An integrative analysis of cancer gene expression studies using Bayesian latent factor modeling

We present an applied study in cancer genomics for integrating data and inferences from laboratory experiments on cancer cell lines with observational data obtained from human breast cancer studies. The biological focus is on improving understanding of transcriptional responses of tumors to changes in the pH level of the cellular microenvironment. The statistical focus is on connecting experimentally defined biomarkers of such responses to clinical outcome in observational studies of breast cancer patients. Our analysis exemplifies a general strategy for accomplishing this kind of integration across contexts. The statistical methodologies employed here draw heavily on Bayesian sparse factor models for identifying, modularizing and correlating with clinical outcome these signatures of aggregate changes in gene expression. By projecting patterns of biological response linked to specific experimental interventions into observational studies where such responses may be evidenced via variation in gene expression across samples, we are able to define biomarkers of clinically relevant physiological states and outcomes that are rooted in the biology of the original experiment. Through this approach we identify microenvironment-related prognostic factors capable of predicting long term survival in two independent breast cancer datasets. These results suggest possible directions for future laboratory studies, as well as indicate the potential for therapeutic advances though targeted disruption of specific pathway components.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS261 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Improved Antireflection Properties of an Optical Film Surface with Mixing Conical Subwavelength Structures

Based on finite difference time domain method, an optical film surface with mixing conical subwavelength structures is numerically investigated to improve antireflection property. The mixing conical subwavelength structure is combined with the pure periodic conical subwavelength structures and the added small conical structures in the gap between the pure periodic conical subwavelength structures. The antireflection properties of two types of subwavelength structures with different aspect ratios in spectral range of 400–800 nm are analyzed and compared. It is shown that, for the mixing type, the average reflectance is decreased and the variances of the reflectance are evidently smaller. When the added structure with a better aspect ratio exists, the average reflectance of the surface can be below 0.30%. Obviously, the antireflection properties of the optical film surface with mixing conical subwavelength structures can be improved

Therapeutic and Radiosensitizing Effects of Armillaridin on Human Esophageal Cancer Cells

Background. Armillaridin (AM) is isolated from Armillaria mellea. We examined the anticancer activity and radiosensitizing effect on human esophageal cancer cells. Methods. Human squamous cell carcinoma (CE81T/VGH and TE-2) and adenocarcinoma (BE-3 and SKGT-4) cell lines were cultured. The MTT assay was used for cell viability. The cell cycle was analyzed using propidium iodide staining. Mitochondrial transmembrane potential was measured by DiOC6(3) staining. The colony formation assay was performed for estimation of the radiation surviving fraction. Human CE81T/VGH xenografts were established for evaluation of therapeutic activity in vivo. Results. AM inhibited the viability of four human esophageal cancer cell lines with an estimated concentration of 50% inhibition (IC50) which was 3.4–6.9 μM. AM induced a hypoploid cell population and morphological alterations typical of apoptosis in cells. This apoptosis induction was accompanied by a reduction of mitochondrial transmembrane potential. AM accumulated cell cycle at G2/M phase and enhanced the radiosensitivity in CE81T/VGH cells. In vivo, AM inhibited the growth of CE81T/VGH xenografts without significant impact on body weight and white blood cell counts. Conclusion. Armillaridin could inhibit growth and enhance radiosensitivity of human esophageal cancer cells. There might be potential to integrate AM with radiotherapy for esophageal cancer treatment

Fucosyltransferase 1 and 2 play pivotal roles in breast cancer cells.

FUT1 and FUT2 encode alpha 1, 2-fucosyltransferases which catalyze the addition of alpha 1, 2-linked fucose to glycans. Glycan products of FUT1 and FUT2, such as Globo H and Lewis Y, are highly expressed on malignant tissues, including breast cancer. Herein, we investigated the roles of FUT1 and FUT2 in breast cancer. Silencing of FUT1 or FUT2 by shRNAs inhibited cell proliferation in vitro and tumorigenicity in mice. This was associated with diminished properties of cancer stem cell (CSC), including mammosphere formation and CSC marker both in vitro and in xenografts. Silencing of FUT2, but not FUT1, significantly changed the cuboidal morphology to dense clusters of small and round cells with reduced adhesion to polystyrene and extracellular matrix, including laminin, fibronectin and collagen. Silencing of FUT1 or FUT2 suppressed cell migration in wound healing assay, whereas FUT1 and FUT2 overexpression increased cell migration and invasion in vitro and metastasis of breast cancer in vivo. A decrease in mesenchymal like markers such as fibronectin, vimentin, and twist, along with increased epithelial like marker, E-cadherin, was observed upon FUT1/2 knockdown, while the opposite was noted by overexpression of FUT1 or FUT2. As expected, FUT1 or FUT2 knockdown reduced Globo H, whereas FUT1 or FUT2 overexpression showed contrary effects. Exogenous addition of Globo H-ceramide reversed the suppression of cell migration by FUT1 knockdown but not the inhibition of cell adhesion by FUT2 silencing, suggesting that at least part of the effects of FUT1/2 knockdown were mediated by Globo H. Our results imply that FUT1 and FUT2 play important roles in regulating growth, adhesion, migration and CSC properties of breast cancer, and may serve as therapeutic targets for breast cancer

Successful Treatment of Intractable Hemothorax with Recombinant Factor VIIa in a Nonhemophilic Patient

Recombinant factor VIIa (rFVIIa) was developed for the treatment of bleeding in hemophilic patients with inhibitors. It has also been used to stop bleeding in nonhemophilic patients who fail to respond to conventional treatment. We report a case of catastrophic hemothorax in which bleeding was stopped by administration of rFVIIa. A 68-year-old woman with chronic hepatitis C-related liver cirrhosis was admitted due to pneumonia and parapneumonic effusion. The patient developed hemothorax and hypovolemic shock after thoracentesis. Conventional therapies including tube thoracostomy and transarterial embolization failed to stop the life-threatening bleeding. The bleeding stopped after administration of rFVIIa 100 μg/kg/BW at 2-hour intervals for a total of two doses on the 3rd day of hospitalization. Despite intensive care, however, the patient died due to nosocomial infection and multiple organ failure on the 12th day of hospitalization. Hemothorax in a nonhemophilic patient can be successfully treated with rFVIIa