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At least 1,729 records · Page 96Linked to original sources
PubMed2002

High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non-small-cell lung cancer.

PURPOSE: E-cadherin (E-cad) and its associated intracellular molecules, catenins, are critical for intercellular epithelial adhesion and are often expressed in non-small-cell lung carcinomas (NSCLCs). We constructed tissue microarrays (TMAs) to investigate the expression of cadherins and catenins and their prognostic significance in NSCLC. PATIENTS AND METHODS: Tumor tissue samples from 193 patients with stages I to III NSCLC were obtained from the University of Colorado Cancer Center and Johns Hopkins Medical Institutions. Viable tumor was sampled in triplicate for the TMAs, and slides were stained by immunohistochemistry with antibodies against E-cad, N-cadherin, alpha (alpha)-, beta (beta)-, and gamma (gamma)-catenin, p120, p27, and adenomatous polyposis coli (APC) gene product. Clinical data were collected by the tumor registries. Patients were followed for a median period of 51 months (range, 18 to 100 months). RESULTS: Absent or severely reduced membranous expression for E-cad, alpha-, beta-, and gamma-catenin, and p120 were observed in 10%, 17%, 8%, 31%, and 61% of the cases, respectively. Tumor cell dedifferentiation correlated with reduced expression for E-cad, beta-catenin, gamma-catenin, and p120 in squamous cell carcinomas but not in adenocarcinomas. There was an inverse correlation between nodal metastasis and expression of E-cad and gamma-catenin. Besides the traditional clinical prognostic variables, E-cad and alpha-, beta-, and gamma-catenin expression were of positive prognostic value in univariate survival analyses. In multivariate analysis, E-cad expression was the only independent prognostic factor for survival in addition to age, node status, tumor status, and pathologic surgical margins. CONCLUSION: Reduced expression of E-cad and catenins is associated with tumor cell dedifferentiation, local invasion, regional metastasis, and reduced survival in NSCLC. E-cad is an independent prognostic factor for NSCLC survival.

Adenomatous Polyposis Coli Protein↗
PubMed2004

The biology and clinical relevance of the PTEN tumor suppressor pathway.

Genetic alterations targeting the PTEN tumor suppressor gene are among the most frequently noted somatic mutations in human cancers. Such lesions have been noted in cancers of the prostate and endometrium and in glioblastoma multiforme, among many others. Moreover, germline mutation of PTEN leads to the development of the related hereditary cancer predisposition syndromes, Cowden disease, and Bannayan-Zonana syndrome, wherein breast and thyroid cancer incidence is elevated. The protein product, PTEN, is a lipid phosphatase, the enzymatic activity of which primarily serves to remove phosphate groups from key intracellular phosphoinositide signaling molecules. This activity normally serves to restrict growth and survival signals by limiting activity of the phosphoinositide-3 kinase (PI3K) pathway. Multiple lines of evidence support the notion that this function is critical to the ability of PTEN to maintain cell homeostasis. Indeed, the absence of functional PTEN in cancer cells leads to constitutive activation of downstream components of the PI3K pathway including the Akt and mTOR kinases. In model organisms, inactivation of these kinases can reverse the effects of PTEN loss. These data raise the possibility that drugs targeting these kinases, or PI3K itself, might have significant therapeutic activity in PTEN-null cancers. Akt kinase inhibitors are still in development; however, as a first test of this hypothesis, phase I and phase II trials of inhibitors of mTOR, namely, rapamycin and rapamycin analogs are underway.

Antineoplastic Agents↗
PubMed2004

TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell survival.

