Standards of pancreaticoduodenectomy in a tertiary referral centre in Hong Kong: retrospective case series.

OBJECTIVE: To evaluate the perioperative outcomes of pancreaticoduodenectomy in a tertiary referral centre in Hong Kong. DESIGN: Retrospective case series. SETTING: University teaching hospital, Hong Kong. PATIENTS: One hundred and forty patients who underwent pancreaticoduodenectomy from July 1989 through June 2001. MAIN OUTCOME MEASURES: Mortality and morbidity. RESULTS: Overall hospital mortality among 140 patients was 2.9% (n=4), and 30-day operative mortality was 2.1% (n=3). There was no significant difference in the hospital mortality rate between 43 elderly patients aged 70 years or older and 97 younger patients (2.3% versus 3.1%). The overall morbidity rate was 38.6% (n=54). Intra-abdominal abscess (13.6%) and pancreaticojejunal anastomotic leakage (12.9%) were the two most common complications. Presence of co-morbid illness (risk ratio, 2.823; 95% confidence interval, 1.541-4.385; P=0.01), preoperative cholangitis (risk ratio, 2.565; 95% confidence interval, 1.166-5.643; P=0.02), and intra-operative blood loss >/=1.5 L (risk ratio, 2.236; 95% confidence interval, 1.132-6.213; P=0.03) were independent risk factors for postoperative morbidity. CONCLUSIONS: Pancreaticoduodenectomy is associated with a low risk of operative death when performed in a tertiary referral setting in Hong Kong. The postoperative morbidity rate remains high, however. Further improvement by reducing intra-operative blood loss may help curtail the high postoperative morbidity.published_or_final_versio

Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease

Background The combination of bevacizumab (B) and erlotinib (E) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients. We aimed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment. Methods Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited. All patients received bevacizumab(B) at 10 mg/kg every 2 weeks with erlotinib(E) at 150 mg daily for a maximum of 6 cycles. Response assessments using both RECIST and modified RECIST criteria were performed after every 6 weeks. The primary endpoint was clinical benefit (CB) rate and a Simon two-stage design was employed. Results The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited. The median age was 47 years (range, 28-61) and all patients were in ECOG performance status 1. Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis. Among these 10 patients, none of the enrolled patients achieved response or stable disease. The median time-to-progression was 1.81 months (95 % confidence interval [C.I.], 1.08-1.74 months) and overall survival was 4.37 months (95 % C.I., 1.08-11.66 months). Rash (70 %), diarrhea (50 %) and malaise (40 %) were the most commonly encountered toxicities. Conclusion The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population. Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population. © 2012 The Author(s).published_or_final_versio

Global Regulation on microRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma

Recent work has revealed the causative links between deregulation of microRNAs (miRNAs) and cancer development. In hepatocellular carcinoma (HCC), aberrant expression of miRNAs has been observed, but the molecular mechanisms that contribute to such changes remains to be elucidated. Here, we reported the analysis of miRNA expression in 94 pairs of tumor and adjacent nontumor tissues from HBV-associated HCC in Chinese patients. We found miRNAs were aberrantly expressed in HCC tissues. To investigate the cause of such deregulation, we detected changes in DNA copy number by measuring locus-specific hybridization intensity, and found changes in expression of several miRNAs are correlated with genomic amplification or deletion. For example, the genomic regions of miR-30d and miR-151 were amplified in ∼50% of HCC tumor tissues, and the expressions of these miRNAs are significantly correlated with DNA copy number. We also employed cDNA microarray data, and provide evidence that key regulators of the miRNA biosynthetic pathway, including DROSHA, DGCR8, AGO1, and AGO2, are frequently overexpressed in HCC. This study provides molecular clues that may contribute to the global changes of miRNA expression in HCC. Copyright © 2011, Mary Ann Liebert, Inc.published_or_final_versio

