Colorectal Cancer: How Does an Existing Tool Perform in Predicting Risk in Young, High-Risk Patients?

https://openworks.mdanderson.org/sumexp22/1101/thumbnail.jp

Chemical modification of extracellular matrix by cold atmospheric plasma-generated reactive species affects chondrogenesis and bone formation.

The goal of this study was to investigate whether cold plasma generated by dielectric barrier discharge (DBD) modifies extracellular matrices (ECM) to influence chondrogenesis and endochondral ossification. Replacement of cartilage by bone during endochondral ossification is essential in fetal skeletal development, bone growth and fracture healing. Regulation of this process by the ECM occurs through matrix remodelling, involving a variety of cell attachment molecules and growth factors, which influence cell morphology and protein expression. The commercially available ECM, Matrigel, was treated with microsecond or nanosecond pulsed (μsp or nsp, respectively) DBD frequencies conditions at the equivalent frequencies (1 kHz) or power (~1 W). Recombinant human bone morphogenetic protein-2 was added and the mixture subcutaneously injected into mice to simulate ectopic endochondral ossification. Two weeks later, the masses were extracted and analysed by microcomputed tomography. A significant increase in bone formation was observed in Matrigel treated with μsp DBD compared with control, while a significant decrease in bone formation was observed for both nsp treatments. Histological and immunohistochemical analysis showed Matrigel treated with μsp plasma increased the number of invading cells, the amount of vascular endothelial growth factor and chondrogenesis while the opposite was true for Matrigel treated with nsp plasma. In support of the in vivo Matrigel study, 10 T1/2 cells cultured in vitro on μsp DBD-treated type I collagen showed increased expression of adhesion proteins and activation of survival pathways, which decreased with nsp plasma treatments. These results indicate DBD modification of ECM can influence cellular behaviours to accelerate or inhibit chondrogenesis and endochondral ossification. Copyright © 2016 John Wiley & Sons, Ltd

Ocean circulation and biogeochemistry moderate interannual and decadal surface water pH changes in the Sargasso Sea

© The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Geophysical Research Letters 42 (2015): 4931–4939, doi:10.1002/2015GL064431.The oceans absorb anthropogenic CO2 from the atmosphere, lowering surface ocean pH, a concern for calcifying marine organisms. The impact of ocean acidification is challenging to predict as each species appears to respond differently and because our knowledge of natural changes to ocean pH is limited in both time and space. Here we reconstruct 222 years of biennial seawater pH variability in the Sargasso Sea from a brain coral, Diploria labyrinthiformis. Using hydrographic data from the Bermuda Atlantic Time-series Study and the coral-derived pH record, we are able to differentiate pH changes due to surface temperature versus those from ocean circulation and biogeochemical changes. We find that ocean pH does not simply reflect atmospheric CO2 trends but rather that circulation/biogeochemical changes account for >90% of pH variability in the Sargasso Sea and more variability in the last century than would be predicted from anthropogenic uptake of CO2 alone.Funding to N.F.G. was provided by the University of Hong Kong and the National Research Foundation Singapore under its Singapore NRF Fellowship scheme (National Research Fellow Award NRF-RF2012-03), as administered by the Earth Observatory of Singapore and the Singapore Ministry of Education under the Research Centres of Excellence initiative. S.C.D. and K.A.H. acknowledge support from the National Science Foundation and Woods Hole Oceanographic Institution

FAK Mediates a Compensatory Survival Signal Parallel to PI3K-AKT in PTEN-Null T-ALL Cells

SummaryMutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) are observed in 15%–25% of cases of human T cell acute lymphoblastic leukemia (T-ALL). Pten deletion induces myeloproliferative disorders (MPDs), acute myeloid leukemia (AML), and/or T-ALL in mice. Previous studies attributed Pten-loss-related hematopoietic defects and leukemogenesis to excessive activation of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling. Although inhibition of this signal dramatically suppresses the growth of PTEN-null T-ALL cells in vitro, treatment with inhibitors of this pathway does not cause a complete remission in vivo. Here, we report that focal adhesion kinase (Fak), a protein substrate of Pten, also contributes to T-ALL development in Pten-null mice. Inactivation of the FAK signaling pathway by either genetic or pharmacologic methods significantly sensitizes both murine and human PTEN-null T-ALL cells to PI3K/AKT/mTOR inhibition when cultured in vitro on feeder layer cells or a matrix and in vivo

An Introduction to the Chandra Carina Complex Project

The Great Nebula in Carina provides an exceptional view into the violent massive star formation and feedback that typifies giant HII regions and starburst galaxies. We have mapped the Carina star-forming complex in X-rays, using archival Chandra data and a mosaic of 20 new 60ks pointings using the Chandra X-ray Observatory's Advanced CCD Imaging Spectrometer, as a testbed for understanding recent and ongoing star formation and to probe Carina's regions of bright diffuse X-ray emission. This study has yielded a catalog of properties of >14,000 X-ray point sources; >9800 of them have multiwavelength counterparts. Using Chandra's unsurpassed X-ray spatial resolution, we have separated these point sources from the extensive, spatially-complex diffuse emission that pervades the region; X-ray properties of this diffuse emission suggest that it traces feedback from Carina's massive stars. In this introductory paper, we motivate the survey design, describe the Chandra observations, and present some simple results, providing a foundation for the 15 papers that follow in this Special Issue and that present detailed catalogs, methods, and science results.Comment: Accepted for the ApJS Special Issue on the Chandra Carina Complex Project (CCCP), scheduled for publication in May 2011. All 16 CCCP Special Issue papers are available at http://cochise.astro.psu.edu/Carina_public/special_issue.html through 2011 at least. 43 pages; 18 figure

