Radiosensitization by BRAF inhibitor therapy—mechanism and frequency of toxicity in melanoma patients

This study shows radiosensitization by BRAF inhibitors in clinical practice and ex vivo by fluorescence in situ hybridization of chromosomal breaks. Nevertheless, radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib in both the patient study and the ex vivo experiment

A systematic review of natural health product treatment for vitiligo

<p>Abstract</p> <p>Background</p> <p>Vitiligo is a hypopigmentation disorder affecting 1 to 4% of the world population. Fifty percent of cases appear before the age of 20 years old, and the disfigurement results in psychiatric morbidity in 16 to 35% of those affected.</p> <p>Methods</p> <p>Our objective was to complete a comprehensive, systematic review of the published scientific literature to identify natural health products (NHP) such as vitamins, herbs and other supplements that may have efficacy in the treatment of vitiligo. We searched eight databases including MEDLINE and EMBASE for vitiligo, leucoderma, and various NHP terms. Prospective controlled clinical human trials were identified and assessed for quality.</p> <p>Results</p> <p>Fifteen clinical trials were identified, and organized into four categories based on the NHP used for treatment. 1) L-phenylalanine monotherapy was assessed in one trial, and as an adjuvant to phototherapy in three trials. All reported beneficial effects. 2) Three clinical trials utilized different traditional Chinese medicine products. Although each traditional Chinese medicine trial reported benefit in the active groups, the quality of the trials was poor. 3) Six trials investigated the use of plants in the treatment of vitiligo, four using plants as photosensitizing agents. The studies provide weak evidence that photosensitizing plants can be effective in conjunction with phototherapy, and moderate evidence that <it>Ginkgo biloba </it>monotherapy can be useful for vitiligo. 4) Two clinical trials investigated the use of vitamins in the therapy of vitiligo. One tested oral cobalamin with folic acid, and found no significant improvement over control. Another trial combined vitamin E with phototherapy and reported significantly better repigmentation over phototherapy only. It was not possible to pool the data from any studies for meta-analytic purposes due to the wide difference in outcome measures and poor quality ofreporting.</p> <p>Conclusion</p> <p>Reports investigating the efficacy of NHPs for vitiligo exist, but are of poor methodological quality and contain significant reporting flaws. L-phenylalanine used with phototherapy, and oral <it>Ginkgo biloba </it>as monotherapy show promise and warrant further investigation.</p

Ginkgo biloba for the treatment of vitilgo vulgaris: an open label pilot clinical trial

<p>Abstract</p> <p>Background</p> <p>Vitiligo is a common hypopigmentation disorder with significant psychological impact if occurring before adulthood. A pilot clinical trial to determine the feasibility of an RCT was conducted and is reported here.</p> <p>Methods</p> <p>12 participants 12 to 35 years old were recruited to a prospective open-label pilot trial and treated with 60 mg of standardized <it>G. biloba </it>two times per day for 12 weeks. The criteria for feasibility included successful recruitment, 75% or greater retention, effectiveness and lack of serious adverse reactions. Effectiveness was assessed using the Vitiligo Area Scoring Index (VASI) and the Vitiligo European Task Force (VETF), which are validated outcome measures evaluating the area and intensity of depigmentation of vitiligo lesions. Other outcomes included photographs and adverse reactions. Safety was assessed by serum coagulation factors (platelets, PTT, INR) at baseline and week 12.</p> <p>Results</p> <p>After 2 months of recruitment, the eligible upper age limit was raised from 18 to 35 years of age in order to facilitate recruitment of the required sample size. Eleven participants completed the trial with 85% or greater adherence to the protocol. The total VASI score improved by 0.5 (P = 0.021) from 5.0 to 4.5, range of scale 0 (no depigmentation) to 100 (completely depigmented). The progression of vitiligo stopped in all participants; the total VASI indicated an average repigmentation of vitiligo lesions of 15%. VETF total vitiligo lesion area decreased 0.4% (P = 0.102) from 5.9 to 5.6 from baseline to week 12. VETF staging score improved by 0.7 (P = 0.101) from 6.6 to 5.8, and the VETF spreading score improved by 3.9 (P < 0.001)) from 2.7 to -1.2. There were no statistically significant changes in platelet count, PTT, or INR.</p> <p>Conclusions</p> <p>The criteria for feasibility were met after increasing the maximum age limit of the successful recruitment criterion; participant retention, safety and effectiveness criteria were also met. Ingestion of 60 mg of <it>Ginkgo biloba </it>BID was associated with a significant improvement in total VASI vitiligo measures and VETF spread, and a trend towards improvement on VETF measures of vitiligo lesion area and staging. Larger, randomized double-blind clinical studies are warranted and appear feasible.</p> <p>Trial Registration</p> <p>Clinical trials.gov registration number <a href="http://www.clinicaltrials.gov/ct2/show/NCT00907062">NCT00907062</a></p

