Mitochondrial stress and activation of PI3K and Akt survival pathway in bladder ischemia

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Yang JH

2017-06-01

Full Text Available Jing-Hua Yang,1 Mike B Siroky,1 Subbarao V Yalla,2 Kazem M Azadzoi3,4 1Department of Urology, VA Boston Healthcare System, Boston University School of Medicine, 2Department of Urology, VA Boston Healthcare System, Harvard Medical School, 3Department of Urology, 4Department of Pathology, VA Boston Healthcare System, Boston University School of Medicine, Boston, MA, USA Purpose: Detrusor overactivity contributes to bothersome constellation of lower urinary tract symptoms (LUTS in men and women as they age. However, the underlying mechanisms of non-obstructive detrusor overactivity and LUTS remain largely unknown. Growing evidence suggests that ischemia may be an independent factor in the development of non-obstructive bladder dysfunction. Our goal was to determine the effects of ischemia on detrusor function and voiding behavior and define redox-mediated cellular stress and cell survival signaling in the ischemic bladder. Materials and methods: Male Sprague Dawley rats were randomly divided into treatment (n=8 and control (n=8 groups. In the treatment group, iliac artery atherosclerosis and chronic bladder ischemia were induced. At 8 weeks after bladder ischemia, voiding patterns were examined in metabolic cages, cystometrograms were recorded in conscious animals, and then bladder blood flow was measured under general anesthesia. Bladder tissues were processed for assessment of transcription factors, markers of cellular and mitochondrial stress, mitochondrial respiration, and cell survival signaling pathway.Results: Atherosclerotic occlusive disease spread from the common iliac arteries to the internal iliac and vesical arteries and produced sustained bladder ischemia. Studies in metabolic cages showed increased micturition frequency and decreased voided volume in bladder ischemia. Conscious cystometrograms produced consistent data showing significant increase in micturition frequency and decreased voided volume and bladder capacity. Voiding

Saposin C promotes survival and prevents apoptosis via PI3K/Akt-dependent pathway in prostate cancer cells

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Lee Tae-Jin

2004-11-01

Full Text Available Abstract Background In addition to androgens, growth factors are also implicated in the development and neoplastic growth of the prostate gland. Prosaposin is a potent neurotrophic molecule. Homozygous inactivation of prosaposin in mice has led to the development of a number of abnormalities in the male reproductive system, including atrophy of the prostate gland and inactivation of mitogen-activated protein kinase (MAPK and Akt in prostate epithelial cells. We have recently reported that prosaposin is expressed at a higher level by androgen-independent (AI prostate cancer cells as compared to androgen-sensitive prostate cancer cells or normal prostate epithelial and stromal cells. In addition, we have demonstrated that a synthetic peptide (prosaptide TX14A, derived from the trophic sequence of the saposin C domain of prosaposin, stimulated cell proliferation, migration and invasion and activated the MAPK signaling pathway in prostate cancer cells. The biological significances of saposin C and prosaposin in prostate cancer are not known. Results Here, we report that saposin C, in a cell type-specific and dose-dependent manner, acts as a survival factor, activates the Akt-signaling pathway, down-modulates caspase-3, -7, and -9 expression and/or activity, and decreases the cleaved nuclear substrate of caspase-3 in prostate cancer cells under serum-starvation stress. In addition, prosaptide TX14A, saposin C, or prosaposin decreased the growth-inhibitory effect, caspase-3/7 activity, and apoptotic cell death induced by etoposide. We also discovered that saposin C activates the p42/44 MAP kinase pathway in a pertussis toxin-sensitive and phosphatidylinositol 3-kinase (PI3K /Akt-dependent manner in prostate cancer cells. Our data also show that the anti-apoptotic activity of saposin C is at least partially mediated via PI3K/Akt signaling pathway. Conclusion We postulate that as a mitogenic, survival, and anti-apoptotic factor for prostate cancer cells

Hydrogen sulfide (H{sub 2}S)/cystathionine γ-lyase (CSE) pathway contributes to the proliferation of hepatoma cells

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Pan, Yan; Ye, Shuang; Yuan, Dexiao; Zhang, Jianghong; Bai, Yang; Shao, Chunlin, E-mail: clshao@shmu.edu.cn

2014-05-15

Highlights: • Inhibition of H{sub 2}S/CSE pathway strongly stimulates cellular apoptosis. • Inhibition of H{sub 2}S/CSE pathway suppresses cell growth by blocking EGFR pathway. • H{sub 2}S/CSE pathway is critical for maintaining the proliferation of hepatoma cells. - Abstract: Hydrogen sulfide (H{sub 2}S)/cystathionine γ-lyase (CSE) pathway has been demonstrated to play vital roles in physiology and pathophysiology. However, its role in tumor cell proliferation remains largely unclear. Here we found that CSE over-expressed in hepatoma HepG2 and PLC/PRF/5 cells. Inhibition of endogenous H{sub 2}S/CSE pathway drastically decreased the proliferation of HepG2 and PLC/PRF/5 cells, and it also enhanced ROS production and mitochondrial disruption, pronounced DNA damage and increased apoptosis. Moreover, this increase of apoptosis was associated with the activation of p53 and p21 accompanied by a decreased ratio of Bcl-2/Bax and up-regulation of phosphorylated c-Jun N-terminal kinase (JNK) and caspase-3 activity. In addition, the negative regulation of cell proliferation by inhibition of H{sub 2}S/CSE system correlated with the blockage of cell mitogenic and survival signal transduction of epidermal growth factor receptor (EGFR) via down-regulating the extracellular-signal-regulated kinase 1/2 (ERK1/2) activation. These results demonstrate that H{sub 2}S/CSE and its downstream pathway contribute to the proliferation of hepatoma cells, and inhibition of this pathway strongly suppress the excessive growth of hepatoma cells by stimulating mitochondrial apoptosis and suppressing cell growth signal transduction.

Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer.

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Lee, Dae-Won; Han, Sae-Won; Cha, Yongjun; Bae, Jeong Mo; Kim, Hwang-Phill; Lyu, Jaemyun; Han, Hyojun; Kim, Hyoki; Jang, Hoon; Bang, Duhee; Huh, Iksoo; Park, Taesung; Won, Jae-Kyung; Jeong, Seung-Yong; Park, Kyu Joo; Kang, Gyeong Hoon; Kim, Tae-You

2017-09-15

Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor β [TGF-β]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse-free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. The mutation rates for the WNT, P53, RTK-RAS, PI3K, and TGF-β pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.99), whereas a mutation in the RTK-RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01-2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and B-Raf proto-oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors. A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK

The EbpA-RpoN Regulatory Pathway of the Pathogen Leptospira interrogans Is Essential for Survival in the Environment

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Hu, Wei-Lin; Pappas, Christopher J.; Zhang, Jun-Jie; Yang, You-Yun; Yan, Jie

2016-01-01

ABSTRACT Leptospira interrogans is the agent of leptospirosis, a reemerging zoonotic disease. It is transmitted to humans through environmental surface waters contaminated by the urine of mammals chronically infected by pathogenic strains able to survive in water for long periods. Little is known about the regulatory pathways underlying environmental sensing and host adaptation of L. interrogans during its enzootic cycle. This study identifies the EbpA-RpoN regulatory pathway in L. interrogans. In this pathway, EbpA, a σ54 activator and putative prokaryotic enhancer-binding protein (EBP), and the alternative sigma factor RpoN (σ54) control expression of at least three genes, encoding AmtB (an ammonium transport protein) and two proteins of unknown function. Electrophoresis mobility shift assay demonstrated that recombinant RpoN and EbpA bind to the promoter region and upstream of these three identified genes, respectively. Genetic disruption of ebpA in L. interrogans serovar Manilae virtually abolished expression of the three genes, including amtB in two independent ebpA mutants. Complementation of the ebpA mutant restored expression of these genes. Intraperitoneal inoculation of gerbils with the ebpA mutant did not affect mortality. However, the ebpA mutant had decreased cell length in vitro and had a significantly lowered cell density at stationary phase when grown with l-alanine as the sole nitrogen source. Furthermore, the ebpA mutant has dramatically reduced long-term survival ability in water. Together, these studies identify a regulatory pathway, the EbpA-RpoN pathway, that plays an important role in the zoonotic cycle of L. interrogans. IMPORTANCE Leptospirosis is a reemerging disease with global importance. However, our understanding of gene regulation of the spirochetal pathogen Leptospira interrogans is still in its infancy, largely due to the lack of robust tools for genetic manipulation of this spirochete. Little is known about how the pathogen

The EbpA-RpoN Regulatory Pathway of the Pathogen Leptospira interrogans Is Essential for Survival in the Environment.

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Hu, Wei-Lin; Pappas, Christopher J; Zhang, Jun-Jie; Yang, You-Yun; Yan, Jie; Picardeau, Mathieu; Yang, X Frank

2017-02-01

Leptospira interrogans is the agent of leptospirosis, a reemerging zoonotic disease. It is transmitted to humans through environmental surface waters contaminated by the urine of mammals chronically infected by pathogenic strains able to survive in water for long periods. Little is known about the regulatory pathways underlying environmental sensing and host adaptation of L. interrogans during its enzootic cycle. This study identifies the EbpA-RpoN regulatory pathway in L. interrogans In this pathway, EbpA, a σ 54 activator and putative prokaryotic enhancer-binding protein (EBP), and the alternative sigma factor RpoN (σ 54 ) control expression of at least three genes, encoding AmtB (an ammonium transport protein) and two proteins of unknown function. Electrophoresis mobility shift assay demonstrated that recombinant RpoN and EbpA bind to the promoter region and upstream of these three identified genes, respectively. Genetic disruption of ebpA in L. interrogans serovar Manilae virtually abolished expression of the three genes, including amtB in two independent ebpA mutants. Complementation of the ebpA mutant restored expression of these genes. Intraperitoneal inoculation of gerbils with the ebpA mutant did not affect mortality. However, the ebpA mutant had decreased cell length in vitro and had a significantly lowered cell density at stationary phase when grown with l-alanine as the sole nitrogen source. Furthermore, the ebpA mutant has dramatically reduced long-term survival ability in water. Together, these studies identify a regulatory pathway, the EbpA-RpoN pathway, that plays an important role in the zoonotic cycle of L. interrogans IMPORTANCE: Leptospirosis is a reemerging disease with global importance. However, our understanding of gene regulation of the spirochetal pathogen Leptospira interrogans is still in its infancy, largely due to the lack of robust tools for genetic manipulation of this spirochete. Little is known about how the pathogen achieves its

Intersection of autophagy with pathways of antigen presentation.

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Patterson, Natalie L; Mintern, Justine D

2012-12-01

Traditionally, macroautophagy (autophagy) is viewed as a pathway of cell survival. Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods of stress. Interestingly, autophagy can also directly intersect with, and impact, other major pathways of cellular function. Here, we will review the contribution of autophagy to pathways of antigen presentation. The autophagy machinery acts to modulate both MHCI and MHCII antigen presentation. As such autophagy is an important participant in pathways that elicit host cell immunity and the elimination of infectious pathogens.

The effect of S1P receptor signaling pathway on the survival and drug resistance in multiple myeloma cells.

