Groundbreaking research published by BIO5 scientists and their collaborators


PubMed Articles

Search form

Regulated vascular endothelial growth factor (VEGF) signaling is required for proper angiogenesis, and excess VEGF signaling results in aberrantly formed vessels that do not function properly. Tumor endothelial cells have excess centrosomes and are aneuploid, properties that probably contribute to the morphologic and functional abnormalities of tumor vessels. We hypothesized that endothelial cell centrosome number is regulated by signaling via angiogenic factors, such as VEGF. We found that endothelial cells in developing vessels exposed to elevated VEGF signaling display centrosome overduplication. Signaling from VEGF, through either MEK/ERK or AKT to cyclin E/Cdk2, is amplified in association with centrosome overduplication, and blockade of relevant pathway components rescued the centrosome overduplication defect. Endothelial cells exposed to elevated FGF also had excess centrosomes, suggesting that multiple angiogenic factors regulate centrosome number. Endothelial cells with excess centrosomes survived and formed aberrant spindles at mitosis. Developing vessels exposed to elevated VEGF signaling also exhibited increased aneuploidy of endothelial cells, which is associated with cellular dysfunction. These results provide the first link between VEGF signaling and regulation of the centrosome duplication cycle, and suggest that endothelial cell centrosome overduplication contributes to aberrant angiogenesis in developing vessel networks exposed to excess angiogenic factors.

Factors related to diet and life style have been identified as primary determinants in about 80% of colorectal cancers. Non-steroidal anti-inflammatory drugs (NSAID) and selective cyclooxygenase-2 (COX-2) inhibitors (COXIB) reduce the relative risk of colon cancer. To overcome systemic COX inhibition associated with NSAID and COXIB, there is a growing interest in developing alternative colon cancer prevention strategies using diet-based approaches that target COX-2. The transition from aberrant crypt foci (ACF) to colon cancer is a multiyear process providing opportunities for nutritional targeting of genes influencing the course of this disease process at early stages of development. The activation of the proinflammatory gene COX-2 and PG production in the colonic mucosa are recognized risk factors in colon cancer. Many natural food components may impact colon cancer risk by interfering with ligand-activated receptors, signal transduction pathways, and transcription factors involved in stimulation of COX-2 expression. In this review, we highlight key upstream features of signaling pathways and transcriptional control of the COX-2 gene and discuss opportunities for dietary modulation of COX-2 expression in gastro-intestinal cancers with special emphasis on prevention of colorectal tumors. Review of the experimental evidence suggests that dietary strategies based on specific or cocktails of bioactive food components as well nutritional-pharmacological combinations targeted to regulation of COX-2 expression and activity may prove useful in the prevention of colon cancer. An integrated approach may offer the advantage of combined higher efficacies. Future studies should investigate the efficacy of combinations of bioactive food compounds on epigenetic regulation of the COX-2 gene and characterize potential synergies and amplification effects resulting from the concomitant use of bioactive food components and COX-2 inhibitors.

The BRCA-1 protein is a tumor suppressor involved in repair of DNA damage. Epigenetic mechanisms contribute to its reduced expression in sporadic breast tumors. Through diet, humans are exposed to a complex mixture of xenobiotics and natural ligands of the aromatic hydrocarbon receptor (AhR), which contributes to the etiology of various types of cancers. The AhR binds xenobiotics, endogenous ligands, and many natural dietary bioactive compounds, including the phytoalexin resveratrol (Res). In estrogen receptor- alpha (ER alpha )-positive and BRCA-1 wild-type MCF-7 breast cancer cells, we investigated the influence of AhR activation with the agonist 2,3,7,8 tetrachlorobenzo(p)dioxin (TCDD) on epigenetic regulation of the BRCA-1 gene and the preventative effects of Res. We report that activation and recruitment of the AhR to the BRCA-1 promoter hampers 17 beta -estradiol (E2)-dependent stimulation of BRCA-1 transcription and protein levels. These inhibitory effects are paralleled by reduced occupancy of ER alpha , acetylated histone (AcH)-4, and AcH3K9. Conversely, the treatment with TCDD increases the association of mono-methylated-H3K9, DNA-methyltransferase-1 (DNMT1), and methyl-binding domain protein-2 with the BRCA-1 promoter and stimulates the accumulation of DNA strand breaks. The AhR-dependent repression of BRCA-1 expression is reversed by small interference for the AhR and DNMT1 or pretreatment with Res, which reduces TCDD-induced DNA strand breaks. These results support the hypothesis that epigenetic silencing of the BRCA-1 gene by the AhR is preventable with Res and provide the molecular basis for the development of dietary strategies based on natural AhR antagonists.