An argument against the focus on Community Resilience in Public Health

Background - It has been suggested that Public Health professionals focus on community resilience in tackling chronic problems, such as poverty and deprivation; is this approach useful? Discussion - Resilience is always i) of something ii) to something iii) to an endpoint, as in i) a rubber ball, ii) to a blunt force, iii) to its original shape. “Community resilience” might be: of a neighbourhood, to a flu pandemic, with the endpoint, to return to normality. In these two examples, the endpoint is as-you-were. This is unsuitable for some examples of resilience. A child that is resilient to an abusive upbringing has an endpoint of living a happy life despite that upbringing: this is an as-you-should-be endpoint. Similarly, a chronically deprived community cannot have the endpoint of returning to chronic deprivation: so what is its endpoint? Roughly, it is an as-you-should-be endpoint: to provide an environment for inhabitants to live well. Thus resilient communities will be those that do this in the face of challenges. How can they be identified? One method uses statistical outliers, neighbourhoods that do better than would be expected on a range of outcomes given a range of stressors. This method tells us that a neighbourhood is resilient but not why it is. In response, a number of researchers have attributed characteristics to resilient communities; however, these generally fail to distinguish characteristics of a good community from those of a resilient one. Making this distinction is difficult and we have not seen it successfully done; more importantly, it is arguably unnecessary. There already exist approaches in Public Health to assessing and developing communities faced with chronic problems, typically tied to notions such as Social Capital. Communityresilience to chronic problems, if it makes sense at all, is likely to be a property that emerges from the various assets in a community such as human capital, built capital and natural capital. Summary - Public Health professionals working with deprived neighbourhoods would be better to focus on what neighbourhoods have or could develop as social capital for living well, rather than on the vague and tangential notion of community resilience.</p

Identification of a gene signature for discriminating metastatic from primary melanoma using a molecular interaction network approach

Understanding the biological factors that are characteristic of metastasis in melanoma remains a key approach to improving treatment. In this study, we seek to identify a gene signature of metastatic melanoma. We configured a new network-based computational pipeline, combined with a machine learning method, to mine publicly available transcriptomic data from melanoma patient samples. Our method is unbiased and scans a genome-wide protein-protein interaction network using a novel formulation for network scoring. Using this, we identify the most influential, differentially expressed nodes in metastatic as compared to primary melanoma. We evaluated the shortlisted genes by a machine learning method to rank them by their discriminatory capacities. From this, we identified a panel of 6 genes, ALDH1A1, HSP90AB1, KIT, KRT16, SPRR3 and TMEM45B whose expression values discriminated metastatic from primary melanoma (87% classification accuracy). In an independent transcriptomic data set derived from 703 primary melanomas, we showed that all six genes were significant in predicting melanoma specific survival (MSS) in a univariate analysis, which was also consistent with AJCC staging. Further, 3 of these genes, HSP90AB1, SPRR3 and KRT16 remained significant predictors of MSS in a joint analysis (HR = 2.3, P = 0.03) although, HSP90AB1 (HR = 1.9, P = 2 × 10−4) alone remained predictive after adjusting for clinical predictors

Original article title: "Comparison of therapeutic efficacy of topical corticosteroid and oral zinc sulfate-topical corticosteroid combination in the treatment of vitiligo patients: a clinical trial"

<p>Abstract</p> <p>Background</p> <p>Vitiligo is the most prevalent pigmentary disorder which occurs worldwide, with an incidence rate between 0.1-4 percent. It is anticipated that the discovery of biological pathways of vitiligo pathogenesis will provide novel therapeutic and prophylactic targets for future approaches to the treatment and prevention of vitiligo. The purposes of this study were evaluating the efficacy of supplemental zinc on the treatment of vitiligo.</p> <p>Methods</p> <p>This randomized clinical trial was conducted for a period of one year. Thirty five patients among 86 participants were eligible to entrance to the study. The patients in two equal randomized groups took topical corticosteroid and combination of oral zinc sulfate-topical corticosteroid.</p> <p>Results</p> <p>The mean of responses in the corticosteroid group and the zinc sulfate-corticosteroid combination group were 21.43% and 24.7%, respectively.</p> <p>Conclusion</p> <p>Although, the response to corticosteroid plus zinc sulfate was more than corticosteroid, there was no statistically significant difference between them. It appeared that more robust long-term randomized controlled trials on more patients, maybe with higher doses of zinc sulfate, are needed to fully establish the efficacy of oral zinc in management of vitiligo.</p> <p>Trial Registration</p> <p>chiCTRTRC10000930</p

