Trust as a mediator in the relationship between childhood sexual abuse and IL-6 level in adulthood

Childhood sexual abuse (CSA) has been shown to predict the coupling of depression and inflammation in adulthood. Trust within intimate relationships, a core element in marital relations, has been shown to predict positive physical and mental health outcomes, but the mediating role of trust in partners in the association between CSA and inflammation in adulthood requires further study. The present study aimed to examine the impact of CSA on inflammatory biomarkers (IL-6 and IL-1β) in adults with depression and the mediating role of trust. A cross-sectional survey data set of adults presenting with mood and sleep disturbance was used in the analysis. CSA demonstrated a significant negative correlation with IL-6 level (r = -0.28, p<0. 01) in adults with clinically significant depression, while trust showed a significant positive correlation with IL-6 level (r = 0.36, p < .01). Sobel test and bootstrapping revealed a significant mediating role for trust between CSA and IL-6 level. CSA and trust in partners were revealed to have significant associations with IL-6 level in adulthood. Counterintuitively, the directions of association were not those expected. Trust played a mediating role between CSA and adulthood levels of IL-6. Plausible explanations for these counterintuitive findings are discussed

Protein profiling in hepatocellular carcinoma by label-free quantitative proteomics in two west african populations.

Background Hepatocellular Carcinoma is the third most common cause of cancer related death worldwide, often diagnosed by measuring serum AFP; a poor performance stand-alone biomarker. With the aim of improving on this, our study focuses on plasma proteins identified by Mass Spectrometry in order to investigate and validate differences seen in the respective proteomes of controls and subjects with LC and HCC. Methods Mass Spectrometry analysis using liquid chromatography electro spray ionization quadrupole time-of-flight was conducted on 339 subjects using a pooled expression profiling approach. ELISA assays were performed on four significantly differentially expressed proteins to validate their expression profiles in subjects from the Gambia and a pilot group from Nigeria. Results from this were collated for statistical multiplexing using logistic regression analysis. Results Twenty-six proteins were identified as differentially expressed between the three subject groups. Direct measurements of four; hemopexin, alpha-1-antitrypsin, apolipoprotein A1 and complement component 3 confirmed their change in abundance in LC and HCC versus control patients. These trends were independently replicated in the pilot validation subjects from Nigeria. The statistical multiplexing of these proteins demonstrated performance comparable to or greater than ALT in identifying liver cirrhosis or carcinogenesis. This exercise also proposed preliminary cut offs with achievable sensitivity, specificity and AUC statistics greater than reported AFP averages. Conclusions The validated changes of expression in these proteins have the potential for development into high-performance tests usable in the diagnosis and or monitoring of HCC and LC patients. The identification of sustained expression trends strengthens the suggestion of these four proteins as worthy candidates for further investigation in the context of liver disease. The statistical combinations also provide a novel inroad of analyses able to propose definitive cut-offs and combinations for evaluation of performance

Genes Influencing Circadian Differences in Blood Pressure in Hypertensive Mice

Essential hypertension is a common multifactorial heritable condition in which increased sympathetic outflow from the central nervous system is involved in the elevation in blood pressure (BP), as well as the exaggerated morning surge in BP that is a risk factor for myocardial infarction and stroke in hypertensive patients. The Schlager BPH/2J mouse is a genetic model of hypertension in which increased sympathetic outflow from the hypothalamus has an important etiological role in the elevation of BP. Schlager hypertensive mice exhibit a large variation in BP between the active and inactive periods of the day, and also show a morning surge in BP. To investigate the genes responsible for the circadian variation in BP in hypertension, hypothalamic tissue was collected from BPH/2J and normotensive BPN/3J mice at the ‘peak’ (n = 12) and ‘trough’ (n = 6) of diurnal BP. Using Affymetrix GeneChip® Mouse Gene 1.0 ST Arrays, validation by quantitative real-time PCR and a statistical method that adjusted for clock genes, we identified 212 hypothalamic genes whose expression differed between ‘peak’ and ‘trough’ BP in the hypertensive strain. These included genes with known roles in BP regulation, such as vasopressin, oxytocin and thyrotropin releasing hormone, as well as genes not recognized previously as regulators of BP, including chemokine (C-C motif) ligand 19, hypocretin and zinc finger and BTB domain containing 16. Gene ontology analysis showed an enrichment of terms for inflammatory response, mitochondrial proton-transporting ATP synthase complex, structural constituent of ribosome, amongst others. In conclusion, we have identified genes whose expression differs between the peak and trough of 24-hour circadian BP in BPH/2J mice, pointing to mechanisms responsible for diurnal variation in BP. The findings may assist in the elucidation of the mechanism for the morning surge in BP in essential hypertension