Mouse models of diabetes, obesity and related kidney disease

© 2016 Glastras et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Multiple rodent models have been used to study diabetic kidney disease (DKD). The purpose of the present study was to compare models of diabetes and obesity-induced metabolic syndrome and determine differences in renal outcomes. C57BL/6 male mice were fed either normal chow or high fat diet (HFD). At postnatal week 8, chow-fed mice were randomly assigned to low-dose streptozotocin (STZ, 55 mg/kg/day, five consecutive days) or vehicle control, whereas HFD-fed mice were given either one high-dose of STZ (100 mg/kg) or vehicle control. Intraperitoneal glucose tolerance tests were performed at Week 14, 20 and 30. Urinary albumin to creatinine ratio (ACR) and serum creatinine were measured, and renal structure was assessed using Periodic Acid Schiff (PAS) staining at Week 32. Results showed that chow-fed mice exposed to five doses of STZ resembled type 1 diabetes mellitus with a lean phenotype, hyperglycaemia, microalbuminuria and increased serum creatinine levels. Their kidneys demonstrated moderate tubular injury with evidence of tubular dilatation and glycogenated nuclear inclusion bodies. HFD-fed mice resembled metabolic syndrome as they were obese with dyslipidaemia, insulin resistance, and significantly impaired glucose tolerance. One dose STZ, in addition to HFD, did not worsen metabolic features (including fasting glucose, non esterified fatty acid, and triglyceride levels). There were significant increases in urinary ACR and serum creatinine levels, and renal structural changes were predominantly related to interstitial vacuolation and tubular dilatation in HFD-fed mice

Hsf1 and Hsp90 orchestrate temperature-dependent global transcriptional remodelling and chromatin architecture in Candida albicans

This is the final version. Available from Nature Research via the DOI in this record.RNA-sequencing data sets are available at ArrayExpress (www.ebi.ac.uk) under accession code E-MTAB-4075. ChIP-seq data sets are available at the NCBI SRA database (http://www.ncbi.nlm.nih.gov) under accession code SRP071687. The authors declare that all other data supporting the findings of this study are available within the article and its supplementary information files, or from the corresponding author upon request.Fever is a universal response to infection, and opportunistic pathogens such as Candida albicans have evolved complex circuitry to sense and respond to heat. Here we harness RNA-seq and ChIP-seq to discover that the heat shock transcription factor, Hsf1, binds distinct motifs in nucleosome-depleted promoter regions to regulate heat shock genes and genes involved in virulence in C. albicans. Consequently, heat shock increases C. albicans host cell adhesion, damage and virulence. Hsf1 activation depends upon the molecular chaperone Hsp90 under basal and heat shock conditions, but the effects are opposite and in part controlled at the level of Hsf1 expression and DNA binding. Finally, we demonstrate that Hsp90 regulates global transcription programs by modulating nucleosome levels at promoters of stress-responsive genes. Thus, we describe a mechanism by which C. albicans responds to temperature via Hsf1 and Hsp90 to orchestrate gene expression and chromatin architecture, thereby enabling thermal adaptation and virulence.Wellcome TrustCanadian Institutes of Health ResearchCanadian Institutes of Health ResearchBiotechnology and Biological Sciences Research Council (BBSRC)European Research Council (ERC)Science and Technology Development Fund of Macau S.A.R (FDCT)Research and Development Administrative Office of the University of MacauNational Institutes of Health (NIH

Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels

Background/aim: To examine the risks for hepatocellular carcinoma (HCC) with respect to hepatitis B virus (HBV) genotypes, specific viral mutations (MT), serum HBV DNA levels, and cirrhosis. Methods: HBV genotypes, 1653/1753/core promoter (CP)/precore MT and HBV DNA levels were determined in 248 HBV patients with HCC and 248 HBV controls. Results: Genotype C, CP-MT, T1653, HBV DNA levels ≥4 log 10 copies/ml and cirrhosis had a higher risk for HCC compared to patients with genotype B (p = 0.001, OR 1.9), CP wild-type (WT) (p<0.001, OR 4.1), C1653 (p = 0.028, OR 2.4), HBV DNA <4 log 10 copies/ml (p = 0.003, OR 2.1) and without cirrhosis (p<0.001, OR 4.0) respectively. Multivariate analysis showed that CP-MT, T1653, HBV DNA ≥4 log 10 copies/ml and cirrhosis were independent factors for HCC (all p<0.05). A receiver operating characteristics curve showed no cut-off HBV DNA level associated with minimal chance of HCC. Patients with CP-MT and cirrhosis had a 22.2-fold increased risk of HCC compared to patients with CP-WT and without cirrhosis. Patients with CP-MT and HBV DNA levels ≥4 log 10 copies/ml had a 7.2-fold increased risk of HCC compared to patients with CP-WT and HBV DNA levels <4 log 10 copies/ml. Patients with CP-MT and T1653 had a 9.9-fold increased risk of HCC compared to patients with wild-type for both regions. Conclusions: CP-MT, T1653, HBV DNA levels ≥4 log 10 copies/ml and cirrhosis are independent factors for development of HCC. The risks increased substantially in patients having these factors in combination.published_or_final_versio