A Novel Therapy for Melanoma Developed in Mice: Transformation of Melanoma into Dendritic Cells with Listeria monocytogenes

Listeria monocytogenes is a gram-positive bacteria and human pathogen widely used in cancer immunotherapy because of its capacity to induce a specific cytotoxic T cell response in tumours. This bacterial pathogen strongly induces innate and specific immunity with the potential to overcome tumour induced tolerance and weak immunogenicity. Here, we propose a Listeria based vaccination for melanoma based in its tropism for these tumour cells and its ability to transform in vitro and in vivo melanoma cells into matured and activated dendritic cells with competent microbicidal and antigen processing abilities. This Listeria based vaccination using low doses of the pathogen caused melanoma regression by apoptosis as well as bacterial clearance. Vaccination efficacy is LLO dependent and implies the reduction of LLO-specific CD4+ T cell responses, strong stimulation of innate pro-inflammatory immune cells and a prevalence of LLO-specific CD8+ T cells involved in tumour regression and Listeria elimination. These results support the use of low doses of pathogenic Listeria as safe melanoma therapeutic vaccines that do not require antibiotics for bacterial removal

ASHTABULA SUCCESSES--MACRO NOW OR FOREVER HOLD YOUR PIECES!

As facility demolition and remediation continued at the DOE Ashtabula Environmental Management Project (AEMP), a DOE closure site located in Ashtabula, OH, the quantity of mixed waste increased by approximately twenty-fold from the original Site Treatment Plan estimates to over 567 m3 (20,000 cubic feet). Also, a greater variety of low-level mixed waste (MW) was identified that was suitable for alternate debris treatment like macroencapsulation (MACRO) instead of traditional shredding, stabilization, and solidification to improve the overall safety and cost-effectiveness. Macroencapsulation is required for lead and authorized for hazardous debris under the alternate debris treatment standards per 40 CFR 268.45. Several polymer encapsulation processes were being explored, developed, and deployed in the mid-1990's by various groups including the DOE Mixed Waste Focus Area, DOE EM-50 Office of Science and Technology, Brookhaven National Laboratory, DOE Macro Working Group, DOE-Albuquerque Mixed Waste/Mobile Treatment Unit, and Envirocare of Utah, Inc. As a result, technically-proven macroencapsulation and microencapsulation processes using extruded polyethylene beads were verified as being technically acceptable for waste treatment to RCRA standards. The AEMP had a variety of waste forms where technically-proven systems were needed to perform on-site treatment of challenging mixed wastes (MW) from production operations (i.e. HEPA filters, barium salt contaminated steel) containing high concentrations of enriched uranium, graphite, salts, and RCRA metals. The AEMP continued with a technology development and deployment process to license, permit, install, and safely operate two proven polymer encapsulation systems for both RCRA microencapsulation and RCRA macroencapsulation using surplus DOE equipment from Rocky Flats to establish cost-effective mobile treatment capability. The AEMP treated approximately 16 m3 (= 579 cf) of challenging mixed wastes onsite at approximately 50 wt% waste loading using polymer microencapsulation and macroencapsulation systems to isolate the hazards from the general public. These wastes were then profiled and buried in fifty-seven (57) containers containing approximately 33 m3 (1,194 cf) of LDR-compliant wastes at NTS and Envirocare of Utah, Inc. However, this paper summarizes only the MACRO technology approval, waste inspection/treatment/certification process, and technology transfer as deployed at AEMP and Sandia National Laboratories (SNL). It describes only the sequences associated with optimizing the process for the polymer MACRO system to meet overall DOE waste management needs. AEMP performed MACRO on 4 m3 (139 cf) of RCRA debris before the system was shut down. The shut down occurred due to new project direction, funding availability, and alternate offsite treatment capabilities at TSCAI and/or commercial facilities for the balance of the mixed wastes