Principles and criteria in the development and optimization of topical therapeutic products : Sponsored by the American Association of Pharmaceutical Scientists (AAPS) and U.S. Food and Drug Administration (FDA)

This report derived from the dermatological workshop discusses the problems and issues in the development and optimization of topical therapeutic drug products. It provides a clear understanding and differentiation between transdermal and dermal products. The report also discusses the bioavailability/bioequivalence issues for topical therapeutic products.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30099/1/0000471.pd

Assessing the feasibility of integrating ecosystem-based with engineered water resource governance and management for water security in semi-arid landscapes: A case study in the Banas catchment, Rajasthan, India

Much of the developing world and areas of the developed world suffer water vulnerability. Engineering solutions enable technically efficient extraction and diversion of water towards areas of demand but, without rebalancing resource regeneration, can generate multiple adverse ecological and human consequences. The Banas River, Rajasthan (India), has been extensively developed for water diversion, particularly from the Bisalpur Dam from which water is appropriated by powerful urban constituencies dispossessing local people. Coincidentally, abandonment of traditional management, including groundwater recharge practices, is leading to increasingly receding and contaminated groundwater. This creates linked vulnerabilities for rural communities, irrigation schemes, urban users, dependent ecosystems and the multiple ecosystem services that they provide, compounded by climate change and population growth. This paper addresses vulnerabilities created by fragmented policy measures between rural development, urban and irrigation water supply and downstream consequences for people and wildlife. Perpetuating narrowly technocentric approaches to resource exploitation is likely only to compound emerging problems. Alternatively, restoration or innovation of groundwater recharge practices, particularly in the upper catchment, can represent a proven, ecosystem-based approach to resource regeneration with linked beneficial socio-ecological benefits. Hybridising an ecosystem-based approach with engineered methods can simultaneously increase the security of rural livelihoods, piped urban and irrigation supplies, and the vitality of river ecosystems and their services to beneficiaries. A renewed policy focus on local-scale water recharge practices balancing water extraction technologies is consistent with emerging Rajasthani policies, particularly Jal Swavlamban Abhiyan (‘water self-reliance mission’). Policy reform emphasising recharge can contribute to water security and yield socio-economic outcomes through a systemic understanding of how the water system functions, and by connecting goals and budgets across multiple, currently fragmented policy areas. The underpinning principles of this necessary paradigm shift are proven and have wider geographic relevance, though context-specific research is required to underpin robust policy and practical implementation

DMA, a Bisbenzimidazole, Offers Radioprotection by Promoting NFκB Transactivation through NIK/IKK in Human Glioma Cells

BACKGROUND: Ionizing radiation (IR) exposure often occurs for human beings through occupational, medical, environmental, accidental and/or other sources. Thus, the role of radioprotector is essential to overcome the complex series of overlapping responses to radiation induced DNA damage. METHODS AND RESULTS: Treatment of human glioma U87 cells with DMA (5- {4-methylpiperazin-1-yl}-2-[2'-(3, 4-dimethoxyphenyl)-5'-benzimidazolyl] in the presence or absence of radiation uncovered differential regulation of an array of genes and proteins using microarray and 2D PAGE techniques. Pathway construction followed by relative quantitation of gene expression of the identified proteins and their interacting partners led to the identification of MAP3K14 (NFκB inducing kinase, NIK) as the candidate gene affected in response to DMA. Subsequently, over expression and knock down of NIK suggested that DMA affects NFκB inducing kinase mediated phosphorylation of IKKα and IKKβ both alone and in the presence of ionizing radiation (IR). The TNF-α induced NFκB dependent luciferase reporter assay demonstrated 1.65, 2.26 and 3.62 fold increase in NFκB activation at 10, 25 and 50 µM DMA concentrations respectively, compared to control cells. This activation was further increased by 5.8 fold in drug + radiation (50 µM +8.5 Gy) treated cells in comparison to control. We observed 51% radioprotection in control siRNA transfected cells that attenuated to 15% in siRNA NIK treated U87 cells, irradiated in presence of DMA at 24 h. CONCLUSIONS: Our studies show that NIK/IKK mediated NFκB activation is more intensified in cells over expressing NIK and treated with DMA, alone or in combination with ionizing radiation, indicating that DMA promotes NIK mediated NFκB signaling. This subsequently leads to the radioprotective effect exhibited by DMA

Research priorities in Maternal, Newborn, & Child Health & Nutrition for India:An Indian Council of Medical Research-INCLEN Initiative

In India, research prioritization in Maternal, Newborn, and Child Health and Nutrition (MNCHN) themes has traditionally involved only a handful of experts mostly from major cities. The Indian Council of Medical Research (ICMR)-INCLEN collaboration undertook a nationwide exercise engaging faculty from 256 institutions to identify top research priorities in the MNCHN themes for 2016-2025. The Child Health and Nutrition Research Initiative method of priority setting was adapted. The context of the exercise was defined by a National Steering Group (NSG) and guided by four Thematic Research Subcommittees. Research ideas were pooled from 498 experts located in different parts of India, iteratively consolidated into research options, scored by 893 experts against five pre-defined criteria (answerability, relevance, equity, investment and innovation) and weighed by a larger reference group. Ranked lists of priorities were generated for each of the four themes at national and three subnational (regional) levels [Empowered Action Group & North-Eastern States, Southern and Western States, & Northern States (including West Bengal)]. Research priorities differed between regions and from overall national priorities. Delivery domain of research which included implementation research constituted about 70 per cent of the top ten research options under all four themes. The results were endorsed in the NSG meeting. There was unanimity that the research priorities should be considered by different governmental and non-governmental agencies for investment with prioritization on implementation research and issues cutting across themes

Impact of Second Primary Malignancy Post–Autologous Transplantation on Outcomes of Multiple Myeloma: A CIBMTR Analysis

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P \u3c .001 and HR 5.01, P \u3c .001, respectively) and OS (HR 3.85, P \u3c .001 and HR 8.13, P \u3c .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT

HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio