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PubMed1996

Coordinating initiatives in critical pathways and information systems.

Health care providers have begun to use critical pathways and order sets to standardize clinical care in order to improve clinical resource management. This article describes ways that critical pathways and order sets can be developed and implemented in a coordinated manner. This approach allows for a process that facilitates automation of critical pathways variance analysis and continuous feedback to clinicians.

Cost Control↗

PubMed2006

Initial transcriptome and proteome analyses of low culture temperature-induced expression in CHO cells producing erythropoietin.

Low culture temperature is known to enhance the specific productivity of Chinese hamster ovary (CHO) cells expressing erythropoietin (EPO) (LGE10-9-27). Genomic and proteomic approaches were taken to better understand the intracellular responses of these CHO cells resulting from use of low culture temperature (33 degrees C). For transcriptome analysis, commercially available rat and mouse cDNA microarrays were used. The data obtained from the rat and mouse cDNA chips were only somewhat informative in understanding the gene expression profile of CHO cells because of their different sequence homologies with CHO transcriptomes. Overall, transcriptome analysis revealed that low culture temperature could lead to changes in gene expression in various cellular processes such as metabolism, transport, and signaling pathways. Proteome analysis was carried out using 2-D PAGE. Based on spot intensity, 60 high intensity protein spots, from a total of more than 800, were chosen for MS analysis. Forty of the 60 protein spots, which represent 26 different kinds of proteins, were identified by MALDI-TOF-MS and validated by MS/MS. Compared to the reference temperature (37 degrees C), the expression levels of seven proteins (PDI, vimentin, NDK B, ERp57, RIKEN cDNA, phosphoglycerate kinase, and heat shock cognate 71 kDa protein) were increased over twofold at 33 degrees C and those of two proteins (HSP90-beta and EF2) were decreased over twofold at 33 degrees C. Taken together, the results demonstrate the potential of combined analysis of transcriptome and proteome analyses as a tool for the systematic comprehension of cellular mechanisms in CHO cells.

Animals↗

PubMed2000

Changes in gene expression in the leafy cotyledon1 (lec1) and fusca3 (fus3) mutants of Arabidopsis thaliana L.

Arabidopsis thaliana L. leafy cotyledon1 (lec1) and fusca3 (fus3) mutants show multiple phenotypic defects during seed development. In this report the effects of these mutations are examined at the molecular level. The patterns of protein accumulation in lec1 and fus3 seeds are severly altered. In lec1 seeds the steady-state mRNA levels of several late embryogenesis genes were reduced. Different patterns of expression were observed, indicating the occurrence of several regulatory pathways. The effect of lec1 mutations on the expression of the late-embryogenesis abundant AtEm1 gene was examined in detail. In lec1-1 seeds, the AtEm1 gene was expressed at a higher level than in the wild type and earlier in development. The activity of an AtEm1 promoter/beta-glucuronidase reporter gene construct in transgenic A. thaliana plants was studied. Changes in promoter activity in lec1-1 with respect to wild-type seeds were correlated with changes in corresponding mRNA steady-state levels. fus3-2 mutation produced similar changes in AtEm1 promoter activity as lec1-1, which is consistent with the hypothesis that LEC1 and FUS3 might act in the same regulatory pathway. Transgenic analysis using 5'-promoter deletions demonstrated that at least two regions of AtEm1 gene promoter interact with the LEC1-dependent transcriptional regulatory pathway. In spite of expression of the AtEm1 promoter and accumulation of AtEm1 mRNA, the corresponding Em1 protein does not accumulate in lec1-1 seeds. The ABA inducibility of the AtEm1 promoter was not affected by the lec1 mutation.

Arabidopsis↗

PubMed1999

Safety and efficacy of outpatient transseptal radiofrequency ablation of atrioventricular accessory pathways.

