tbuckley/cabot-search huggingface dataset:
Sunbed use among subjects at high risk of melanoma: an Italian survey after the ban
Authors: I. Stanganelli, S. Gandini, S. Magi, L. Mazzoni, M. Medri, V. Agnoletti, L. Lombi, F. Falcini
Journal: British Journal of Dermatology (2013)

The World Health Organization classified the entire ultraviolet (UV) spectrum and artificial UV tanning devices as carcinogenic to humans. Italian law has prohibited the use of tanning equipment by children under 18 years of age and by high-risk populations.The present large survey aimed to determine the prevalence of current sunbed use in Italy and to identify user characteristics. This study identifies starting points for future national interventions to reduce the health risks of exposure to artificial UV radiation.In 2011 we conducted a survey of 4703 people in an area on the sunny Mediterranean coast in Italy. Through multivariate logistic models we investigated the associations of sunbed use with phenotypical factors.Overall prevalence of sunbed use was 20%, higher among women (22% vs. 16%; P < 0·0001), and young (22% vs. 17% for age < 35 years; P < 0·0001) and highly educated people (22% vs. 14%; P < 0·0001). Subjects at high risk of melanoma used sunbeds significantly more; i.e. people with freckles (25% vs. 18%; P < 0·0001), red hair (30% vs. 19%; P = 0·01) or fair eyes (22% vs. 19%; P = 0·006). Associations were confirmed in multivariate models.More skin cancer monitoring is needed at tanning centres, and educational campaigns should be promoted, especially for young women and subjects at high risk of melanoma.
Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group
Authors: Xuexia Wang, Wei Liu, Can-Lan Sun, Saro H. Armenian, Hakon Hakonarson, Lindsey Hageman, Yan Ding, Wendy Landier, Javier G. Blanco, Lu Chen, Adolfo Quiñones, Daniel Ferguson, Naomi Winick, Jill P. Ginsberg, Frank Keller, Joseph P. Neglia, Sunil Desai, Charles A. Sklar, Sharon M. Castellino, Irene Cherrick, ZoAnn E. Dreyer, Melissa M. Hudson, Leslie L. Robison, Yutaka Yasui, Mary V. Relling, Smita Bhatia
Journal: Journal of Clinical Oncology (2014)

The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed.By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease.By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10(-7)). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m(2)) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09).Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.
MB-29 * DISSECTING THE ROLE OF EPIGENETIC MODULATORS IN SHH-DRIVEN MEDULLOBLASTOMA
Authors: T. Dobson, R.-H. Tao, S. Shaik, P. Taylor, R. Hatcher, E. Busschers, S. Khatua, S. Goldman, R. Lulla, V. Rajaram, T. MacDonald, J. Fangusaro, V. Gopalakrishnan
Journal: Neuro-Oncology (2015)

The Repressor Element-1 Silencing Transcription Factor (REST) negatively regulates neurogenesis. It epigenetically silences the expression of neuronal differentiation genes through modulation of histone acetylation and histone methylation. REST levels are elevated in over 80% of human medulloblastomas, and spans all four molecular sub-groups. Interestingly, a subset of patients with sonic hedgehog (Shh)-driven medulloblastomas with high REST expression (+3/ + 4 on a scale of 0-4) had a significantly elevated incidence of metastatic disease compared to patients with low-REST or no-REST expressing Shh-driven tumors. To understand if REST is a driver of metastatic disease, we generated a novel REST knock-in (RESTKI) mouse model in which transgene expression is conditionally elevated in cerebellar granule neuron progenitors (GNPs), the cells of origin of Shh-driven medulloblastomas. RESTKI mice were then crossed with mice exhibiting constitutive activation of Shh signaling (Ptc +/−), and REST transgene expression was induced in the progeny (RESTKI/Ptc +/−) on postnatal day 2. While RESTKI mice exhibited pre-neoplastic lesions, both Ptc +/− and RESTKI/Ptc +/− mice formed cerebellar tumors. However, a significant increase in tumor penetrance (100%) was seen in RESTKI/Ptc +/− mice compared to 20% in Ptc +/− mice. A substantial decrease in tumor latency (10-40 days) was also observed in RESTKI/Ptc +/− in contrast to 3-7 months in Ptc +/− mice. Histopathological analyses of mice brains revealed leptomeningeal and infiltrative medulloblastoma with significant changes in the tumor microenvironment in RESTKI/Ptc +/− mice. In contrast, cerebella of Ptc +/− mice exhibited localized disease. Importantly, RESTKI/ Ptc +/− tumors expressed very high levels of neural stem cell (NSC) markers such as Nestin, GFAP and Vimentin when compared with Ptc +/− tumors, suggesting that REST elevation in GNPs may have resulted in their de-differentiation into a more primitive state, and driven medulloblastoma genesis in the context of Shh hyperactivation. Our studies implicate REST in the modulation of the oncogenic potential of Shh signaling and medulloblastoma development.
Increased expression of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of noninsulin-dependent diabetes mellitus subjects.
Authors: M Federici, L Zucaro, O Porzio, R Massoud, P Borboni, D Lauro, G Sesti
Journal: Journal of Clinical Investigation (1996)

Insulin receptors (IR) and IGF-I receptors (IGF-IR) have been shown to form hybrid receptors in tissues coexpressing both molecules. To date there is no information about the distribution of hybrids in tissues of normal or diabetic subjects. We developed a microwell-based immunoassay to quantitate hybrids in small human tissues samples. Microwells were coated with MA-20 anti-IR antibody or alpha-IGF-IR-PA antibody directed against the IGF-IR alpha-subunit, and incubated with skeletal muscle extracts of patients with noninsulin-dependent diabetes mellitus (NIDDM) and normal controls. Immobilized receptors were incubated with 125I-insulin or 125I-IGF-I in the presence or absence of the two unlabeled ligands. Hybrids were quantified as the fraction of 125I-IGF-I binding immunoadsorbed with MA-20 and expressed as percentage of total IGF-IR (type I+hybrids) immobilized with alpha-IGF-IR-PA. The immunoassay was validated using Western blotting analysis. Relative abundance of hybrids detected in NIDDM patients was higher than in controls. The percentage of hybrids was negatively correlated with IR number and in vivo insulin sensitivity measured by an insulin tolerance test, whereas the percentage was positively correlated with insulinemia. Insulin binding affinity was lower in NIDDM patients than in controls, and was correlated with the percentage of hybrids. Maximal IGF-I binding was significantly higher in muscle from NIDDM patients compared to controls and was positively correlated with the percentage of hybrid receptors whereas IGF-I binding affinity did not differ between the two groups. These results raise the possibility that alterations in expression of hybrid receptors may contribute to decreased insulin sensitivity, and to increased sensitivity to IGF-I. Because IGF-I has been proposed as a hypoglycemic agent in NIDDM, these results are relevant to the development of new approaches to the treatment of insulin resistance of NIDDM.
Ectopic Gene Conversions Increase the G + C Content of Duplicated Yeast and Arabidopsis Genes
Authors: David Benovoy, Robert T. Morris, Antoine Morin, Guy Drouin
Journal: Molecular Biology and Evolution (2005)

Allelic recombination has previously been shown to increase the GC-content of the sequences of a wide variety of eukaryotic species. Ectopic recombination between clustered tandemly repeated genes has also been shown to increase their GC-content. Here we show that gene conversions between the dispersed genes found in the duplicated regions of the yeast and Arabidopsis genomes also increase their GC-content when these genes are more than 88% similar.
Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial
Authors: Juris J. Meier, Julio Rosenstock, Agnès Hincelin-Méry, Christine Roy-Duval, Astrid Delfolie, Hans-Veit Coester, Bjoern A. Menge, Thomas Forst, Christoph Kapitza
Journal: Diabetes Care (2015)

