Blood-Based Biomarkers of Aggressive Prostate Cancer

Purpose: Prostate cancer is a bimodal disease with aggressive and indolent forms. Current prostate-specific-antigen testing and digital rectal examination screening provide ambiguous results leading to both under-and over-treatment. Accurate, consistent diagnosis is crucial to risk-stratify patients and facilitate clinical decision making as to treatment versus active surveillance. Diagnosis is currently achieved by needle biopsy, a painful procedure. Thus, there is a clinical need for a minimally-invasive test to determine prostate cancer aggressiveness. A blood sample to predict Gleason score, which is known to reflect aggressiveness of the cancer, could serve as such a test. Materials and Methods: Blood mRNA was isolated from North American and Malaysian prostate cancer patients/controls. Microarray analysis was conducted utilizing the Affymetrix U133 plus 2·0 platform. Expression profiles from 255 patients/controls generated 85 candidate biomarkers. Following quantitative real-time PCR (qRT-PCR) analysis, ten disease-associated biomarkers remained for paired statistical analysis and normalization. Results: Microarray analysis was conducted to identify 85 genes differentially expressed between aggressive prostate cancer (Gleason score ≥8) and controls. Expression of these genes was qRT-PCR verified. Statistical analysis yielded a final seven-gene panel evaluated as six gene-ratio duplexes. This molecular signature predicted as aggressive (ie, Gleason score ≥8) 55% of G6 samples, 49% of G7(3+4), 79% of G7(4+3) and 83% of G8-10, while rejecting 98% of controls. Conclusion: In this study, we have developed a novel, blood-based biomarker panel which can be used as the basis of a simple blood test to identify men with aggressive prostate cancer and thereby reduce the overdiagnosis and overtreatment that currently results from diagnosis using PSA alone. We discuss possible clinical uses of the panel to identify men more likely to benefit from biopsy and immediate therapy versus those more suited to an “active surveillance” strategy

Predictors of mortality in HIV-1 infected children on antiretroviral therapy in Kenya: a prospective cohort

<p>Abstract</p> <p>Background</p> <p>Among children, early mortality following highly active antiretroviral therapy (HAART) remains high. It is important to define correlates of mortality in order to improve outcome.</p> <p>Methods</p> <p>HIV-1-infected children aged 18 months-12 years were followed up at Kenyatta National Hospital, Nairobi after initiating NNRTI-based HAART. Cofactors for mortality were determined using multivariate Cox regression models.</p> <p>Results</p> <p>Between August 2004 and November 2008, 149 children were initiated on HAART of whom 135 were followed for a total of 238 child-years (median 21 months) after HAART initiation. Baseline median CD4% was 6.8% and median HIV-1-RNA was 5.98-log₁₀copies/ml. Twenty children (13.4%) died at a median of 35 days post-HAART initiation. Mortality during the entire follow-up period was 8.4 deaths per 100 child-years (46 deaths/100 child-years in first 4 months and 1.0 deaths/100 child-years after 4 months post-HAART initiation). On univariate Cox regression, baseline hemoglobin (Hb) <9 g/dl, weight-for-height z-score (WHZ) < -2, and WHO clinical stage 4 were associated with increased risk of death (Hb <9 g/dl HR 3.00 [95% C.I. 1.21-7.39], p = 0.02, WHZ < -2 HR 3.41 [95% C.I. 1.28-9.08], p = 0.01, and WHO clinical stage 4, HR 3.08 [1.17-8.12], p = 0.02). On multivariate analysis Hb < 9 g/dl remained predictive of mortality after controlling for age, baseline CD4%, WHO clinical stage and weight-for-height z-score (HR 2.95 (95% C.I. 1.04-8.35) p = 0.04).</p> <p>Conclusion</p> <p>High early mortality was observed in this cohort of Kenyan children receiving HAART, and low baseline hemoglobin was an independent risk factor for death.</p

A case of late recurrence of Burkitt’s Lymphoma presenting with abdominal masses and haematemesis

In August, 2005, a 10 year old boy was admitted to a district hospital with marked haematemesis and a huge abdominal mass. Initially, he was treated for ruptured oesophageal varices, but in vain. Then he was transferred to Mzuzu Central Hospital. The history revealed a previous clinical diagnosis of Burkitt’s lymphoma (BL) in 2002, without pathological confirmation, when he had bilateral jaw masses and an epigastric mass. He had received four doses of cyclophosphamide (CPM) chemotherapy, 40mg/kg/dose fortnightly and responded partially with shrinkage of abdominal mass. One dose of intravenous combined chemotherapy of CPM, vincristine (1.5mg/sq.m/dose) and methotrexate (20mg/sq.m/dose) (COM) was then administered before he was lost to follow up

Anti-Inflammatory Butenolides from a Marine-Derived <i>Streptomyces</i> sp. 13G036

Butenolides are a family of lactones containing a double bond and have been frequently found in the extracts of Streptomyces bacterial species with various pharmacological activities. In this study, seven butenolides (1–7) were discovered and isolated from the culture broth of a marine-derived Streptomyces sp. 13G036 based on a molecular networking analysis. Among the seven isolates, compound 7 was first isolated as a natural product in this study. The structures of compounds 1–7 were determined by combined analysis of 1D/2D Nuclear Magnetic Resonance (NMR) spectra, Mass Spectrometry (MS) spectra and electronic circular dichroism (ECD) data. Compounds 1–6 showed potential anti-inflammatory activities by inhibiting the production of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukine-6 (IL-6) in lipopolysaccharide-stimulated macrophages

Risk factors for early mortality in children on adult fixed-dose combination antiretroviral treatment in a central hospital in Malawi.