A retrospective analysis of 60 consecutive patients who underwent outpatient transseptal radiofrequency ablation of left sided accessory pathways at Westchester County Medical Center/New York Medical College from September 1994 to December 1997 was performed. Patients were followed for a mean duration of 22 months. No complications either local or related to the transseptal method were observed. All patients had successful ablation of the accessory pathway. One patient had a recurrence of symptoms. This study suggests transseptal radiofrequency ablation of the left sided accessory pathways to be safe, feasible and an effective procedure when performed in an outpatient setting. These results were obtained at a high volume center with experience using the transseptal technique.

Adult↗

PubMed2025

Identifying potential biomarkers in the hippocampus of chronic fatigue syndrome rats treated with moxibustion at Zusanli (ST36): a proteomics study.

OBJECTIVE: To observe the effects of moxibustion at Zusanli (ST36) on rats with chronic fatigue syndrome (CFS) and to analyze the mechanisms of moxibustion through hippocampal Proteomics. METHODS: Male Sprague-Dawley (SD) rats were randomly divided into three groups: control group (CON), model group (MOD), and moxibustion group (MOX), with 12 rats in each group. The MOD and MOX groups underwent chronic multi-factor stress stimulation for 35 d to establish the CFS model. After modeling, the rats in the MOX group received mild moxibustion at Zusanli (ST36) (bilateral) for 10 minutes daily for 28 d. During the treatment period, rats in both the MOD and MOX groups continued modeling, while the CON group was kept under normal breeding conditions. The general condition of the rats was monitored, and behaviors were assessed using the Open Field Test (OFT), Exhaustion Treadmill Test, and Morris Water Maze (MWM). Hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM) were employed to observe morphological changes in the hippocampus. Label-free Proteomics were utilized to identify differentially expressed proteins (DEPs) in the hippocampus, followed by bioinformatics analysis. The reliability of the Proteomics results was verified using Parallel Reaction Monitoring. RESULTS: A: Moxibustion at Zusanli (ST36) significantly reduced the general condition score of CFS rats, improved their behavioral performance in OFT, treadmill and MWM, and repaired the pathological and synaptic structural damage in the hippocampus.B: We identified DEPs by applying a fold change threshold of 1.2 and a significance level of P < 0.05. In the comparison between the CON and the MOD, we identified a total of 72 DEPs (31 up-regulated and 41 down-regulated) associated with the development of CFS. In the comparison between the MOX and the MOD group, we identified a total of 103 DEPs (40 up-regulated and 63 down-regulated) related to the therapeutic effects of moxibustion. Gene Ontology (GO) enrichment analysis showed that CFS and moxibustion treatment were related to multiple biological processes, molecular functions, and cellular components. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that CFS pathogenesis was linked to base excision repair, steroid biosynthesis, and systemic lupus erythematosus, Furthermore, the treatment of CFS with moxibustion was relevant to terpenoid skeleton biosynthesis.C: Compared with the two comparison groups, we identified 16 potential biomarkers, noting that moxibustion reversed the up-regulation of 14 DEPs and the down-regulation of 2 DEPs in CFS. These proteins are mainly associated with synaptic plasticity, ribosomal function, neurotransmitter secretion, glycine metabolism, and mitochondrial function. CONCLUSION: Moxibustion at Zusanli (ST36) is effective in treating CFS, the potential biomarkers identified by Proteomics confirm that the mechanisms of moxibustion involve multiple targets and pathways, which may be key to regulating the structural and functional damage in the hippocampus associated with CFS, highlighting their significant value for future research.

Animals↗

PubMed2004

Mapping and quantitative analysis of gephyrin cytoplasmic trafficking pathways in motoneurons, using an optimized Transmission Electron Microscopy Color Imaging (TEMCI) procedure.

In the present study, an optimized Transmission Electron Microscopy Color Imaging (TEMCI) procedure was used to map and quantify the pathways involved in the trafficking and subcellular targeting of gephyrin in identified abducens motoneurons. Gephyrin is a scaffolding protein, which plays a crucial role in the clustering of the GABA(A) and glycine receptors to the cytoskeleton. TEMCI associated several accurate tools: (i) nanogold immunodetection of gephyrin in motoneurons identified on the basis of their immunoreactivity to Choline Acetyl Transferase, (ii) low magnification color scale coding of gephyrin densities on series of ultrathin sections of motoneurons, which gave a map of the cytoplasmic distribution of the protein, (iii) statistical analysis of the subcellular distribution of the immunolabeling. The color map of gephyrin densities in the cell bodies reflected the distribution of inhibitory synapses over the membrane. The TEMCI analysis of motoneurons with various patterns of synaptic covering made it possible to visualize for the first time the cytoplasmic transport pathway of gephyrin towards its target at synaptic contact. A high magnification quantitative analysis, including the study of 109 inhibitory synapses, showed that most gephyrin-associated immunogold particles (67%) were located in the subsynaptic regions facing the active zones, and the second most densely occupied regions were the perisynaptic regions (19.5% of immunogold particles). A consistent proportion of the gephyrin (11.5%), significantly higher than densities present in the rest of the cytoplasm (2%), was detected in the extrasynaptic submembrane region.

Abducens Nerve↗

PubMed2000

Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice.

During recent years, our understanding of TGFbeta signalling through serine/threonine kinase receptors and Smads has increased enormously. Activation of R-Smads by receptor induced phosphorylation is followed by complex formation with co-Smads and translocation to the nucleus, where the transcription of specific genes is affected and ultimately results in changes in cell behaviour. Experimental analysis primarily of epithelial cells in culture has revealed that a number of members of the TGFbeta family are interchangeable in the effect they have on growth and differentiation. On the other hand, different ligands of the TGFbeta superfamily can result in different responses because of cell type specific expression of other components of the signalling pathway. The relative expression levels of receptors and Smads within the cell is an important determinant of TGFbeta induced responses. Functional analysis of genes in the TGFbeta superfamily signal transduction cascade in vivo in mice either lacking entire genes, or expressing dominant negative forms of particular proteins, are providing profound new insights into the signalling cascades, their interaction and their specificity (Table 3). For example, by phenotypical comparison and intercrossing different heterozygous mutants, it has become clear that nodal, until recently an orphan protein without receptor/signal complex, probably signals through the activin type II receptor, ALK-4 and Smad2 (Nomura and Li, 1998; Song et al., 1999). Many of the genes of this cascade that have been targeted in the mouse result in early embryonic lethal phenotypes, demonstrating an important function for the BMP and TGFbeta/activin-activated pathways in mesoderm formation and differentiation, but masking a possible role in later events. For example mutations in BMP2 and 4 are lethal at or soon after gastrulation so that their putative role in skeletogenesis cannot be studied in mice lacking these genes. The difference in severity of the phenotypes between ligand, receptor and Smad deficient mice suggest that other receptors and ligands may partially compensate for the loss of one protein. Chimeric analysis provides one tool for analysing later developmental functions. By rescuing the early defects it was demonstrated that TGFbeta family members have an important function in anterior development and left/right asymmetry. Temporal and spatial specific gene targeting will be a powerful tool for analysing the function of TGFbeta family members in for example, bone formation, angiogenesis and carcinogenesis. Isolation of cells from the different gene targeted mice provides a unique source of material to gain more insight in the biochemical mechanisms of specific pathways. For example, use of cells deficient in Smad2 for biochemical and cell biological assays could give a better view of the function of Smad3. Smad3 deficient mice already demonstrate that there is a clear difference between Smad2 and Smad3 during development. Full descriptions of the remaining gene ablation studies of this signal transduction cascade, namely those for ALK-5, BMPR-II and Smad1 and -7 are eagerly awaited to complete the puzzle. As more of these superfamily of ligands and their signalling pathways have been functionally dissected, it has become evident that this superfamily of growth factors plays a pivotal role in epiblast formation and gastrulation, signalling from both the epiblast as well as the extraembryonic tissues. Furthermore, it becomes clear that TGFbeta is indeed important for proper vessel formation and that it might use endoglin, as well as ALK-1, ALK-5 and Smad5 to mediate this function. Further analyses of these mice should provide a clearer understanding of the mechanism of TGFbeta action in vascular development and remodelling.