OBJECTIVE This mechanistic trial compared the pharmacodynamics and safety of lixisenatide and liraglutide in combination with optimized insulin glargine with/without metformin in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This was a multicenter, randomized, open-label, three-arm trial comparing lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg once daily for 8 weeks in combination with insulin glargine after optimized titration. The primary end point was change from baseline to week 8 in incremental area under the postprandial plasma glucose curve for 4 h after a standardized solid breakfast (AUC PPG0030–0430 h). Changes from baseline in gastric emptying, 24-h plasma glucose profile, HbA1c, fasting plasma glucose (FPG), 24-h ambulatory heart rate and blood pressure, amylase and lipase levels, and adverse events (AEs) were also assessed. RESULTS In total, 142 patients were randomized and treated. Lixisenatide 20 µg achieved greater reductions of AUC PPG0030−0430 h compared with liraglutide (marginal mean [95% one-sided CI] treatment difference, −6.0 [−7.8] h ⋅ mmol/L [−108.3 (−140.0) h ⋅ mg/dL] vs. liraglutide 1.2 mg and −4.6 [−6.3] h ⋅ mmol/L [−83.0 (−114.2) h ⋅ mg/dL] vs. liraglutide 1.8 mg; P &amp;lt; 0.001 for both), and gastric emptying was delayed to a greater extent than with liraglutide 1.2 and 1.8 mg (P &amp;lt; 0.001 for treatment comparisons). FPG was unchanged in all treatment arms. At week 8, mean ± SD HbA1c was 6.2 ± 0.4% (44 ± 5 mmol/mol), 6.1 ± 0.3% (44 ± 4 mmol/mol), and 6.1 ± 0.3% (44 ± 4 mmol/mol) for lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg, respectively. At week 8, both liraglutide doses increased marginal mean ± SE 24-h heart rate from baseline by 9 ± 1 bpm vs. 3 ± 1 bpm with lixisenatide (P &amp;lt; 0.001). Occurrence of symptomatic hypoglycemia was higher with lixisenatide; gastrointestinal AEs were more common with liraglutide. Lipase levels were significantly increased from baseline with liraglutide 1.2 and 1.8 mg (marginal mean ± SE increase 21 ± 7 IU/L for both; P &amp;lt; 0.05). CONCLUSIONS Lixisenatide and liraglutide improved glycemic control in optimized insulin glargine-treated T2D albeit with contrasting mechanisms of action and differing safety profiles.
The European Medicines Agency Review of Eribulin for the Treatment of Patients with Locally Advanced or Metastatic Breast Cancer: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use
Authors: Elias Pean, Sigrid Klaar, Eva Gil Berglund, Tomas Salmonson, Jeanett Borregaard, Kenneth F. Hofland, Jens Ersbøll, Eric Abadie, Rosa Giuliani, Francesco Pignatti
Journal: Clinical Cancer Research (2012)

The European Commission issued on March 17, 2011, a marketing authorization valid throughout the European Union (EU) for eribulin (Halaven; Eisai Limited). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a marketing authorization for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least 2 chemotherapeutic regimens for advanced disease. Eribulin mesylate is a structurally simplified synthetic analogue of halichondrin B, which is a natural product isolated from the marine sponge Halichondria okadai (ATC code L01XX41). Eribulin is a nontaxane, microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates leading to G(2)-M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. The recommended dose of eribulin is 1.23 mg/m(2) (equivalent to 1.4 mg/m(2) eribulin mesylate) to be administered intravenously over 2 to 5 min on days 1 and 8 of a 3-week cycle. In the pivotal trial, eribulin was associated with increased overall survival in patients with locally advanced or metastatic breast cancer who received at least 2 prior chemotherapy lines for advanced disease (median overall survival was 13.2 months in the eribulin arm vs. 10.6 months in the control arm; HR = 0.805; 95% confidence interval, 0.677-0.958; P = 0.014). The most common side effects are asthenia or fatigue and neutropenia. The objective of this article is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary report and product information, including product characteristics, are available on the European Medicines Agency website.
Influence of age on the outcome of antitumour necrosis factor alpha therapy in rheumatoid arthritis
Authors: B J Radovits, W Kievit, J Fransen, M A F J van de Laar, T L Jansen, P L C M van Riel, R F J M Laan
Journal: Annals of the Rheumatic Diseases (2008)

To investigate the influence of age on the effectiveness and tolerance of antitumour necrosis factor alpha (TNFalpha) therapy in rheumatoid arthritis (RA).730 patients of the Dutch Rheumatoid Arthritis Monitoring (DREAM) register were categorised into three groups according to their age at initiation of anti-TNFalpha therapy (<45, 45-65 and >65 years). Effectiveness of anti-TNFalpha therapy was primarily assessed by longitudinal analysis of the DAS28 during the first 12 months of treatment.Improvement in disease activity and physical functioning was significantly less in elderly patients, correcting for relevant confounders. Elderly patients reached the EULAR categories of good responders and remission less often than younger patients. Drug survival, co-medication use and tolerance were comparable between the three age groups.Anti-TNFalpha therapy significantly reduced disease activity in all age groups of patients; however, it appeared less effective in elderly compared with younger RA patients.
What's new in the other general journals
Authors: Kristina Fister
Journal: BMJ (2006)

Harm reduction programmes have been criticised for giving a false impression to adolescents that heroin use doesn't have to be associated with as much harm to the individual as is traditionally thought. Switzerland has had a liberal policy towards harm reduction. And a recent study shows that the incidence of heroin misuse has been falling under an extensive harm reduction programme, which includes methadone substitution with low threshold of illicit use.