Alteration of protein trafficking and localization is associated with several diseases, including cystic fibrosis, breast cancer, colorectal cancer, leukemia and diabetes. Specifically, aberrant nuclear localization of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is a poor prognostic indicator in several epithelial carcinomas. It is now appreciated that in addition to signaling from the plasma membrane, EGFR also trafficks to the nucleus, and can directly bind the promoter regions of genes encoding cyclin D1 (CCND1) and B-Myb (MYBL2). We have previously established that loss of MUC1 in an EGFR-dependent transgenic mouse model of breast cancer correlates with the loss of cyclin D1 expression. Here, we provide evidence for a novel regulatory function of MUC1 in the trafficking and nuclear activity of EGFR. We found that MUC1 and EGFR interact in the nucleus of breast cancer cells, which promotes the accumulation of chromatin-bound EGFR. Additionally, the presence of MUC1 results in significant colocalization of EGFR and phosphorylated RNA polymerase II, indicating that MUC1 influences the association of EGFR with transcriptionally active promoter regions. Importantly, we found that the loss of MUC1 expression resulted in a decrease in the interaction between EGFR and the CCND1 promoter, which translated to a significant decrease in cyclin D1 protein expression. This data offers insights into a novel regulatory mechanism of EGFR nuclear function and could have important implications for evaluating nuclear localization in cancer.

This study examines whether differing types of victimization and coping strategies influence the type of social reactions experienced by 173 current victims of intimate partner violence (IPV). Results of path analyses showed that psychological and sexual IPV victimization were related to positive social reactions, whereas physical, psychological, and sexual IPV victimization were related to negative social reactions. Indirect relationships between victimization and social reactions differed by types of coping strategies (social support, problem solving, and avoidance) examined. Implications are discussed regarding the development of interventions with women's support networks and the augmentation of services to help victims modify their coping strategies.

Conjugated linoleic acid (CLA) is a class of commercially available fatty acids that have been associated with anticancer properties in rodent models of chemical carcinogenesis. We conducted a pilot study to examine the antitumor effect of dietary CLA in a polyoma virus-middle T antigen (PyMT) mouse model of invasive breast cancer. Virgin 4-week-old PyMT mice were administered a mixed-isomer CLA diet (1% wt/wt) or control AIN-93G diet for 4 weeks (N = 6 and 5, respectively) and tumor burden was assessed at 8 weeks of age. Thoracic mammary glands were prepared as whole mounts with other glands being formalin fixed and paraffin embedded for histology and immunohistochemistry (IHC). Total RNA was prepared for microarray and real-time reverse transcription-polymerase chain reaction analysis. Western blots were performed for protein expression analysis. Tumor incidence was significantly increased in CLA-treated animals compared with controls (P = 0.009) and occurred with extensive lobular-alveolar expansion and loss of mammary adipose tissue. More than 100 genes were downregulated > or = 2-fold in the CLA-treated group compared with controls, including adipose-specific markers, as wells as cytoskeletal and adhesion-related genes. This was supported by dramatic decreases in the epithelial adherens E-cadherin and beta-catenin as demonstrated by IHC. Taken together, these results suggest that dietary CLA affects the mammary stromal environment, leading to tumor progression and cellular expansion in the PyMT mouse model. Further studies of the potential for cancer promotion are needed, especially because mixed-isomer CLA formulations are sold commercially as a nutritional supplement.

Cell penetrating peptides (CPPs) are 9-35mer cationic and/or amphipathic peptides that are rapidly internalized across cell membranes. Importantly, they can be linked to a variety of cargo, including anti-cancer therapeutics, making CPPs an efficient, effective and non-toxic mechanism for drug delivery. In this review, we discuss a number of CPP conjugated therapies (CTTs) that are either patented are in the progress of patenting, and show strong promise for clinical efficacy. The CTTs discussed here target a number of different processes specific to cancer progression, including proliferation, survival and migration. In addition, many of these CTTs also increase sensitivity to current anti-cancer therapy modalities, including radiation and other DNA damaging chemotherapies, thereby decreasing the toxic dosage required for effective treatment. Mechanistically, these CTTs function in a dominant-negative manner by blocking tumor-specific protein-protein interactions with the CPP-conjugated peptide or protein. The treatment of both cell lines and mouse models demonstrates that this method of molecular targeting results in equal if not greater efficacy than current standards of care, including DNA damaging agents and topoisomerase inhibitors. For the treatment of invasive carcinoma, these CTTs have significant clinical potential to deliver highly targeted therapies without sacrificing the patient's quality of life.

Background. Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD) characterized by the development of an extensive fibrosis of the visceral peritoneum that may eventually lead to intestinal constriction. Its cause remains elusive. Nephrogenic systemic fibrosis (NSF), a disabling disease that can follow gadolinium-based contrast injection during magnetic resonance imaging, is characterized by systemic fibrosis of the skin, joints, liver, heart and vessels. Affected tissues are infiltrated by CD34+ and CD68+ fibroblasts. In the present study, we tested the hypothesis that EPS could have been triggered by a previous gadolinium injection. Methods. We performed histopathological analysis of the peritoneal membrane of two EPS and two control patients all exposed to long-term PD, including immunostaining with CD34 and CD68. The presence of gadolinium and other metals was also assessed by conventional and energy-filtered transmission electron microscopy. RESULTS: Numerous CD34+ and CD68+ cells were found in both the EPS and control patients within the vascular endothelium and in macrophages, respectively, but not in interstitial fibrocytes, as it could be expected in NSF. No trace of gadolinium deposits could be found in the four peritoneal samples; dispersed tiny iron inclusions were evidenced in the connective tissue of both EPS patients. CONCLUSIONS: These findings argue against the implication of gadolinium in the development of EPS in long-term PD patients.

The promise, status and challenges of developing fusion power are outlined. The key physics and engineering principles are described and recent progress quantified. As the successful demonstration of 16 MW of fusion in 1997 in the Joint European Torus showed, fusion works. The central issue is therefore to make it work reliably and economically on the scale of a power station. We argue that to meet this challenge in 30 years we must follow the aggressive programme known as the 'Fast Track to Fusion'. This programme is described in some detail.

Stability in frontal brain electrical activity (i.e., electroencephalographic or EEG) asymmetry at 10 and 24 months was examined with respect to maternal ratings of internalizing and externalizing behaviors at 30 months in a sample of 48 children. Children with stable left frontal EEG asymmetry during infancy were rated higher in externalizing behaviors by their mothers, whereas children with stable right frontal EEG asymmetry were rated higher in internalizing behaviors. These findings highlight the need to focus on the early stability in physiological measures that may be implicated later in developing behavioral problems.

Phenotype ontologies are typically constructed to serve the needs of a particular community, such as annotation of genotype-phenotype associations in mouse or human. Here we demonstrate how these ontologies can be improved through assignment of logical definitions using a core ontology of phenotypic qualities and multiple additional ontologies from the Open Biological Ontologies library. We also show how these logical definitions can be used for data integration when combined with a unified multi-species anatomy ontology.

Gene expression microarrays are the most widely used technique for genome-wide expression profiling. However, microarrays do not perform well on formalin fixed paraffin embedded tissue (FFPET). Consequently, microarrays cannot be effectively utilized to perform gene expression profiling on the vast majority of archival tumor samples. To address this limitation of gene expression microarrays, we designed a novel procedure (3'-end sequencing for expression quantification (3SEQ)) for gene expression profiling from FFPET using next-generation sequencing. We performed gene expression profiling by 3SEQ and microarray on both frozen tissue and FFPET from two soft tissue tumors (desmoid type fibromatosis (DTF) and solitary fibrous tumor (SFT)) (total n = 23 samples, which were each profiled by at least one of the four platform-tissue preparation combinations). Analysis of 3SEQ data revealed many genes differentially expressed between the tumor types (FDR<0.01) on both the frozen tissue (approximately 9.6K genes) and FFPET (approximately 8.1K genes). Analysis of microarray data from frozen tissue revealed fewer differentially expressed genes (approximately 4.64K), and analysis of microarray data on FFPET revealed very few (69) differentially expressed genes. Functional gene set analysis of 3SEQ data from both frozen tissue and FFPET identified biological pathways known to be important in DTF and SFT pathogenesis and suggested several additional candidate oncogenic pathways in these tumors. These findings demonstrate that 3SEQ is an effective technique for gene expression profiling from archival tumor samples and may facilitate significant advances in translational cancer research.

No abstract given.

A Photonic-based multi-wavelength sensor capable of discriminating objects is proposed and demonstrated for intruder detection and identification. The sensor uses a laser combination module for input wavelength signal multiplexing and beam overlapping, a custom-made curved optical cavity for multi-beam spot generation through internal beam reflection and transmission and a high-speed imager for scattered reflectance spectral measurements. Experimental results show that five different wavelengths, namely 473 nm, 532 nm, 635 nm, 670 nm and 785 nm, are necessary for discriminating various intruding objects of interest through spectral reflectance and slope measurements. Objects selected for experiments were brick, cement sheet, cotton, leather and roof tile.

Increasing evidence links genomic and epigenomic instability, including multiple fragile sites regions to neuropsychiatric diseases including schizophrenia and autism. Cancer is the only other disease associated with multiple fragile site regions, and genome and epigenomic instability is a characteristic of cancer. Research on cancer is far more advanced than research on neuropsychiatric disease; hence, insight into neuropsychiatric disease may be derived from cancer research results. Towards this end, this article will review the evidence linking schizophrenia and other neuropsychiatric diseases (especially autism) to genomic and epigenomic instability, and fragile sites. The results of studies on genetic, epigenetic and environmental components of schizophrenia and autism point to the importance of the folate-methionine-transulfuration metabolic hub that is diseases also perturbed in cancer. The idea that the folate-methionine-transulfuration hub is important in neuropsychiatric is exciting because this hub present novel targets for drug development, suggests some drugs used in cancer may be useful in neuropsychiatric disease, and raises the possibility that nutrition interventions may influence the severity, presentation, or dynamics of disease.

Small molecules stabilize specific protein conformations from a larger ensemble, enabling molecular switches that control diverse cellular functions. We show here that the converse also holds true: the conformational state of the estrogen receptor can direct distinct orientations of the bound ligand. 'Gain-of-allostery' mutations that mimic the effects of ligand in driving protein conformation allowed crystallization of the partial agonist ligand WAY-169916 with both the canonical active and inactive conformations of the estrogen receptor. The intermediate transcriptional activity induced by WAY-169916 is associated with the ligand binding differently to the active and inactive conformations of the receptor. Analyses of a series of chemical derivatives demonstrated that altering the ensemble of ligand binding orientations changes signaling output. The coupling of different ligand binding orientations to distinct active and inactive protein conformations defines a new mechanism for titrating allosteric signaling activity.

