Disturbed myelinogenesis and recovery in hyperphenylalaninemia in rats: An immunohistochemical study

Chronic hyperphenylalaninemia (HPA) in rats has been used as an experimental model of the human inborn error of metabolism phenylketonuria (PKU). Impaired brain development in PKU and HPA is reflected in reduced myelin formation. We have used immunohistochemistry, with antibodies to cell-specific antigenic markers, to investigate the cellular basis of the hypomyelination in the corpus callosum and cerebral cortex of rats made hyperphenylalaninemic from Postnatal Days 3-17. The rats were then allowed to recover until Day 59. No effects were seen on the number and differentiation pattern of ganglioside GD3-expressing glial progenitors. Myelin basic protein and 2'3'-cyclic nucleotide 3'-phosphohydrolase (CNP) immunostaining demonstrated a reduction in myelin formation in the corpus callosum and subcortical white matter at 12 and 17 days postnatal. However, numbers of CNP+ oligodendrocytes appeared normal throughout development. No reactive astrogliosis was seen at any stage. The intensity of axonal neurofilament immunostaining was reduced in the corpus callosum at 17 days. In layers II and III of the cortical gray matter there was an increase in the cell packing density and a concomitant decrease in cell body size. Myelination in the corpus callosum was rapid during the recovery period with no difference noted at Day 59. Axonal neurofilament staining also returned to normal in the corpus callosum. However, recovery became increasingly incomplete away from the corpus callosum into the cortical gray matter. Our data suggest a primary effect of HPA on axonal maturation with hypomyelination consequential upon this.     

A Systematic Review of the Evidence for the Decipher Genomic Classifier in Prostate Cancer

ContextMolecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use.ObjectiveTo perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC).Evidence acquisitionThe review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446–52) and American Urology Association (AUA) criteria.Evidence synthesisIn total, 42 studies and 30 407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n = 12 141), prospective registries (n = 17 053), and prospective and post hoc randomized trial analyses (n = 1213). In 32 studies (n = 12 600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n = 8543). GC use changed the management in active surveillance (number needed to test [NNT] = 9) and postprostatectomy (NNT = 1.5–4) settings in five studies (n = 4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state.ConclusionsConsistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making.Patient summaryIn this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making.     

Medicinal chemistry of oxazines as promising agents in drug discovery

Oxazines have brought much synthetic interest due to their extensive biological activities. These are the important category of heterocycles, which may be formally derived from benzene and its reduction products by convenient substitution of carbon (and hydrogen) atoms by nitrogen and oxygen. In the last few decades, oxazine derivatives have documented as worthy synthetic intermediates and also blessed with notable sedative, analgesic, anticonvulsant, antipyretic, antimicrobial, antitubercular, antimalarial, antioxidant, and anticancer activities. Nowadays, it is important to develop new classes of compounds with more effective mechanisms due to drug resistance activity in which the ability of drug to effectively treat disease can be reduced. The aim of the article is to collect and make a more generalized review on the synthesis of oxazine derivatives and their pharmaceutical and biological activities. We hope this review will provide ample references for the researchers concerned with azines in generally and oxazines in particular.     

Structural approaches to HIV prevention

Recognition that social, economic, political, and environmental factors directly affect HIV risk and vulnerability has stimulated interest in structural approaches to HIV prevention. Progress in the use of structural approaches has been limited for several reasons: absence of a clear definition; lack of operational guidance; and limited data on the effectiveness of structural approaches to the reduction of HIV incidence. In this paper we build on evidence and experience to address these gaps. We begin by defining structural factors and approaches. We describe the available evidence on their effectiveness and discuss methodological challenges to the assessment of these often complex efforts to reduce HIV risk and vulnerability. We identify core principles for implementing this kind of work. We also provide recommendations for ensuring the integration of structural approaches as part of combined prevention strategies.     

Getting back to equal: The influence of insurance status on racial disparities in the treatment of African American men with high-risk prostate cancer

ObjectivesTreating high-risk prostate cancer (CaP) with definitive therapy improves survival. We evaluated whether having health insurance reduces racial disparities in the use of definitive therapy for high-risk CaP.Materials and methodsThe Surveillance, Epidemiology, and End Results Program was used to identify 70,006 men with localized high-risk CaP (prostate-specific antigen level >20 ng/ml or Gleason score 8–10 or stage>cT3a) diagnosed from 2007 to 2010. We used multivariable logistic regression to analyze the 64,277 patients with complete data to determine the factors associated with receipt of definitive therapy.ResultsCompared with white men, African American (AA) men were significantly less likely to receive definitive treatment (adjusted odds ratio [AOR] = 0.60; 95% CI: 0.56–0.64; P<0.001) after adjusting for sociodemographics and known CaP prognostic factors. There was a significant interaction between race and insurance status (P_interaction = 0.01) such that insurance coverage was associated with a reduction in racial disparity between AA and white patients regarding receipt of definitive therapy. Specifically, the AOR for definitive treatment for AA vs. white was 0.38 (95% CI: 0.27–0.54, P<0.001) among uninsured men, whereas the AOR was 0.62 (95% CI: 0.57–0.66, P<0.001) among insured men.ConclusionsAA men with high-risk CaP were significantly less likely to receive potentially life-saving definitive treatment when compared with white men. Having health insurance was associated with a reduction in this racial treatment disparity, suggesting that expansion of health insurance coverage may help reduce racial disparities in the management of aggressive cancers.