The dynamics of gene expression changes in a mouse model of oral tumorigenesis may help refine prevention and treatment strategies in patients with oral cancer.

A better understanding of the dynamics of molecular changes occurring during the early stages of oral tumorigenesis may help refine prevention and treatment strategies. We generated genome-wide expression profiles of microdissected normal mucosa, hyperplasia, dysplasia and tumors derived from the 4-NQO mouse model of oral tumorigenesis. Genes differentially expressed between tumor and normal mucosa defined the "tumor gene set" (TGS), including 4 non-overlapping gene subsets that characterize the dynamics of gene expression changes through different stages of disease progression. The majority of gene expression changes occurred early or progressively. The relevance of these mouse gene sets to human disease was tested in multiple datasets including the TCGA and the Genomics of Drug Sensitivity in Cancer project. The TGS was able to discriminate oral squamous cell carcinoma (OSCC) from normal oral mucosa in 3 independent datasets. The OSCC samples enriched in the mouse TGS displayed high frequency of CASP8 mutations, 11q13.3 amplifications and low frequency of PIK3CA mutations. Early changes observed in the 4-NQO model were associated with a trend toward a shorter oral cancer-free survival in patients with oral preneoplasia that was not seen in multivariate analysis. Progressive changes observed in the 4-NQO model were associated with an increased sensitivity to 4 different MEK inhibitors in a panel of 51 squamous cell carcinoma cell lines of the areodigestive tract. In conclusion, the dynamics of molecular changes in the 4-NQO model reveal that MEK inhibition may be relevant to prevention and treatment of a specific molecularly-defined subgroup of OSCC

The sonic hedgehog signaling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth

<p>Abstract</p> <p>Background</p> <p>Human clear cell renal cell carcinoma (CRCC) remains resistant to therapies. Recent advances in Hypoxia Inducible Factors (HIF) molecular network led to targeted therapies, but unfortunately with only limited clinical significance. Elucidating the molecular processes involved in kidney tumorigenesis and resistance is central to the development of improved therapies, not only for kidney cancer but for many, if not all, cancer types. The oncogenic PI3K/Akt, NF-kB and MAPK pathways are critical for tumorigenesis. The sonic hedgehog (SHH) signaling pathway is crucial to normal development.</p> <p>Results</p> <p>By quantitative RT-PCR and immunoblot, we report that the SHH signaling pathway is constitutively reactivated in tumors independently of the von Hippel-Lindau (VHL) tumor suppressor gene expression which is inactivated in the majority of CRCC. The inhibition of the SHH signaling pathway by the specific inhibitor cyclopamine abolished CRCC cell growth as assessed by cell counting, BrdU incorporation studies, fluorescence-activated cell sorting and β-galactosidase staining. Importantly, inhibition of the SHH pathway induced tumor regression in nude mice through inhibition of cell proliferation and neo-vascularization, and induction of apoptosis but not senescence assessed by in vivo studies, immunoblot and immunohistochemistry. Gli1, cyclin D1, Pax2, Lim1, VEGF, and TGF-β were exclusively expressed in tumors and were shown to be regulated by SHH, as evidenced by immunoblot after SHH inhibition. Using specific inhibitors and immunoblot, the activation of the oncogenic PI3K/Akt, NF-kB and MAPK pathways was decreased by SHH inhibition.</p> <p>Conclusions</p> <p>These findings support targeting SHH for the treatment of CRCC and pave the way for innovative and additional investigations in a broad range of cancers.</p

228 Blood pressure in HIV-infected patients

ObjectifveTo determine the prevalence of hypertension in a cohort of HIV-infected patients (HIV+).MethodsHIV+ patients were enrolled consecutively at ambulatory cardiology consultation. We evaluated:cardiovascular risk factors,office blood pressure,24 hours ambulatory blood pressure monitoring (ABPM).We identified patients with known hypertension, masked hypertension and white-coat effect.Results258 HIV+ patients (mean age 49±7 ans, 91% men) were consecutively included in this study between 2005 and 2009. Cardiovascular risk factors were as follows: 52% had dyslipidemia, 51% were active smokers, 40% with known hypertension and 9% were diabetics. Body mass index of the entire cohort was 24±4kg/mΣ and 89% were under antiretrovirals. Data on blood pressure are depicted in Table 1. 19% (29) were discovered to have hypertension.ConclusionHypertension is frequent in HIV-infected patients and more and more common with aging. The number of non-dipper HIV+ was high in this cohort. Studies on the impact of HIV infection and antiretrovirals on the autonomic nervous system should be performed.ParametersN=258Office systolic BP, mmHg131±19Office diastolic BP, mmHg81±10Mean 24h-systolic BP, mmHg125±13Mean 24-diastolic BP, mmHg77±9Daytime systolic BP, mmHg129±13Daytime diastolic BP, mmHg80±9Nighttime systolic BP, mmHg115±17Nighttime diastolic BP, mmHg68±10BP profile in known hypertensive patientsN=103Number of patients with appropriate BP control, %45%Number of patients with white-coat effect, %17%Non dipper, %43% in known hypertensive patients 39% in unknown hypertensive patient

High-affinity DNA binding sites for H-NS provide a molecular basis for selective silencing within proteobacterial genomes

The global transcriptional regulator H-NS selectively silences bacterial genes associated with pathogenicity and responses to environmental insults. Although there is ample evidence that H-NS binds preferentially to DNA containing curved regions, we show here that a major basis for this selectivity is the presence of a conserved sequence motif in H-NS target transcriptons. We further show that there is a strong tendency for the H-NS binding sites to be clustered, both within operons and in genes contained in the pathogenicity-associated islands. In accordance with previously published findings, we show that these motifs occur in AT-rich regions of DNA. On the basis of these observations, we propose that H-NS silences extensive regions of the bacterial chromosome by binding first to nucleating high-affinity sites and then spreading along AT-rich DNA. This spreading would be reinforced by the frequent occurrence of the motif in such regions. Our findings suggest that such an organization enables the silencing of extensive regions of the genetic material, thereby providing a coherent framework that unifies studies on the H-NS protein and a concrete molecular basis for the genetic control of H-NS transcriptional silencing

Inflammatory Properties and Adjuvant Potential of Synthetic Glycolipids Homologous to Mycolate Esters of the Cell Wall of Mycobacterium tuberculosis

&lt;p&gt;The cell wall of mycobacteria is characterised by glycolipids composed of different classes of mycolic acids (MAs; alpha-, keto-, and methoxy-) and sugars (trehalose, glucose, and arabinose). Studies using mutant Mtb strains have shown that the structure of MAs influences the inflammatory potential of these glycolipids. As mutant Mtb strains possess a complex mixture of glycolipids, we analysed the inflammatory potential of single classes of mycolate esters of the Mtb cell wall using 38 different synthetic analogues. Our results show that synthetic trehalose dimycolate (TDM) and trehalose, glucose, and arabinose monomycolates (TMM, GMM, and AraMM) activate bone marrow-derived dendritic cells in terms of the production of pro-inflammatory cytokines (IL-6 and TNF-&amp;alpha;) and reactive oxygen species, upregulation of costimulatory molecules, and activation of NLRP3 inflammasome by a mechanism dependent on Mincle. These findings demonstrate that Mincle receptor can also recognise pentose esters and seem to contradict the hypothesis that production of GMM is an escape mechanism used by pathogenic mycobacteria to avoid recognition by the innate immune system. Finally, our experiments indicate that TMM and GMM, as well as TDM, can promote Th1 and Th17 responses in mice in an OVA immunisation model, and that further analysis of their potential as novel adjuvants for subunit vaccines is warranted.&lt;/p&gt;</p

Is Impact of Statin Therapy on All-Cause Mortality Different in HIV-Infected Individuals Compared to General Population? Results from the FHDH-ANRS CO4 Cohort

French Hospital Database on HIVInternational audienceBackgroundThe effect of statins on all-cause mortality in the general population has been estimated as 0.86 (95%CI 0.79-0.94) for primary prevention. Reported values in HIV-infected individuals have been discordant. We assessed the impact of statin-based primary prevention on all-cause mortality among HIV-infected individuals.MethodsPatients were selected among controls from a multicentre nested case-control study on the risk of myocardial infarction. Patients with prior cardiovascular or cerebrovascular disorders were not eligible. Potential confounders, including variables that were associated either with statin use and/or death occurrence and statin use were evaluated within the last 3 months prior to inclusion in the case-control study. Using an intention to continue approach, multiple imputation of missing data, Cox’s proportional hazard models or propensity based weighting, the impact of statins on the 7-year all-cause mortality was evaluated.ResultsAmong 1,776 HIV-infected individuals, 138 (8%) were statins users. During a median follow-up of 53 months, 76 deaths occurred, including 6 in statin users. Statin users had more cardiovascular risk factors and a lower CD4 T cell nadir than statin non-users. In univariable analysis, the death rate was higher in statins users (11% vs 7%, HR 1.22, 95%CI 0.53-2.82). The confounders accounted for were age, HIV transmission group, current CD4 T cell count, haemoglobin level, body mass index, smoking status, anti-HCV antibodies positivity, HBs antigen positivity, diabetes and hypertension. In the Cox multivariable model the estimated hazard ratio of statin on all-cause mortality was estimated as 0.86 (95%CI 0.34-2.19) and it was 0.83 (95%CI 0.51-1.35) using inverse probability treatment weights.ConclusionThe impact of statin for primary prevention appears similar in HIV-infected individuals and in the general population