Insulin-like growth factor-I (IGF-I) receptors and insulin receptors belong to the same subfamily of receptor tyrosine kinases and share a similar set of intracellular signaling pathways, despite their distinct biological actions. In the present study, we evaluated T cell death-associated gene 51 (TDAG51), which we previously identified by cDNA microarray analysis as a gene specifically induced by IGF-I. We characterized the signaling pathways by which IGF-I induces TDAG51 gene expression and the functional role of TDAG51 in IGF-I signaling in NIH-3T3 (NWTb3) cells, which overexpress the human IGF-I receptor. Treatment with IGF-I increased TDAG51 mRNA and protein levels in NWTb3 cells. This effect of IGF-I was specifically mediated by the IGF-IR, because IGF-I did not induce TDAG51 expression in NIH-3T3 cells overexpressing a dominant-negative IGF-I receptor. Through the use of specific inhibitors of various protein kinases, we found that IGF-I induced TDAG51 expression via the p38 MAPK pathway. The ERK, JNK, and phosphatidylinositol 3-kinase pathways were not involved in IGF-I-induced regulation of TDAG51. To assess the role of TDAG51 in IGF-I signaling, we used small interfering RNA (siRNA) expression vectors directed at two different target sites to reduce the level of TDAG51 protein. In cells expressing these siRNA vectors, TDAG51 protein levels were decreased by 75-80%. Furthermore, TDAG51 siRNA expression abolished the ability of IGF-I to rescue cells from serum starvation-induced apoptosis. These findings suggest that TDAG51 plays an important role in the anti-apoptotic effects of IGF-I.

Animals↗
PubMed2003

Apoptosome-independent pathway for apoptosis. Biochemical analysis of APAF-1 defects and biological outcomes.

Induction and execution of apoptosis programs are generally believed to be mediated through a hierarchy of caspase activation. By using two cellular variants obtained from the L1210 cell line (L1210/S and L1210/0), we have shown previously that staurosporine induces apoptotic cell death through both caspase-dependent and caspase-independent pathways. Both pathways normally coexisted in L1210/S cells, whereas L1210/0 cells lacked the ability to activate caspases despite the confirmed presence of both procaspase-3 and -9. Here we show that this defect in caspase activation is not due to mechanisms such as an absence of cytochrome c release, the expression of non-functional caspases, or the presence of an endogenous inhibitor but results from the loss of apoptosis protease activator protein-1 (APAF-1) expression. This absence of APAF-1 protein results from multiple alterations at both genomic and transcriptional levels. However, although this lack of APAF-1 delays the apoptotic program, it does not hamper its execution. Importantly, in these cells, apoptosis develops not only in an APAF-1-independent way but also in the absence of caspase-3 and -9 activation. Altogether these findings provide evidence that apoptosis may occur through alternative signaling pathways independent of APAF-1 expression and totally dissociated from any caspase processing. Therefore, the L1210/0 variant sub-line provides a valuable tool for the elucidation of these pathways.

Animals↗
PubMed2005

Acute activation of Erk1/Erk2 and protein kinase B/akt proceed by independent pathways in multiple cell types.

We used two inhibitors of the signaling enzyme phosphatidylinositol 3-kinase (PtdIns3K), wortmannin and LY294002, to evaluate the potential involvement of PtdIns3K in the activation of the MAP kinases (MAPK), Erk1 and Erk2. In dose-response studies carried out on six different cell lines and a primary cell culture, we analyzed the ability of the inhibitors to block phosphorylation of protein kinase B/akt (PKB/akt) at Ser473 as a measure of PtdIns3K activity, or the phosphorylation of Erk1/2 at activating Thr/Tyr sites as a measure of the extent of activation of MAPK/Erk kinase (MEK/Erk). In three different hemopoietic cell lines stimulated with cytokines, and in HEK293 cells, stimulated with serum, either wortmannin or LY294002, but never both, could partially block phosphorylation of Erks. The same observations were made in a B-cell line and in primary fibroblasts. In only one cell type, the A20 B cells, was there a closer correlation between the PtdIns3K inhibition by both inhibitors, and their corresponding effects on Erk phosphorylation. However, this stands out as an exception that gives clues to the mechanism by which cross-talk might occur. In all other cells, acute activation of the pathway leading to Erk phosphorylation could proceed independently of PtdIns3K activation. In a biological assay comparing these two pathways, the ability of LY294002 and the MEK inhibitor, U0126, to induce apoptosis were tested. Whereas LY294002 caused death of cytokine-dependent hemopoietic cells, U0126 had little effect, but both inhibitors together had a synergistic effect. The data show that these two pathways are regulating very different downstream events involved in cell survival.

Androstadienes↗
PubMed2005

The structural biology of type II fatty acid biosynthesis.

The type II fatty acid synthetic pathway is the principal route for the production of membrane phospholipid acyl chains in bacteria and plants. The reaction sequence is carried out by a series of individual soluble proteins that are each encoded by a discrete gene, and the pathway intermediates are shuttled between the enzymes as thioesters of an acyl carrier protein. The Escherichia coli system is the paradigm for the study of this system, and high-resolution X-ray and/or NMR structures of representative members of every enzyme in the type II pathway are now available. The structural biology of these proteins reveals the specific three-dimensional features of the enzymes that explain substrate recognition, chain length specificity, and the catalytic mechanisms that define their roles in producing the multitude of products generated by the type II system. These structures are also a valuable resource to guide antibacterial drug discovery.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗
PubMed2026

Knowledge-driven interpretable neural networks provide mechanistic insight.

Analyzing omics data in the context of pathway knowledge is critical for understanding the molecular mechanisms underlying pathological changes. However, current pathway analysis methods do not model the detailed mechanistic nature of biological interactions, limiting the understanding of pathway behavior to a relatively shallow level. To address this issue, we present a knowledge-driven machine learning framework that embeds features into pathway graphs and models reactions analytically, producing interpretable feature hierarchies and subnetworks in which functional associations are estimated to model biological interactions. The approach is agnostic to feature selection, enabling the use of full omics data sets without discarding weak signals. Applications to breast cancer microRNA-gene regulation data and COVID-19 metabolomic data highlight immune and metabolic pathways relevant to disease progression. This framework bridges predictive modeling with mechanistic interpretation and offers a foundation for integrative pathway analysis.

Humans↗
PubMed2003

Design and synthesis of novel pyridoxine 5'-phosphonates as potential antiischemic agents.

On the basis of previous reports that the natural cofactor pyridoxal 5'-phosphate 1 appears to display cardioprotective properties, a series of novel mimetics of this cofactor were envisioned. As pyridoxal 5'-phosphate is a natural compound and is subject to biological degradation and elimination pathways, the objective was to generate active phosphonates that are potentially less light sensitive and more stable in vivo than the parent vitamer. Several phosphonates were designed and synthesized, and in particular, compounds 10 and 14 displayed similar biological traits to natural phosphate 1 in the rat model of regional myocardial ischemia and reperfusion. A reduction in infarct size was observed in animals treated with these compounds. In an effort to identify other relevant cardioprotective models in order to potentially define structure-activity relationships, these three compounds were tested in the rat working heart model. Compounds 1, 10, and 14 were compared to dichloroacetic acid (DCA) as positive control in this model. As with DCA, compounds 1, 10, and 14 were found to induce a shift from fatty acid oxidation toward glucose oxidation.

Animals↗
PubMed2006

Proteomic analysis identifies alterations in cellular morphology and cell death pathways in mouse brain after chronic corticosterone treatment.

Some patients with Major Depression and other neurological afflictions display hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. HPA hyperactivity may be due to impaired feedback inhibition and manifested as increased levels of circulating cortisol. Subcutaneous implants of corticosterone pellets were used to mimic this situation in mice to gain insight into any effects on brain function by comparative proteomic analysis using two-dimensional Differential In-Gel Electrophoresis. A total of 150 different protein spots were altered by corticosterone treatment in the hypothalamus, hippocampus and cerebral cortex. Of these, 117 spots were identified by matrix-assisted laser desorption/ionization-time of flight mass fingerprinting equating to 51 different proteins. Association of these corticosterone-modulated proteins with biological functions using the Ingenuity Pathways Analysis tool showed that cell morphology was significantly altered in the hippocampus and cerebral cortex, whereas the hypothalamus showed significant changes in cell death. Ingenuity Pathways Analysis of the canonical signaling pathways showed that glycolysis and gluconeogenesis were altered in the hypothalamus and the hippocampus and all three brain regions showed changes in phenylalanine, glutamate and nitrogen metabolism. Further elucidation of these pathways could lead to identification of biomarkers for the development of pharmacological therapies targeted at neuropsychiatric disorders.