OBJECTIVES: In children aged less than 15 years, to determine the cumulative proportion of deaths occurring within 3 and 6 months of starting split-tablet adult fixed-dose combination antiretroviral therapy (ART) and to identify risk factors associated with early deaths. DESIGN: A retrospective cohort analysis. METHODS: Data were collected and analysed from ART patient master cards and the ART register of all children registered for treatment between July 2004 and September 2006 in the ART clinic at Mzuzu Central Hospital, northern Malawi. RESULTS: A total of 439 children started on ART, of whom 220 (50%) were male; 37 (8%) were aged less than 18 months, 172 (39%) 18 months to 5 years, and 230 (52%) were 6-14 years. By September 2006, 49 children (11%) had died, of whom 35 (71%) died by 3 months and 44 (89%) by 6 months. The cumulative incidence of death at 3, 6, 12 and 24 months after ART was 8, 12, 13 and 15%, respectively. After multivariate analysis, being in World Health Organization clinical stage 4, having severe wasting and severe immunodeficiency were factors significantly associated with 3-month mortality and 6-month mortality, respectively. CONCLUSION: Although children do well on ART, there is high early mortality. Scaling up HIV testing and simple diagnostic tests for infants and children, expanding routine provision of cotrimoxazole prophylaxis, and investigating the role of nutritional interventions are three measures that, if implemented and expanded countrywide, may improve ART outcomes

miR-204 downregulates EphB2 in aging mouse hippocampal neurons

Hippocampal synaptic function and plasticity deteriorate with age, often resulting in learning and memory deficits. As MicroRNAs (miRNAs) are important regulators of neuronal protein expression, we examined whether miRNAs may contribute to this age-associated decline in hippocampal function. We first compared the small RNA transcriptome of hippocampal tissues from young and old mice. Among 269 hippocampal miRNAs, 80 were differentially expressed (≥ ;twofold) among the age groups. We focused on 36 miRNAs upregulated in the old mice compared with those in the young mice. The potential targets of these 36 miRNAs included 11 critical Eph/Ephrin synaptic signaling components. The expression levels of several genes in the Eph/Ephrin pathway, including EphB2, were significantly downregulated in the aged hippocampus. EphB2 is a known regulator of synaptic plasticity in hippocampal neurons, in part by regulating the surface expression of the NMDA receptor NR1 subunit. We found that EphB2 is a direct target of miR-204 among miRNAs that were upregulated with age. The transfection of primary hippocampal neurons with a miR-204 mimic suppressed both EphB2 mRNA and protein expression and reduced the surface expression of NR1. Transfection of miR-204 also decreased the total expression of NR1. miR-204 induces senescence-like phenotype in fully matured neurons as evidenced by an increase in p16-positive cells. We suggest that aging is accompanied by the upregulation of miR-204 in the hippocampus, which downregulates EphB2 and results in reduced surface and total NR1 expression. This mechanism may contribute to age-associated decline in hippocampal synaptic plasticity and the related cognitive functions. © 2016 The Anatomical Society and John Wiley &amp; Sons Ltd.

High grade prostate cancer (Gleason score 8 and above) biomarker gene list and differential expression ratio in Cohort II verification sample set (80 disease and 102 controls).

<p># The 7 biomarkers were picked up from the 10 that were verified in Cohort II samples, using gene-ratio algorithm, based on the best AUC of combined gene-pair.</p>†<p>Determined by qRT-PCR analysis using SAMSN1 as a partner gene, gene ratio was calculated using delta delta Ct calculation.</p>‡<p>Calculated by Mann-Whitney test.</p>*<p>area under receiver-operating-characteristic curve.</p

PCR data from a sample set of 122 PAXgene samples of prostate cancer from the G8 group and 138 PAXgene samples from the control group were performed in a 1000×2-fold cross-validation test.

<p>Histograms of AUC were plotted and compared; results showed AUCs from the PCR data were well separated from the null sets, with an overlap of less than 5%.</p

Predictions for independent Cohort III and Cohort IV samples.

<p>The negative prediction rate for control cases is charted along with the positive prediction rates for cancer cases. PSA alone has high positive predictive rates for all cancer grades (>87%) but the combined PSA and RNA panel has lower positive prediction rates for the less aggressive G6 and G7(3+4) subgroups, 55%, and 49% respectively) while nearly the same positive prediction rate for the more aggressive G7(4+3) as G8 groups (79% and 83% respectively.</p