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Fu, Di; Li, Yingchun; Li, Jia; Shi, Xiaoyan; Yang, Ronghui; Zhong, Yuan; Wang, Huihan; Liao, Aijun

2017-01-01

Multiple myeloma (MM) remains incurable by conventional chemotherapy. Sphingosine-1-phosphate (S1P) receptor-mediated signaling has been recently demonstrated to have critical roles in cell survival and drug resistance in a number of hematological malignancies. To dissect the roles of S1P receptor pathway in MM, we systematically examined cell viability and protein expression associated with cell survival and drug resistance in MM cell lines upon treatment with either pathway activator (S1P) or inhibitor (FTY720). Our results reveal that FTY720 inhibits cell proliferation by downregulating expression of target genes, while S1P has an opposite effect. Knocking down of S1P receptor S1P5R results in a reduction of cell survival-related gene expression; however, it does not have impacts on expression of drug resistance genes. These results suggest that S1P signaling plays a role in cell proliferation and drug resistance in MM, and targeting this pathway will provide a new therapeutic direction for MM management.

Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human.

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Zanotto-Filho, Alfeu; Dashnamoorthy, Ravi; Loranc, Eva; de Souza, Luis H T; Moreira, José C F; Suresh, Uthra; Chen, Yidong; Bishop, Alexander J R

2016-01-01

Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray) prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair), DNA-mRNA-protein metabolism (transcription/translation) and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH)-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress)/Unfolded Protein Responses (UPR) in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival.

Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human.

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Alfeu Zanotto-Filho

Full Text Available Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair, DNA-mRNA-protein metabolism (transcription/translation and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress/Unfolded Protein Responses (UPR in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival.

Phosphoketolase pathway contributes to carbon metabolism in cyanobacteria.

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Xiong, Wei; Lee, Tai-Chi; Rommelfanger, Sarah; Gjersing, Erica; Cano, Melissa; Maness, Pin-Ching; Ghirardi, Maria; Yu, Jianping

2015-12-07

Central carbon metabolism in cyanobacteria comprises the Calvin-Benson-Bassham (CBB) cycle, glycolysis, the pentose phosphate (PP) pathway and the tricarboxylic acid (TCA) cycle. Redundancy in this complex metabolic network renders the rational engineering of cyanobacterial metabolism for the generation of biomass, biofuels and chemicals a challenge. Here we report the presence of a functional phosphoketolase pathway, which splits xylulose-5-phosphate (or fructose-6-phosphate) to acetate precursor acetyl phosphate, in an engineered strain of the model cyanobacterium Synechocystis (ΔglgC/xylAB), in which glycogen synthesis is blocked, and xylose catabolism enabled through the introduction of xylose isomerase and xylulokinase. We show that this mutant strain is able to metabolise xylose to acetate on nitrogen starvation. To see whether acetate production in the mutant is linked to the activity of phosphoketolase, we disrupted a putative phosphoketolase gene (slr0453) in the ΔglgC/xylAB strain, and monitored metabolic flux using (13)C labelling; acetate and 2-oxoglutarate production was reduced in the light. A metabolic flux analysis, based on isotopic data, suggests that the phosphoketolase pathway metabolises over 30% of the carbon consumed by ΔglgC/xylAB during photomixotrophic growth on xylose and CO2. Disruption of the putative phosphoketolase gene in wild-type Synechocystis also led to a deficiency in acetate production in the dark, indicative of a contribution of the phosphoketolase pathway to heterotrophic metabolism. We suggest that the phosphoketolase pathway, previously uncharacterized in photosynthetic organisms, confers flexibility in energy and carbon metabolism in cyanobacteria, and could be exploited to increase the efficiency of cyanobacterial carbon metabolism and photosynthetic productivity.

The notch and TGF-β signaling pathways contribute to the aggressiveness of clear cell renal cell carcinoma.

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Jonas Sjölund

Full Text Available BACKGROUND: Despite recent progress, therapy for metastatic clear cell renal cell carcinoma (CCRCC is still inadequate. Dysregulated Notch signaling in CCRCC contributes to tumor growth, but the full spectrum of downstream processes regulated by Notch in this tumor form is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We show that inhibition of endogenous Notch signaling modulates TGF-β dependent gene regulation in CCRCC cells. Analysis of gene expression data representing 176 CCRCCs showed that elevated TGF-β pathway activity correlated significantly with shortened disease specific survival (log-rank test, p = 0.006 and patients with metastatic disease showed a significantly elevated TGF-β signaling activity (two-sided Student's t-test, p = 0.044. Inhibition of Notch signaling led to attenuation of both basal and TGF-β1 induced TGF-β signaling in CCRCC cells, including an extensive set of genes known to be involved in migration and invasion. Functional analyses revealed that Notch inhibition decreased the migratory and invasive capacity of CCRCC cells. CONCLUSION: An extensive cross-talk between the Notch and TGF-β signaling cascades is present in CCRCC and the functional properties of these two pathways are associated with the aggressiveness of this disease.