Animals↗
PubMed2026

Exploring the impact of syndecans in prostate cancer: Stage-specific roles and therapeutic implications.

Syndecans (SDCs) 1-4 are a family of transmembrane heparan sulfate proteoglycans (HSPGs) that regulate cell-cell communication, adhesion, extracellular matrix organization, and signaling pathways involved in tumor biology. In prostate cancer (PCa), accumulating evidence suggests that SDCs contribute to tumor progression, therapeutic resistance, and interactions within the tumor microenvironment. However, their specific, stage-dependent roles remain incompletely understood. This review provides an integrated synthesis of current experimental and clinical evidence on SDC1-SDC4 in PCa, complemented by exploratory analyses of publicly available transcriptomic, genomic, and proteomic datasets. In contrast, copy-number alteration (CNA) strata dichotomized by the mean for SDC1, SDC2, and SDC4 showed differences in progression-free interval. Specific CNA subclasses and relationships between CNA values and SDC mRNA or protein abundance could not be determined. Proteomic pseudotime analysis further suggested that SDC4 expression increases during PCa progression, supporting its potential involvement in advanced disease. We discuss the regulation and modulation of SDCs by androgen deprivation therapy (ADT), enzymatic shedding, integrin-mediated signaling, extracellular matrix interactions, lipid signaling pathways, and microRNA networks. In particular, SDC1-microRNA interactions may influence PCa cell proliferation, cellular senescence, epithelial-mesenchymal transition (EMT), and intracellular signaling pathways. Overall, this review highlights SDCs as context-dependent regulators of PCa biology with potential relevance as biomarkers or therapeutic targets. However, clinical translation will require independent validation, standardized assays, compartment-resolved analyses, and mechanistic confirmation.

Prognosis↗
PubMed2004

Oxytocin and oxytocin receptors in cancer cells and proliferation.

The hypothalamic nonapeptide oxytocin plays a crucial role in many reproductive and behavioural functions. However, in recent years, an additional new role for oxytocin has been identified in neoplastic pathology. In tumours, oxytocin acts as a growth regulator, through the activation of a specific G-coupled transmembrane receptor, the oxytocin receptor. In vitro, oxytocin inhibits proliferation of neoplastic cells of either epithelial (mammary and endometrial), nervous or bone origin, all expressing oxytocin receptor. Furthermore, an oxytocin growth-inhibiting effect was also tested and confirmed in vivo in mouse and rat mammary carcinomas. In neoplastic cells derived from two additional oxytocin target tissues, trophoblast and endothelium, oxytocin was found to promote cell proliferation, an effect opposite to that previously described in all other neoplastic oxytocin-responsive cells. The signal transduction pathways coupled to the biological effects of oxytocin are different in oxytocin growth-inhibited or growth-stimulated cells, and may depend on the membrane localization of the oxytocin receptor itself. The inhibitory effect of oxytocin is apparently mediated by activation of the cAMP-protein kinase A pathway, a nonconventional oxytocin signalling pathway, whereas the mitogenic effect is coupled to the increase of intracellular [Ca(2+)] and tyrosine phosphorylation, 'classical' oxytocin transducers. Moreover, the oxytocin receptor localization in lipid rafts enriched in caveolin-1 turns the inhibition of cell growth into a proliferative response, eliciting different epidermal growth factor receptor/mitogen-activated protein kinase activation patterns. This unexpected role of oxytocin (and oxytocin analogues) in regulating cell proliferation, as well as the widespread expression of oxytocin receptors in neoplastic tissues of different origin, opens up new perspectives on the biological role of the oxytocin-oxytocin receptor system in cancer.

Cell Division↗
PubMed2002

Brain Areas Active during Visual Perception of Biological Motion.

Theories of vision posit that form and motion are represented by neural mechanisms segregated into functionally and anatomically distinct pathways. Using point-light animations of biological motion, we examine the extent to which form and motion pathways are mutually involved in perceiving figures depicted by the spatio-temporal integration of local motion components. Previous work discloses that viewing biological motion selectively activates a region on the posterior superior temporal sulcus (STSp). Here we report that the occipital and fusiform face areas (OFA and FFA) also contain neural signals capable of differentiating biological from nonbiological motion. EBA and LOC, although involved in perception of human form, do not contain neural signals selective for biological motion. Our results suggest that a network of distributed neural areas in the form and motion pathways underlie the perception of biological motion.

Brain Mapping↗
PubMed2001

Bacterial alginate: physiology, product quality and process aspects.

Alginate, a copolymer of beta-D-mannuronic acid and alpha-L-guluronic acid and currently commercially produced from the marine brown algae, can also be biologically produced by bacteria such as Azotobacter vinelandii, A. chroococcum and several species of Pseudomonas. The ever-increasing applications of this polymer in the food and pharmaceutical sectors have led to continuing research interest aimed at better understanding the metabolic pathways, the physiological or biological function of this polymer, the regulation of its formation and composition, and optimising the microbial production process. These aspects are reviewed here, with particular attention to alginate formation in the soil bacterium A. vinelandii. In addition, the biotechnological and industrial applications of alginate are summarised.

Alginates↗
PubMed2005

Increased anti-oxidant enzyme activity and biological oxidation in placentae of pregnancies complicated by maternal asthma.

Our previous work has demonstrated that alterations in placental function are associated with changes in fetal development in pregnancies complicated by asthma. The pathophysiology of asthma in adults and children and intrauterine growth restriction during pregnancy are associated with oxidative stress. Based on this information, we examined whether placental anti-oxidant pathways and markers of biological oxidation were altered in pregnancies complicated by asthma. Anti-oxidant enzyme activities of superoxide dismutase, glutathione peroxidase and thioredoxin reductase, thioredoxin concentrations, lipid and protein oxidation levels were measured in placentae of pregnancies complicated by asthma and compared to uncomplicated, non-asthmatic pregnancies. Placental tissue homogenates of pregnancies complicated by asthma demonstrated significantly increased levels of lipid peroxidation (25.7+/-1.8 micromol/mg protein versus 12.1+/-1.6 micromol/mg protein, P=0.008) and protein carbonyl concentrations (414.6+/-51.4 units/mg protein versus 222.3+/-32.6 units/mg protein, P=0.0032) when compared to non-asthmatic controls. The activities of the anti-oxidant proteins superoxide dismutase (2.17+/-0.09 units/mg protein versus 1.67+/-0.09 units/mg protein, P=0.014) and thioredoxin reductase (54.0+/-6.9 units/mg protein versus 28.7+/-6.0 units/mg protein, P=0.009) were significantly increased in the presence of maternal asthma. Placental thioredoxin levels (102.9+/-5.3 ng/mg protein versus 92.9+/-8.6 ng/mg protein, P=0.37) and glutathione peroxidase activity (27.3+/-2.2 mmol/min/mg protein versus 28.3+/-2.2 mmol/min/mg, P=0.83) were not significantly different in pregnancies complicated by asthma and non-asthmatic pregnancies. There was no effect of fetal sex, asthma severity or treatment for asthma on these pathways. Maternal asthma during pregnancy is associated with increased placental enzymatic anti-oxidant capacity and also increased protein oxidation suggesting there is a compensatory increase in anti-oxidant activity in response to increased oxidative stress.

Adult↗