Credit: LANCET



The researchers analysed an anonymised treatment register of almost 80% of the heroin addicts treated between 1991 and March 2005 in the canton of Zurich, which included more than 7000 people. Using the conditional lag time distribution, they estimated the proportion of addicts not yet in substitution treatment programmes and modelled the overall prevalence of heroin misuse as a function of incidence and cessation rate.



Credit: ANN INT MED



After its all time peak in 1990, the incidence of regular heroin use declined fourfold in the next decade, more than in any other country with data permitting such analysis. The data showed a decline, by 4% a year, in the population of problematic heroin addicts, defined as people who sought and entered treatment. However, the rates of cessation (leaving the substitution programme and not re-entering within a decade) in Switzerland are among the lowest recorded.

 Lancet 2006;367: 1830–4

[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4]

Children who had ventricular fibrillation or tachycardia before the onset of cardiac arrest have better prognosis than children in cardiac arrest who develop ventricular fibrillation or tachycardia during cardiopulmonary resuscitation. This finding is from a multicentre register study of more than 1000 consecutive children with cardiac arrest. It contradicts previous evidence, which was based on studies from single institutions with small sample sizes, and the traditional view that ventricular fibrillation and tachycardia are “good” cardiac arrest rhythms.

Children who develop ventricular fibrillation …

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Association between male circumcision and incidence of syphilis in men and women: a prospective study in HIV-1 serodiscordant heterosexual African couples
Authors: Jillian Pintye, Jared M Baeten, Lisa E Manhart, Connie Celum, Allan Ronald, Nelly Mugo, Andrew Mujugira, Craig Cohen, Edwin Were, Elizabeth Bukusi, James Kiarie, Renee Heffron
Journal: The Lancet Global Health (2014)

BackgroundMale circumcision is a primary HIV-1 prevention intervention for men, but whether the procedure reduces the risk of syphilis among men and their female partners is uncertain. We aimed to assess whether male circumcision was associated with incident syphilis in men and in their female partners.MethodsIn this large prospective cohort study, participants were members of Kenyan and Ugandan HIV-1 serodiscordant heterosexual couples enrolled in a randomised safety and efficacy clinical trial of pre-exposure prophylaxis for HIV-1 prevention (the Partners PrEP Study). Participants attended monthly or quarterly follow-up visits for up to 36 months. Annually, syphilis serology testing was done and male circumcision status was assessed. We used multivariate Andersen-Gill survival methods, adjusted for age, sexual behaviour, and plasma HIV RNA levels of the HIV-infected partner.Findings4716 HIV-1 serodiscordant couples (38%) with a man with HIV were followed for a median of 2·75 years. At enrolment, 1575 (53%) men with HIV and 560 (32%) men without HIV were circumcised; an additional 69 (4%) men with HIV and 132 (5%) men without HIV were circumcised during study follow-up. 221 incident syphilis infections were reported: 46 (21%) in men with HIV (incidence 1·10 per 100 person-years), 76 (34%) in men without HIV (1·09), 54 (24%) in women with HIV (0·77), and 45 (24%) in women without HIV (1·11). Male circumcision was associated with a 42% reduction in incident syphilis in men (adjusted hazard ratio [aHR] 0·58, 95% CI 0·37–0·91) including a 62% reduction in men with HIV (0·38, 0·18–0·81), and a non-significant reduction in incident syphilis in men without HIV (0·64, 0·36–1·11). In women, circumcision of their male partners was associated with a 59% reduction in incident syphilis (aHR 0·41, 95% CI 0·25–0·69), including a 75% reduction in women without HIV (0·25, 0·08–0·76) and a 48% reduction in women with HIV (0·52, 0·27–0·97).InterpretationMale circumcision was associated with decreased risk of incident syphilis in men and women. If confirmed, these results suggest that medical male circumcision could substantially reduce incidence of syphilis and its sequelae.FundingBill & Melinda Gates Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Electronic nicotine delivery systems
Authors: Kristiaan Nackaerts, Luk Joossens
Journal: European Respiratory Journal (2015)

While reading the editorial on electronic nicotine delivery systems by Blasi and Ward [1], we noticed an inaccuracy in the section on The post-2016 regimen (p. 586). It is wrongly stated that "there will be a maximum nicotine volume for e-cigarettes of 10 mL for refillable cartridges". The volume of 10 mL was stated by the European Union in its 2014/40/EU Directive to be applicable to "refill containers" for the e-liquids that are used to refill the (maximally) 2 mL-containing refillable cartridges of an e-cigarette [2]. A correction is needed on electronic nicotine delivery systems <http://ow.ly/EWkzj>