Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas.

Non-coding microRNAs (miRs) are a vital component of post-transcriptional modulation of protein expression and, like coding mRNAs harbour oncogenic properties. However, the mechanisms governing miR expression and the identity of the affected transcripts remain poorly understood. Here we identify the inositol phosphatase SHIP1 as a bonafide target of the oncogenic miR-155. We demonstrate that in diffuse large B cell lymphoma (DLBCL) elevated levels of miR-155, and consequent diminished SHIP1 expression are the result of autocrine stimulation by the pro-inflammatory cytokine tumour necrosis factor a (TNFalpha). Anti-TNFalpha regimen such as eternacept or infliximab were sufficient to reduce miR-155 levels and restored SHIP1 expression in DLBCL cells with an accompanying reduction in cell proliferation. Furthermore, we observed a substantial decrease in tumour burden in DLBCL xenografts in response to eternacept. These findings strongly support the concept that cytokine-regulated miRs can function as a crucial link between inflammation and cancer, and illustrate the feasibility of anti-TNFalpha therapy as a novel and immediately accessible (co)treatment for DLBCL

Human behavior as origin of traffic phases

It is shown that the desire for smooth and comfortable driving is directly responsible for the occurrence of complex spatio-temporal structures (``synchronized traffic'') in highway traffic. This desire goes beyond the avoidance of accidents which so far has been the main focus of microscopic modeling and which is mainly responsible for the other two phases observed empirically, free flow and wide moving jams. These features have been incorporated into a microscopic model based on stochastic cellular automata and the results of computer simulations are compared with empirical data. The simple structure of the model allows for very fast implementations of realistic networks. The level of agreement with the empirical findings opens new perspectives for reliable traffic forecasts.Comment: 4 pages, 4 figures, colour figures with reduced resolutio

Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases

Mice lacking both PTEN and SHIP phosphatases develop spontaneous B cell lymphoma

Water safety plans and climate change mitigation

[Excerpt] Definition Quality water at affordable prices for all is a key condition for the promotion of public health, environmental sustainability, and quality and safety of life. In a context of growing external uncertainties arising from changes in the climate and the environment, ensuring these conditions is an upward concern and is of utmost relevance to increase scientific research on the impacts of climate change on water quality modification and in minimization/mitigation strategies

Complement C3d Conjugation to Anthrax Protective Antigen Promotes a Rapid, Sustained, and Protective Antibody Response

B. anthracis is the causative agent of anthrax. Pathogenesis is primarily mediated through the exotoxins lethal factor and edema factor, which bind protective antigen (PA) to gain entry into the host cell. The current anthrax vaccine (AVA, Biothrax™) consists of aluminum-adsorbed cell-free filtrates of unencapsulated B. anthracis, wherein PA is thought to be the principle target of neutralization. In this study, we evaluated the efficacy of the natural adjuvant, C3d, versus alum in eliciting an anti-PA humoral response and found that C3d conjugation to PA and emulsion in incomplete Freund's adjuvant (IFA) imparted superior protection from anthrax challenge relative to PA in IFA or PA adsorbed to alum. Relative to alum-PA, immunization of mice with C3d-PA/IFA augmented both the onset and sustained production of PA-specific antibodies, including neutralizing antibodies to the receptor-binding portion (domain 4) of PA. C3d-PA/IFA was efficacious when administered either i.p. or s.c., and in adolescent mice lacking a fully mature B cell compartment. Induction of PA-specific antibodies by C3d-PA/IFA correlated with increased efficiency of germinal center formation and plasma cell generation. Importantly, C3d-PA immunization effectively protected mice from intranasal challenge with B. anthracis spores, and was approximately 10-fold more effective than alum-PA immunization or PA/IFA based on dose challenge. These data suggest that incorporation of C3d as an adjuvant may overcome shortcomings of the currently licensed aluminum-based vaccine, and may confer protection in the early days following acute anthrax exposure

Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma

We have recently described the enzymatic subunit of telomerase (hTERT) as an important prognostic marker for paediatric ependymoma. Because of the lack of good, representative pre-clinical models for ependymoma, we took advantage of our large cohort of ependymoma patients, some with multiple recurrences, to investigate telomere biology in these tumours. Our cohort consisted of 133 ependymomas from 83 paediatric patients and included 31 patients with recurrences. Clinical outcome was measured as overall survival, progression-free survival and response to therapy. In all 133 tumours, hTERT expression correlated with proliferative markers, including MIB-1 index (P<0.0001) and mitotic index (P=0.005), as well as overall tumour grade (P=0.001), but not with other markers of anaplasia. There was no correlation between telomere length and hTERT expression or survival. Surprisingly, prior radiation or chemotherapy neither induced sustained DNA damage nor affected telomere maintenance in recurrent tumours. There was an inverse correlation between hTERT expression and telomere dysfunction as measured by γH2AX expression (P=0.016). Combining γH2AX and hTERT expressions could segregate tumours into three different survival groups (log rank, P<0.0001) such that those patients whose tumours expressed hTERT and showed no evidence of DNA damage had the worst outcome. This study emphasises the importance of telomere biology as a prognostic tool and telomerase inhibition as a therapeutic target for paediatric ependymoma. Furthermore, we have demonstrated that analysing tumours as they progress in vivo is a viable approach to studying tumour biology in humans

Evaluation of a school-based HIV prevention intervention among Yemeni adolescents

<p>Abstract</p> <p>Background</p> <p>This article describes an evaluation of a school-based peer education intervention for HIV prevention among students in twenty seven high schools in Aden, Yemen. The intervention was developed after a survey among the same population in 2005, which revealed a high level of stigma towards people living with HIV (PLWH) and a low level of HIV knowledge.</p> <p>Methods</p> <p>In a quasi-experimental design students who received the peer education intervention (78.6%) were compared with students who did not receive the intervention (21.4%). No systematic procedure was applied in selecting students for the intervention condition. Data were collected using a self-administered questionnaire from a sample of 2510 students from all 27 high-schools in Aden governorate. To increase internal validity, students were also compared with a cohort control sample surveyed in 2005, which was a random sample of 2274 students from the same schools.</p> <p>Results</p> <p>Sixty eight percent of students targeted by peer education had good knowledge scores, compared with 43.3% of students not targeted by peer education (χ²= (df = 1) = 111.15, p < .01). Multi-level regression analysis revealed that, although there was a significant difference among schools, the intervention effect of peer education at the individual level was significant; students who received peer education had a statistically higher knowledge score(9.24 out of 12.0) compared with those not targeted (7.89 out of 12.0), OR = 2.11, 95% CI = 1.04-4.27, p < .05). Compared with the 2005 cohort control sample, students targeted by peer education had better knowledge on the modes of transmission and prevention and fewer misconceptions; and knowledge on the use of condoms increased from 49.4% to 67.8%. In addition, students who received the peer education interventions suggested significantly more actions to provide care and support for PLWH. Also, the levels of stigma and discrimination were much higher among the 2005 cohort control group, compared with those who received the peer education intervention.</p> <p>Conclusion</p> <p>The school-based peer education intervention has succeeded in improving levels of knowledge on modes of transmission and prevention, and in decreasing levels of stigma and discrimination in a culturally conservative setting.</p

Malignant germ cell tumours of childhood: new associations of genomic imbalance

Malignant germ cell tumours (MGCTs) of childhood are a rare group of neoplasms that comprise many histological subtypes and arise at numerous different sites. Genomic imbalances have been described in these tumours but, largely because of the paucity of cases reported in the literature, it is unclear how they relate to abnormalities in adult MGCTs and impact on potential systems for classifying GCTs. We have used metaphase-based comparative genomic hybridisation to analyse the largest series of paediatric MGCTs reported to date, representing 34 primary tumours (22 yolk sac tumours (YSTs), 11 germinomatous tumours and one metastatic embryonal carcinoma) occurring in children from birth to age 16, including 17 ovarian MGCTs. The large dataset enabled us to undertake statistical analysis, with the aim of identifying associations worthy of further investigation between patterns of genomic imbalance and clinicopathological parameters. The YSTs showed an increased frequency of 1p- (P=0.003), 3p+ (P=0.02), 4q− (P=0.07) and 6q− (P=0.004) compared to germinomatous tumours. Gain of 12p, which is invariably seen in adult MGCTs, was present in 53% of primary MGCTs of children aged 5–16 and was also observed in four of 14 YSTs affecting children less than 5. Two of these cases (14% of MGCTs in children less than 5) showed gain of the 12p11 locus considered to be particularly relevant in adult MGCTs. Gain of 12p showed a significant association with gain of 12q. Conversely, MGCTs without 12p gain displayed a significantly increased frequency of loss on 16p (P=0.04), suggesting that this imbalance may contribute to tumour development in such cases. This data provides new insight into the biology of this under-investigated tumour group and will direct future studies on the significance of specific genetic abnormalities