Polymorphisms at the microRNA binding-site of the stem cell marker gene CD133 modify susceptibility to and survival of gastric cancer.

CD133 is one of the most common stem cell markers, and functional single nucleotide polymorphisms (SNPs) of CD133 may modulate its gene functions and thus cancer risk and patient survival. We hypothesized that potentially functional CD133 SNPs are associated with gastric cancer (GC) risk and survival. To test this hypothesis, we conducted a case-control study of 371 GC patients and 313 cancer-free controls frequency-matched by age, sex, and ethnicity. We genotyped four selected, potentially functional CD133 SNPs (rs2240688A>C, rs7686732C>G, rs10022537T>A, and rs3130C>T) and used logistic regression analysis for associations of these SNPs with GC risk and Cox hazards regression analysis for survival. We found that compared with the miRNA binding site rs2240688 AA genotype, AC + CC genotypes were associated with significantly increased GC risk (adjusted OR = 1.52, 95% CI = 1.09-2.13); for another miRNA binding site rs3130C>T SNP, the TT genotype was associated with significantly reduced GC risk (adjusted OR = 0.68, 95% CI = 0.48-0.97), compared with CC + CT genotypes. In all patients, the risk rs3130 TT variant genotype was significantly associated with overall survival (OS) (adjusted P(trend) = 0.016 and 0.007 under additive and recessive models, respectively). These findings suggest that these two CD133 miRNA binding site variants, rs2240688 and rs3130, may be potential biomarkers for genetic susceptibility to GC and possible predictors for survival in GC patients but require further validation by larger studies.

Diversity index of mucosal resident T lymphocyte repertoire predicts clinical prognosis in gastric cancer

© 2015 Taylor & Francis Group, LLC.A characteristic immunopathology of human cancers is the induction of tumor antigen-specific T lymphocyte responses within solid tumor tissues. Current strategies for immune monitoring focus on the quantification of the density and differentiation status of tumor-infiltrating T lymphocytes; however, properties of the TCR repertoire - including antigen specificity, clonality, as well as its prognostic significance β remain elusive. In this study, we enrolled 28 gastric cancer patients and collected tumor tissues, adjacent normal mucosal tissues, and peripheral blood samples to study the landscape and compartmentalization of these patients’ TCR β repertoire by deep sequencing analyses. Our results illustrated antigen-driven expansion within the tumor compartment and the contracted size of shared clonotypes in mucosa and peripheral blood. Most importantly, the diversity of mucosal T lymphocytes could independently predict prognosis, which strongly underscores critical roles of resident mucosal T-cells in executing post-surgery immunosurveillance against tumor relapse.

Analytic Torsion, the Eta Invariant, and Closed Differential Forms on Spaces of Metrics

The central idea of this dissertation is to interpret certain invariants constructed from Laplace spectral data on a compact Riemannian manifold as regularized integrals of closed differential forms on the space of Riemannian metrics, or more generally on a space of metrics on a vector bundle. We apply this idea to both the Ray-Singer analytic torsion

and the eta invariant, explaining their dependence on the metric used to define them with a Stokes' theorem argument. We also introduce analytic multi-torsion, a generalization of analytic torsion, in the context of certain manifolds with local product structure; we prove that it is metric independent in a suitable sense.

Communication practices in physician decision-making for an unstable critically ill patient with end-stage cancer.

BACKGROUND: Shared decision-making has become the standard of care for most medical treatments. However, little is known about physician communication practices in the decision making for unstable critically ill patients with known end-stage disease. OBJECTIVE: To describe communication practices of physicians making treatment decisions for unstable critically ill patients with end-stage cancer, using the framework of shared decision-making. DESIGN: Analysis of audiotaped encounters between physicians and a standardized patient, in a high-fidelity simulation scenario, to identify best practice communication behaviors. The simulation depicted a 78-year-old man with metastatic gastric cancer, life-threatening hypoxia, and stable preferences to avoid intensive care unit (ICU) admission and intubation. Blinded coders assessed the encounters for verbal communication behaviors associated with handling emotions and discussion of end-of-life goals. We calculated a score for skill at handling emotions (0-6) and at discussing end of life goals (0-16). SUBJECTS: Twenty-seven hospital-based physicians. RESULTS: Independent variables included physician demographics and communication behaviors. We used treatment decisions (ICU admission and initiation of palliation) as a proxy for accurate identification of patient preferences. Eight physicians admitted the patient to the ICU, and 16 initiated palliation. Physicians varied, but on average demonstrated low skill at handling emotions (mean, 0.7) and moderate skill at discussing end-of-life goals (mean, 7.4). We found that skill at discussing end-of-life goals was associated with initiation of palliation (p = 0.04). CONCLUSIONS: It is possible to analyze the decision making of physicians managing unstable critically ill patients with end-stage cancer using the framework of shared decision-making.

Intake, digestibility, and passage of a commercially designed diet by two Propithecus species.

The digestibility and passage of an experimental diet was used to compare the digestive physiology of two Propithecus species: P. verreauxi and P. tattersalli. Though both animals have a similar feeding ecology, the captive status of P. verreauxi is considered more stable than that of P. tattersalli. The test diet included a local tree species, Rhus copallina, at 15% of dry matter intake (DMI) and Mazuri Leafeater Primate Diet at 85% of DMI. The chemical composition of the diet (dry matter basis) was 25% crude protein, 34% neutral detergent fiber (NDF), and 22% acid detergent fiber (ADF) with a gross energy of 4.52 kcal/g. After a 6 week acclimation to the experimental diet, animals were placed in research caging. After a 7 day adjustment period, animals were dosed with chromium mordant and Co-EDTA as markers for digesta passage and all feed refusals and feces were collected at timed intervals for 7 days. Digestibility values, similar for both species, were approximately 65% for dry matter, crude protein, and energy, and 40% and 35% respectively, for NDF and ADF. Transit times (17-18.5 hr) and mean retention times (31-34 hr) were not significantly different between species, and there was no difference between the chromium mordant and Co-EDTA. Serum values for glucose, urea, and non-esterified fatty acids (NEFA) were obtained during four different time periods to monitor nutritional status. While there was no change in serum glucose, serum urea increased over time. The NEFAs increased across all four time periods for P. verreauxi and increased for the first three periods then decreased in the last period for P. tattersalli. Results obtained indicate no difference in digestibility nor digesta passage between species, and that both Propithecus species were similar to other post-gastric folivores.

Development of a Novel c-MET-Based CTC Detection Platform.

UNLABELLED: Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45(+) leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET-amplified cells, sensitive (40%-80%) for c-MET-overexpressed cells, and specific (100%) for both c-MET-negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers. IMPLICATIONS: This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539-47. ©2016 AACR.