kg. Tumor volumes and body weights were assessed weekly. Tumor tissues and blood were collected prior to dose increments. In selected patients treated with 50 mg sunitinib and presenting minimal toxicities, dose was escalated to 62.5 and 75 mg at the time of tumor progression. Results: Our preclinical results show that patient-derived tumors (RP-01 and RP-02), although initially responsive to sunitinib 40 mg/kg, eventually became resistant to treatment. Following dose increase to 60 mg/kg, we observed again tumor response but eventually the tumors became resistant. A similar effect was noticed when we further escalated sunitinib to 80 mg/kg. Immunohistochemistry analysis shows decreased tumor vascularization during response to sunitinib, but then hypervascularization at the time of resistance. Associated increase in expression of the methyltransferase EZH2, the histone marks H3K27me3, H3k4me2 and H3K9me2 in tumors resistant to sunitinib was observed. Analysis of sunitinib and VEGF/VEFGR2 blood and tumor levels will be reported. In parallel, our clinical experience shows that intra-patient sunitinib dose-escalation was safe and clinical benefit was observed. Details on tumor responses and toxicities will be reported. Conclusions: Overall, our results suggest that sunitinib-induced resistance may be overcome in part by increasing the dose of the VEGF receptor tyrosine kinase inhibitor in mouse models and ccRCC patients, and highlights the potential role of epigenetic changes associated with sunitinib resistance.
Abstract P056: Emerging Lifestyle Markers Predict Regression of Carotid Intima-Media Thickness Scores
Authors: Steven C Masley, Richard Roetzheim, Lucas V Masley, Timothy McNamara, Douglas D Schocken
Journal: Circulation (2015)

Introduction: CVD remains the number one cause of mortality in the western world. Carotid intima-media thickness (IMT) is a safe &amp; reliable predictor of future CVD risk. This study assesses which lifestyle factors best predict a change in IMT over time. Hypothesis: We assessed the null hypothesis that all lifestyle changes are effective. Methods: A prospective cross-sectional analysis of 289 men &amp; women undergoing health &amp; cardiovascular risk screening every 1-2 years at an outpatient wellness center in Florida. This study reflects the first visit at the clinic, &amp; a second visit that occurred on average 2.8 years later. These subjects ranged in age from 23-65 (mean = 48.2). In addition to testing, subjects received nutrition, fitness, &amp; health coaching. Measurements were made of fitness using VO2max stress testing, diet intake using a 3-day dietary intake survey. Laboratory &amp; anthropometric measures were obtained fasting. Mean IMT scores used high resolution B-mode ultrasonography of the common carotid arteries. Each subject had ≥10 images collected from the far wall of both distal 1 cm of the common carotid arteries at end diastole. The carotid intimal thickness was measured as a continuous variable, using both multivariate &amp; bivariate linear regression, adjusting for age &amp; gender; as our site IMT precision was = 3%, we selected a 4% change as significant. Results: The average decrease in IMT score in this cohort was -0.018 mm over 2.8 years, a 2.04% reduction. The bivariate analyses showing a significant association with a ≥4% reduction in IMT in 62 of 288 subjects; they were a decrease in: Body mass index (BMI) (p=0.047), body fat (p=0.025), total cholesterol (TC) (p=0.031), LDL cholesterol (p=0.028), TC/HDL (0.002), or an increase in dietary intake of: magnesium (p=0.0001), fiber (p=0.017), vitamin D (p=0.016), vitamin K (p=0.001), potassium (p=0.001), &amp; calcium (p=0.024). In a multivariate analysis, starting a statin medication (p=0.0007), a decrease in BMI (p=0.042), baseline IMT, male gender, diastolic BP decrease, &amp; years of follow up were predictive of 4% IMT decline. Prior use of a statin medication was not significant. Conclusions: In conclusion, this study shows that a reduction in IMT score over 2.8 years is associated with a decrease in: BMI, body fat, TC, LDL, TC/HDL ratio, &amp; diastolic BP; or, an increase in intake of: magnesium, fiber, vitamins K &amp; D, potassium, &amp; calcium; or, starting a statin medication.
Arrhythmogenic Cardiomyopathy
Authors: Silvia G. Priori, Demetrio J. Santiago
Journal: Circulation Research (2017)

