DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

The impact of the demographic transition on dengue in Thailand: Insights from a statistical analysis and mathematical modeling

Background: An increase in the average age of dengue hemorrhagic fever (DHF) cases has been reported in Thailand. The cause of this increase is not known. Possible explanations include a reduction in transmission due to declining mosquito populations, declining contact between human and mosquito, and changes in reporting. We propose that a demographic shift toward lower birth and death rates has reduced dengue transmission and lengthened the interval between large epidemics. Methods and Findings: Using data from each of the 72 provinces of Thailand, we looked for associations between force of infection (a measure of hazard, defined as the rate per capita at which susceptible individuals become infected) and demographic and climactic variables. We estimated the force of infection from the age distribution of cases from 1985 to 2005. We find that the force of infection has declined by 2% each year since a peak in the late 1970s and early 1980s. Contrary to recent findings suggesting that the incidence of DHF has increased in Thailand, we find a small but statistically significant decline in DHF incidence since 1985 in a majority of provinces. The strongest predictor of the change in force of infection and the mean force of infection is the median age of the population. Using mathematical simulations of dengue transmission we show that a reduced birth rate and a shift in the population's age structure can explain the shift in the age distribution of cases, reduction of the force of infection, and increase in the periodicity of multiannual oscillations of DHF incidence in the absence of other changes. Conclusions: Lower birth and death rates decrease the flow of susceptible individuals into the population and increase the longevity of immune individuals. The increase in the proportion of the population that is immune increases the likelihood that an infectious mosquito will feed on an immune individual, reducing the force of infection. Though the force of infection has decreased by half, we find that the critical vaccination fraction has not changed significantly, declining from an average of 85% to 80%. Clinical guidelines should consider the impact of continued increases in the age of dengue cases in Thailand. Countries in the region lagging behind Thailand in the demographic transition may experience the same increase as their population ages. The impact of demographic changes on the force of infection has been hypothesized for other diseases, but, to our knowledge, this is the first observation of this phenomenon

Intra-arterial induction high-dose chemotherapy with cisplatin for oral and oropharyngeal cancer: long-term results

Intra-arterial (IA) chemotherapy for curative treatment of head and neck cancer experienced a revival in the last decade. Mainly, it was used in concurrent combination with radiation in organ-preserving settings. The modern method of transfemoral approach for catheterisation, superselective perfusion of the tumour-feeding vessel, and high-dose (150 mg m−2) administration of cisplatin with parallel systemic neutralisation with sodium thiosulphate (9 g m−2) made preoperative usage feasible. The present paper presents the results of a pilot study on a population of 52 patients with resectable stage 1–4 carcinomas of the oral cavity and the oropharynx, who were treated with one cycle of preoperative IA chemotherapy executed as mentioned above and radical surgery. There have been no interventional complications of IA chemotherapy, and acute side effects have been low. One tracheotomy had to be carried out due to swelling. The overall clinical local response has been 69%. There was no interference with surgery, which was carried out 3–4 weeks later. Pathological complete remission was assessed in 25%. The mean observation time was 3 years. A 3-year overall and disease-free survival was 82 and 69%, respectively, and at 5 years 77 and 59%, respectively. Survival results were compared to a treatment-dependent prognosis index for the same population. As a conclusion, it can be stated that IA high-dose chemotherapy with cisplatin and systemic neutralisation in a neoadjuvant setting should be considered a feasible, safe, and effective treatment modality for resectable oral and oropharyngeal cancer. The low toxicity of this local chemotherapy recommends usage especially in stage 1–2 patients. The potential of survival benefit as indicated by the comparison to the prognosis index should be controlled in a randomised study

Cancer-selective, single agent chemoradiosensitising gold nanoparticles

Two nanometre gold nanoparticles (AuNPs), bearing sugar moieties and/or thiol-polyethylene glycol-amine (PEG-amine), were synthesised and evaluated for their in vitro toxicity and ability to radiosensitise cells with 220 kV and 6 MV X-rays, using four cell lines representing normal and cancerous skin and breast tissues. Acute 3 h exposure of cells to AuNPs, bearing PEG-amine only or a 50:50 ratio of alpha-galactose derivative and PEG-amine resulted in selective uptake and toxicity towards cancer cells at unprecedentedly low nanomolar concentrations. Chemotoxicity was prevented by co-administration of N-acetyl cysteine antioxidant, or partially prevented by the caspase inhibitor Z-VAD-FMK. In addition to their intrinsic cancer-selective chemotoxicity, these AuNPs acted as radiosensitisers in combination with 220 kV or 6 MV X-rays. The ability of AuNPs bearing simple ligands to act as cancer-selective chemoradiosensitisers at low concentrations is a novel discovery that holds great promise in developing low-cost cancer nanotherapeutics

Longevity - Extending the lifespan of long-lived mice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62803/1/414412a0.pd

After surgery: the effects of life-saving caesarean sections in Burkina Faso:BMC Pregnancy Childbirth

Background In African countries, caesarean sections are usually performed to save mothers and babies’ lives, sometimes in extremis and at considerable costs. Little is known about the health and lives of women once discharged after such surgery. We investigated the long-term effects of life-saving caesarean section on health, economic and social outcomes in Burkina Faso. Methods We conducted a 4 year prospective cohort study of women and their babies using mixed methods. The quantitative sample was selected in seven hospitals and included 950 women: 100 women with a caesarean section associated with near-miss complication (life-saving caesareans); 173 women with a vaginal birth associated with near-miss complication; and 677 women with uncomplicated vaginal childbirth. Structured interviews were conducted at 3 months, 6 months, 12 months and 3 and 4 years postpartum. These were supplemented by medical record data on delivery and physical examinations at 6 and 12 months postpartum. The lives and experiences of 21 women were documented ethnographically. Data were analysed with multivariable logistic regressions, using survival analysis and thematic analysis. Results The physical effects of life-saving caesareans appeared to be similar to women who had an uncomplicated childbirth, although 55 % of women with life-saving caesareans had another caesarean in their next pregnancy. The negative effects were generally economic, social and reproductive when compared to vaginal births, including increased debts (AOR = 3.91 (1.46–10.48) and sexual violence (AOR = 4.71 (1.04–21.3)) and lower fertility (AOR = 0.44 (0.24–0.80)) 4 years after life-saving caesareans. In the short and medium term, women with life-saving caesareans appeared to suffer increased psychological distress compared to uncomplicated births. They were more likely to use contraceptives (AOR = 5.95 (1.53–23.06); 3 months). Mortality of the index child was increased in both near-miss groups, independent of delivery mode. Ethnographic data suggest that these consequences are significant for Burkinabe women, whose well-being and social standing are mostly determined by their fertility, marriage strength and family links. Conclusions Life-saving caesareans have broad consequences beyond clinical sequelae. The recent policy to subsidise emergency obstetric care costs implemented in Burkina Faso should help avoid the majority of catastrophic costs, shown to be problematic for women undergoing emergency caesarean section

Ezrin interacts with the SARS coronavirus spike protein and restrains infection at the entry stage

© 2012 Millet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Entry of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and its envelope fusion with host cell membrane are controlled by a series of complex molecular mechanisms, largely dependent on the viral envelope glycoprotein Spike (S). There are still many unknowns on the implication of cellular factors that regulate the entry process. Methodology/Principal Findings: We performed a yeast two-hybrid screen using as bait the carboxy-terminal endodomain of S, which faces the cytosol during and after opening of the fusion pore at early stages of the virus life cycle. Here we show that the ezrin membrane-actin linker interacts with S endodomain through the F1 lobe of its FERM domain and that both the eight carboxy-terminal amino-acids and a membrane-proximal cysteine cluster of S endodomain are important for this interaction in vitro. Interestingly, we found that ezrin is present at the site of entry of S-pseudotyped lentiviral particles in Vero E6 cells. Targeting ezrin function by small interfering RNA increased S-mediated entry of pseudotyped particles in epithelial cells. Furthermore, deletion of the eight carboxy-terminal amino acids of S enhanced S-pseudotyped particles infection. Expression of the ezrin dominant negative FERM domain enhanced cell susceptibility to infection by SARS-CoV and S pseudotyped particles and potentiated S-dependent membrane fusion. Conclusions/Significance: Ezrin interacts with SARS-CoV S endodomain and limits virus entry and fusion. Our data present a novel mechanism involving a cellular factor in the regulation of S-dependent early events of infection.This work was supported by the Research Grant Council of Hong Kong (RGC#760208)and the RESPARI project of the International Network of Pasteur Institutes

Qualidade dos frutos de variedades de videira do Banco Ativo de Germoplasma da Embrapa Semiárido.

O objetivo deste trabalho foi caracterizar a qualidade de uvas tintas para consumo in natura e para processamento, conservadas no Banco Ativo de Germoplasma (BAG) de videira da Embrapa Semiárido

Stakeholder perceptions of mental health stigma and poverty in Uganda

<p>Abstract</p> <p>Background</p> <p>World wide, there is plentiful evidence regarding the role of stigma in mental illness, as well as the association between poverty and mental illness. The experiences of stigma catalyzed by poverty revolve around experiences of devaluation, exclusion, and disadvantage. Although the relationship between poverty, stigma and mental illness has been documented in high income countries, little has been written on this relationship in low and middle income countries.</p> <p>The paper describes the opinions of a range of mental health stakeholders regarding poverty, stigma, mental illness and their relationship in the Ugandan context, as part of a wider study, aimed at exploring policy interventions required to address the vicious cycle of mental ill-health and poverty.</p> <p>Methods</p> <p>Semi-structured interviews and focus group discussions (FGDs) were conducted with purposefully selected mental health stakeholders from various sectors. The interviews and FGDs were audio-recorded, and transcriptions were coded on the basis of a pre-determined coding frame. Thematic analysis of the data was conducted using NVivo7, adopting a framework analysis approach.</p> <p>Results</p> <p>Most participants identified a reciprocal relationship between poverty and mental illness. The stigma attached to mental illness was perceived as a common phenomenon, mostly associated with local belief systems regarding the causes of mental illness. Stigma associated with both poverty and mental illness serves to reinforce the vicious cycle of poverty and mental ill-health. Most participants emphasized a relationship between poverty and internalized stigma among people with mental illness in Uganda.</p> <p>Conclusion</p> <p>According to a range of mental health stakeholders in Uganda, there is a strong interrelationship between poverty, stigma and mental illness. These findings re-affirm the need to recognize material resources as a central element in the fight against stigma of mental illness, and the importance of stigma reduction programmes in protecting the mentally ill from social isolation, particularly in conditions of poverty.</p