Animals↗

PubMed2025

The impact of Iso-mukaadial acetate on Plasmodium falciparum transcriptional gene regulation.

Malaria remains prevalent globally despite various intervention strategies aimed at preventing its transmission. With the decreasing effectiveness of antimalarial drugs, medicinal plant extracts have been proposed as alternatives. Iso-mukaadial acetate extracted from Warburgia salutaris has shown anti-plasmodial activity, but the mechanism of inhibition is unknown. In this study, RNA sequencing analysis of P. falciparum NF54 strain treated with IMA was conducted to determine the possible targets of IMA. The expression profiles of P. falciparum genes regulated by IMA and chloroquine (antimalarial control) during the intraerythrocytic stage were analyzed with gene ontology tools, including PlasmoDB, ShinyGO and g: Profiler. IMA and chloroquine upregulated genes linked to parasite biological processes and cell adhesion molecular binding functions, including PfEMP1, RIFIN, and STEVOR. Chloroquine specifically downregulated DNA replication processes involving DNA replication licensing factors MCM3 and DNA helicase, while IMA downregulated peptidyl-proline modification and glycolytic pathways. KEGG analysis suggested glycolysis-gluconeogenesis and pentose phosphate pathway enzymes (e.g., glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6-phosphate dehydrogenase (G6PD)-6-phosphogluconolactonase) as theoretical IMA targets, whose suppression could hypothetically reduce ATP and NADPH production, weakening parasite energy supply and antioxidant defenses. The inhibition of DNA replication components (MCM complex, DNA topoisomerases) by IMA, and the downregulation of DNA replication/repair proteins by chloroquine, may both impair genome integrity, contributing to the observed anti-plasmodial effects. IMA treatment was assumed to be associated with impairment of parasite energy metabolism, redox balance and DNA replication machinery. These effects differ from chloroquine, which primarily targeted DNA replication and repair processes, yet both drugs upregulated adhesion-associated gene families. Changes in the expression of metabolic and replication genes induced by IMA suggest the compounds potential as an anti-plasmodial candidate, warranting further biochemical validation of its mechanism of effect.

Plasmodium falciparum↗

PubMed2025

Potential biomarkers for human Ascending aortic aneurysm identified through metagenomic and metabolomic analyses: A case-control study.

INTRODUCTION: Ascending aortic aneurysm (AsAA) is a high-risk cardiovascular condition; recent research indicates a possible association between gut microbiota, plasma metabolites, and the pathogenesis of AsAA. OBJECTIVE: This study aims to investigate the compositional and metabolic alterations in the gut microbiota of AsAA patients to identify potential biomarkers for AsAA. METHODS: This study enlisted 72 participants, comprising 44 individuals with AsAA and 28 healthy controls. All participants underwent examination for clinical features, and fecal and plasma samples were obtained for metagenomic and metabolomic studies. RESULTS: Metagenomic analysis revealed a significant reduction of 23 bacterial species in AsAA patients, including Bifidobacterium adolescentis, Bifidobacterium longum, Lactiplantibacillus plantarum, Enterococcus faecalis, and Streptococcus thermophilus, while 52 bacterial species, such as Prevotella copri, Phascolarctobacterium faecium, and Eubacterium ventriosum, were found to be enriched. Furthermore, we identified seven microbial co-abundance groups (CAGs), of which three (predominantly comprising Roseburia, Agathobacter, and Prevotella) were significantly elevated in AsAA patients, whereas one (predominantly comprising Escherichia) was substantially diminished. KEGG pathway enrichment analysis indicated that the biosynthesis of unsaturated fatty acids pathway displayed the most pronounced differences between groups. Metabolomics data revealed that 22 metabolites, including ceramides, were significantly elevated, while 8 metabolites, such as threonine, were notably downregulated. Moreover, clinical indicators like C-reactive protein (CRP) and complement components C3 and C4 have shown strong correlations with specific gut microbiota (Streptococcus, Prevotella) and plasma metabolites (threonine, ceramides). These findings indicate that inflammatory responses, metabolic dysregulation, and gut microbiota imbalance are pivotal in the etiology of AsAA. CONCLUSION: This study demonstrates substantial alterations in gut microbiota composition and plasma metabolites in patients with AsAA. Prevotella and ceramides exhibit potential as biomarkers for AsAA diagnosis. Furthermore, a synergy of Prevotella and ceramides may function as a potent disease prediction classifier, offering novel perspectives on the early diagnosis and targeted treatment of AsAA.

Humans↗

PubMed2025

Exploring biosynthetic potential of the endophytic Penicillium turbatum BLH34 using whole-genome sequence analysis and molecular networking.

An in-depth genomic and metabolomic investigation was conducted on the endophytic fungus Penicillium turbatum BLH34, isolated from Macleaya cordata. Hybrid sequencing (Illumina-Nanopore) generated a high-quality 27.9 Mb genome (GC 48.6%) encoding 9798 proteins, with functional annotation linking 5350 genes to the NCBI non-redundant database and 3404 to KEGG pathways. AntiSMASH analysis uncovered 35 biosynthetic gene clusters (BGCs), 23 of which lacked homology to known pathways, highlighting BLH34's potential for novel metabolite discovery. Molecular networking (GNPS) and LC-MS/MS identified 19 specialised metabolites, including antimicrobial polyketides. Bioassays demonstrated potent inhibition against Staphylococcus aureus (36 mm), Bacillus subtilis (28 mm) and Escherichia coli (24 mm), underscoring its pharmaceutical relevance.

Penicillium↗

PubMed1993

Uptake and degradation of glyceraldehyde-3-phosphate dehydrogenase by rat liver lysosomes.

The molecular mechanisms involved in the degradation of individual cellular proteins are probably unique and characteristic. We have investigated in rat liver the degradation of glyceraldehyde-3-phosphate dehydrogenase, an abundant cytosolic enzyme of the glycolytic pathway. Immunoblot analysis of isolated liver lysosomes from rats treated with lysosomal inhibitors show that this protein is degraded, at least in part, by a lysosomal pathway. This pathway was further investigated by incubating the enzyme with lysosomes in a cell-free system, followed by proteolysis measurements, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of lysosomes, and electron microscopic immunocytochemistry. We postulate that the degradative mechanism of glyceraldehyde-3-phosphate dehydrogenase includes a temperature-dependent lysosomal pathway, different from classical nonspecific macroautophagy. The postulated pathway involves: binding of the enzyme to the lysosomal membrane, entry into the lysosomal matrix, and degradation. This cell-free system, which can also incorporate in vitro synthesized proteins, should allow further advances toward clarifying the complex signals that regulate protein degradation as well as its close interrelationship with protein synthesis.

Animals↗

PubMed2002

Analysis of protein localization and secretory pathway function using the yeast Saccharomyces cerevisiae.

The isolation and characterization of mutants has been crucial in understanding a number of processes in the field of cell biology. In this exercise, students examine the effects of mutations in the secretory pathway on protein localization. Yeast strains deficient for synthesis of histidinol dehydrogenase are transformed with a plasmid encoding a chimeric protein. The chimera contains a signal sequence fused to histidinol dehydrogenase. A strain with a defect in the translocation of secretory proteins into the endoplasmic reticulum (ER) accumulates sufficient histidinol dehydrogenase in the cytoplasm to grow on media lacking histidine. In contrast, yeast proficient for secretion, or yeast with secretion defects later in the pathway, are unable to grow on media lacking histidine. Student analysis of the experimental yeast transformants and appropriate controls allows investigation into the effects of conditional defects in the secretory pathway on both cell viability and protein localization. The exercise is usually performed in a manner that allows students to execute a number of techniques common in molecular biology laboratories, including plasmid minipreps, restriction digestions, and Southern blots. Student understanding and enjoyment of the exercise was assessed by laboratory reports, oral and written examinations, and questionnaires. After completion of these experiments, students can describe the utility of protein fusions, the roles of mutant analysis in cell biology, and the steps taken by proteins transiting the secretory pathway.

Biology↗

PubMed2006

Application of Petri net based analysis techniques to signal transduction pathways.

BACKGROUND: Signal transduction pathways are usually modelled using classical quantitative methods, which are based on ordinary differential equations (ODEs). However, some difficulties are inherent in this approach. On the one hand, the kinetic parameters involved are often unknown and have to be estimated. With increasing size and complexity of signal transduction pathways, the estimation of missing kinetic data is not possible. On the other hand, ODEs based models do not support any explicit insights into possible (signal-) flows within the network. Moreover, a huge amount of qualitative data is available due to high-throughput techniques. In order to get information on the systems behaviour, qualitative analysis techniques have been developed. Applications of the known qualitative analysis methods concern mainly metabolic networks. Petri net theory provides a variety of established analysis techniques, which are also applicable to signal transduction models. In this context special properties have to be considered and new dedicated techniques have to be designed. METHODS: We apply Petri net theory to model and analyse signal transduction pathways first qualitatively before continuing with quantitative analyses. This paper demonstrates how to build systematically a discrete model, which reflects provably the qualitative biological behaviour without any knowledge of kinetic parameters. The mating pheromone response pathway in Saccharomyces cerevisiae serves as case study. RESULTS: We propose an approach for model validation of signal transduction pathways based on the network structure only. For this purpose, we introduce the new notion of feasible t-invariants, which represent minimal self-contained subnets being active under a given input situation. Each of these subnets stands for a signal flow in the system. We define maximal common transition sets (MCT-sets), which can be used for t-invariant examination and net decomposition into smallest biologically meaningful functional units. CONCLUSION: The paper demonstrates how Petri net analysis techniques can promote a deeper understanding of signal transduction pathways. The new concepts of feasible t-invariants and MCT-sets have been proven to be useful for model validation and the interpretation of the biological system behaviour. Whereas MCT-sets provide a decomposition of the net into disjunctive subnets, feasible t-invariants describe subnets, which generally overlap. This work contributes to qualitative modelling and to the analysis of large biological networks by their fully automatic decomposition into biologically meaningful modules.

Algorithms↗

PubMed2005

Divergent mechanisms of cis9, trans11-and trans10, cis12-conjugated linoleic acid affecting insulin resistance and inflammation in apolipoprotein E knockout mice: a proteomics approach.

Conjugated linoleic acids (CLA) affect atherogenesis, but mechanisms are not well understood. We explored how two isomers of CLA, cis9, trans11-CLA and trans10, cis12-CLA, affected lipid and glucose metabolism, as well as hepatic protein expression, in apolipoprotein E knockout mice. After 12 wk of intervention, plasma triglyceride, NEFA, and glucose concentrations were significantly higher in the trans10, cis12-CLA group, whereas plasma triglyceride, NEFA, glucose, and insulin concentrations were significantly lower in the cis9, trans11-CLA group, compared with control mice consuming linoleic acid. Proteomics identified significant up- or down-regulation of 113 liver cytosolic proteins by either CLA isomer. Principal component analysis revealed that the treatment effect of cis9, trans11-CLA was mainly explained by the up-regulation of different posttranslational forms of heat shock protein 70 kD. In contrast, the treatment effect of trans10, cis12-CLA was mainly explained by up-regulation of key enzymes in the gluconeogenic, beta-oxidation, and ketogenesic pathways. Correlation analysis again emphasized the divergent effects of both CLA isomers on different pathways, but also revealed a linkage between insulin resistance and increased levels of hepatic serotransferrin. Thus, our systems biology approach provided novel insights into the mechanisms by which individual CLA isomers differentially affect pathways related to atherogenesis, such as insulin resistance and inflammation.

Animal Feed↗

PubMed2003

Towards understanding the polycystins.

Autosomal dominant polycystic kidney disease (ADPKD) is a very common inherited disease caused by mutations in PKD1 or PKD2 genes characterized by progressive enlargement of fluid-filled cysts and loss of renal function [1]. Previous studies proposed a role for human polycystin-1 in renal morphogenesis acting as a matrix receptor in focal adhesions and for polycystin-2 as a putative calcium channel [2, 3]. The genome of Caenorhabditis elegans contains 2 new members of the polycystin family: lov-1, the homolog for PKD1; and pkd-2, the homolog for PKD2 [4; this paper]. Mutation analysis in C. elegans showed similarly compromised male mating behaviors in all single and double lov-1 and pkd-2 mutants, indicating their participation in a single genetic pathway. Expression analysis localized LOV-1 and PKD-2 to the ends of sensory neurons in male tails and to the tips of CEM neurons in the head, consistent with functions as chemo- or mechanosensors. Human and C. elegans PKD1 and PKD2 homologs, transfected into mammalian renal epithelial cells, co-localized with paxillin in focal adhesions suggesting function in a single biological pathway. Based on the role of polycystins in C. elegans sensory neuron function and the conservation of PKD pathways we suggest that polycystins act as sensors of the extracellular environment, initiating, via focal adhesion assembly, intracellular transduction events in neuronal or morphogenetic processes.

Amino Acid Sequence↗

PubMed2002

The APC/beta-catenin pathway in ulcerative colitis-related colorectal carcinomas: a mutational analysis.

BACKGROUND: Although the APC/beta-catenin pathway is known to play a crucial role in sporadic colorectal carcinogenesis, its influence on ulcerative colitis (UC)-related neoplastic progression is unknown. To elucidate the role of the APC-/beta-catenin pathway in UC-related carcinogenesis, the authors identified APC and beta-catenin mutations in a set of UC-related and sporadic colorectal carcinomas. METHODS: The mutational cluster region of APC (codon 1267 to 1529) and exon 3 of the beta-catenin were directly sequenced. RESULTS: Only 1 of 30 UC-related tumors (3%) showed an APC mutation whereas 11 of the 42 sporadic carcinomas (26%) had mutations within the mutational cluster region. Within the sporadic carcinoma group, only 8% of the right-sided carcinomas showed APC mutations whereas 50% of the left-sided carcinomas had mutations within the mutational cluster region. None of the tumors in either group showed a beta-catenin mutation. CONCLUSIONS: Mutations of the APC and beta-catenin are rare in UC-related tumors. These genes may be altered because of mutations outside the regions studied, or by epigenetic silencing. Alternatively, other proteins involved in the APC/beta-catenin signaling cascade may be altered, or this pathway may be involved infrequently in UC-related carcinogenesis. The significant difference in frequency of APC mutations between right- and left-sided sporadic tumors suggests different molecular pathways in these two tumor sites.

Adenomatous Polyposis Coli Protein↗

PubMed2007

Inflammation and IGF-I activate the Akt pathway in breast cancer.

Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p < 0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (p <or= 0.05; Spearman rank correlation). The association with Akt phosphorylation at Thr308 remained statistically significant in the multivariate analysis. Akt pathway activation was not associated with overall survival in the unstratified analysis, but we observed a statistical interaction between Akt phosphorylation and tumor phagocyte density on breast cancer survival (p(interaction) < 0.05). We further corroborated our findings in cell culture models by demonstrating that ANA-1 macrophages, nitric oxide and prostaglandin E(2) induce Akt phosphorylation in human breast cancer cells. In summary, a proinflammatory environment was found to activate the Akt pathway in breast cancer, and may modify the association between the Akt phosphorylation status and breast cancer survival.

Animals↗

PubMed2004

Visual afferent information dominates other sources of afferent information during mixed practice of a video-aiming task.

The goal of the present study was to determine whether learning of a manual video-aiming task that would have to be performed in a target-only condition (transfer test) would be improved, unaffected or hindered by alternating practice between a normal vision and a target-only condition. The results of the present study indicate that a mixed schedule of practice hindered learning of the task. Specifically, participants who practiced the task in the mixed schedule showed larger direction constant error in transfer than participants who practiced only in the target-only condition. The results suggest that participants in the mixed condition continued to rely on the rapidly decaying information that was extracted in the normal vision condition to plan and control their movement in the target-only condition, which ultimately led to biased movement endpoints.

Adult↗