Proteomics analysis of vesicles isolated from plasma and urine of prostate cancer patients using a multiplex, aptamer-based protein array

Proteomics analysis of biofluid-derived vesicles holds enormous potential for discovering non-invasive disease markers. Obtaining vesicles of sufficient quality and quantity for profiling studies has, however, been a major problem, as samples are often replete with co-isolated material that can interfere with the identification of genuine low abundance, vesicle components. Here, we used a combination of ultracentrifugation and size-exclusion chromatography to isolate and analyse vesicles of plasma or urine origin. We describe a sample-handling workflow that gives reproducible, quality vesicle isolations sufficient for subsequent protein profiling. Using a semi-quantitative aptamer-based protein array, we identified around 1,000 proteins, of which almost 400 were present at comparable quantities in plasma versus urine vesicles. Significant differences were, however, apparent with elements like HSP90, integrin αVβ5 and Contactin-1 more prevalent in urinary vesicles, while hepatocyte growth factor activator, prostate-specific antigen–antichymotrypsin complex and many others were more abundant in plasma vesicles. This was also applied to a small set of specimens collected from men with metastatic prostate cancer, highlighting several proteins with the potential to indicate treatment refractory disease. The study provides a practical platform for furthering protein profiling of vesicles in prostate cancer, and, hopefully, many other disease scenarios

Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years

<p>Abstract</p> <p>Background</p> <p>The once-weekly (QW) formulation of the glucagon-like peptide-1 receptor agonist exenatide has been demonstrated to improve A1C, fasting plasma glucose (FPG), body weight, serum lipid profiles, and blood pressure in patients with type 2 diabetes through 52 weeks of treatment. In this report, we describe the 2-year results of the open-label, open-ended extension to the DURATION-1 trial of exenatide QW for type 2 diabetes.</p> <p>Methods</p> <p>A 2-stage protocol was used: patients received either exenatide QW (2 mg) or exenatide twice daily for 30 weeks (5 μg for the first 4 weeks and 10 μg thereafter), followed by 1.5 years of treatment with exenatide QW (2 mg), for a total of 2 years (104 weeks) of exenatide treatment. Of the 295 (intent-to-treat [ITT]) patients who entered the trial, 73% (n = 216) completed 2 years of treatment (completer population). Baseline characteristics (mean ± SE) for these patients were: A1C, 8.2 ± 0.1%; FPG, 168.4 ± 43.0 mg/dL; body weight, 101.1 ± 18.7 kg; and diabetes duration, 7 ± 5 years.</p> <p>Results</p> <p>In the completer population, significant improvements (LS mean ± SE [95% CI]) were maintained after 2 years of treatment in A1C (-1.71 ± 0.08% [-1.86 to -1.55%]), FPG (-40.1 ± 2.9 mg/dL [-45.7 to -34.5 mg/dL]), and body weight (-2.61 ± 0.52 kg [-3.64 to -1.58 kg]) compared with baseline. The percentages of patients who achieved an A1C of <7.0% and ≤6.5% at 2 years were 60% and 39%, respectively. A significant reduction in systolic blood pressure (SBP; -3.0 ± 1.0 mmHg [-4.9 to -1.1 mmHg]) was maintained through 2 years of treatment. Serum lipid profiles were also significantly improved, including triglycerides (geometric LS mean change from baseline, -15 ± 2.7% [-21% to -10%]), total cholesterol (-8.6 ± 2.8 mg/dL [-14.0 to -3.1 mg/dL]), and low-density lipoproteins (-4.5 ± 2.2 mg/dL [-8.9 to -0.01 mg/dL]). Changes in A1C, body weight, FPG, SBP, and lipids in the ITT population were similar to those seen in the completer population. Nausea (predominantly mild in intensity) was the most common adverse event, although the frequency and intensity of nausea decreased over time. No severe hypoglycemia was observed.</p> <p>Conclusions</p> <p>Exenatide QW was well tolerated during the 2-year treatment period. This study demonstrated sustained glucose control and weight loss throughout 2 years of treatment with exenatide QW.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00308139">NCT00308139</a></p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Positive sexuality: HIV disclosure, gender, violence and the law-A qualitative study.

While a growing body of research points to the shortcomings of the criminal law in governing HIV transmission, there is limited understanding of how cis and trans women living with HIV (WLWH) negotiate their sexuality and HIV disclosure in a criminalized environment. Given the ongoing criminalization of HIV non-disclosure and prevalence of gender-based violence, there is a critical need to better understand the dynamics of negotiating sexual relationships and HIV disclosure among WLWH. We conducted 64 qualitative interviews with cis and trans WLWH in Vancouver, Canada between 2015 and 2017. The interviews were conducted by three experienced researchers, including a cis and a trans WLWH using a semi-structured interview guide. Drawing on a feminist analytical framework and concepts of structural violence, the analysis sought to characterize the negotiation of sexual relationships and HIV disclosure among WLWH in a criminalized setting. For many participants their HIV diagnosis initially symbolized the end of their sexuality due to fear of rejection and potential legal consequences. WLWH recounted that disclosing their HIV status shifted the power dynamics in sexual relationships and many feared rejection, violence, and being outed as living with HIV. Participants' narratives also highlighted that male condom refusal was common and WLWH were not only subjected to the gendered interpersonal violence of male condom refusal but also to the structural violence of legislation that requires condom use but fails to account for the gendered power imbalance that shapes condom negotiation. Despite frequently being represented as a law that 'protects' women, our findings indicate that the criminalization of HIV non-disclosure constitutes a form of gendered structural violence that exacerbates risk for interpersonal violence among WLWH. In line with recommendations by, the WHO and UNAIDS these findings demonstrate the negative impacts of regulating HIV prevention through the use of criminal law for WLWH

Indigenous Women Voicing Experiences of HIV Stigma and Criminalization Through Art

Indigenous women living with HIV are disproportionately affected by the criminalization of HIV nondisclosure. The purpose of this paper is to better understand how the criminalization of HIV nondisclosure shapes the lived experiences of HIV-related stigma, disclosure, and health service among cis and transgender Indigenous women living with HIV (IWLWH). This study was developed based on a community roundtable on HIV criminalization with engagement of legal experts, HIV service organizations, and IWLWH on the unceded traditional territory of the Coast Salish Peoples, including the ter̓ritories of the xwməθkwəy̓ əm (Musqueam), Sḵwx̱ wú7mesh (Squamish), and Səlílwətaɬ (Tsleil-Waututh) Nations (Vancouver, British Columbia, Canada) in 2016 to 2018. Drawing on community-based participatory photovoice methodology, Indigenous Peer Researchers played a central role throughout this project, including planning, facilitation of photo-voice workshops, and analysis. This analysis includes 17 IWLWH. Through a peer-engaged analysis process, the photovoice images and narratives illustrated how the criminalization of HIV nondisclosure is intertwined with colonial violence to shape experiences of social isolation and exclusion, disclosure, access to safe health care, responsibility, fear, and resilience. The legal requirements of HIV nondisclosure are unattainable for many IWLWH who are not able to safely disclose their HIV status, negotiate condom use, and maintain a low viral load. In line with the Truth and Reconciliation Commission of Canada and National Inquiry into Missing and Murdered Indigenous Women and Girls, the justice system must be reoriented from punishment and oppression to healing and wellbeing for all Indigenous women living with HIV. Simultaneously, we call for culturally safe services that protect privacy and recognize strengths of IWLWH