Factors associated with failed treatment : an analysis of 121,744 women embarking on their first IVF cycles

Peer reviewedPublisher PD

Expression and DNA methylation of TNF, IFNG and FOXP3 in colorectal cancer and their prognostic significance.

BACKGROUND: Colorectal cancer (CRC) progression is associated with suppression of host cell-mediated immunity and local immune escape mechanisms. Our aim was to assess the immune function in terms of expression of TNF, IFNG and FOXP3 in CRC. METHODS: Sixty patients with CRC and 15 matched controls were recruited. TaqMan quantitative PCR and methylation-specific PCR was performed for expression and DNA methylation analysis of TNF, IFNG and FOXP3. Survival analysis was performed over a median follow-up of 48 months. RESULTS: TNF was suppressed in tumour and IFNG was suppressed in peripheral blood mononuclear cells (PBMCs) of patients with CRC. Tumours showed enhanced expression of FOXP3 and was significantly higher when tumour size was >38 mm (median tumour size; P=0.006, Mann-Whitney U-test). Peripheral blood mononuclear cell IFNG was suppressed in recurrent CRC (P=0.01). Methylated TNFpromoter (P=0.003) and TNFexon1 (P=0.001) were associated with significant suppression of TNF in tumours. Methylated FOXP3cpg was associated with significant suppression of FOXP3 in both PBMC (P=0.018) and tumours (P=0.010). Reduced PBMC FOXP3 expression was associated with significantly worse overall survival (HR=8.319, P=0.019). CONCLUSIONS: We have detected changes in the expression of immunomodulatory genes that could act as biomarkers for prognosis and future immunotherapeutic strategies

Phenoloxidase activity acts as a mosquito innate immune response against infection with semliki forest virus

Several components of the mosquito immune system including the RNA interference (RNAi), JAK/STAT, Toll and IMD pathways have previously been implicated in controlling arbovirus infections. In contrast, the role of the phenoloxidase (PO) cascade in mosquito antiviral immunity is unknown. Here we show that conditioned medium from the Aedes albopictus-derived U4.4 cell line contains a functional PO cascade, which is activated by the bacterium Escherichia coli and the arbovirus Semliki Forest virus (SFV) (Togaviridae; Alphavirus). Production of recombinant SFV expressing the PO cascade inhibitor Egf1.0 blocked PO activity in U4.4 cell- conditioned medium, which resulted in enhanced spread of SFV. Infection of adult female Aedes aegypti by feeding mosquitoes a bloodmeal containing Egf1.0-expressing SFV increased virus replication and mosquito mortality. Collectively, these results suggest the PO cascade of mosquitoes plays an important role in immune defence against arboviruses

Elevated Incidence of Dental Caries in a Mouse Model of Cystic Fibrosis

Saliva bicarbonate constitutes the main buffering system which neutralizes the pH fall generated by the plaque bacteria during sugar metabolism. We found that the saliva pH is severely decreased in a mouse model of cystic fibrosis disease (CF). Given the close relationship between pH and caries development, we hypothesized that caries incidence might be elevated in the mouse CF model.). are enhanced at low pH values, we speculate that the decrease in the bicarbonate content and pH buffering of the saliva is at least partially responsible for the increased severity of lesions observed in the CF mouse

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Aspirin use and survival after the diagnosis of breast cancer:a population-based cohort study