Although the ability of coactivators to enhance the expression of estrogen receptor-alpha (ERalpha) target genes is well established, the role of corepressors in regulating 17beta-estradiol (E2)-induced gene expression is poorly understood. Previous studies revealed that the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor is required for full ERalpha transcriptional activity in MCF-7 breast cancer cells, and we report herein the E2-dependent recruitment of SMRT to the regulatory regions of the progesterone receptor (PR) and cyclin D1 genes. Individual depletion of SMRT or steroid receptor coactivator (SRC)-3 modestly decreased E2-induced PR and cyclin D1 expression; however, simultaneous depletion revealed a cooperative effect of this coactivator and corepressor on the expression of these genes. SMRT and SRC-3 bind directly in an ERalpha-independent manner, and this interaction promotes E2-dependent SRC-3 binding to ERalpha measured by co-IP and SRC-3 recruitment to the cyclin D1 gene as measured by chromatin IP assays. Moreover, SMRT stimulates the intrinsic transcriptional activity of all of the SRC family (p160) coactivators. Our data link the SMRT corepressor directly with SRC family coactivators in positive regulation of ERalpha-dependent gene expression and, taken with the positive correlation found for SMRT and SRC-3 in human breast tumors, suggest that SMRT can promote ERalpha- and SRC-3-dependent gene expression in breast cancer.

Multidrug-resistant (MDR) gram-negative bacilli are important nosocomial pathogens.

To determine the incidence of transmission of MDR Acinetobacter baumannii and Pseudomonas aeruginosa from patients to healthcare workers (HCWs) during routine patient care.

Prospective cohort study.

Medical and surgical intensive care units. Methods. We observed HCWs who entered the rooms of patients colonized with MDR A. baumannii or colonized with both MDR A. baumannii and MDR P. aeruginosa. We examined their hands before room entry, their disposable gloves and/or gowns upon completion of patient care, and their hands after removal of gloves and/or gowns and before hand hygiene.

Sixty-five interactions occurred with patients colonized with MDR A. baumannii and 134 with patients colonized with both MDR A. baumannii and MDR P. aeruginosa. Of 199 interactions between HCWs and patients colonized with MDR A. baumannii, 77 (38.7% [95% confidence interval {CI}, 31.9%-45.5%]) resulted in HCW contamination of gloves and/or gowns, and 9 (4.5% [95% CI, 1.6%-7.4%]) resulted in contamination of HCW hands after glove removal before hand hygiene. Of 134 interactions with patients colonized with MDR P. aeruginosa, 11 (8.2% [95% CI, 3.6%-12.9%]) resulted in HCW contamination of gloves and/or gowns, and 1 resulted in HCW contamination of hands. Independent risk factors for contamination with MDR A. baumannii were manipulation of wound dressing (adjusted odds ratio [aOR], 25.9 [95% CI, 3.1-208.8]), manipulation of artificial airway (aOR, 2.1 [95% CI, 1.1-4.0]), time in room longer than 5 minutes (aOR, 4.3 [95% CI, 2.0-9.1]), being a physician or nurse practitioner (aOR, 7.4 [95% CI, 1.6-35.2]), and being a nurse (aOR, 2.3 [95% CI, 1.1-4.8]).

Gowns, gloves, and unwashed hands of HCWs were frequently contaminated with MDR A. baumannii. MDR A. baumannii appears to be more easily transmitted than MDR P. aeruginosa and perhaps more easily transmitted than previously studied methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus. This ease of transmission may help explain the emergence of MDR A. baumannii.

No abstract given.

In a sample of 18-, 30-, and 42-month-olds, the relations among parenting, effortful control (EC), and maladjustment were examined. Parenting was assessed with mothers' reports and observations; EC was measured with mothers' and caregivers' reports, as well as a behavioral task; and externalizing and internalizing symptoms were assessed with parents' and caregivers' reports. Although 18-month unsupportive (vs. supportive) parenting negatively predicted EC at 30 months, when the stability of these variables was taken into account, there was no evidence of additional potentially causal relations between these two constructs. Although EC was negatively related to both internalizing and externalizing problems within all three ages as well as across 1 year, EC did not predict maladjustment once the stability of the constructs and within time covariation between the constructs were taken into account. In addition, externalizing problems at 30 months negatively predicted EC at 42 months, and internalizing problems at 30 months positively predicted EC at 42 months, but only when the effects of externalizing on EC were controlled. The findings are discussed in terms of the reasons for the lack of causal relations over time.