Risk factors for bone mineral density at the calcaneus in 40–59 year-old male workers: A cross-sectional study in Korea

<p>Abstract</p> <p>Background</p> <p>Few epidemiologic studies have attempted to investigate the prevalence and risk factors for osteopenia and osteoporosis in middle-aged Asian men. We performed this study to determine the prevalence and risk factors of osteopenia and osteoporosis in this population.</p> <p>Methods</p> <p>This cross-sectional study was conducted from March to July, 2004. The subjects were 2,073 males aged from 40 to 59 years in the KHNP (Korea Hydro & Nuclear Power) workplace-based cohort. Bone mineral density (BMD) was measured by peripheral, dual-energy, X-ray absorptiometry (DXA) at the calcaneus. Anthropometric and lifestyle factors were investigated using a standard, self-reported questionnaire.</p> <p>Results</p> <p>BMD was 0.60 ± 0.09 g/cm²(mean ± standard deviation) and was negatively correlated with age (r = -0.18, <it>P </it>< 0.001), but positively correlated with waist-to-hip ratio (WHR; r = 0.15, <it>P </it>< 0.001), body fat (r = 0.10, <it>P </it>< 0.001), BMI (r = 0.35, <it>P </it>< 0.001), height (r = 0.26, <it>P </it>< 0.001), and weight (r = 0.43, <it>P </it>< 0.001).</p> <p>In multiple linear regression analysis, the independent determinants associated with BMD were increasing age (coefficient = -0.002, <it>P </it>< 0.001), physical activity (≤ 2/week vs. ≥ 3/week; coefficient = 0.017, <it>P </it>< 0.001), WHR (coefficient = -0.796, <it>P </it>< 0.001), body mass index (BMI; coefficient = 0.023, <it>P </it>< 0.001) and smoking status (never vs. ever; coefficient = -0.018, <it>P </it>< 0.001).</p> <p>Conclusion</p> <p>We suggest that BMD of the calcaneus is correlated negatively with exposure to smoke and increased WHR, but positively with regular exercise and increased BMI.</p

Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) and serine biosynthetic pathway genes are co-ordinately increased during anabolic agent-induced skeletal muscle growth

We aimed to identify novel molecular mechanisms for muscle growth during administration of anabolic agents. Growing pigs (Duroc/(Landrace/Large-White)) were administered Ractopamine (a beta-adrenergic agonist; BA; 20ppm in feed) or Reporcin (recombinant growth hormone; GH; 10mg/48hours injected) and compared to a control cohort (feed only; no injections) over a 27-day time course (1, 3, 7, 13 or 27-days). Longissimus Dorsi muscle gene expression was analyzed using Agilent porcine transcriptome microarrays and clusters of genes displaying similar expression profiles were identified using a modified maSigPro clustering algorithm. Anabolic agents increased carcass (p=0.002) and muscle weights (Vastus Lateralis: p<0.001; Semitendinosus: p=0.075). Skeletal muscle mRNA expression of serine/one-carbon/glycine biosynthesis pathway genes (Phgdh, Psat1 and Psph) and the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase-M (Pck2/PEPCK-M), increased during treatment with BA, and to a lesser extent GH (p<0.001, treatment x time interaction). Treatment with BA, but not GH, caused a 2-fold increase in phosphoglycerate dehydrogenase (PHGDH) protein expression at days 3 (p<0.05) and 7 (p<0.01), and a 2-fold increase in PEPCK-M protein expression at day 7 (p<0.01). BA treated pigs exhibit a profound increase in expression of PHGDH and PEPCK-M in skeletal muscle, implicating a role for biosynthetic metabolic pathways in muscle growth

Inclusion of maintenance energy improves the intracellular flux predictions of CHO

Chinese hamster ovary (CHO) cells are the leading platform for the production of biopharmaceuticals with human-like glycosylation. The standard practice for cell line generation relies on trial and error approaches such as adaptive evolution and high-throughput screening, which typically take several months. Metabolic modeling could aid in designing better producer cell lines and thus shorten development times. The genome-scale metabolic model (GSMM) of CHO can accurately predict growth rates. However, in order to predict rational engineering strategies it also needs to accurately predict intracellular fluxes. In this work we evaluated the agreement between the fluxes predicted by parsimonious flux balance analysis (pFBA) using the CHO GSMM and a wide range of 13C metabolic flux data from literature. While glycolytic fluxes were predicted relatively well, the fluxes of tricarboxylic acid (TCA) cycle were vastly underestimated due to too low energy demand. Inclusion of computationally estimated maintenance energy significantly improved the overall accuracy of intracellular flux predictions. Maintenance energy was therefore determined experimentally by running continuous cultures at different growth rates and evaluating their respective energy consumption. The experimentally and computationally determined maintenance energy were in good agreement. Additionally, we compared alternative objective functions (minimization of uptake rates of seven nonessential metabolites) to the biomass objective. While the predictions of the uptake rates were quite inaccurate for most objectives, the predictions of the intracellular fluxes were comparable to the biomass objective function.COMET center acib: Next Generation Bioproduction, which is funded by BMK, BMDW, SFG, Standortagentur Tirol, Government of Lower Austria and Vienna Business Agency in the framework of COMET - Competence Centers for Excellent Technologies. The COMET-Funding Program is managed by the Austrian Research Promotion Agency FFG; D.S., J.S., M.W., M.H., D. E.R. This work has also been supported by the PhD program BioToP of the Austrian Science Fund (FWF Project W1224)info:eu-repo/semantics/publishedVersio

Small molecule compounds targeting the p53 pathway: are we finally making progress?

Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful

Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments.

BACKGROUND: Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid biosynthesis has been predicted to be an essential process in cancer cells. However, it is unclear which enzymes within this pathway offer the best selectivity for cancer cells and could be suitable therapeutic targets. RESULTS: Using functional genomics, we identified stearoyl-CoA desaturase (SCD), an enzyme that controls synthesis of unsaturated fatty acids, as essential in breast and prostate cancer cells. SCD inhibition altered cellular lipid composition and impeded cell viability in the absence of exogenous lipids. SCD inhibition also altered cardiolipin composition, leading to the release of cytochrome C and induction of apoptosis. Furthermore, SCD was required for the generation of poly-unsaturated lipids in cancer cells grown in spheroid cultures, which resemble those found in tumour tissue. We also found that SCD mRNA and protein expression is elevated in human breast cancers and predicts poor survival in high-grade tumours. Finally, silencing of SCD in prostate orthografts efficiently blocked tumour growth and significantly increased animal survival. CONCLUSIONS: Our data implicate lipid desaturation as an essential process for cancer cell survival and suggest that targeting SCD could efficiently limit tumour expansion, especially under the metabolically compromised conditions of the tumour microenvironment

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability