Molecular assays for the detection of prostate tumor derived nucleic acids in peripheral blood

<p>Abstract</p> <p>Background</p> <p>Prostate cancer is the second leading cause of cancer mortality in American men. Although serum PSA testing is widely used for early detection, more specific prognostic tests are needed to guide treatment decisions. Recently, the enumeration of circulating prostate epithelial cells has been shown to correlate with disease recurrence and metastasis following definitive treatment. The purpose of our study was to investigate an immunomagnetic fractionation procedure to enrich circulating prostate tumor cells (CTCs) from peripheral blood specimens, and to apply amplified molecular assays for the detection of prostate-specific markers (PSA, PCA3 and TMPRSS2:ERG gene fusion mRNAs).</p> <p>Results</p> <p>As few as five prostate cancer cells were detected per 5 mL of whole blood in model system experiments using anti-EpCAM magnetic particles alone or in combination with anti-PSMA magnetic particles. In our experiments, anti-EpCAM magnetic particles alone exhibited equivalent or better analytical performance with patient samples compared to a combination of anti-EpCAM + anti-PSMA magnetic particles. Up to 39% of men with advanced prostate cancer tested positive with one or more of the molecular assays tested, whereas control samples from men with benign prostate hyperplasia gave consistently negative results as expected. Interestingly, for the vast majority of men who tested positive for PSA mRNA following CTC enrichment, their matched plasma samples also tested positive, although CTC enrichment gave higher overall mRNA copy numbers.</p> <p>Conclusion</p> <p>CTCs were successfully enriched and detected in men with advanced prostate cancer using an immunomagnetic enrichment procedure coupled with amplified molecular assays for PSA, PCA3, and TMPRSS2:ERG gene fusion mRNAs. Our results indicate that men who test positive following CTC enrichment also exhibit higher detectable levels of non-cellular, circulating prostate-specific mRNAs.</p

Clarifying and Expanding Concepts of Cross-Jurisdictional Sharing: Early Lessons Learned from Conducting QI with Georgia’s Health Districts

Research Objective: Assess the legal and organization cultural foundations for Cross-Jurisdictional Sharing (CJS) in support of local public health accreditation and QI in Georgia. Data Sets and Sources: Archival data (primarily state statutes), secondary data from previous qualitative comparative research on Deep South public health organization, secondary data from previous surveys, and oral interviews and written communication. Study Design: Primarily Qualitative design combining ethnographic and participatory research methods. Analysis: Qualitative Content analysis based on predetermined and emergent themes. Principal Findings: Georgia’s Health Districts have emerged as major CJS entities that support delivery of essential services and local public health (LPH) QI and LPH accreditation readiness, driven primarily by local organizational leadership and culture that is facilitated through enabling statutes in contrast to more top-down state-mandating statutes, regulations and directives. Conclusion: Georgia’s use of districts as multi-county public health entities serves as a primary structure for providing local public health services and has become a critical structure to address the looming demands for QI and accreditation, even though the statutes clearly establish the county as the primary local public health entity. Implications for the Field of PHSSR: This CJS structure to facilitate public health QI and accreditation in Georgia illustrates how agency cultures can emerge from local demands for economies of scale, more than formal policies generated at state level. This is a model that could be very important for advancing CJS in other regions of the country

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Indigenous Cultural Values Counter the Damages of White Settler Colonialism

Settler colonialism is a violent process that harms all beings. We build upon environmental justice frameworks and argue for Indigenous values affirmation as a strategy for countering the violence of settler colonialism. We discuss the findings of a pilot project to create an Indigenous values affirmation tool with Indigenous peoples in the U.S. to provide context for our argument. We draw from Indigenous-centered literature, including Bacon’s colonial ecological violence, and assert that settler systems, and analyses rooted in settler logics, are inadequate because of their inherent inability to meaningfully and critically engage with colonization. This ignorance causes academic fields of study to be damaged-centred in their gaze on Indigenous peoples, or to ignore or render Indigenous peoples invisible or disappeared. Equity is not imaginable, and justice is impossible, within these frameworks. Centring Indigenous people and values have great potential to contribute to environmental sociology. We urge environmental sociologists to honour Indigenous ways of knowing and being in efforts to counter settler colonial violence that plagues all peoples. Doing so will open up new possibilities for healing the environment, and humans’ relations with Mother Earth and all beings