Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs

OBJECTIVE: To determine the influence of the single nucleotide polymorphism (SNP) rs4245739 on the binding and expression ofmicroRNAs and subsequent MDM4 expression and the correlation of these factors with clinical determinants of ER-negativebreast cancers. METHODS: FindTar and miRanda were used to detect the manner in which potential microRNAs are affected by the SNPrs4245739-flanking sequence. RNA sequencing data for ER-negative breast cancer from The Cancer Genome Atlas (TCGA) wereused to compare the expression of miR-184, miR-191, miR-193a, miR-378, and MDM4 in different rs4245739 genotypes. RESULTS: Comparison of ER-negative cancer patients with and without the expression of miR-191 as well as profile microRNAs(miR-184, miR-191, miR-193a and miR-378 altogether) can differentiate the expression of MDM4 among different rs4245739genotypes. Although simple genotyping alone did not reveal significant clinical relationships, the combination of genotyping andmicroRNA profiles was able to significantly differentiate individuals with larger tumor size and lower number of involved lymphnodes (P < 0.05) in the risk group (A allele). CONCLUSIONS: We present two novel methods to analyze SNPs within 3′UTRs that use: (i) a single miRNA marker expression and(ii) an expression profile of miRNAs predicted to bind to the SNP region. We demonstrate that the application of these twomethods, in particular the miRNA profile approach, permits detection of new molecular and clinical features related to thers4245739 variant in ER-negative breast cancer

THE EXPRESSION OF Hsa-miR-21-5p AS MINIMAL INVASIVE MARKER TO ADJUVANT CHEMOTHERAPY IN BREAST CANCER PATIENTS

AbstractBreast cancer remains the leading cause of death among women, and there is a need to develop minimally invasive marker. In our previous study based on clinicopathologic in pre-chemotherapy patients showed miR-21 was upregulated 1.32 times higher at advanced stage compared with early stage. Therefore the matched patients for post-chemotherapy samples were used. The aim of this research is to examine the expression of miR-21 as potential marker to adjuvant chemotherapy in breast cancer patients. The samples were taken by using cross sectional method with total 39 blood plasma samples from breast cancer patients in adjuvant chemotherapy and 12 healthy control samples. Plasma was obtained from blood samples and then RNA isolated were performed. Total RNA was reverse transcribed using cDNA synthesis. The expression of miR-21 was then analyzed using specific primer for miR-21 and miR-16 as the reference gene. Livak Method was used to calculate the expression level in each group. The result showed that there is significant downregulated expression of miR-21 in postchemotherapy 2.61 fold compared with pre-chemotherapy (p<0.05). The expression of miR-21 upregulated 2.2 folds (p<0.05) in pre-chemotherapy compared with healthy control, while in post-chemotherapy compared with healthy control, the expression of miR-21 was 0.8 fold (p<0.05). In conclusion, Hsa-miR-21-5p can be used as marker for adjuvant chemotherapy response in breast cancer because there is significant different expression between prechemotherapy, post-chemotherapy and healthy control. The continuation research in the near future for detecting the expression of tumor suppressor protein regulated by miR-21 is needed.Keywords: breast cancer, adjuvant chemotherapy, miR-21, minimal invasive marke

Diet, physical activity, and adiposity in children in poor and rich neighbourhoods: a cross-sectional comparison

BACKGROUND: Obesity in Canadian children increased three-fold in twenty years. Children living in low-income neighborhoods exercise less and are more overweight than those living in more affluent neighborhoods after accounting for family socio-economic status. Strategies to prevent obesity in children have focused on personal habits, ignoring neighborhood characteristics. It is essential to evaluate diet and physical activity patterns in relation to socio-economic conditions to understand the determinants of obesity. The objective of this pilot study was to compare diet, physical activity, and the built environment in two Hamilton area elementary schools serving socio-economically different communities. METHODS: We conducted a cross-sectional study (November 2005-March 2006) in two public elementary schools in Hamilton, Ontario, School A and School B, located in low and high socioeconomic areas respectively. We assessed dietary intake, physical activity, dietary restraint, and anthropometric measures in consenting children in grades 1 and higher. From their parents we assessed family characteristics and walkability of the built environment. RESULTS: 160 children (n = 48, School A and n = 112, School B), and 156 parents (n = 43, School A and n = 113, School B) participated in this study. The parents with children at School A were less educated and had lower incomes than those at School B. The School A neighborhood was perceived to be less walkable than the School B neighborhood. Children at School A consumed more baked foods, chips, sodas, gelatin desserts, and candies and less low fat dairy, and dark bread than those at School B. Children at School A watched more television and spent more time in front of the computer than children studying at School B, but reported spending less time sitting on weekdays and weekends. Children at both schools were overweight but there was no difference in their mean BMI z-scores (School A = 0.65 versus School B = 0.81, p-value = 0.38). CONCLUSION: The determinants of overweight in children may be more complex than imagined. In future intervention programs researchers may consider addressing environmental factors, and customizing lifestyle interventions so that they are closer to community needs

Effect of Air Injection Depth on Big-bubble Formation in Lamellar Keratoplasty: an Ex Vivo Study