Background: Aspirin use has been associated with a reduced cancer incidence and fewer deaths from cancer. This study examined whether women with breast cancer prescribed aspirin postdiagnosis had improved survival.Methods:An observational, population cohort study was undertaken using data linkage of cancer registry, dispensed prescriptions and death records in Tayside, Scotland. All community prescriptions for aspirin in women with breast cancer were extracted and use postdiagnosis for each individual examined using Cox's proportional hazard models. The main outcome measures were all-cause mortality and breast cancer-specific mortality.Results:Four thousand six hundred and twenty-seven patients diagnosed with breast cancer between 1 January 1998 and 31 December 2008 were followed up until 28 February 2010. Median age at diagnosis was 62 (IQR 52-74). One thousand eight hundred and two (39%) deaths were recorded, with 815 (18%) attributed to breast cancer. One thousand and thirty-five (22%) patients were prescribed aspirin postdiagnosis. Such aspirin use was associated with lower risk of all-cause mortality (HR=0.53, 95% CI=0.45-0.63, P<0.001) and breast cancer-specific mortality (HR=0.42, 95% CI=0.31-0.55, P<0.001) after adjusting for age, socioeconomic status, TNM stage, tumour grade, oestrogen receptor status, surgery, radiotherapy, chemotherapy, adjuvant endocrine therapy and aspirin use prediagnosis. Conclusions:Aspirin use postdiagnosis of breast cancer may reduce both all-cause and breast cancer-specific mortality. Further investigation seeking a causal relationship and which subgroups of patients benefit most await ongoing randomised controlled trials.Publisher PDFPeer reviewe

Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay

The decay channel $\psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p})$ is studied using a sample of $1.06\times 10^8$ $\psi^\prime$ events collected by the BESIII experiment at BEPCII. A strong enhancement at threshold is observed in the $p\bar{p}$ invariant mass spectrum. The enhancement can be fit with an $S$-wave Breit-Wigner resonance function with a resulting peak mass of $M=1861^{+6}_{-13} {\rm (stat)}^{+7}_{-26} {\rm (syst)} {\rm MeV/}c^2$ and a narrow width that is $\Gamma<38 {\rm MeV/}c^2$ at the 90% confidence level. These results are consistent with published BESII results. These mass and width values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics

Balancing hydrogen adsorption/desorption by orbital modulation for efficient hydrogen evolution catalysis

Hydrogen adsorption/desorption behavior plays a key role in hydrogen evolution reaction (HER) catalysis. The HER reaction rate is a trade-off between hydrogen adsorption and desorption on the catalyst surface. Herein, we report the rational balancing of hydrogen adsorption/desorption by orbital modulation using introduced environmental electronegative carbon/nitrogen (C/N) atoms. Theoretical calculations reveal that the empty d orbitals of iridium (Ir) sites can be reduced by interactions between the environmental electronegative C/N and Ir atoms. This balances the hydrogen adsorption/ desorption around the Ir sites, accelerating the related HER process. Remarkably, by anchoring a small amount of Ir nanoparticles (7.16 wt%) in nitrogenated carbon matrixes, the resulting catalyst exhibits significantly enhanced HER performance. This includs the smallest reported overpotential at 10 mA cm(-2) (4.5 mV), the highest mass activity at 10 mV (1.12 A mg(Ir)(-1)) and turnover frequency at 25 mV (4.21 H2 s(-1)) by far, outperforming Ir nanoparticles and commercial Pt/C

Genetic and cellular aspects of the establishment of histocompatible stem cells: information gained from an animal model

The establishment of patient-specific histocompatible stem cells may be an alternative for overcoming current limitations in stem cell engineering. We are developing an animal model to assist the establishment of histocompatible, autologous stem cells. In this process, we obtained valuable information on establishing and characterizing stem cells. As an initial step, we succeeded in establishing histocompatible stem cells using preantral follicle cultures and subsequent parthenogenetic activation. The gene expression profile of the established stem cells was similar to that of embryonic stem cells (ESCs) derived from normal fertilization. On the other hand, we propose a way to derive histocompatible, ESC-like cells by co-culturing ovarian stromal cells with feeder fibroblasts, which may allow the derivation of stem cells from somatic tissue. However, more progress regarding the establishment and elucidation on origination of established cell lines is necessary to use this genetic manipulation-free procedure. Nevertheless, relevant information on the process will help to stimulate preclinical research on cell transformation into differentiated, undifferentiated, and even cancerous cells, as well as clinical studies on the application of induced pluripotent cells