0578: Valvular atrial fibrillation and the risk of stroke and deaths: additional prognostic value of the CHA2DS2-VASc score

PurposeThe CHA2DS2-VASc score has been validated and is widely used to stratify the risk of thromboembolism in patients with non-valvular atrial fibrillation (AF). We sought to investigate whether this score could also be useful to predict the risk of stroke and death in patients with valvular AF.MethodsBetween 1998 and 2011, 1,592 consecutive patients, hospitalised for AF, 300 with valvular AF (mitral and/or aortic valve disease) and 1,292 with non-valvular AF were enrolled in the cohort. All patients were followed-up at least 6 months and cardiovascular events recorded. The end-point was defined as the first occurrence of stroke or death. The Cox analysis was adjusted on warfarin, antiplatelet and antiarrhythmic treatments at discharge.ResultsMean age was 73±14 years in valvular AF and 68±15 in non-valvular AF (p=0.0001). At baseline, in the valvular AF group CHA2DS2-VASc score were = 0 for 14 (5%) patients, = 1 for 28 (9%), ? 2 for 258 (86%). Non-valvular AF CHA2DS2-VASc scores were = 0 for 158 (12%), = 1 for 189 (15), ?2 for 945 (73%). The difference was statistically significant (p<0.0001). During a mean follow-up of 4.6±3.5 years, the patients with valvular AF experienced 154 (51%) and the patients with non-valvular AF experienced 409 (32%) strokes or deaths. The Kaplan-Meier curves (figure) show that patients with a CHA2DS2-VASc score ?2 were at higher risk of stroke or death. The adjusted Cox model, showed that valvular AF (HR, 1.57, 95%CI 1.30-1.89, p<0.0001) and a CHA2DS2-VASc score ?2 (HR, 5.30, 95%CI 3.77-7.45, p<0.0001) were predictors of risk of stroke or death.ConclusionThese results suggest that a CHA2DS2-VASc score ?2 is associated with a higher risk of stroke and deaths, at mid-term follow-up, in patients with valvular AF (figure next page).Abstract 0578 - Figure: Kaplan-Meier survival curve

Vertical Organic Electrochemical Transistors and Electronics for Low Amplitude Micro‐Organ Signals

Electrical signals are fundamental to key biological events such as brain activity, heartbeat, or vital hormone secretion. Their capture and analysis provide insight into cell or organ physiology and a number of bioelectronic medical devices aim to improve signal acquisition. Organic electrochemical transistors (OECT) have proven their capacity to capture neuronal and cardiac signals with high fidelity and amplification. Vertical PEDOT:PSS-based OECTs (vOECTs) further enhance signal amplification and device density but have not been characterized in biological applications. An electronic board with individually tuneable transistor biases overcomes fabrication induced heterogeneity in device metrics and allows quantitative biological experiments. Careful exploration of vOECT electric parameters defines voltage biases compatible with reliable transistor function in biological experiments and provides useful maximal transconductance values without influencing cellular signal generation or propagation. This permits successful application in monitoring micro-organs of prime importance in diabetes, the endocrine pancreatic islets, which are known for their far smaller signal amplitudes as compared to neurons or heart cells. Moreover, vOECTs capture their single-cell action potentials and multicellular slow potentials reflecting micro-organ organizations as well as their modulation by the physiological stimulator glucose. This opens the possibility to use OECTs in new biomedical fields well beyond their classical applications.Transistors multimodaux sensibles aux ions à polymères ambivalents pour biocapteurs hybridesCapteurs bio-électroniques intégrant l'algorithme des îlots pour le contrôle de la glycémie en boucle ouverte et fermé