Progress Toward a Human CD4/CCR5 Transgenic Rat Model for De Novo Infection by Human Immunodeficiency Virus Type 1

The development of a permissive small animal model for the study of human immunodeficiency virus type (HIV)-1 pathogenesis and the testing of antiviral strategies has been hampered by the inability of HIV-1 to infect primary rodent cells productively. In this study, we explored transgenic rats expressing the HIV-1 receptor complex as a susceptible host. Rats transgenic for human CD4 (hCD4) and the human chemokine receptor CCR5 (hCCR5) were generated that express the transgenes in CD4+ T lymphocytes, macrophages, and microglia. In ex vivo cultures, CD4+ T lymphocytes, macrophages, and microglia from hCD4/hCCR5 transgenic rats were highly susceptible to infection by HIV-1 R5 viruses leading to expression of abundant levels of early HIV-1 gene products comparable to those found in human reference cultures. Primary rat macrophages and microglia, but not lymphocytes, from double-transgenic rats could be productively infected by various recombinant and primary R5 strains of HIV-1. Moreover, after systemic challenge with HIV-1, lymphatic organs from hCD4/hCCR5 transgenic rats contained episomal 2–long terminal repeat (LTR) circles, integrated provirus, and early viral gene products, demonstrating susceptibility to HIV-1 in vivo. Transgenic rats also displayed a low-level plasma viremia early in infection. Thus, transgenic rats expressing the appropriate human receptor complex are promising candidates for a small animal model of HIV-1 infection

Colorectal surveillance outcomes from an institutional longitudinal cohort of lynch syndrome carriers

ObjectiveLynch Syndrome (LS) carriers have a significantly increased risk of developing colorectal cancer (CRC) during their lifetimes. Further stratification of this patient population may help in identifying additional risk factors that predispose to colorectal carcinogenesis. In most LS patients CRC may arise from adenomas, although an alternative non-polypoid carcinogenesis pathway has been proposed for PMS2 carriers. Using data from our institutional LS cohort, our aim was to describe our current colorectal screening outcomes with a focus on the incidence of adenomas in the context of different MMR genotypes and patient demographics such as gender, race, and ethnicity.DesignWe collected demographics, genetic, colonoscopy, and pathology results from a total of 163 LS carriers who obtained regular screening care at MD Anderson Cancer Center. Data were extracted from the electronic health records into a REDCap database for analysis. Logistic regressions were performed to measure the association between MMR variants and the likelihood of adenomas, advanced adenomas, and CRC. Then, we analyzed the cumulative incidences of these outcomes for the first 36 months following enrollment using Kaplan-Meier incidence curves, and Cox proportional hazard regressions.ResultsOn multivariate analysis, age (≥45 years old) was associated with an increased risk of developing adenomas (P=0.034). Patients with a prior or active cancer status were less likely to develop adenomas (P=0.015), despite of the lack of association between surgical history with this outcome (P=0.868). We found no statistically significant difference in likelihood of adenoma development between MLH1 and MSH2/EPCAM, MSH6, and PMS2 carriers. Moreover, we observed no statistically significant difference in the likelihood of advanced adenomas or CRC for any measured covariates. On Cox proportional hazard, compared to MLH1 carriers, the incidence of adenomas was highest among MSH2/EPCAM carriers during for the first 36-months of follow-up (P<0.001). We observed a non-statistically significant trend for Hispanics having a higher and earlier cumulative incidence of adenomas compared to non-Hispanics (P=0.073). No MMR carrier was more likely to develop advanced adenomas. No difference in the incidence of CRC by MMR gene (P=0.198).ConclusionScreening recommendations for CRC in LS patients should be based on specific MMR variants and should also be tailored to consider patient demographics

Social disparities in the use of colonoscopy by primary care physicians in Ontario

<p>Abstract</p> <p>Background</p> <p>It is unclear if all persons in Ontario have equal access to colonoscopy. This research was designed to describe long-term trends in the use of colonoscopy by primary care physicians (PCPs) in Ontario, and to determine whether PCP characteristics influence the use of colonoscopy.</p> <p>Methods</p> <p>We conducted a population-based retrospective study of PCPs in Ontario between the years 1996-2005. Using administrative data we identified a screen-eligible group of patients aged 50-74 years in Ontario. These patients were linked to the PCP who provided the most continuous care to them during each year. We determined the use of any colonoscopy among these patients. We calculated the rate of colonoscopy for each PCP as the number of patients undergoing colonoscopies per 100 screen eligible patients. Negative binomial regression was used to identify factors associated with the rate of colonoscopy, using generalized estimating equations to account for clustering of patients within PCPs.</p> <p>Results</p> <p>Between 7,955 and 8,419 PCPs in Ontario per year (median age 43 years) had at least 10 eligible patients in their practices. The use of colonoscopy by PCPs increased sharply in Ontario during the study period, from a median rate of 1.51 [inter quartile range (IQR) 0.57-2.62] per 100 screen eligible patients in 1996 to 4.71 (IQR 2.70-7.53) in 2005. There was substantial variation between PCPs in their use of colonoscopy. PCPs who were Canadian medical graduates and with more years of experience were more likely to use colonoscopy after adjusting for their patient characteristics. PCPs were more likely to use colonoscopy if their patient populations were predominantly women, older, had more illnesses, and if their patients resided in less marginalized neighborhoods (lower unemployment, fewer immigrants, higher income, higher education, and higher English/French fluency).</p> <p>Conclusions</p> <p>There is substantial variation in the use of colonoscopy by PCPs, and this variation has increased as the overall use of colonoscopy increased over time. PCPs whose patients were more marginalized were less likely to use colonoscopy, suggesting that there are inequities in access.</p