Overexpression of the Axl tyrosine kinase receptor in cutaneous SCC-derived cell lines and tumours

The molecular mechanisms that underlie the development of squamous cell skin cancers (SSC) are poorly understood. We have used oligonucleotide microarrays to compare the differences in cellular gene expression between a series of keratinocyte cell that mimic disease progression with the aim of identifying genes that may potentially contribute towards squamous cell carcinoma (SCC) progression in vivo, and in particular to identify markers that may serve as potential therapeutic targets for SCC treatment. Gene expression differences were corroborated by polymerase chain reaction and Western blotting. We identified Axl, a receptor tyrosine kinase with transforming potential that has also been shown to have a role in cell survival, adhesion and chemotaxis, was upregulated in vitro in SCC-derived cells compared to premalignant cells. Extending the investigation to tumour biopsies showed that the Axl protein was overexpressed in vivo in a series of SCCs

The Role of Vaccine Coverage within Social Networks in Cholera Vaccine Efficacy

Traditional vaccine trial methods have an underlying assumption that the effect of a vaccine is the same throughout the trial area. There are, however, many spatial and behavioral factors that alter the rates of contact among infectious and susceptible individuals and result in different efficacies across a population. We reanalyzed data from a field trial in Bangladesh to ascertain whether there is evidence of indirect protection from cholera vaccines when vaccination rates are high in an individual's social network.We analyzed the first year of surveillance data from a placebo-controlled trial of B subunit-killed whole-cell and killed whole-cell-only oral cholera vaccines in children and adult women in Bangladesh. We calculated whether there was an inverse trend for the relation between the level of vaccine coverage in an individual's social network and the incidence of cholera in individual vaccine recipients or placebo recipients after controlling for potential confounding variables.Using bari-level social network ties, we found incidence rates of cholera among placebo recipients were inversely related to levels of vaccine coverage (5.28 cases per 1000 in the lowest quintile vs 3.27 cases per 1000 in the highest quintile; p = 0.037 for trend). Receipt of vaccine by an individual and the level of vaccine coverage of the individual's social network were independently related to a reduced risk of cholera.Findings indicate that progressively higher levels of vaccine coverage in bari-level social networks can lead to increasing levels of indirect protection of non-vaccinated individuals and could also lead to progressively higher levels of total protection of vaccine recipients

The Human Endogenous Circadian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors

Platelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (~9 AM), potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1) platelet function and (2) platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise.We studied 12 healthy adults (6 female) who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP) IIb-IIIa, GPIb and P-selectin (6-17% peak-trough amplitudes; p ≤ 0.01). These circadian peaks occurred at a circadian phase corresponding to 8-9 AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3-8 PM). The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors.These data demonstrate robust effects of the endogenous circadian system on platelet activation in humans--independent of the sleep/wake cycle, other behavioral influences and the environment. The 9 AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the final common pathway of platelet aggregation, suggests that endogenous circadian influences on platelet function could contribute to the morning peak in adverse cardiovascular events as seen in many epidemiological studies

Climate Change Hastens the Conservation Urgency of an Endangered Ungulate

Global climate change appears to be one of the main threats to biodiversity in the near future and is already affecting the distribution of many species. Currently threatened species are a special concern while the extent to which they are sensitive to climate change remains uncertain. Przewalski's gazelle (Procapra przewalskii) is classified as endangered and a conservation focus on the Qinghai-Tibetan Plateau. Using measures of species range shift, we explored how the distribution of Przewalski's gazelle may be impacted by projected climate change based on a maximum entropy approach. We also evaluated the uncertainty in the projections of the risks arising from climate change. Modeling predicted the Przewalski's gazelle would be sensitive to future climate change. As the time horizon increased, the strength of effects from climate change increased. Even assuming unlimited dispersal capacity of gazelles, a moderate decrease to complete loss of range was projected by 2080 under different thresholds for transforming the probability prediction to presence/absence data. Current localities of gazelles will undergo a decrease in their occurrence probability. Projections of the impacts of climate change were significantly affected by thresholds and general circulation models. This study suggests climate change clearly poses a severe threat and increases the extinction risk to Przewalski's gazelle. Our findings 1) confirm that endangered endemic species is highly vulnerable to climate change and 2) highlight the fact that forecasting impacts of climate change needs an assessment of the uncertainty. It is extremely important that conservation strategies consider the predicted geographical shifts and be planned with full knowledge of the reliability of projected impacts of climate change

External validation of risk prediction models for incident colorectal cancer using UK Biobank.