A meta-analysis of two randomised trials of early chemotherapy in asymptomatic metastatic colorectal cancer

This report constitutes a prospectively planned meta-analysis combining two almost identical trials undertaken in Australasia and Canada to study the effect of starting chemotherapy immediately in asymptomatic patients with metastatic colorectal cancer. Patients (n=168) were randomised to receive either immediate or delayed treatment (at onset of predefined symptoms). Australasian patients received either weekly 5-fluorouracil and leucovorin (500 and 20 mg m−2, respectively) (n=59) or the daily × 5 Mayo Clinic schedule (425 and 20 mg m−2, respectively) (n=42). Canadian patients were treated with the Mayo schedule (n=67). Otherwise, the two studies were almost identical in design and each used the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 instrument for measuring quality of life (QoL). Treatment was continued until 6 months had elapsed or disease progression occurred. Low accrual led to trial suspension before the predetermined sample size for either study was reached. Median survival was not significantly better with immediate treatment (median 13.0 vs 11.0 months; hazard ratio, 1.15; 95% confidence interval (CI) 0.79–1.72; P=0.49). There was no statistically significant difference in progression-free survival (time from randomisation until first evidence of progression after chemotherapy, 10.2 vs 10.8 months; hazard ratio, 1.08; 95% CI 0.71–1.64; P=0.73). There was no difference in overall QoL or its individual domains between the two treatment strategies at baseline or at any subsequent time point. Early treatment of asymptomatic patients with metastatic colorectal cancer did not provide a survival benefit or improved QoL compared to withholding treatment until symptoms occurred

Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy

Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet whether neurological injury can progress in this setting remains uncertain

RET Mutational Spectrum in Hirschsprung Disease: Evaluation of 601 Chinese Patients

Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial)

An Intronic Variant in the GRP78, a Stress-Associated Gene, Improves Prediction for Liver Cirrhosis in Persistent HBV Carriers

Background: Our previous study indicated that a common variant (rs430397 G>A) in the intron 5 of glucose-regulated protein 78 (GRP78) gene was associated with risk and prognosis of primary hepatocellular carcinoma (HCC), including HBV- and cirrhosis-related HCC. rs430397 polymorphism may be a contributing factor or biomarker of HBV infection or HBV-related cirrhosis. Methodology/Principal Findings: 539 non-HBV-infected individuals, 205 self-limited infection and 496 persistent HBV infection were recruited between January 2001 and April 2005 from the hospitals in Southern China. Genomic DNA was genotyped for rs430397. The associations between the variation and susceptibility to liver cirrhosis (LC) in persistent HBV infection were examined. We observed that individuals carrying allele rs430397A were more likely to become HBV-related LC. When persistently infected patients were divided into four subgroups, patients with phase IV had an increased allele A and genotype AG compared with phase I and/or phase III. Decreased serum albumin and prolonged plasma prothrombin time (PT) were showed in LC patients carrying genotype AA. Furthermore, rs430397 genotype had an increased susceptibility to LC with dose-dependent manners (P-trend = 0.005), and the genotype did constitute a risk factor for the development of advanced LC (Child-Pugh classification C and B, P-trend = 0.021). Conclusions/Significance: rs430397 polymorphism may be a contributing factor to LC in persistent HBV carriers. © 2011 Zhu et al.published_or_final_versio

Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73.

Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers