Gene expression profiles of primary retinal pigment epithelial cells from apolipoprotein E knockout and human apolipoprotein E2 transgenic mice.

Age-related macular degeneration (AMD) causes visual impairment in the elderly. In non-neovascular AMD, studies involving human subjects have suggested potential involvement of aberrant lipid metabolism. However, there have been no reports on gene expression patterns in animal models of non-neovascular AMD with abnormal lipid metabolism such as apolipoprotein E knockout and human apolipoprotein E2 transgenic mice. Transcriptome analysis was performed using retinal pigment epithelium cells of apoE knockout and apolipoprotein E2 mice using microarray analysis. C57BL/6, Rxrb, Pparbp, Vldlr, and Edf1, which are primarily related to lipid metabolism, were upregulated, while Tgfbr1 and Pdgfb, which are related to pathologic angiogenesis in AMD, were downregulated in both types of mice. Apolipoprotein E knockout and apolipoprotein E2 mice showed characteristic gene expression patterns in the transcriptome analysis of primary retinal pigment epithelium cells. These results suggest that specific genes associated with lipid metabolism and angiogenesis are involved in the pathogenesis and progression of AMD.

Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type epidermal growth factor receptor (EGFR) and loss of the tumor suppressor genes Ink4a/Arf and PTEN are salient features of this deadly cancer. Surprisingly, targeted inhibition of EGFR has been clinically disappointing, demonstrating an innate ability for GBM to develop resistance. Efforts at modeling GBM in mice using wild-type EGFR have proven unsuccessful to date, hampering endeavors at understanding molecular mechanisms of therapeutic resistance. Here, we describe a unique genetically engineered mouse model of EGFR-driven gliomagenesis that uses a somatic conditional overexpression and chronic activation of wild-type EGFR in cooperation with deletions in the Ink4a/Arf and PTEN genes in adult brains. Using this model, we establish that chronic activation of wild-type EGFR with a ligand is necessary for generating tumors with histopathological and molecular characteristics of GBMs. We show that these GBMs are resistant to EGFR kinase inhibition and we define this resistance molecularly. Inhibition of EGFR kinase activity using tyrosine kinase inhibitors in GBM tumor cells generates a cytostatic response characterized by a cell cycle arrest, which is accompanied by a substantial change in global gene expression levels. We demonstrate that an important component of this pattern is the transcriptional activation of the MET receptor tyrosine kinase and that pharmacological inhibition of MET overcomes the resistance to EGFR inhibition in these cells. These findings provide important new insights into mechanisms of resistance to EGFR inhibition and suggest that inhibition of multiple targets will be necessary to provide therapeutic benefit for GBM patients.

Different relation between ERCC1 overexpression and treatment outcomes of two platinum agents in advanced biliary tract adenocarcinoma patients.

PURPOSE: The aim of this study is to evaluate the effect of excision repair cross-complementation group 1 (ERCC1) expression on treatment outcomes in advanced biliary tract adenocarcinoma (ABTA) patients treated with platinum-based chemotherapy. METHODS: One hundred and six patients with histologically confirmed adenocarcinoma of biliary tract were enrolled at 5 institutions in South Korea between January 2002 and September 2008. Of 106 patients, 93 were assessed by immunohistochemistry from tissue specimens. Sixty-five patients were treated with cisplatin-based regimens and the other 28 treated with oxaliplatin-based ones. RESULTS: For total study population, no significant differences were noted in progression-free survival (PFS) and overall survival (OS) between ERCC1-negative and ERCC1-positive patients, respectively (4.2 vs. 2.9 months, p = 0.116; 7.0 vs. 7.8 months, p = 0.143). In patients treated with cisplatin-based regimens, median PFS and OS were significantly longer in ERCC1-negative group than in ERCC1-positive group, respectively (4.6 vs. 1.9 months, p = 0.014; 9.1 vs. 7.9 months, p = 0.017). Disease control rate (DCR) was better in patients with ERCC1 negative than in patients with ERCC1 positive (p = 0.048). On the other hand, in patients treated with oxaliplatin-containing regimens, median PFS and OS tended to be longer in ERCC1-positive group, but these did not reach statistical significances. Response rate was better in patients with ERCC1 positive (p = 0.005). CONCLUSIONS: ERCC1 shows a significant prognostic value in ABTA patients treated with cisplatin. A survival benefit was observed in ERCC1-negative patients from cisplatin-containing chemotherapy but not from oxaliplatin-containing ones. The action mechanism of ERCC1 on cisplatin may be different from that on oxaliplatin.

Hypertension in adult survivors of child abuse: observations from the Nurses' Health Study II.