In the current issue of the Circulation Research, Karmouch et al 1 present a provocative study attributing a pivotal role in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) to the loss of DSP (desmoplakin) gene in a subpopulation of the cells of the conduction system.This hypothesis is in sharp departure from the current view on the disease, and it opens the question on whether the data reported in mice with a selective expression of the genetic defects in the specialized cells of the conduction system replicate the clinical phenotype found in patients.ACM is a genetic disease of the heart muscle caused, in most instances, by mutations in genes encoding for desmosomal proteins that is predominantly inherited as an autosomal dominant trait.1 Two syndromic recessive forms of the disease have been described and both present abnormalities in skin 2 and heart.Carvajal Syndrome 3 presents a striate type of keratoderma, is associated with a cardiomyopathy with preferred involvement of the left ventricle, and is associated with DSP mutations.Occasionally, Carvajal is inherited as a dominant disease that also presents hypodontia. 4Naxos disease 5 is associated with mutations in the plakoglobin gene and manifests diffuse keratoderma and right ventricular cardiomyopathy.Occasionally, Naxos disease with dominant inheritance has been reported.Karmouch et al 1 investigate the recessive form of ACM caused by mutations in the DSP gene that manifests with palmo-plantar keratosis, wooly hair, and dilatation of both ventricular chambers with fibro-fatty infiltration and life-threatening arrhythmias. 3There is general consensus that cardiac manifestations of the disease are the consequence of DSP mutations that alter the function of cardiac myocytes (CMs).The assumption that mutations in cardiac genes affect CMs is not unique to ACM; rather, it is the paradigm in the study of most inherited cardiomyopathies and channelopathies, and, therefore, reading the study of Karmouch et al, 1 it is reasonable to wonder on which bases the authors explore the effect of mutations beyond CMs.Data in support of the view that non-CMs are implicated in arrhythmogenesis come from studies originating in the electrophysiology field demonstrating the role of fibroblasts and endothelial cells 2 in the modulation of heart rhythm.These observations confirm that cells that have traditionally been considered innocent bystanders are electrically coupled with CMs and interfere with their physiological and pathological responses.The most explored interaction between non-CMs and myocytes concerns cardiac fibroblasts. 6For a long time, these cells have been considered merely as a structural support for CMs and only
Particulate Matter Air Pollution Exposure and Heart Disease Mortality Risks by Race and Ethnicity in the United States
Authors: Jennifer D. Parker, Nataliya Kravets, Ambarish Vaidyanathan
Journal: Circulation (2017)

Most US studies of mortality and air pollution have been conducted on largely non-Hispanic white study populations. However, many health and mortality outcomes differ by race and ethnicity, and non-Hispanic white persons experience lower air pollution exposure than those who are non-Hispanic black or Hispanic. This study examines whether associations between air pollution and heart disease mortality differ by race/ethnicity.We used data from the 1997 to 2009 National Health Interview Survey linked to mortality records through December 2011 and annual estimates of fine particulate matter (PM2.5) by census tract. Proportional hazards models were used to estimate hazard ratios and 95% confidence intervals between PM2.5 (per 10 µg/m3) and heart disease mortality using the full sample and the sample adults, which have information on additional health variables. Interaction terms were used to examine differences in the PM2.5-mortality association by race/ethnicity.Overall, 65 936 of the full sample died during follow-up, and 22 152 died from heart disease. After adjustment for several factors, we found a significant positive association between PM2.5 and heart disease mortality (hazard ratio, 1.16; 95% confidence interval, 1.08-1.25). This association was similar in sample adults with adjustment for smoking and body mass index (hazard ratio, 1.18; 95% confidence interval, 1.06-1.31). Interaction terms for non-Hispanic black and Hispanic groups compared with the non-Hispanic white group were not statistically significant.Using a nationally representative sample, the association between PM2.5 and heart disease mortality was elevated and similar to previous estimates. Associations for non-Hispanic black and Hispanic adults were not statistically significantly different from those for non-Hispanic white adults.
Abstract 18300: Cardiac Arrest in the Pediatric Post-Operative Cardiac Population: An Opportunity to Further Enhance PALS Guidelines
Authors: Kristen Nelson McMillan, Jordan Duval-Arnould, Kristen Brown, Leann McNamara, Diane Alejo, Mayuri Machado Alvarez, Narutoshi Hibino, Luca A Vricella, Donald H Shaffner, Elizabeth A Hunt
Journal: Circulation (2016)

Introduction: Despite cardiopulmonary arrest (CPA) occurring 10 times more frequently in children admitted to pediatric intensive care units with cardiac disease than other diagnoses, there is a pa...
Abstract 20762: Diesel Exhaust Induces Hyperlipidemia in Association With Downregulation of PPAR Alpha and Changes in Gut Microbiota
Authors: Fen Yin, Will S Driscoll, Dawoud Sulaiman, Galalakshmi Ramanathan, James A Stewart, Margarete Mehrabian, Simon Beaven, Aldons J Lusis, Michael E Rosenfeld, Jesus A Araujo
Journal: Circulation (2016)

Introduction: Air pollution is associated with increased cardiovascular morbidity and mortality. Inhalation of ambient particulate matter has been shown to induce functional changes in plasma lipop...
Prevention of hospital infections by intervention and training (PROHIBIT): results of a pan-European cluster-randomized multicentre study to reduce central venous catheter-related bloodstream infections
Authors: Tjallie van der Kooi, Hugo Sax, Didier Pittet, Jaap van Dissel, Birgit van Benthem, Bernhard Walder, Vanessa Cartier, Lauren Clack, Sabine de Greeff, Martin Wolkewitz, Stefanie Hieke, Hendriek Boshuizen, Jan van de Kassteele, Annemie Van den Abeele, Teck Wee Boo, Magda Diab-Elschahawi, Uga Dumpis, Camelia Ghita, Susan FitzGerald, Tatjana Lejko, Kris Leleu, Mercedes Palomar Martinez, Olga Paniara, Márta Patyi, Paweł Schab, Annibale Raglio, Emese Szilágyi, Mirosław Ziętkiewicz, Albert W. Wu, Hajo Grundmann, Walter Zingg
Journal: Intensive Care Medicine (2017)