Hypoxia Suppresses High Fat Diet-Induced Steatosis And Development Of Hepatic Adenomas.

Purpose: Nonalcoholic fatty liver disease (NAFLD) is considered the most common form of silent liver disease in the United States and obesity is associated with increased risk of NAFLD. Obstructive sleep apnea (OSA) which is common in obese individuals is associated with a greater incidence of NAFLD, which in turn, increases the risk for hepatocellular carcinoma (HCC). It is unclear how obesity, OSA and NAFLD interrelate nor how they collectively contribute to an increased risk for developing HCC.

Intraperitoneal injections as an alternative method for micro-CT contrast enhanced detection of murine liver tumors.

Micro-computed tomography (micro-CT) coupled with tissue, or vascular, specific contrast agent has emerged as a powerful tool for detecting and monitoring tumor growth in the liver of murine animals. Intravenous injections of contrast agents can be technically challenging and lead to errors that can considerably influence the outcome of a preclinical study, prompting an alternative method. Here we assessed the effectiveness of intraperitoneal injections of polyiodinated triglycerides emulsions (Fenestra LC) in micro-CT imaging of young SCID (8 weeks) and old BALB/c (48 weeks) mice with xenograft or carcinogen-induced liver tumors, respectively, and determined an optimal acquisition time.

Measuring DNA content in live cells by fluorescence microscopy.

Background: Live-cell fluorescence microscopy (LCFM) is a powerful tool used to investigate cellular dynamics in real time. However, the capacity to simultaneously measure DNA content in cells being tracked over time remains challenged by dye-associated toxicities. The ability to measure DNA content in single cells by means of LCFM would allow cellular stage and ploidy to be coupled with a variety of imaging directed analyses.

Double-negative (CD27IgD) B cells are expanded in NSCLC and inversely correlate with affinity-matured B cell populations.

Background: The presence of B cells in early stage non-small cell lung cancer (NSCLC) is associated with longer survival, however, the role these cells play in the generation and maintenance of anti-tumor immunity is unclear. B cells differentiate into a variety of subsets with differing characteristics and functions. To date, there is limited information on the specific B cell subsets found within NSCLC.

The induction of endoreduplication and polyploidy by elevated expression of 14-3-3γ.

Several studies have demonstrated that specific 14-3-3 isoforms are frequently elevated in cancer and that these proteins play a role in human tumorigenesis. 14-3-3γ, an isoform recently demonstrated to function as an oncoprotein, is overexpressed in a variety of human cancers; however, its role in promoting tumorigenesis remains unclear. We previously reported that overexpression of 14-3-3γ caused the appearance of polyploid cells, a phenotype demonstrated to have profound tumor promoting properties.

Key Strategies for Building Research Capacity of University Faculty Members.

Universities are under pressure to increase external research funding, and some federal agencies offer programs to expand research capacity in certain kinds of institutions. However, conflicts within faculty roles and other aspects of university operations influence the effectiveness of particular strategies for increasing research activity. We review conventional approaches to increasing research, focusing on outcomes for individual faculty members and use one federally-funded effort to build cancer-related research capacity at a public university as an example to explore the impact of various strategies on research outcomes.

The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer.

The receptor tyrosine kinases (RTKs) TYRO3, AXL and MERTK (TAM) have well-described oncogenic functions in a number of cancers. Notwithstanding, TAM RTKs are also potent and indispensable inhibitors of inflammation. The combined deletion of Axl and Mertk in mice enhances chronic inflammation and autoimmunity, including increased inflammation in the gut and colitis-associated cancer.

Deoxycholic acid mediates non-canonical EGFR-MAPK activation through the induction of calcium signaling in colon cancer cells.

Obesity and a western diet have been linked to high levels of bile acids and the development of colon cancer. Specifically, increased levels of the bile acid deoxycholic acid (DCA), an established tumor promoter, has been shown to correlate with increased development of colorectal adenomas and progression to carcinoma. Herein we investigate the mechanism by which DCA leads to EGFR-MAPK activation, a candidate mechanism by which DCA may promote colorectal tumorigenesis.

Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells.

Background: The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention.

Comparative analysis of 14-3-3 isoform expression and epigenetic alterations in colorectal cancer.

Background: The 14-3-3 family is a group of intracellular proteins found in all eukaryotic organisms. Humans have seven isoforms that serve as scaffolds to promote interactions of regulatory phospho-proteins involved in many vital cellular processes and previous studies have shown that disturbances in native 14-3-3 levels can contribute significantly to the development of various cancers.

Methods: DNA and RNA was extracted from frozen tissue samples collected by the Human Cooperative Tissue Network.

Differential regulation of EGFR-MAPK signaling by deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) in colon cancer.

A high-fat diet coincides with increased levels of bile acids. This increase in bile acids, particularly deoxycholic acid (DCA), has been strongly associated with the development of colon cancer. Conversely, ursodeoxycholic acid (UDCA) may have chemopreventive properties.

Using logistic regression to improve the prognostic value of microarray gene expression data sets: application to early-stage squamous cell carcinoma of the lung and triple negative breast carcinoma.

Background: Numerous microarray-based prognostic gene expression signatures of primary neoplasms have been published but often with little concurrence between studies, thus limiting their clinical utility. We describe a methodology using logistic regression, which circumvents limitations of conventional Kaplan Meier analysis. We applied this approach to a thrice-analyzed and published squamous cell carcinoma (SQCC) of the lung data set, with the objective of identifying gene expressions predictive of early death versus long survival in early-stage disease.

pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1).

Cortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr(421)) is required for cancer cell motility and invasion.