BACKGROUND: Limited research has shown a possible association between exposure to physical or sexual abuse prior to age 18 and the risk of developing hypertension as an adult. The factors mediating this relationship are unknown. METHODS: Questionnaire data from 68 505 female participants in the Nurses' Health Study II were analysed regarding exposure to physical and sexual abuse prior to age 18. Cox proportional hazards regression was used to assess the relationship between abuse exposure and hypertension. RESULTS: 64% of the participants (n=41 792) reported physical and/or sexual abuse prior to age 18; 17% reported hypertension. All forms of abuse had a dose-response relationship with hypertension. Adjustments for smoking, alcohol, family history of hypertension, exercise and oral contraceptives did not alter risk estimates. Adjustment for body mass index (BMI) significantly attenuated the associations between abuse and risk of hypertension and accounted for approximately 50% of the observed association between abuse exposure and hypertension. Women experiencing forced sexual activity as a child and as an adolescent had a 20% increased risk for developing hypertension (95% CI 8% to 32%) that was independent of BMI. Similarly, women reporting severe physical abuse in childhood and/or adolescence had risk estimates ranging from 14% (95% CI 5% to 24%) to 22% (95% CI 11% to 33%). CONCLUSION: Early interpersonal violence may be a widespread risk factor for the development of hypertension in women. BMI is a significant mediator in the relationship between early abuse and adult hypertension.

Community violence and urban childhood asthma: a multilevel analysis.

We examined the association between community violence exposure and childhood asthma risk in a multilevel, multimethod, longitudinal study controlling for individual- and neighbourhood-level confounders and pathway variables. Analyses included 2,071 children aged 0-9 yrs at enrolment from the Project on Human Development in Chicago Neighborhoods. Multilevel logistic regression models estimated the likelihood of asthma, controlling for individual-level (child's age, sex, race/ethnicity, maternal asthma, socioeconomic status and family violence in the home) and neighbourhood-level confounders (concentrated disadvantage, collective efficacy and social disorder), and pathway variables (maternal smoking, breastfeeding). In adjusted analyses, medium (OR 1.60, 95% CI 1.17-2.19) and high levels (OR 1.56, 95% CI 1.12-2.18) of community violence were associated with increased asthma risk, relative to low levels. The increased asthma risk remained for African Americans when models included community violence and all other individual-level covariates, but attenuated to borderline nonsignificance when further adjusting for collective efficacy. Community violence is associated with asthma risk when controlling for individual- and neighborhood-level confounders. Neither community violence, nor the other individual-level factors, fully accounted for the excess asthma burden among African Americans. These data suggest that public health interventions outside the biomedical model may be needed to reduce asthma in disadvantaged populations.

ERCC1 expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation.

The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway and is associated with resistance to platinum-based chemotherapy. The purpose of this study was to evaluate the role of ERCC1 expression as a predictive marker of survival in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) treated with cisplatin-based concurrent chemoradiotherapy (CCRT). ERCC1 expression was assessed by immunohistochemical staining. The median age of the 45 patients analysed was 56 years (range 27-75 years), and 82% were men; 73% of all specimens showed high expression of ERCC1. The overall tumour response rate after CCRT was 89%. The median follow-up was 53.6 months (95% CI, 34.5-72.7 months). The 3-year progression-free survival (PFS) and overall survival (OS) rates were 58.7 and 61.3%, respectively. Univariate analyses showed that patients with low expression of ERCC1 had a significantly higher 3-year PFS (83.3 vs 49.4%, P=0.036) and OS (91.7 vs 45.5%, P=0.013) rates. Multivariate analysis showed that low expression of ERCC1 was an independent predictor for prolonged survival (HR, 0.120; 95% CI, 0.016-0.934, P=0.043). These results suggest that ERCC1 expression might be a useful predictive marker of locally advanced SCCHN in patients treated with cisplatin-based CCRT.

Partial trisomy of chromosome 10(q22-q24) due to maternal insertional translocation (15;10).

Interchromosomal insertional translocations are rare chromosome rearrangements with an incidence of about 1:80,000 live births. We report on the clinical and cytogenetic findings of a newborn baby with partial trisomy 10q22-10q24 due to a maternal insertional translocation 15;10. Partial trisomy of the long arm of chromosome 10 is a distinctive chromosome aberration characterized by prenatal-onset growth retardation and craniofacial, skeletal, and other somatic anomalies. Most cases are unbalanced products from reciprocal chromosome translocations, and insertional translocations are rarely involved. The proband was initially referred because of severe intrauterine growth retardation, and fluorescence in situ hybridization (FISH) using painting probes confirmed the maternal balanced (15;10) insertion.

Simplified retrograde systemic perfusion for removal of air from the aorta in an infant.

Total circulatory arrest with full venous drainage can result in air entering the arterial system through several possible sites such as the aortic cannulation site or collateral vessels. Air present in the arterial system during total circulatory arrest imposes a special problem. We describe a simple technique of short-term retrograde systemic perfusion to remove air from the arterial system before restarting systemic arterial perfusion after total circulatory arrest.

Revascularization of the ischemic colon transplant using the internal mammary vessels.

We describe a successful reconstruction of the esophagus with the isoperistaltic right colon and terminal ileum, which had very poor continuity of the marginal artery. The stomach and the left colon were not available because of corrosive injury and intraabdominal adhesions. The blood supply of the ischemic transplant was augmented by anastomosis of the internal mammary vessels to the iliocolic vessels.