Lessons learned from a peri-urban needle exchange

<p>Abstract</p> <p>Background</p> <p>Injection drug users continue to be at high risk of HIV and HCV. Research has shown that needle exchange programs (NEP) decrease injection frequency, reduce syringe reuse, and reduce needle sharing, though some results have been mixed.</p> <p>Methods</p> <p>This evaluation of a small, peri-urban, legal NEP near Ypsilanti, Michigan describes the operation of the NEP and its clients. It uses interviews conducted with NEP participants between 2003 and 2006, describing the population served by the program, and draws on limited comparisons between matched baseline and follow-up measures as well as aggregate baseline and follow-up comparisons.</p> <p>Results</p> <p>The HIV/AIDS Resource Center (HARC) Harm Reduction NEP serves a diverse population from a wide geographical area. NEP participants at follow-up reused their syringes significantly fewer times before getting new ones, were significantly less likely to report giving another IDU a previously used syringe, and were more likely to clean their skin with alcohol either before or after injecting than the baseline comparison group.</p> <p>Conclusions</p> <p>The limited data presented here suggest that a NEP can be an effective method of harm reduction even in low-volume, non-urban settings and are an important venue for intervention in peri-urban areas.</p

The spirit that wins

A sermon preached to the third graduating class of the RIce Institute, by James G. K. McClure, President of McCormick Theological Seminary, Chicago, Illinois

Srs2 promotes synthesis-dependent strand annealing by disrupting DNA polymerase δ-extending D-loops.

Synthesis-dependent strand annealing (SDSA) is the preferred mode of homologous recombination in somatic cells leading to an obligatory non-crossover outcome, thus avoiding the potential for chromosomal rearrangements and loss of heterozygosity. Genetic analysis identified the Srs2 helicase as a prime candidate to promote SDSA. Here, we demonstrate that Srs2 disrupts D-loops in an ATP-dependent fashion and with a distinct polarity. Specifically, we partly reconstitute the SDSA pathway using Rad51, Rad54, RPA, RFC, DNA Polymerase δ with different forms of PCNA. Consistent with genetic data showing the requirement for SUMO and PCNA binding for the SDSA role of Srs2, Srs2 displays a slight but significant preference to disrupt extending D-loops over unextended D-loops when SUMOylated PCNA is present, compared to unmodified PCNA or monoubiquitinated PCNA. Our data establish a biochemical mechanism for the role of Srs2 in crossover suppression by promoting SDSA through disruption of extended D-loops

An immunotherapy survivor population: health-related quality of life and toxicity in patients with metastatic melanoma treated with immune checkpoint inhibitors

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose The immune checkpoint inhibitors (ICIs) have resulted in subgroups of patients with metastatic melanoma achievinghigh-quality durable responses. Metastatic melanoma survivors are a new population in the era of cancer survivorship. The aimofthis study was to evaluate metastatic melanoma survivors in terms of health-related quality of life (HRQoL), immune-relatedadverse events (irAEs) and exposure to immunosuppressive agents in a large single centre in the UK.Methods We defined the survivor population as patients with a diagnosis of metastatic melanoma who achieved a durableresponse to an ICI and had been followed-up for a minimum of 12 months from initiation of ICI without disease progression.HRQoL was assessed using SF-36. Electronic health records were accessed to collect data on demographics, treatments, irAEsand survival. HRQoL data was compared with two norm-based datasets.Results Eighty-four metastatic melanoma survivors were eligible and 87% (N = 73) completed the SF-36. ICI-related toxicity ofany grade occurred in 92%of patients and 43%had experienced a grade 3 or 4 toxicity. Almost half (49%) of the patients requiredsteroids for the treatment of ICI-related toxicity, whilst 14% required treatment with an immunosuppressive agent beyondsteroids.Melanoma survivors had statistically significant lower HRQoL scores with regard to physical, social and physical rolefunctioning and general health compared with the normative population. There was a trend towards inferior scores in patientswith previous exposure to ipilimumab compared with those never exposed to ipilimumab.Conclusions Our results show that metastatic melanoma survivors have potentially experienced significant ICI-related toxicityand experience significant impairments in specific HRQoL domains. Future service planning is required to meet this population’sunique survivorship needs.Peer reviewe

Integrated stress response is critical for gemcitabine resistance in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with marked chemoresistance and a 5-year survival rate of 7%. The integrated stress response (ISR) is a cytoprotective pathway initiated in response to exposure to various environmental stimuli. We used pancreatic cancer cells (PCCs) that are highly resistant to gemcitabine (Gem) and an orthotopic mouse model to investigate the role of the ISR in Gem chemoresistance. Gem induced eIF2 phosphorylation and downstream transcription factors ATF4 and CHOP in PCCs, and these effects occurred in an eIF2α-S51 phosphorylation-dependent manner as determined using PANC-1 cells, and wild type and S51 mutant mouse embryo fibroblasts. Blocking the ISR pathway in PCCs with the ISR inhibitor ISRIB or siRNA-mediated depletion of ATF4 resulted in enhanced Gem-mediated apoptosis. Polyribosomal profiling revealed that Gem caused repression of global translation and this effect was reversed by ISRIB or by expressing GADD34 to facilitate eIF2 dephosphorylation. Moreover, Gem promoted preferential mRNA translation as determined in a TK-ATF4 5'UTR-Luciferase reporter assay, and this effect was also reversed by ISRIB. RNA-seq analysis revealed that Gem upregulated eIF2 and Nrf2 pathways, and that ISRIB significantly inhibited these pathways. Gem also induced the expression of the antiapoptotic factors Nupr1, BEX2, and Bcl2a1, whereas ISRIB reduced their expression. In an orthotopic tumor model using PANC-1 cells, ISRIB facilitated Gem-mediated increases in PARP cleavage, which occurred in conjunction with decreased tumor size. These findings indicate that Gem chemoresistance is enhanced by activating multiple ISR-dependent pathways, including eIF2, Nrf2, Nupr1, BEX2, and Bcl2A1. It is suggested that targeting the ISR pathway may be an efficient mechanism for enhancing therapeutic responsiveness to Gem in PDAC

Analysis of Limiters for ADITYA Tokamak

ADITYA Tokamak is a medium size ohmically heated tokamak. The hot plasma interacts with the vacuum vessel wall introducing impurities in the plasma and also damages the vacuum vessel wall. Limiter is used to reduce plasma - wall interaction and protect the vacuum vessel wall as well as inside components. It also controls impurity generation. ADITYA has a set of two types of limiters (i) Safety limiter (ii) a Poloidal limiter. Formally all the limiters are made of shaped graphite tiles fixed on stainless steel base plates. But graphite tiles are responsible for low Z impurities in plasma. To avoid these low Z impurities Molybdenum tiles are suggested. In this paper, we are going to present ansys analysis of surface temperature rise of molybdenum tiles compared to graphite tiles when used as Poloidal Limiter during plasma discharges in Aditya tokamak. The analysis is carried by ANSYS 11.0 software using Transient Thermal Analysis module. The results are compared with experimental results for graphite tiles. The graphite and molybdenum tiles are analyzed under same conditions