Development and evaluation of a biomedical search engine using a predicate-based vector space model.

Although biomedical information available in articles and patents is increasing exponentially, we continue to rely on the same information retrieval methods and use very few keywords to search millions of documents. We are developing a fundamentally different approach for finding much more precise and complete information with a single query using predicates instead of keywords for both query and document representation. Predicates are triples that are more complex datastructures than keywords and contain more structured information.

Activation of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling and the consequent induction of transformation by overexpressed 14-3-3γ protein require specific amino acids within 14-3-3γ N-terminal variable region II.

Members of the 14-3-3 superfamily regulate numerous cellular functions by binding phosphoproteins. The seven human isoforms (and the myriad of other eukaryotic 14-3-3 proteins) are highly conserved in amino acid sequence and secondary structure, yet there is abundant evidence that the various isoforms manifest disparate as well as common functions. Several of the human 14-3-3 isoforms are dysregulated in certain cancers and thus have been implicated in oncogenesis; experimentally, 14-3-3γ behaves as an oncogene, whereas 14-3-3σ acts as a tumor suppressor.

The significance of p53 isoform expression in serous ovarian cancer.

Epithelial ovarian cancer still carries a high mortality rate and remains the leading cause of gynecologic cancer death in the USA, despite decades of research. Hence, there is considerable interest in developing biomarkers that could be used to stratify patients for subsequent treatment. Mutation of the p53 tumor suppressor gene occurs very frequently (∼96%) in high-grade serous ovarian cancer.

P53 suppresses expression of the 14-3-3 gamma oncogene.

Background: 14-3-3 proteins are a family of highly conserved proteins that are involved in a wide range of cellular processes. Recent evidence indicates that some of these proteins have oncogenic activity and that they may promote tumorigenesis. We previously showed that one of the 14-3-3 family members, 14-3-3 gamma, is over expressed in human lung cancers and that it can induce transformation of rodent cells in vitro.

Hypomethylation of the 14-3-3σ promoter leads to increased expression in non-small cell lung cancer.

The 14-3-3 proteins are a set of seven highly conserved proteins that have recently been implicated in having a role in human tumorigenesis. However, the mechanism by which 14-3-3 proteins may act in this capacity is not well understood. In this study, we examined the expression of one of the 14-3-3 family members, 14-3-3σ, since it was shown previously to be aberrantly altered in human tumors.

Loss of HSF1 results in defective radiation-induced G(2) arrest and DNA repair.

HSF1 is a transcription factor that plays a key role in the response to heat stress and was previously shown by us to also be essential for importation of p53 into the nucleus. Here we extend these studies and show that loss of HSF1 renders cells more sensitive to killing by ionizing radiation. Cells that lack a functional HSF1 were unable to arrest in G(2) after exposure to ionizing radiation, suggesting that HSF1 activity was essential for activation of this cell cycle checkpoint.

P53 is transported into the nucleus via an Hsf1-dependent nuclear localization mechanism.

Loss of p53 function can occur through disruption of its ability to localize to the nucleus. Previously we showed through characterization a set of mutant cell lines that lacked the ability to import p53 into the nucleus that nuclear translocation of p53 appeared to be mechanistically different from that of the SV40 T-antigen (SV40TAg). Here we extend that work by examining nuclear importation of p53 and SV40TAg using both in vivo and in vitro assays for nuclear localization.

Restoring p53 tumor suppressor activity as an anticancer therapeutic strategy.

Loss of p53 tumor suppressor function is a key event in the genesis of most human tumors. This observation has prompted efforts to restore p53 activity as an anticancer therapeutic approach. Recent developments that have extended our understanding of how p53 activity is regulated and how mutations disrupt that regulation have provided the insight needed to develop therapeutic strategies that take advantage of this knowledge.

14-3-3gamma induces oncogenic transformation by stimulating MAP kinase and PI3K signaling.

The 14-3-3 proteins are a set of highly conserved scaffolding proteins that have been implicated in the regulation of a variety of important cellular processes such as the cell cycle, apoptosis and mitogenic signaling. Recent evidence indicates that the expression of some of the family members is elevated in human cancers suggesting that they may play a role in tumorigenesis. In the present study, the oncogenic potential of 14-3-3gamma was shown by focus formation and tumor formation in SCID mice using 14-3-3gamma transfected NIH3T3 mouse fibroblast cells.

Transient dephosphorylation of p53 serine 376 as an early response to ionizing radiation.

In a previous paper we reported that the cytoplasmic sequestered p53 in cells of the SK-N-SH neuroblastoma cell line could be induced to translocate to the nucleus by exposure to ionizing radiation. We have extended these studies to determine the fate of p53 in HCT116 colorectal carcinoma cells where constitutive p53 protein resides in the nucleus. A continuous increase in the nuclear p53 protein was observed in irradiated cells beginning 1 h after irradiation that persisted for 8 h.

Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR.

Ursodeoxycholic acid (UDCA) has been shown to prevent colon tumorigenesis in animal models and in humans. In vitro work indicates that this bile acid can suppress cell growth and mitogenic signaling suggesting that UDCA may be an anti-proliferative agent. However, the mechanism by which UDCA functions is unclear.

Hsf1 is required for the nuclear translocation of p53 tumor suppressor.

Although the p53 tumor suppressor is most frequently inactivated by genetic mutations, exclusion from the nucleus is also seen in human tumors. We have begun to examine p53 nuclear importation by isolating a series of mutant cells in which the temperature-sensitive murine p53(Val135) mutant is sequestered in the cytoplasm. We previously showed that that three of them (ALTR12, ALTR19, and ALTR25) constituted a single complementation group.