Pleiotropic effects of the trichloroethylene-associated P81S VHL mutation on metabolism, apoptosis, and ATM-mediated DNA damage response.

Background: The risk relevance of the P81S von Hippel-Lindau (VHL) gene hotspot mutation identified in clear cell renal cell carcinoma from individuals exposed occupationally to trichloroethylene (TCE) is not known. VHL mutations in hereditary VHL syndrome strongly correlate with phenotypic associations, but specific sporadic mutations in VHL that uniquely alter its protein function may provide a selective growth advantage for somatic cells harboring these mutations.

Methods: VHL deficient (Vhl (-/-) ) mouse embryonic stem cells were generated that stably express wild-type, P81S, or R167Q human VHL protein.

Biliary tree stem cells, precursors to pancreatic committed progenitors: evidence for possible life-long pancreatic organogenesis.

Peribiliary glands (PBGs) in bile duct walls, and pancreatic duct glands (PDGs) associated with pancreatic ducts, in humans of all ages, contain a continuous, ramifying network of cells in overlapping maturational lineages. We show that proximal (PBGs)-to-distal (PDGs) maturational lineages start near the duodenum with cells expressing markers of pluripotency (NANOG, OCT4, and SOX2), proliferation (Ki67), self-replication (SALL4), and early hepato-pancreatic commitment (SOX9, SOX17, PDX1, and LGR5), transitioning to PDG cells with no expression of pluripotency or self-replication markers, maintenance of pancreatic genes (PDX1), and expression of markers of pancreatic endocrine maturation (NGN3, MUC6, and insulin). Radial-axis lineages start in PBGs near the ducts' fibromuscular layers with stem cells and end at the ducts' lumens with cells devoid of stem cell traits and positive for pancreatic endocrine genes.

Ethical challenges: managing oncology drug shortages.

This vignette highlights the ethical issues surrounding restricted access to oncology drugs caused by drug shortages. A review of selected literature and a framework for creating institutional guidelines for reacting to shortage is provided.

Mapping six new susceptibility to colon cancer (Scc) loci using a mouse interspecific backcross.

Colorectal cancer (CRC) has a complex etiology resulting from the combination of multiple genetic and environmental factors, each with small effects. Interactions among susceptibility modifier loci make many of the loci difficult to detect in human genome-wide association studies. Previous analyses in mice have used classical inbred strains, which share large portions of their genomes due to common ancestry.

Pericytes regulate vascular basement membrane remodeling and govern neutrophil extravasation during inflammation.

During inflammation polymorphonuclear neutrophils (PMNs) traverse venular walls, composed of the endothelium, pericyte sheath and vascular basement membrane. Compared to PMN transendothelial migration, little is known about how PMNs penetrate the latter barriers. Using mouse models and intravital microscopy, we show that migrating PMNs expand and use the low expression regions (LERs) of matrix proteins in the vascular basement membrane (BM) for their transmigration.

Efficacy of EGFR inhibition is modulated by model, sex, genetic background and diet: implications for preclinical cancer prevention and therapy trials.

Molecule-targeted therapies are being widely developed and deployed, but they are frequently less effective in clinical trials than predicted based upon preclinical studies. Frequently, only a single model or genetic background is utilized using diets that are not relevant to that consumed by most cancer patients, which may contribute to the lack of predictability of many preclinical therapeutic studies. Inhibition of epidermal growth factor receptor (EGFR) in colorectal cancer was used to investigate potential causes for low predictive values of many preclinical studies.

Analyzing and engineering cell signaling modules with synthetic biology.

Signaling pathways lie at the heart of cellular responses to environmental cues. The ability to reconstruct specific signaling modules ex vivo allows us to study their inherent properties in an isolated environment, which in turn enables us to elucidate fundamental design principles for such motifs. This synthetic biology approach for analyzing natural, well-defined signaling modules will help to bridge the gap between studies on isolated biochemical reactions-which can provide great mechanistic detail but do not capture the complexity of endogenous signaling pathways-and those on entire networks of protein interactions-which offer a systems-level view of signal transduction but obscure the mechanisms that underlie signal transmission and processing.

Dietary calcium supplementation enhances efficacy but also toxicity of EGFR inhibitor therapy for colon cancer.

The inverse correlation between levels of dietary calcium and colorectal cancer (CRC) incidence has been extensively investigated. However, the impact of supplemental calcium on cancer therapy remains unknown. We used four models of CRC, Caco-2 and HCT116 human cancer cell lines and Apc (Min/+) and azoxymethane carcinogen-induced mouse models, to investigate the impact of a western-style diet low in calcium (0.

Imaging the coordination of multiple signalling activities in living cells.

Cellular signal transduction occurs in complex and redundant interaction networks, which are best understood by simultaneously monitoring the activation dynamics of multiple components. Recent advances in biosensor technology have made it possible to visualize and quantify the activation of multiple network nodes in the same living cell. The precision and scope of this approach has been greatly extended by novel computational approaches (referred to as computational multiplexing) that can reveal relationships between network nodes imaged in separate cells.

In vitro analyses of endothelial cell permeability.

