AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer

Deregulation of mitotic spindle genes has been reported to contribute to the development and progression of malignant tumours. The aim of the present study was to explore the association between the expression profiles of Aurora kinases (AURKA, AURKB and AURKC), cytoskeleton-associated protein 5 (CKAP5), discs large-associated protein 5 (DLGAP5), kinesin-like protein 11 (KIF11), microtubule nucleation factor (TPX2), monopolar spindle 1 kinase (TTK), and β-tubulins (TUBB) and (TUBB3) genes and clinicopathological characteristics in human non-small cell lung carcinoma (NSCLC). Reverse transcription-quantitative polymerase chain reaction-based RNA gene expression profiles of 132 NSCLC and 44 adjacent wild-type tissues were generated, and Cox's proportional hazard regression was used to examine associations. With the exception of AURKC, all genes exhibited increased expression in NSCLC tissues. Of the 10 genes examined, only AURKA was significantly associated with prognosis in NSCLC. Multivariate Cox's regression analysis demonstrated that AURKA mRNA expression [hazard ratio (HR), 1.81; 95% confidence interval (CI), 1.16-2.84; P=0.009], age (HR, 1.03; 95% CI, 1.00-1.06; P=0.020), pathological tumour stage 2 (HR, 2.43; 95% CI, 1.16-5.10; P=0.019) and involvement of distal nodes (pathological node stage 2) (HR, 3.14; 95% CI, 1.24-7.99; P=0.016) were independent predictors of poor prognosis in patients with NSCLC. Poor prognosis of patients with increased AURKA expression suggests that those patients may benefit from surrogate therapy with AURKA inhibitors

Molecular pathogenesis of proliferative verrucous leukoplakia: a systematic review

Proliferative verrucous leukoplakia (PVL) is a potentially premalignant lesion that undergoes malignant transformation in over 40% of cases. Its clinical homogeneity suggests that a single or a small number of molecular pathogenic pathways may exist. Using the Cochrane protocol for systematic reviews, we have looked at the reported evidence of the molecular aetiology and pathogenesis of PVL and compared it with that of conventional oral epithelial dysplasia (OED). Of the 43 papers studied, 19 met the inclusion criteria including 13 proteins assayed in 344 tissues, and genes investigated were TP53, p14ARF, and p16INK4A. In all studies the research objectives were defined and outcomes were clearly stated. This review has shown that the transformation of PVL does not follow the same pathway as that of OED. There was weak evidence to suggest possible correlations between DNA aneuploidy, loss of heterozygosity at locus 9p21, and specific expression of Mcm (mini chromosome maintenance) protein, to transformation of PVL. To show important or distinct pathways of this condition, further studies are needed to access the somatic genomic alterations that are found in malignancies

The epigenetic landscape of oral squamous cell carcinoma

BACKGROUND: There is relatively little methylation array data available specifically for oral squamous cell carcinoma (OSCC). This study aims to compare the DNA methylome across a large cohort of tumour/normal pairs. METHODS: DNA was extracted from 44 OSCCs and paired normal mucosa. DNA methylation analysis employed the Illumina GoldenGate high-throughput array comprising 1505 CpG loci selected from 807 epigenetically regulated genes. This data was correlated with extracapsular spread (ECS), human papilloma virus (HPV) status, recurrence and 5-year survival. RESULTS: Differential methylation levels of a number of genes distinguished the tumour tissue sample from the matched normal. Putative methylation signatures for ECS and recurrence were identified. The concept of concordant methylation or CpG island methylator phenotype (CIMP) in OSCC is supported by our data, with an association between ‘CIMP-high' and worse prognosis. Epigenetic deregulation of NOTCH4 signalling in OSCC was also observed, as part of a possible methylation signature for recurrence, with parallels to recently discovered NOTCH mutations in HNSCC. Differences in methylation in HPV-driven cases were seen, but are less significant than that has been recently proposed in other series. CONCLUSION: Although OSCC seems as much an ‘epigenetic' as a genetic disease, the translational potential of cancer epigenetics has yet to be fully exploited. This data points to the application of epigenetic biomarkers and targets available to further the development of therapy in OSCC

Prediction of photoperiodic regulators from quantitative gene circuit models

Photoperiod sensors allow physiological adaptation to the changing seasons. The external coincidence hypothesis postulates that a light-responsive regulator is modulated by a circadian rhythm. Sufficient data are available to test this quantitatively in plants, though not yet in animals. In Arabidopsis, the clock-regulated genes CONSTANS (CO) and FLAVIN, KELCH, F-BOX (FKF1) and their lightsensitive proteins are thought to form an external coincidence sensor. We use 40 timeseries of molecular data to model the integration of light and timing information by CO, its target gene FLOWERING LOCUS T (FT), and the circadian clock. Among other predictions, the models show that FKF1 activates FT. We demonstrate experimentally that this effect is independent of the known activation of CO by FKF1, thus we locate a major, novel controller of photoperiodism. External coincidence is part of a complex photoperiod sensor: modelling makes this complexity explicit and may thus contribute to crop improvement

Dairy consumption and cardiometabolic diseases: systematic review and updated meta-analyses of prospective cohort studies

Purpose of Review Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies. Recent Findings We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3–4% lower risk of diabetes. Yogurt was non-linearly inversely associatedwith diabetes (RR = 0.86, 95%CI: 0.83–0.90 at 80 g/ d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke. Summary The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases

A case study of bovine tuberculosis in an area of County Donegal, Ireland

A descriptive analysis, to investigate the potential risk factors that might have contributed to the increased incidence of bovine tuberculosis (BTB) herd-breakdowns in the reference area of Co. Donegal during the fifth year of the four-area project (FAP), was performed. Seventy two different herds were restricted for BTB during the FAP; 10 of these herds were restricted twice, resulting in a total of 82 BTB breakdowns. During the first four years of the FAP, the number of BTB herd breakdowns in the area varied from a lowest of nine to a maximum of 18 per year, and were geographically dispersed. In the fifth year of the study a considerable increase in the number of BTB breakdowns (n = 32) was observed, and there was a spatial 'cluster' of infected herds in the eastern part of the study area. The increased number of BTB breakdowns during the fifth year most likely occurred because of the recrudescence of infection, herd-to-herd transmission and, to a lesser extent, purchase of infected cattle. Infected badgers remain as a possible but less likely source of infection, especially as an explanation for the cluster of infected herds. The analysis supports the hypothesis that BTB in herds is a problem that cannot be addressed successfully by dedicating our efforts to the elimination of single risk factors. Neither is it a problem that needs to be investigated only at the herd level, but rather at the area level, including groups of contiguous herds

Selected hematologic and biochemical measurements in African HIV-infected and uninfected pregnant women and their infants: the HIV Prevention Trials Network 024 protocol

Reference values for hematological and biochemical assays in pregnant women and in newborn infants are based primarily on Caucasian populations. Normative data are limited for populations in sub-Saharan Africa, especially comparing women with and without HIV infection, and comparing infants with and without HIV infection or HIV exposure. We determined HIV status and selected hematological and biochemical measurements in women at 20-24 weeks and at 36 weeks gestation, and in infants at birth and 4-6 weeks of age. All were recruited within a randomized clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV (HPTN024). We report nearly complete laboratory data on 2,292 HIV-infected and 367 HIV-uninfected pregnant African women who were representative of the public clinics from which the women were recruited. Nearly all the HIV-infected mothers received nevirapine prophylaxis at the time of labor, as did their infants after birth (always within 72 hours of birth, but typically within just a few hours at the four study sites in Malawi (2 sites), Tanzania, and Zambia. HIV-infected pregnant women had lower red blood cell counts, hemoglobin, hematocrit, and white blood cell counts than HIV-uninfected women. Platelet and monocyte counts were higher among HIV-infected women at both time points. At the 4-6-week visit, HIV-infected infants had lower hemoglobin, hematocrit and white blood cell counts than uninfected infants. Platelet counts were lower in HIV-infected infants than HIV-uninfected infants, both at birth and at 4-6 weeks of age. At 4-6 weeks, HIV-infected infants had higher alanine aminotransferase measures than uninfected infants. Normative data in pregnant African women and their newborn infants are needed to guide the large-scale HIV care and treatment programs being scaled up throughout the continent. These laboratory measures will help interpret clinical data and assist in patient monitoring in a sub-Saharan Africa context

Effectiveness of Compounded Bioidentical Hormone Replacement Therapy: An Observational Cohort Study

<p>Abstract</p> <p>Background</p> <p>Bioidentical Hormone Replacement Therapy (BHRT) is believed it to be a safer and equally effective alternative to Conventional Hormone Therapy for the relief of menopausal symptoms; however, data are needed to support these claims. The objective of this study is to evaluate the effectiveness of compounded BHRT provided in six community pharmacies.</p> <p>Methods</p> <p>This was an observational cohort study of women between the ages of 18-89 who received a compounded BHRT product from January 1, 2003 to April 30, 2010 in six community pharmacies. Data included patient demographics, comorbidities, therapeutic outcomes, and hormone therapies. Women self-rated menopausal symptoms as absent, mild, moderate, or severe. Descriptive statistics were used to characterize the patient population, BHRT use, and adverse events. Patient symptom severity was compared at baseline and 3 to 6 months follow-up using the Wilcoxon signed-rank test.</p> <p>Results</p> <p>Women (n = 296) receiving BHRT at Oakdell Pharmacy had a mean (standard deviation) age of 52 (9) years. The most common BHRT dosage forms utilized were topical (71%) and oral (43%). Compounded BHRT regimens were generally initiated at low doses regardless of route. Women experienced a 25% decrease in emotional lability (p < 0.01), a 25% decrease in irritability (p < 0.01), and a 22% reduction in anxiety (p = 0.01) within 3 to 6 months. These women also experienced a 14% reduction in night sweats (p = 0.09) and a 6% reduction in hot flashes (p = 0.50).</p> <p>Conclusions</p> <p>This study demonstrates that compounded BHRT improves mood symptoms. Larger studies are needed to examine the impact on vasomotor symptoms, myocardial infarction and breast cancer.</p

Increased High Density Lipoprotein-levels associated with Age-related Macular degeneration. Evidence from the EYE-RISK and E3 Consortia

Purpose Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. Design Pooled analysis of cross-sectional data. Participants Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. Methods AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. Main Outcome Measures AMD features and stage; lipid measurements. Results HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14–1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91–0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10–1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10–7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10–6 and P = 1.6 × 10–4). Conclusions Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.</p