This study evaluated the effect of air injection depth in the big-bubble (BB) technique, which is used for corneal tissue preparation in lamellar keratoplasty. The BB technique was performed on ex vivo human corneoscleral buttons using a depth-sensing needle, based on optical coherence tomography (OCT) imaging technology. The needle tip, equipped with a miniaturized OCT depth-sensing probe, was inserted for air injection at a specified depth. Inside the corneal tissue, our needle obtained OCT line profiles, from which residual thickness below the needle tip was measured. Subjects were classified into Groups I, II, III, and IV based on injection depths of 75-80%, 80-85%, 85-90%, and &gt; 90% of the full corneal thickness, respectively. Both Type I and II BBs were produced when the mean residual thicknesses of air injection were 109.7 +/- 38.0 mu m and 52.4 +/- 19.2 mu m, respectively. Type II BB (4/5) was dominant in group IV. Bubble burst occurred in 1/16 cases of type I BB and 3/16 cases of type II BB, respectively. Injection depth was an important factor in determining the types of BBs produced. Deeper air injection could facilitate formation of Type II BBs, with an increased risk of bubble bursts

The construction of ethnic identity: insights from identity process theory

Ethnicity has received much empirical and theoretical attention in the social sciences. Yet, it has scarcely been explored in terms of its relationship with the motivational principles of identity. Here it is argued that there is much heuristic and predictive value in applying identity process theory (IPT), a socio-psychological model of identity threat, to the substantive literature on ethnicity. The paper explores the potential psychological benefits of ethnic identification. Key theoretical strands from anthropology and sociology, such as the ‘relational self’ in ethnic identification, are discussed in relation to IPT. The intergroup dimension of ethnic identification is explored through the discussion of ethnic 'boundaries'. Finally, the paper discusses the construct of 'hybridization' in relation to social psychology. This paper attempts to reconcile psychological and sociological perspectives on ethnic identification, advocating a multi-methodological approach. Key theoretical points are outlined in the form of testable hypotheses which are open to empirical exploration

Sexual Dimorphic Regulation of Body Weight Dynamics and Adipose Tissue Lipolysis

BACKGROUND: Successful reduction of body weight (BW) is often followed by recidivism to obesity. BW-changes including BW-loss and -regain is associated with marked alterations in energy expenditure (EE) and adipose tissue (AT) metabolism. Since these processes are sex-specifically controlled, we investigated sexual dimorphisms in metabolic processes during BW-dynamics (gain-loss-regain). RESEARCH DESIGN: Obesity was induced in C57BL/6J male (m) and female (f) mice by 15 weeks high-fat diet (HFD) feeding. Subsequently BW was reduced (-20%) by caloric restriction (CR) followed by adaptive feeding, and a regain-phase. Measurement of EE, body composition, blood/organ sampling were performed after each feeding period. Lipolysis was analyzed ex-vivo in gonadal AT. RESULTS: Male mice exhibited accelerated BW-gain compared to females (relative BW-gain m:140.5±3.2%; f:103.7±6.5%; p<0.001). In consonance, lean mass-specific EE was significantly higher in females compared to males during BW-gain. Under CR female mice reached their target-BW significantly faster than male mice (m:12.2 days; f:7.6 days; p<0.001) accompanied by a sustained sex-difference in EE. In addition, female mice predominantly downsized gonadal AT whereas the relation between gonadal and total body fat was not altered in males. Accordingly, only females exhibited an increased rate of forskolin-stimulated lipolysis in AT associated with significantly higher glycerol concentrations, lower RER-values, and increased AT expression of adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Analysis of AT lipolysis in estrogen receptor alpha (ERα)-deficient mice revealed a reduced lipolytic rate in the absence of ERα exclusively in females. Finally, re-feeding caused BW-regain faster in males than in females. CONCLUSION: The present study shows sex-specific dynamics during BW-gain-loss-regain. Female mice responded to CR with an increase in lipolytic activity, and augmented lipid-oxidation leading to more efficient weight loss. These processes likely involve ERα-dependent signaling in AT and sexual dimorphic regulation of genes involved in lipid metabolism

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Trends in type 2 diabetes incidence and mortality in Scotland between 2004 and 2013

No abstract available

Striatal Dopamine Transmission Is Subtly Modified in Human A53Tα-Synuclein Overexpressing Mice

Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn), cause familial Parkinson's disease (PD). Mouse lines overexpressing the mutant human A53Tα-syn may represent a model of early PD. They display progressive motor deficits, abnormal cellular accumulation of α-syn, and deficits in dopamine-dependent corticostriatal plasticity, which, in the absence of overt nigrostriatal degeneration, suggest there are age-related deficits in striatal dopamine (DA) signalling. In addition A53Tα-syn overexpression in cultured rodent neurons has been reported to inhibit transmitter release. Therefore here we have characterized for the first time DA release in the striatum of mice overexpressing human A53Tα-syn, and explored whether A53Tα-syn overexpression causes deficits in the release of DA. We used fast-scan cyclic voltammetry to detect DA release at carbon-fibre microelectrodes in acute striatal slices from two different lines of A53Tα-syn-overexpressing mice, at up to 24 months. In A53Tα-syn overexpressors, mean DA release evoked by a single stimulus pulse was not different from wild-types, in either dorsal striatum or nucleus accumbens. However the frequency responsiveness of DA release was slightly modified in A53Tα-syn overexpressors, and in particular showed slight deficiency when the confounding effects of striatal ACh acting at presynaptic nicotinic receptors (nAChRs) were antagonized. The re-release of DA was unmodified after single-pulse stimuli, but after prolonged stimulation trains, A53Tα-syn overexpressors showed enhanced recovery of DA release at old age, in keeping with elevated striatal DA content. In summary, A53Tα-syn overexpression in mice causes subtle changes in the regulation of DA release in the striatum. While modest, these modifications may indicate or contribute to striatal dysfunction