Citations

AbstractBackground: It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways.Methods: In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls).Results: The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the “effective” number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency < 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822.Conclusions: Our results provide new evidence of association between PPARG variants and colorectal cancer risk.Impact: Further replication in independent samples is warranted. Cancer Epidemiol Biomarkers Prev; 22(11); 2094–101. ©2013 AACR.

Key PointsPhenotypic and genotypic profiling of MDM2 in DLBCL. MDM2 as a negative regulator of p53 tumor suppressor function.

Significance We describe a genomic disorder that causes obesity, intellectual disability, and seizures. Children with this syndrome carry an unbalanced chromosome translocation that results in the duplication of over 100 genes, including G protein β3 ( GNB3 ). Although GNB3 polymorphisms have been associated with obesity, hypertension, and diabetes, the mechanism of GNB3 pathogenesis is unknown. We created a transgenic mouse model that carries a duplication of GNB3 , weighs significantly more than wild-type mice, and has excess abdominal fat. GNB3 is highly expressed in the brain and may be important for signaling related to satiety and/or metabolism.

Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus‐induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine‐activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus‐loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand‐off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL‐12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune‐mediated tumor cell killing.

ABSTRACT We assessed the performance of a duplex real-time PCR assay for bla KPC and bla NDM performed directly (D-PCR) on perianal and perirectal swabs and stool. Spiked specimens and 126 clinical surveillance swabs (comprising a sensitivity panel of 46 perirectal double swabs previously determined to be culture positive for bla KPC -PCR-positive Enterobacteriaceae and a specificity panel of 80 perianal swabs from patients at risk of carbapenemase-producing Enterobacteriaceae [CPE] colonization) were studied. For the surveillance swabs, D-PCR was compared to PCR after broth enrichment (BE-PCR) and two culture-based methods: the HardyCHROM ESBL agar (HC-A) and the CDC screening (CDC-A) methods. PCR was performed on morphologically distinct colonies that were isolated by culture. All of the initial PCR testing was done without extraction using a simple lysis procedure. The analytical sensitivities of D-PCR for bla KPC were 9 CFU/μl (for swabs) and 90 CFU/μl (for stool), and for bla NDM , it was 1.9 CFU/μl (for both swabs and stool). In the clinical sensitivity panel, D-PCR and BE-PCR were initially positive for bla KPC in 41/46 (89.1%) and 43/46 (93.5%) swabs, respectively. The swabs that were initially negative by D-PCR ( n = 5) and BE-PCR ( n = 3) were visibly stool soiled; all swabs were bla KPC positive upon repeat testing after lysate extraction. The CDC-A and HC-A yielded bla KPC -positive Enterobacteriaceae from 36/46 (78.3%) and 35/46 (76.1%) swabs, respectively (sensitivities of D-PCR/BE-PCR postextraction of soiled specimens versus HC-A, P = 0.0009, and versus CDC-A, P = 0.0016). All swabs in the specificity panel were negative for CPE by all four methods. D-PCR allows for the timely detection of bla KPC and bla NDM carriage with excellent sensitivity when specimens visibly soiled with stool undergo preparatory extraction.