BACKGROUND: This study aimed to compare and externally validate risk scores developed to predict incident colorectal cancer (CRC) that include variables routinely available or easily obtainable via self-completed questionnaire. METHODS: External validation of fourteen risk models from a previous systematic review in 373 112 men and women within the UK Biobank cohort with 5-year follow-up, no prior history of CRC and data for incidence of CRC through linkage to national cancer registries. RESULTS: There were 1719 (0.46%) cases of incident CRC. The performance of the risk models varied substantially. In men, the QCancer10 model and models by Tao, Driver and Ma all had an area under the receiver operating characteristic curve (AUC) between 0.67 and 0.70. Discrimination was lower in women: the QCancer10, Wells, Tao, Guesmi and Ma models were the best performing with AUCs between 0.63 and 0.66. Assessment of calibration was possible for six models in men and women. All would require country-specific recalibration if estimates of absolute risks were to be given to individuals. CONCLUSIONS: Several risk models based on easily obtainable data have relatively good discrimination in a UK population. Modelling studies are now required to estimate the potential health benefits and cost-effectiveness of implementing stratified risk-based CRC screening

A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far

Large-Scale Profiling of Kinase Dependencies in Cancer Cell Lines

One approach to identifying cancer-specific vulnerabilities and therapeutic targets is to profile genetic dependencies in cancer cell lines. Here, we describe data from a series of siRNA screens that identify the kinase genetic dependencies in 117 cancer cell lines from ten cancer types. By integrating the siRNA screen data with molecular profiling data, including exome sequencing data, we show how vulnerabilities/genetic dependencies that are associated with mutations in specific cancer driver genes can be identified. By integrating additional data sets into this analysis, including protein-protein interaction data, we also demonstrate that the genetic dependencies associated with many cancer driver genes form dense connections on functional interaction networks. We demonstrate the utility of this resource by using it to predict the drug sensitivity of genetically or histologically defined subsets of tumor cell lines, including an increased sensitivity of osteosarcoma cell lines to FGFR inhibitors and SMAD4 mutant tumor cells to mitotic inhibitors

Diabetes susceptibility in ethnic minority groups from Turkey, Vietnam, Sri Lanka and Pakistan compared with Norwegians - the association with adiposity is strongest for ethnic minority women

<p>Abstract</p> <p>Background</p> <p>The difference in diabetes susceptibility by ethnic background is poorly understood. The aim of this study was to assess the association between adiposity and diabetes in four ethnic minority groups compared with Norwegians, and take into account confounding by socioeconomic position.</p> <p>Methods</p> <p>Data from questionnaires, physical examinations and serum samples were analysed for 30-to 60-year-olds from population-based cross-sectional surveys of Norwegians and four immigrant groups, comprising 4110 subjects born in Norway (n = 1871), Turkey (n = 387), Vietnam (n = 553), Sri Lanka (n = 879) and Pakistan (n = 420). Known and screening-detected diabetes cases were identified. The adiposity measures BMI, waist circumference and waist-hip ratio (WHR) were categorized into levels of adiposity. Gender-specific logistic regression models were applied to estimate the risk of diabetes for the ethnic minority groups adjusted for adiposity and income-generating work, years of education and body height used as a proxy for childhood socioeconomic position.</p> <p>Results</p> <p>The age standardized diabetes prevalence differed significantly between the ethnic groups (women/men): Pakistan: 26.4% (95% CI 20.1-32.7)/20.0% (14.9-25.2); Sri Lanka: 22.5% (18.1-26.9)/20.7% (17.3-24.2), Turkey: 11.9% (7.2-16.7)/12.0% (7.6-16.4), Vietnam: 8.1% (5.1-11.2)/10.4% (6.6-14.1) and Norway: 2.7% (1.8-3.7)/6.4% (4.6-8.1). The prevalence increased more in the minority groups than in Norwegians with increasing levels of BMI, WHR and waist circumference, and most for women. Highly significant ethnic differences in the age-standardized prevalence of diabetes were found for both genders in all categories of all adiposity measures (<it>p </it>< 0.001). The Odds Ratio (OR) for diabetes adjusted for age, WHR, body height, education and income-generating work with Norwegians as reference was 2.9 (1.30-6.36) for Turkish, 2.7 (1.29-5.76) for Vietnamese, 8.0 (4.19-15.14) for Sri Lankan and 8.3 (4.37-15.58) for Pakistani women. Men from Sri Lanka and Pakistan had identical ORs (3.0 (1.80-5.12)).</p> <p>Conclusions</p> <p>A high prevalence of diabetes was found in 30-to 60-year-olds from ethnic minority groups in Oslo, with those from Sri Lanka and Pakistan at highest risk. For all levels of adiposity, a higher susceptibility for diabetes was observed for ethnic minority groups compared with Norwegians. The association persisted after adjustment for socioeconomic position for all minority women and for men from Sri Lanka and Pakistan.</p

Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early