Effect of Novel Dietary Supplement on Metabolism in \u3cem\u3evitro\u3c/em\u3e and \u3cem\u3ein vivo\u3c/em\u3e

Obesity is an increasingly prevalent and preventable morbidity with multiple behavioral, surgical and pharmacological interventions currently available. Commercial dietary supplements are often advertised to stimulate metabolism and cause rapid weight and/or fat loss, although few well-controlled studies have demonstrated such effects. We describe a commercially available dietary supplement (purportedly containing caffeine, catechins, and other metabolic stimulators) on resting metabolic rate in humans, and on metabolism, mitochondrial content, and related gene expression in vitro. Human males ingested either a placebo or commercially available supplement (RF) in a randomized double-blind placebo-controlled cross-over fashion. Metabolic rate, respiratory exchange ratio, and blood pressure were measured hourly for 3 h post-ingestion. To investigate molecular effects, human rhabdomyosarcoma cells (RD) and mouse myocytes (C2C12) were treated with various doses of RF for various durations. RF enhanced energy expenditure and systolic blood pressure in human males without altering substrate utilization. In myocytes, RF enhanced metabolism, metabolic gene expression, and mitochondrial content suggesting RF may target common energetic pathways which control mitochondrial biogenesis. RF appears to increase metabolism immediately following ingestion, although it is unclear if RF provides benefits beyond those provided by caffeine alone. Additional research is needed to examine safety and efficacy for human weight loss

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Low rates of antibiotic resistance and infectious mortality in a cohort of high-risk hematology patients: A single center, retrospective analysis of blood stream infection.

Febrile neutropenia (FN) is a medical emergency and can represent a life-threatening complication for hematology patients treated with intensive chemotherapy regimens. In clinical practice, the diagnostic yield of blood cultures and other investigations which aim to identify a causative organism or site of infection is low. We have retrospectively examined all blood cultures collected in a "real world" cohort of patients receiving chemotherapy for acute leukemia and patients with aggressive lymphoma treated with Hyper-CVAD/MTX-cytarabine, at a single tertiary center over a five-year period. In this cohort, the 30-day mortality following confirmed blood stream infection (BSI) was 5.9%, which is lower than most reports in the recent literature. We compared the blood culture results of inpatients undergoing induction chemotherapy and outpatients presenting with fevers and found a significantly higher rate of proven BSI in the outpatient group. In all settings, gram-negative organisms were most common. The rate of resistance to first-line empiric antibiotics among pathogenic isolates was 11.6% in the whole cohort, independent of blood culture circumstances. There was a trend to higher resistance rates among inpatients undergoing induction chemotherapy compared to patients presenting to the emergency department (17.4% vs 7.5%) but this did not reach statistical significance. We also report low rates of ciprofloxacin resistance (5% of isolates), in a center where universal fluoroquinolone prophylaxis is not employed. Our low resistance and mortality rates support our current therapeutic strategies, however presence of resistant organisms across the spectrum of indications for BC collection highlights the importance of surveilling local patterns, escalating antimicrobial therapy in the deteriorating patient, and considering advanced techniques for the rapid identification of resistance in this patient population

Effect of post-exercise caffeine and green coffee bean extract consumption on blood glucose and insulin concentrations

Objective The aim of this study was to investigate the effects of ingesting caffeine and green coffee bean extract on blood glucose and insulin concentrations during a post-exercise oral glucose tolerance test. Methods Ten male cyclists (age: 26 ± 5 y; height: 179.9 ± 5.4 cm; weight: 77.6 ± 13.3 kg; body mass index: 24 ± 4.3 kg/m2; VO2 peak: 55.9 ± 8.4 mL·kg·min−1) participated in this study. In a randomized order, each participant completed three 30-min bouts of cycling at 60% of peak power output. Immediately after exercise, each participant consumed 75 g of dextrose with either 5 mg/kg body weight of caffeine, 10 mg/kg of green coffee bean extract (5 mg/kg chlorogenic acid), or placebo. Venous blood samples were collected immediately before and after exercise during completion of the oral glucose tolerance test. Results No significant time × treatment effects for blood glucose and insulin were found. Two-h glucose and insulin area under the curve values, respectively, for the caffeine (658 ± 74 mmol/L and 30,005 ± 13,304 pmol/L), green coffee bean extract (637 ± 100 mmol/L and 31,965 ± 23,586 pmol/L), and placebo (661 ± 77 mmol/L and 27,020 ± 12,339 pmol/L) trials were not significantly different (P \u3e 0.05). Conclusion Caffeine and green coffee bean extract did not significantly alter postexercise blood glucose and insulin concentrations when compared with a placebo. More human research is needed to determine the impact of these combined nutritional treatments and exercise on changes in blood glucose and insulin

Blood culture episodes among inpatients receiving induction chemotherapy and outpatients presenting to the emergency department.

<p>A) Blood culture episodes among the 161 patients admitted for induction chemotherapy, divided as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0178059#pone.0178059.g001" target="_blank">Fig 1</a>. B) Blood culture episodes among patients presenting to the emergency department with a febrile episode.</p

High risk patient demographics, 2010–2014.

<p>High risk patient demographics, 2010–2014.</p

Organisms isolated in the cohort, by ANC at time of collection.

<p>Organisms isolated in the cohort, by ANC at time of collection.</p