Common Familial Colorectal Cancer Linked to Chromosome 7q31: A Genome-Wide Analysis

Present investigations suggest that approximately 30% of colorectal cancer (CRC) cases arise on the basis of inherited factors. We hypothesize that the majority of inherited factors are moderately penetrant genes, common in the population. We use an affected sibling pair approach to identify genetic regions that are coinherited by siblings with CRC. Individuals from families with at least two siblings diagnosed with colorectal adenocarcinoma or high grade dysplasia were enrolled. Known familial CRC syndromes were excluded. A genome-wide scan on 151 DNA samples from 70 kindreds was completed using deCODE's 1100 short tandem repeat marker set at an average 4 cM density. Fine mapping on a total of 184 DNAs from 83 kindreds was done in regions suggesting linkage. Linkage analysis was accomplished with MERLIN analysis package. Linkage analysis revealed three genetic regions with NPL LOD scores ≥ 2.0: Ch. 3q29, LOD 2.61 (p=0.0003); Ch. 4q31.3, LOD 2.13 (p=0.0009); and Ch. 7q31.31, LOD 3.08 (p=0.00008). Affected siblings with increased sharing at the 7q31 locus have an 3.8 year (±3.5) earlier age of CRC onset although this is not statistically significant (p=0.11). No significant linkage was found near genes causing known syndromes or, regions previously reported (8q24, 9q22, and 11q23). The chromosome 3q21-q24 region reported to be linked in CRC relative pairs, is supported by our study, albeit a minor peak (LOD 0.9, p=0.02). No known familial cancer genes reside in the 7q31 locus, thus the identified region may contain a novel susceptibility gene responsible for common familial CRC

Non-compliance is the predominant cause of aspirin resistance in chronic coronary arterial disease patients

Abstract Background Our previous publication showed that 9% of patients with a history of myocardial infarction MI. could be labeled as aspirin resistant; all of these patients were aspirin resistant because of non-compliance. This report compares the relative frequency of aspirin resistance between known compliant and non-compliance subjects to demonstrate that non-compliance is the predominant cause of aspirin resistance. Methods The difference in the slopes of the platelet prostaglandin agonist (PPA) light aggregation curves off aspirin and 2 hours after observed aspirin ingestion was defined as net aspirin inhibition. Results After supposedly refraining from aspirin for 7 days, 46 subjects were judged non-compliant with the protocol. Of the remaining 184 compliant subjects 39 were normals and 145 had a past history of MI. In known compliant subjects there was no difference in net aspirin inhibition between normal and MI subjects. Net aspirin inhibition in known compliant patients was statistically normally distributed. Only 3% of compliant subjects (2 normals and 5 MI) had a net aspirin inhibitory response of less than one standard deviation which could qualify as a conservative designation of aspirin resistance. A maximum of 35% of the 191 post MI subjects could be classified as aspirin resistant and/or non-compliant: 9% aspirin resistant because of non-compliance, 23% non-compliant with the protocol and possibly 3% because of a decreased net aspirin inhibitory response in known compliant patients. Conclusion Our data supports the thesis that the predominant cause of aspirin resistance is noncompliance.</p

Right hepatectomy for living donation: Role of remnant liver volume in predicting hepatic dysfunction and complications

BACKGROUND: Extensive attention has been placed on remnant liver volume (RLV) above other factors to ensure donor safety. METHODS: We performed a retrospective review of 137 right hepatectomies in live donors between June 1999 and November 2010. RESULTS: Median right lobe volume was 1,029 cm(3), which correlated with its actual weight (r = 0.63, P 3 mg/dL or prothrombin time >18 s on postoperative day 4). RLV did not predict postoperative hepatic dysfunction (P = .9), but it was associated with peak international normalized ratio (INR) (P = .04). Donor age and male gender were predictors of increased bilirubin at postoperative day 4 (age, P = .03; gender, P = .02). Of the donors, 45 (33%) experienced complications, and 24 donors had RLVs <30%; 42% experienced complications compared to 31% of donors whose RLVs were greater than 30% (P = .3). Cell-saver utilization and aspartate-aminotransferase (AST) levels (OR = 3) were associated with complications. Volumetric assessment can predict RLV accurately. CONCLUSION: Although no demonstrable association between RLV <30% and complications was found, an RLV of 30% should remain the threshold for donor safety. Age and gender should be balanced in donors with a near threshold RLV of 30%. Surgical complexity, suggested by the need for intraoperative autoinfusion of blood and postoperative levels of AST, remained the independent predictor of complications.Fil: Facciuto, Marcelo. Mount Sinai Medical Center; Estados UnidosFil: Contreras Saldivar, Alan. Mount Sinai Medical Center; Estados UnidosFil: Singh, Manoj K.. Mount Sinai Medical Center; Estados UnidosFil: Rocca, Juan Pablo. Mount Sinai Medical Center; Estados UnidosFil: Taouli, Bachir. Mount Sinai Medical Center; Estados UnidosFil: Oyfe, Irina. Columbia University; Estados UnidosFil: LaPointe Rudow, Dianne. Mount Sinai Medical Center; Estados UnidosFil: Gondolesi, Gabriel Eduardo. Fundación Favaloro; Argentina. Universidad Favaloro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schiano, Thomas. Mount Sinai Medical Center; Estados UnidosFil: Kim Schluger, Leona. Mount Sinai Medical Center; Estados UnidosFil: Schwartz, Myron E.. Mount Sinai Medical Center; Estados UnidosFil: Miller, Charles M.. Cleveland Clinic. Digestive Disease Institute. Department of Hepato-Pancreato-Biliary and Transplant Surgery ; Estados UnidosFil: Florman, Sander. Mount Sinai Medical Center; Estados Unido

Activation of ERα Signaling Differentially Modulates IFN-γ Induced HLA-Class II Expression in Breast Cancer Cells

The coordinate regulation of HLA class II (HLA-II) is controlled by the class II transactivator, CIITA, and is crucial for the development of anti-tumor immunity. HLA-II in breast carcinoma is associated with increased IFN-γ levels, reduced expression of the estrogen receptor (ER) and reduced age at diagnosis. Here, we tested the hypothesis that estradiol (E2) and ERα signaling contribute to the regulation of IFN-γ inducible HLA-II in breast cancer cells. Using a panel of established ER− and ER+ breast cancer cell lines, we showed that E2 attenuated HLA-DR in two ER+ lines (MCF-7 and BT-474), but not in T47D, while it augmented expression in ER− lines, SK-BR-3 and MDA-MB-231. To further study the mechanism(s), we used paired transfectants: ERα+ MC2 (MDA-MB-231 c10A transfected with the wild type ERα gene) and ERα− VC5 (MDA-MB-231 c10A transfected with the empty vector), treated or not with E2 and IFN-γ. HLA-II and CIITA were severely reduced in MC2 compared to VC5 and were further exacerbated by E2 treatment. Reduced expression occurred at the level of the IFN-γ inducible CIITA promoter IV. The anti-estrogen ICI 182,780 and gene silencing with ESR1 siRNA reversed the E2 inhibitory effects, signifying an antagonistic role for activated ERα on CIITA pIV activity. Moreover, STAT1 signaling, necessary for CIITA pIV activation, and selected STAT1 regulated genes were variably downregulated by E2 in transfected and endogenous ERα positive breast cancer cells, whereas STAT1 signaling was noticeably augmented in ERα− breast cancer cells. Collectively, these results imply immune escape mechanisms in ERα+ breast cancer may be facilitated through an ERα suppressive mechanism on IFN-γ signaling