Endothelial cells lining the vessels of the vasculature and the cell-cell junctions, which join them, -provide the primary barrier to the passage of fluids, immune cells, and macromolecules between the bloodstream and the tissues. Appropriate and dynamic regulation of this barrier is required during normal -physiological processes; however, if not tightly controlled, increased permeability of the endothelium can also contribute to many pathological situations, including chronic inflammatory diseases and edema. The development of in vitro methods to study endothelial barrier function has been key in the identification of molecular mechanisms underlying many of these disease states.

Conjoint analysis versus rating and ranking for values elicitation and clarification in colorectal cancer screening.

Purpose: To compare two techniques for eliciting and clarifying patient values for decision making about colorectal cancer (CRC) screening: choice-based conjoint analysis and a rating and ranking task.

Methods: Using our decision lab registry and university e-mail lists, we recruited average risk adults ages 48-75 for a written, mailed survey. Eligible participants were given basic information about CRC screening and six attributes of CRC screening tests, then randomized to complete either a choice-based conjoint analysis with 16 discrete choice tasks or a rating and ranking task.

Spatiotemporal control of small GTPases with light using the LOV domain.

Signaling networks in living systems are coordinated through subcellular compartmentalization and precise timing of activation. These spatiotemporal aspects ensure the fidelity of signaling while contributing to the diversity and specificity of downstream events. This is studied through development of molecular tools that generate localized and precisely timed protein activity in living systems.

Effectiveness of a patient and practice-level colorectal cancer screening intervention in health plan members: the CHOICE trial.

Background: Colorectal cancer (CRC) screening reduces CRC incidence and mortality but is underused. Effective interventions to increase screening that can be implemented broadly are needed.

Methods: A controlled trial was conducted to evaluate a patient-level and practice-level intervention to increase the use of recommended CRC screening tests among health plan members.

Coming of age: breast cancer in seniors.

In the U.S., cancer is a disease of aging.

Irving Page Lecture: 5-HT(2A) serotonin receptor biology: interacting proteins, kinases and paradoxical regulation.

5-Hydroxytryptamine(2A) (5-HT(2A)) serotonin receptors are important pharmacological targets for a large number of central nervous system and peripheral serotonergic medications. In this review article I summarize work mainly from my lab regarding serotonin receptor anatomy, pharmacology, signaling and regulation. I highlight the role of serotonin receptor interacting proteins and the emerging paradigm of G-protein coupled receptor functional selectivity.

Coming of age: breast cancer in seniors.

In the U.S., cancer is a disease of aging.

Maternal dioxin exposure combined with a diet high in fat increases mammary cancer incidence in mice.

Background: RESULTS from previous studies have suggested that breast cancer risk correlates with total lifetime exposure to estrogens and that early-life 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or diets high in fat can also increase cancer risk.

Objectives: Because both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility.

Methods: We exposed pregnant female FVB/NJ mice (12.

Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma.

Purpose: The multitargeted tyrosine kinase inhibitor sorafenib is used for the treatment of advanced-stage renal cell carcinoma. However, the safety and efficacy of this agent have yet to be evaluated in the preoperative period, where there may be potential advantages including tumor downstaging. This prospective trial evaluates the safety and feasibility of sorafenib in the preoperative setting.

Hijacking the chromatin remodeling machinery: impact of SWI/SNF perturbations in cancer.

There is increasing evidence that alterations in chromatin remodeling play a significant role in human disease. The SWI/SNF chromatin remodeling complex family mobilizes nucleosomes and functions as a master regulator of gene expression and chromatin dynamics whose functional specificity is driven by combinatorial assembly of a central ATPase and association with 10 to 12 unique subunits. Although the biochemical consequence of SWI/SNF in model systems has been extensively reviewed, the present article focuses on the evidence linking SWI/SNF perturbations to cancer initiation and tumor progression in human disease.

The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species.

Vascular permeability is a complex process involving the coordinated regulation of multiple signaling pathways in the endothelial cell. It has long been documented that vascular endothelial growth factor (VEGF) greatly enhances microvascular permeability; however, the molecular mechanisms controlling VEGF-induced permeability remain unknown. Treatment of microvascular endothelial cells with VEGF led to an increase in reactive oxygen species (ROS) production.

Ena/VASP: towards resolving a pointed controversy at the barbed end.

Ena/VASP proteins are conserved regulators of actin dynamics that have important roles in several physiological processes such as morphogenesis, axon guidance, endothelial barrier function, and cancer cell invasion and metastasis. Although considerable evidence points towards an anti-capping mechanism for Ena/VASP function, some controversy remains. Here, we evaluate the evidence for and against the anti-capping hypothesis, including results from some recent structural and biochemical studies that shed new light on this issue.

Murine models of colorectal cancer.

Colorectal cancer is one of the most prevalent cancers of humans. To experimentally investigate this common disease, numerous murine models have been established. These models accurately recapitulate the molecular and pathologic characteristics of human colorectal cancers, including activation of the myelocytomatosis oncogene (MYC), which has recently been suggested to be a key mediator of colorectal cancer development.