Downregulation of TOMM40 expression in the blood of Alzheimer disease subjects compared with matched controls

Translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene has been reported in several GWAS to be associated with Alzheimer disease (AD). Gene expression studies thus far only showed TOMM40 differential expression in one study on brain cortex and not in peripheral blood. We studied the gene expression profiles of AD blood versus controls in an Asian population in Singapore. In this first analysis we focused on genes that have been previously reported on GWAS. We found TOMM40 to be significantly down-regulated in blood samples of AD in one discovery and two validation sets, totalling 45 subjects (mean age 76.90, SD 6.46) and 45 controls (mean age 76.23, SD 5.09), matched for ethnicity and gender. The function of TOMM40 is not yet fully characterized but is believed to be involved in import and trafficking of protein into mitochondria. Therefore TOMM40 downregulation, found in the brain in severe AD and in our blood profile, may be a potential marker for AD, disease severity or progression and merit further investigation.     

An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors

Pazopanib, an oral inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit kinases, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of pazopanib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe drugs in the presence and absence of pazopanib. The probes used included midazolam (CYP3A specific), warfarin (CYP2C9 specific), omeprazole (CYP2C19 specific), caffeine (CYP1A2 specific), and dextromethorphan (CYP2D6 specific). The estimated ratios of the geometric means (90% confidence interval (CI)) for the area under the curve to the last measurable point (AUC(0-t)) for these probe drugs with/without pazopanib were as follows: midazolam, 1.35 (1.18-1.54); omeprazole, 0.81 (0.59-1.12); caffeine, 1.00 (0.77-1.30); and S-warfarin, 0.93 (0.84-1.03). The geometric least-squares (LS) mean ratio of urine dextromethorphan:dextrorphan ranged from 1.33 (0-4-h interval) to 1.64 (4-8-h interval). The data suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2D6 and has no effect on CYP1A2, CYP2C9, and CYP2C19 in patients with advanced cancer.     

Evaluation of a head-mounted display (HMD) in the performance of a simulated laparoscopic task

BACKGROUND: Head-mounted display (HM) units are used in various industries, but they have been tried only recently in surgery. In this study, we evaluated whether a commercially available HMD would improve or impede a laparoscopic task-in this case, suturing. METHODS: Six participants performed a total of 120 laparoscopic suture knots in an experimental model. The Olympus FMD011 model with a two-dimensional image was used. The order of each task with or without the head display unit was random. The time to complete each knot was recorded, and the results were analyzed. RESULTS: The display unit prolonged the suturing times of the subjects by 10% (p < 0.04). CONCLUSIONS: In this experimental model, the HMD we utilized did not appear to improve laparoscopic suturing. More developments, such as improved depth perception and better resolution, may increase its usefulness for laparoscopic tasks.     

Frequent concomitant epigenetic silencing of the stress‐responsive tumor suppressor gene CADM1, and its interacting partner DAL‐1 in nasal NK/T‐cell lymphoma

Nasal NK/T‐cell lymphoma (NL) is a rare but clinically important entity of lymphoma. Its preferential incidence in Orientals but not Caucasians suggests possible genetic predisposition. 11q deletion is common in NL, indicating certain tumor suppressor genes (TSGs) at this locus involved in its pathogenesis. We investigated the expression and methylation of an 11q23.2 TSG, CADM1 (or TSLC1), and its partner DAL‐1 (or EPB41L3) in NL. Methylation and silencing of CADM1 were detected in 2 NL and 4 of 8 (50%) of non‐Hodgkin lymphoma (NHL) cell lines, but not in normal NK cells and normal PBMC. Absence of CADM1 protein was also detected in NL cell lines. 5‐aza‐2′‐deoxycytidine (Aza) demethylation or genetic knockout of both DNMT1 and 3B genes restored CADM1 and DAL‐1 expression. CADM1 methylation was further detected in 36 of 45 (80%) of NL tumors. Concomitantly, DAL‐1 was epigenetically inactivated in NL cell lines and virtually all the tumors with methylated CADM1. A significant correlation between the methylation of both genes was found (p < 0.0001). Homozygous deletion of CADM1 was detected in only 3 of 18 (17%) of tumors. The stress‐response of CADM1 was abolished when its promoter becomes methylated. Our results demonstrate a frequent, predominant epigenetic silencing of CADM1 and DAL‐1 in NL, which likely play a synergic role in NL pathogenesis. © 2008 Wiley‐Liss, Inc.     

Predicting breast cancer risk: implications of a “weak” family history

Published guidelines adopted in many countries recommend that women whose family history of breast cancer places them at a risk ≥1.7 times that of the age-matched general population, should be considered for inclusion in special surveillance programmes. However validation of risk assessment models has been called for as a matter of urgency. The databases of the four Scottish Familial Breast Cancer clinics and the Scottish Cancer Registry have been searched to identify breast cancers occurring among 1,125 women aged 40–56, with family histories placing them below the “moderate” level of genetic risk. The observed incidence over 6 years was compared with age-specific data for the Scottish population. Our findings confirm that when there are two affected relatives (one first degree) the relative risk (RR) exceeds 1.7 regardless of their ages at diagnosis. When only one (first degree) relative was affected at any age from 40 to 55, the RR does not reach 1.7 if that relative was a mother but exceeds it if the relative was a sister. The probable explanation is that sisters are more likely than mother/daughter pairs to share homozygosity for a risk allele. Surveillance programmes might therefore accommodate sisters of women affected before age 55. Evidence that “low penetrance” alleles contributing to breast cancer risk may be recessive should be taken into account in strategies for identifying them. All the authors are from the Scottish Cancer Family Clinical Centres.     

Familial nasopharyngeal carcinoma in a cohort of 200 patients

OBJECTIVES: To describe the characteristics of familial nasopharyngeal carcinoma (NPC) in a high-risk population and to determine the role of screening first-degree relations. DESIGN: An analysis on a cohort of 200 patients newly diagnosed as having NPC. SETTING: A tertiary-level institution. PATIENTS: The patients were divided into 2 groups. Patients in group 1 had a first-degree relative with NPC, and those in group 2 did not. For patients in group 1, the relationship and the time interval between affected relatives were noted. The clinical and pathological factors of the 2 groups were obtained and statistically analyzed. RESULTS: There were 15.5% of NPC patients who had an affected first-degree relative. Of the affected relatives, 71% were siblings and 29% were parents. The mean interval between affected siblings was 5.3 years, while that between an affected parent and a child was 24.5 years. No differences were noted in the clinical factors between familial and nonfamilial NPC patients. Most patients in both groups were diagnosed as having stage III or IV NPC. CONCLUSIONS: The rate of familial NPC in our study is 15.5%. Siblings are more commonly affected, and the interval between 2 affected siblings is relatively short. No distinct clinical pattern exists in familial NPC. We recommend that siblings of NPC patients be screened as soon as possible once the index case is diagnosed.