Demand forecasting: a case study in the food industry

The use of forecasting methods is nowadays regarded as a business ally since it supports both the operational and the strategic decision-making processes. This paper is based on a research project aiming the development of demand forecasting models for a company (designated here by PR) that operates in the food business, more specifically in the delicatessen segment. In particular, we focused on demand forecasting models that can serve as a tool to support production planning and inventory management at the company. The analysis of the company’s operations led to the development of a new demand forecasting tool based on a combination of forecasts, which is now being used and tested by the company.This work has been supported by FCT – Fundação para a Ciência e Tecnologia within the Project Scope: UID/CEC/00319/201

The temporal reliability of serum estrogens, progesterone, gonadotropins, SHBG and urinary estrogen and progesterone metabolites in premenopausal women

BACKGROUND: There is little existing research to guide researchers in estimating the minimum number of measurement occasions required to obtain reliable estimates of serum estrogens, progesterone, gonadotropins, sex hormone-binding globulin (SHBG), and urinary estrogen and progesterone metabolites in premenopausal women. METHODS: Using data from a longitudinal study of 34 women with a mean age of 42.3 years (SD = 2.6), we calculated the minimum number of measurement occasions required to obtain reliable estimates of 12 analytes (8 in blood, 4 in urine). Five samples were obtained over 1 year: at baseline, and after 1, 3, 6, and 12 months. We also calculated the percent of true variance accounted for by a single measurement and intraclass correlation coefficients (ICC) between measurement occasions. RESULTS: Only 2 of the 12 analytes we examined, SHBG and estrone sulfate (E(1)S), could be adequately estimated by a single measurement using a minimum reliability standard of having the potential to account for 64% of true variance. Other analytes required from 2 to 12 occasions to account for 81% of the true variance, and 2 to 5 occasions to account for 64% of true variance. ICCs ranged from 0.33 for estradiol (E(2)) to 0.88 for SHBG. Percent of true variance accounted for by single measurements ranged from 29% for luteinizing hormone (LH) to 92% for SHBG. CONCLUSIONS: Experimental designs that take the natural variability of these analytes into account by obtaining measurements on a sufficient number of occasions will be rewarded with increased power and accuracy

Phosphodiesterase type 4 expression and anti-proliferative effects in human pulmonary artery smooth muscle cells

BACKGROUND: Pulmonary arterial hypertension is a proliferative vascular disease, characterized by aberrant regulation of smooth muscle cell proliferation and apoptosis in distal pulmonary arteries. Prostacyclin (PGI(2)) analogues have anti-proliferative effects on distal human pulmonary artery smooth muscle cells (PASMCs), which are dependent on intracellular cAMP stimulation. We therefore sought to investigate the involvement of the main cAMP-specific enzymes, phosphodiesterase type 4 (PDE4), responsible for cAMP hydrolysis. METHODS: Distal human PASMCs were derived from pulmonary arteries by explant culture (n = 14, passage 3–12). Responses to platelet-derived growth factor-BB (5–10 ng/ml), serum, PGI(2 )analogues (cicaprost, iloprost) and PDE4 inhibitors (roflumilast, rolipram, cilomilast) were determined by measuring cAMP phosphodiesterase activity, intracellular cAMP levels, DNA synthesis, apoptosis (as measured by DNA fragmentation and nuclear condensation) and matrix metalloproteinase-2 and -9 (MMP-2, MMP-9) production. RESULTS: Expression of all four PDE4A-D genes was detected in PASMC isolates. PDE4 contributed to the main proportion (35.9 ± 2.3%, n = 5) of cAMP-specific hydrolytic activity demonstrated in PASMCs, compared to PDE3 (21.5 ± 2.5%), PDE2 (15.8 ± 3.4%) or PDE1 activity (14.5 ± 4.2%). Intracellular cAMP levels were increased by PGI(2 )analogues and further elevated in cells co-treated with roflumilast, rolipram and cilomilast. DNA synthesis was attenuated by 1 μM roflumilast (49 ± 6% inhibition), rolipram (37 ± 6%) and cilomilast (30 ± 4%) and, in the presence of 5 nM cicaprost, these compounds exhibited EC(50 )values of 4.4 (2.6–6.1) nM (Mean and 95% confidence interval), 59 (36–83) nM and 97 (66–130) nM respectively. Roflumilast attenuated cell proliferation and gelatinase (MMP-2 and MMP-9) production and promoted the anti-proliferative effects of PGI(2 )analogues. The cAMP activators iloprost and forskolin also induced apoptosis, whereas roflumilast had no significant effect. CONCLUSION: PDE4 enzymes are expressed in distal human PASMCs and the effects of cAMP-stimulating agents on DNA synthesis, proliferation and MMP production is dependent, at least in part, on PDE4 activity. PDE4 inhibition may provide greater control of cAMP-mediated anti-proliferative effects in human PASMCs and therefore could prove useful as an additional therapy for pulmonary arterial hypertension

Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited