Interfering with inflammation: a new strategy to block breast cancer self-renewal and progression?

Two recent studies show that epigenetics and inflammation play a relevant role in the regulation of transformation and cancer cell self-renewal in breast tumours, opening up the possibility that cancer progression can be controlled by interfering with inflammation cascades. Struhl's group showed that transient activation of the Src oncoprotein induces transformation and self-renewal of immortal cells via an epigenetic switch involving NF-κB, Lin28, Let-7 microRNA and IL-6. Concomitantly, Wicha's laboratory developed a strategy to selectively target cancer stem cells, retarding tumour growth and reducing metastasis by blocking the IL-8 receptor CXCR1 using either an inhibitor, repertaxin or a specific blocking antibody

Informing patients of familial diabetes mellitus risk: How do they respond? A cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>A strong family history of type 2 diabetes mellitus (DM) confers increased DM risk. This survey analysis determined whether patients who were informed by their doctors of familial DM risk acknowledged that risk and took steps to reduce it.</p> <p>Methods</p> <p>We conducted an analysis of the National <it>Health Styles 2004 </it>mail survey. All non-diabetic participants who responded to the question of whether their doctor had or had not informed them of their familial DM risk (<it>n </it>= 3,323) were compared for their risk-reducing behaviour and attitude to DM risk.</p> <p>Results</p> <p>Forty-one percent (<it>n </it>= 616) of the question responders that had DM family histories were informed by their doctors of their familial risk; the chance of being informed increased with the number of relatives that had the disease. Members of the informed group were more likely than those in the non-informed group to report lifestyle changes to prevent DM (odds ratio [OR] 4.3, 95% confidence interval [CI] 3.5–5.2) and being tested for DM (OR 2.9, 95% CI 2.4–3.6), although no significant improvement occurred in their U.S.-recommended exercise activity (OR 0.9, 95% CI 0.7–1.1). Overall, informed responders recognised both their familial and personal DM risk; most discussed diabetes with their family (69%), though less so with friends (42%); however, 44% of them still did not consider themselves to be at risk.</p> <p>Conclusion</p> <p>Responders who were informed by their doctors of being at familial DM risk reported greater incidences of lifestyle changes, DM screening, and awareness of risk than non-informed responders. Doctors were more likely to inform patients with stronger DM family histories. Identifying this higher risk group, either in isolation or in combination with other recognised risk factors, offers doctors the opportunity to target limited health promotion resources efficiently for primary DM prevention.</p

Recent Food Shortage Is Associated with Leprosy Disease in Bangladesh: A Case-Control Study

Although intensive control programs reduced the prevalence of leprosy worldwide, new cases of this infectious disease are still detected in several of the poorest areas of the world. Therefore the disease is known as a disease of poverty. To be able to control the disease it is important to know which aspects of poverty play a role in transmission and acquiring clinical signs of disease. In this study socio-economic circumstances of recently diagnosed leprosy patients were compared with those of a control population in the poverty stricken northwest area of Bangladesh where leprosy is common. A recent period of food shortage was the only socio-economic factor that was found related to leprosy disease in this study and not poverty as such. Food shortage is seasonal and poverty related in northwest Bangladesh, while malnutrition is known to lower immunity and make people more vulnerable to infectious diseases. Therefore it was concluded that malnutrition as an aspect of poverty played an important role in the development of the clinical signs of leprosy. We therefore recommend that nutritional support for high risk groups should be included in leprosy control programmes to reduce risk of disease in areas where leprosy is common

DiAlert: a lifestyle education programme aimed at people with a positive family history of type 2 diabetes and overweight, study protocol of a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Family history is a known risk factor for type 2 diabetes (T2DM), and more so in the presence of overweight. This study aims to develop and evaluate the effectiveness of a new lifestyle education programme 'DiAlert' targeted at 1st degree relatives of people with T2DM and overweight. In view of the high risk for diabetes and cardiovascular disease in immigrants from Turkish origin living in Western Europe, a culturally appropriate Turkish version of DiAlert will be developed and tested.</p> <p>Methods/design</p> <p>In this RCT, 268 (134 Dutch and 134 Turkish) overweight 1st degree relatives of patients with T2DM will be allocated to either the intervention or control group (leaflet). The intervention DiAlert aims to promote intrinsic motivation to change lifestyle, and sustain achieved behaviour changes during follow-up. Primary outcome is weight loss. Secondary outcomes include biological, behavioural and psychological indices, along with process indicators. Measurements will take place at baseline and after 3 and 9 months. Changes in outcomes are tested between intervention and control group at 3 months; effects over time are tested within and between both ethnic groups at 3 and 9 months.</p> <p>Discussion</p> <p>The DiAlert intervention is expected to be more effective than the control condition in achieving significant weight loss at 3 months, in both Dutch and Turkish Dutch participants.</p> <p>Trial registration</p> <p>Netherlands National Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2036">NTR2036</a></p

Beta-HPV E6 Contributes To Skin Cancer by Hindering DNA Repair

<div><p>Recent work has explored a putative role for the E6 protein from some β-human papillomavirus genus (β-HPVs) in the development of non-melanoma skin cancers, specifically β-HPV 5 and 8 E6. Because these viruses are not required for tumor maintenance, they are hypothesized to act as co-factors that enhance the mutagenic capacity of UV-exposure by disrupting the repair of the resulting DNA damage. Supporting this proposal, we have previously demonstrated that UV damage signaling is hindered by β-HPV 5 and 8 E6 resulting in an increase in both thymine dimers and UV-induced double strand breaks (DSBs). Here we show that β-HPV 5 and 8 E6 further disrupt the repair of these DSBs and provide a mechanism for this attenuation. By binding and destabilizing a histone acetyltransferase, p300, β-HPV 5 and 8 E6 reduce the enrichment of the transcription factor at the promoter of two genes critical to the homology dependent repair of DSBs (BRCA1 and BRCA2). The resulting diminished BRCA1/2 transcription not only leads to lower protein levels but also curtails the ability of these proteins to form repair foci at DSBs. Using a GFP-based reporter, we confirm that this reduced foci formation leads to significantly diminished homology dependent repair of DSBs. By deleting the p300 binding domain of β-HPV 8 E6, we demonstrate that the loss of robust repair is dependent on viral-mediated degradation of p300 and confirm this observation using a combination of p300 mutants that are β-HPV 8 E6 destabilization resistant and p300 knock-out cells. In conclusion, this work establishes an expanded ability of β-HPV 5 and 8 E6 to attenuate UV damage repair, thus adding further support to the hypothesis that β-HPV infections play a role in skin cancer development by increasing the oncogenic potential of UV exposure.</p></div

Multi-species sequence comparison reveals dynamic evolution of the elastin gene that has involved purifying selection and lineage-specific insertions/deletions

BACKGROUND: The elastin gene (ELN) is implicated as a factor in both supravalvular aortic stenosis (SVAS) and Williams Beuren Syndrome (WBS), two diseases involving pronounced complications in mental or physical development. Although the complete spectrum of functional roles of the processed gene product remains to be established, these roles are inferred to be analogous in human and mouse. This view is supported by genomic sequence comparison, in which there are no large-scale differences in the ~1.8 Mb sequence block encompassing the common region deleted in WBS, with the exception of an overall reversed physical orientation between human and mouse. RESULTS: Conserved synteny around ELN does not translate to a high level of conservation in the gene itself. In fact, ELN orthologs in mammals show more sequence divergence than expected for a gene with a critical role in development. The pattern of divergence is non-conventional due to an unusually high ratio of gaps to substitutions. Specifically, multi-sequence alignments of eight mammalian sequences reveal numerous non-aligning regions caused by species-specific insertions and deletions, in spite of the fact that the vast majority of aligning sites appear to be conserved and undergoing purifying selection. CONCLUSIONS: The pattern of lineage-specific, in-frame insertions/deletions in the coding exons of ELN orthologous genes is unusual and has led to unique features of the gene in each lineage. These differences may indicate that the gene has a slightly different functional mechanism in mammalian lineages, or that the corresponding regions are functionally inert. Identified regions that undergo purifying selection reflect a functional importance associated with evolutionary pressure to retain those features

Factors affecting the motivation of healthcare professionals providing care to Emiratis with type 2 diabetes

OBJECTIVE: We aimed to identify facilitators of and barriers to healthcare professionals' motivation in a diabetes centre in the United Arab Emirates (UAE). DESIGN: A qualitative research approach was employed using semistructured interviews to assess perception of and attitudes regarding healthcare professionals' motivation in providing good quality diabetes care. SETTING: A diabetes centre located in Abu-Dhabi, UAE. PARTICIPANTS: Healthcare professionals including specialist physicians, dieticians, podiatrists, health educators and nurses were recruited through purposive sampling. MAIN OUTCOME MEASURES: After data collection, the audiotaped interviews were transcribed verbatim and subjected to content analysis. RESULTS: Nine semistructured interviews were conducted with healthcare professionals of various professional backgrounds. Important facilitators and barriers related to patient, professional, organization and cultural factors were identified. Barriers that related to heavy workload, disjointed care, lack of patient compliance and awareness, and cultural beliefs and attitudes about diabetes were common. Key facilitators included the patient's role in achieving therapeutic outcomes as well as compliance, cooperation and communication. CONCLUSION: This qualitative study provides some unique insights about factors affecting healthcare professionals' motivation in providing good quality care. To improve the motivation of healthcare professionals in the management of diabetes and therefore the quality of diabetes care, several steps are needed. Importantly, the role of primary care should be reinforced and strengthened regarding the management of type 2 diabetes mellitus, privacy of the consultation time should be highly protected and regulated, and awareness of the Emirate culture and its impact on health should be disseminated to the healthcare professionals providing care to Emirates with diabetes. Also, greater emphasis should be placed on educating Emiratis with diabetes on, and involving them in, the management of their condition

9-Genes Reinforce the Phylogeny of Holometabola and Yield Alternate Views on the Phylogenetic Placement of Strepsiptera

Background: The extraordinary morphology, reproductive and developmental biology, and behavioral ecology of twisted wing parasites (order Strepsiptera) have puzzled biologists for centuries. Even today, the phylogenetic position of these enigmatic “insects from outer space” [1] remains uncertain and contentious. Recent authors have argued for the placement of Strepsiptera within or as a close relative of beetles (order Coleoptera), as sister group of flies (order Diptera), or even outside of Holometabola.Methodology/Principal Findings Here, we combine data from several recent studies with new data (for a total of 9 nuclear genes and ∼13 kb of aligned data for 34 taxa), to help clarify the phylogenetic placement of Strepsiptera. Our results unequivocally support the monophyly of Neuropteroidea ( = Neuropterida + Coleoptera) + Strepsiptera, but recover Strepsiptera either derived from within polyphagan beetles (order Coleoptera), or in a position sister to Neuropterida. All other supra-ordinal- and ordinal-level relationships recovered with strong nodal support were consistent with most other recent studies. Conclusions/Significance: These results, coupled with the recent proposed placement of Strepsiptera sister to Coleoptera, suggest that while the phylogenetic neighborhood of Strepsiptera has been identified, unequivocal placement to a specific branch within Neuropteroidea will require additional study.Organismic and Evolutionary Biolog

A parathyroid-hormone-related-protein (PTH-rP)-specific cytotoxic T cell response induced by in vitro stimulation of tumour-infiltrating lymphocytes derived from prostate cancer metastases, with epitope peptide-loaded autologous dendritic cells and low-dose IL-2

Bone metastases are one of the most common events in patients with prostate carcinoma. PTH-rP, a protein produced by prostate carcinoma and other epithelial cancers, is a key agent for the development of bone metastases. A PTH-rP-derived peptide, designated PTR-4 was identified, which is capable to bind HLA-A2.1 molecules and to generate PTH-rP-specific cytotoxic T cell (CTL) lines from healthy HLA-A2.1+ individual peripheral-blood-mononuclear-cells (PBMC). In this model, we investigated the in vitro possibility of generating an efficient PTH-rP specific CTL response by cyclical stimulations with IL-2 and PTR-4 peptide-pulsed autologous dendritic cells (DC), of HLA-A2.1+ tumour infiltrating lymphocytes (TIL) derived from a patient with metastatic prostate carcinoma. A T cell line generated in this way (called TM-PTR-4) had a CD3+, CD5+, CD4−, CD8+, CD45Ro+, CD56− immunophenotype and a HLA-A2.1 restricted cytotoxic activity to PTR-4-peptide pulsed CIR-A2 (HLA-A2.1+) target cells, PTH-rP+/HLA-A2.1+ CIR-A2 transfected with PTH-rP gene, prostate carcinoma LNCaP cells, and autologous metastatic prostate cancer cells (M-CaP). These lymphocytes were not cytotoxic to HLA-A2.1+ targets not producing PTH-rP, such as peptide-unpulsed CIR-A2 and colon carcinoma SW-1463, cell lines. Our results provide evidence that PTR-4 peptide-pulsed autologous DC may break the tolerance of human TIL against the autologous tumour by inducing a PTH-rP-specific CTL immune reaction. In conclusion PTR-4 peptide-pulsed autologous DC may be a promising approach for vaccine-therapy and antigen-specific CTL adoptive immunotherapy of hormone-resistant prostrate cancer. © 2001 Cancer Research Campaign http://www.bjcancer.co