Regional imbalanced activation of the calcineurin/BAD apoptotic pathway and the PI3K/Akt survival pathway after myocardial infarction.

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Li, Tieluo; Kilic, Ahmet; Wei, Xufeng; Wu, Changfu; Schwartzbauer, Gary; Yankey, G Kwame; DeFilippi, Christopher; Bond, Meredith; Wu, Zhongjun J; Griffith, Bartley P

2013-06-05

The underlying molecular mechanisms of the remodeling after myocardial infarction (MI) remain unclear. The purpose of this study was to investigate the role of a survival pathway (PI3K/Akt) and an apoptosis pathway (calcineurin/BAD) in the remodeling after MI in a large animal model. Ten Dorset hybrid sheep underwent 25% MI in the left ventricle (LV, n=10). Five sheep were used as sham control. The regional strain was calculated from sonomicrometry. Apoptosis and the activation of the PI3K/Akt and calcineurin/BAD pathways were evaluated in the non-ischemic adjacent zone and the remote zone relative to infarct by immunoblotting, immunoprecipitation, and immunofluorescence staining. Dilation and dysfunction of LV were present at 12 weeks after MI. The regional strain in the adjacent zone was significantly higher than in the remote zone at 12 weeks (36.6 ± 4.0% vs 9.5 ± 3.6%, pBAD pathways were activated in the adjacent zone. Dephosphorylation and translocation of BAD were evident in the adjacent zone. Regional correlation between the strain and the expression of calcineurin/BAD indicated that the activation was strain-related (R(2)=0.46, 0.48, 0.39 for calcineurin, BAD, mitochondrial BAD, respectively, pBAD apoptotic pathways were concomitantly activated in the non-ischemic adjacent zone after MI. The calcineurin/BAD pathway is strain related and its imbalanced activation may be one of the causes of progressive remodeling after MI. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Horizontal acquisition of a hypoxia-responsive molybdenum cofactor biosynthesis pathway contributed to Mycobacterium tuberculosis pathoadaptation.

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Levillain, Florence; Poquet, Yannick; Mallet, Ludovic; Mazères, Serge; Marceau, Michael; Brosch, Roland; Bange, Franz-Christoph; Supply, Philip; Magalon, Axel; Neyrolles, Olivier

2017-11-01

The unique ability of the tuberculosis (TB) bacillus, Mycobacterium tuberculosis, to persist for long periods of time in lung hypoxic lesions chiefly contributes to the global burden of latent TB. We and others previously reported that the M. tuberculosis ancestor underwent massive episodes of horizontal gene transfer (HGT), mostly from environmental species. Here, we sought to explore whether such ancient HGT played a part in M. tuberculosis evolution towards pathogenicity. We were interested by a HGT-acquired M. tuberculosis-specific gene set, namely moaA1-D1, which is involved in the biosynthesis of the molybdenum cofactor. Horizontal acquisition of this gene set was striking because homologues of these moa genes are present all across the Mycobacterium genus, including in M. tuberculosis. Here, we discovered that, unlike their paralogues, the moaA1-D1 genes are strongly induced under hypoxia. In vitro, a M. tuberculosis moaA1-D1-null mutant has an impaired ability to respire nitrate, to enter dormancy and to survive in oxygen-limiting conditions. Conversely, heterologous expression of moaA1-D1 in the phylogenetically closest non-TB mycobacterium, Mycobacterium kansasii, which lacks these genes, improves its capacity to respire nitrate and grants it with a marked ability to survive oxygen depletion. In vivo, the M. tuberculosis moaA1-D1-null mutant shows impaired survival in hypoxic granulomas in C3HeB/FeJ mice, but not in normoxic lesions in C57BL/6 animals. Collectively, our results identify a novel pathway required for M. tuberculosis resistance to host-imposed stress, namely hypoxia, and provide evidence that ancient HGT bolstered M. tuberculosis evolution from an environmental species towards a pervasive human-adapted pathogen.

The Spalt transcription factors regulate cell proliferation, survival and epithelial integrity downstream of the Decapentaplegic signalling pathway

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María F. Organista

2012-10-01

The expression of the spalt genes is regulated by the Decapentaplegic signalling pathway in the Drosophila wing. These genes participate in the patterning of the longitudinal wing veins by regulating the expression of vein-specific genes, and in the establishment of cellular affinities in the central region of the wing blade epithelium. The Spalt proteins act as transcription factors, most likely regulating gene expression by repression, but the identity of their target genes in the wing is still unknown. As a preliminary step to unravel the genetic hierarchy controlled by the Spalt proteins, we have analysed their requirements during wing development, and addressed to what extent they mediate all the functions of the Decapentaplegic pathway in this developmental system. We identify additional functions for Spalt in cell division, survival, and maintenance of epithelial integrity. Thus, Spalt activity is required to promote cell proliferation, acting in the G2/M transition of the cell cycle. The contribution of Spalt to cell division is limited to the central region of the wing blade, as they do not mediate the extra growth triggered by Decapentaplegic signalling in the peripheral regions of the wing disc. In addition, Spalt function is required to maintain cell viability in cells exposed to high levels of Decapentaplegic signalling. This aspect of Spalt function is related to the repression of JNK signalling in the spalt domain of expression. Finally, we further characterise the requirements of Spalt to maintain epithelial integrity by regulating cellular affinities between cells located in the central wing region. Our results indicate that Spalt function mediates most of the requirements identified for Decapentaplegic signalling, contributing to establish the cellular qualities that differentiate central versus peripheral territories in the wing blade.

Epigallocatechin-3-Gallate (EGCG Promotes Autophagy-Dependent Survival via Influencing the Balance of mTOR-AMPK Pathways upon Endoplasmic Reticulum Stress

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Marianna Holczer

2018-01-01

Full Text Available The maintenance of cellular homeostasis is largely dependent on the ability of cells to give an adequate response to various internal and external stimuli. We have recently proposed that the life-and-death decision in endoplasmic reticulum (ER stress response is defined by a crosstalk between autophagy, apoptosis, and mTOR-AMPK pathways, where the transient switch from autophagy-dependent survival to apoptotic cell death is controlled by GADD34. The aim of the present study was to investigate the role of epigallocatechin-3-gallate (EGCG, the major polyphenol of green tea, in promoting autophagy-dependent survival and to verify the key role in connecting GADD34 with mTOR-AMPK pathways upon prolonged ER stress. Our findings, obtained by using HEK293T cells, revealed that EGCG treatment is able to extend cell viability by inducing autophagy. We confirmed that EGCG-induced autophagy is mTOR-dependent and PKA-independent; furthermore, it also required ULK1. We show that pretreatment of cells with EGCG diminishes the negative effect of GADD34 inhibition (by guanabenz or siGADD34 treatment on autophagy. EGCG was able to delay apoptotic cell death by upregulating autophagy-dependent survival even in the absence of GADD34. Our data suggest a novel role for EGCG in promoting cell survival via shifting the balance of mTOR-AMPK pathways in ER stress.

α-Syntrophin is involved in the survival signaling pathway in myoblasts under menadione-induced oxidative stress.

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Lim, Jeong-A; Choi, Su Jin; Moon, Jae Yun; Kim, Hye Sun

2016-05-15

Dystrophin-deficient muscle is known to be more vulnerable to oxidative stress, but not much is known about the signaling pathway(s) responsible for this phenomenon. α-Syntrophin, a component of the dystrophin-glycoprotein complex, can function as a scaffold protein because of its multiple protein interaction domains. In this study, we investigated the role of α-syntrophin in C2 myoblasts under menadione-induced oxidative stress. We found that the protein level of α-syntrophin was elevated when cells were exposed to menadione. To investigate the function of α-syntrophin during oxidative stress, we established α-syntrophin-overexpressing and knockdown cell lines. The α-syntrophin-overexpressing cells were resistant to the menadione-induced oxidative stress. In addition, survival signalings such as protein kinase B (Akt) phosphorylation and the Bcl-2/BAX ratio were increased in these cells. On the other hand, apoptotic signals such as cleavage of caspase-3 and poly ADP ribose polymerase (PARP) were increased in the α-syntrophin knockdown cells. Furthermore, Ca(2+)influx, which is known to increase when cells are exposed to oxidative stress, decreased in the α-syntrophin-overexpressing cells, but increased in the knockdown cells. These results suggest that α-syntrophin plays a pivotal role in the survival pathway triggered by menadione-induced oxidative stress in cultured myoblasts. Copyright © 2016 Elsevier Inc. All rights reserved.

No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival.

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Li Luo

Full Text Available The prognostic improvement attributed to genetic markers over current prognostic system has not been well studied for melanoma. The goal of this study is to evaluate the added prognostic value of Vitamin D Pathway (VitD SNPs to currently known clinical and demographic factors such as age, sex, Breslow thickness, mitosis and ulceration (CDF. We utilized two large independent well-characterized melanoma studies: the Genes, Environment, and Melanoma (GEM and MD Anderson studies, and performed variable selection of VitD pathway SNPs and CDF using Random Survival Forest (RSF method in addition to Cox proportional hazards models. The Harrell's C-index was used to compare the performance of model predictability. The population-based GEM study enrolled 3,578 incident cases of cutaneous melanoma (CM, and the hospital-based MD Anderson study consisted of 1,804 CM patients. Including both VitD SNPs and CDF yielded C-index of 0.85, which provided slight but not significant improvement by CDF alone (C-index = 0.83 in the GEM study. Similar results were observed in the independent MD Anderson study (C-index = 0.84 and 0.83, respectively. The Cox model identified no significant associations after adjusting for multiplicity. Our results do not support clinically significant prognostic improvements attributable to VitD pathway SNPs over current prognostic system for melanoma survival.

Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival.

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Marsit, Carmen J; Liu, Mei; Nelson, Heather H; Posner, Marshall; Suzuki, Makoto; Kelsey, Karl T

2004-01-29

Inactivation of the FANC-BRCA pathway via promoter methylation of the FANCF gene renders cells sensitive to DNA crosslinking agents, and has been identified in ovarian cancer cell lines and sporadic primary tumor tissues. We investigated epigenetic alterations in the FANC-BRCA pathway in head and neck squamous cell carcinomas (HNSCC) and non-small-cell lung cancers (NSCLC) using methylation-specific PCR. Promoter methylation of FANCF occurred in 15% (13/89) of HNSCCs and 14% (22/158) of NSCLCs. Methylation of BRCA1 occurred only in 6/158 NSCLC, and was limited to adenocarcinomas and large-cell carcinomas of the lung. No methylation of BRCA2 was detected. FANCF methylation was associated with a shorter duration of tobacco use (P=0.03) and a younger age of starting smoking (P=0.06) in NSCLC, and with a greater number of years of alcohol drinking (P=0.02) in HNSCC. In adenocarcinomas of the lung, FANCF promoter methylation was a significant predictor of poor survival with a hazard ratio of 3.1 (95% CI 1.2-7.9). This study demonstrates that inactivation of the FANC-BRCA pathway is relatively common in solid tumors and may be related to tobacco and alcohol exposure and survival of these patients.

The Fas/Fas ligand death receptor pathway contributes to phenylalanine-induced apoptosis in cortical neurons.

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Xiaodong Huang

Full Text Available Phenylketonuria (PKU, an autosomal recessive disorder of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH gene, leads to childhood mental retardation by exposing neurons to cytotoxic levels of phenylalanine (Phe. A recent study showed that the mitochondria-mediated (intrinsic apoptotic pathway is involved in Phe-induced apoptosis in cultured cortical neurons, but it is not known if the death receptor (extrinsic apoptotic pathway and endoplasmic reticulum (ER stress-associated apoptosis also contribute to neurodegeneration in PKU. To answer this question, we used specific inhibitors to block each apoptotic pathway in cortical neurons under neurotoxic levels of Phe. The caspase-8 inhibitor Z-IETD-FMK strongly attenuated apoptosis in Phe-treated neurons (0.9 mM, 18 h, suggesting involvement of the Fas receptor (FasR-mediated cell death receptor pathway in Phe toxicity. In addition, Phe significantly increased cell surface Fas expression and formation of the Fas/FasL complex. Blocking Fas/FasL signaling using an anti-Fas antibody markedly inhibited apoptosis caused by Phe. In contrast, blocking the ER stress-induced cell death pathway with salubrinal had no effect on apoptosis in Phe-treated cortical neurons. These experiments demonstrate that the Fas death receptor pathway contributes to Phe-induced apoptosis and suggest that inhibition of the death receptor pathway may be a novel target for neuroprotection in PKU patients.

Estimating pathway-specific contributions to biodegradation in aquifers based on dual isotope analysis: Theoretical analysis and reactive transport simulations

NARCIS (Netherlands)

Centler, F.; Heße, F.; Thullner, M.

2013-01-01

At field sites with varying redox conditions, different redox-specific microbial degradation pathways contribute to total contaminant degradation. The identification of pathway-specific contributions to total contaminant removal is of high practical relevance, yet difficult to achieve with current

Mechanical unloading of the failing human heart fails to activate the protein kinase B/Akt/glycogen synthase kinase-3beta survival pathway.

Science.gov (United States)

Razeghi, Peter; Bruckner, Brian A; Sharma, Saumya; Youker, Keith A; Frazier, O H; Taegtmeyer, Heinrich

2003-01-01

Left ventricular assist device (LVAD) support of the failing human heart improves myocyte function and increases cell survival. One potential mechanism underlying this phenomenon is activation of the protein kinase B (PKB)/Akt/glycogen synthase kinase-3beta (GSK-3beta) survival pathway. Left ventricular tissue was obtained both at the time of implantation and explantation of the LVAD (n = 11). Six patients were diagnosed with idiopathic dilated cardiomyopathy, 4 patients with ischemic cardiomyopathy and 1 patient with peripartum cardiomyopathy. The mean duration of LVAD support was 205 +/- 35 days. Myocyte diameter and phosphorylation of ERK were used as indices for reverse remodeling. Transcript levels of genes required for the activation of PKB/Akt (insulin-like growth factor-1, insulin receptor substrate-1) were measured by quantitative RT-PCR. In addition, we measured the relative activity of PKB/Akt and GSK-3beta, and assayed for molecular and histological indices of PKB/Akt activation (cyclooxygenase mRNA levels and glycogen levels). Myocyte diameter and phosphorylation of ERK decreased with LVAD support. In contrast, none of the components of the PKB/Akt/GSK-3beta pathway changed significantly with mechanical unloading. The PKB/Akt/GSK-3beta pathway is not activated during LVAD support. Other signaling pathways must be responsible for the improvement of cellular function and cell survival during LVAD support. Copyright 2003 S. Karger AG, Basel

Transitional-2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival.

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Moreau, Aurélie; Blair, Paul A; Chai, Jian-Guo; Ratnasothy, Kulachelvy; Stolarczyk, Emilie; Alhabbab, Rowa; Rackham, Chloe L; Jones, Peter M; Smyth, Lesley; Elgueta, Raul; Howard, Jane K; Lechler, Robert I; Lombardi, Giovanna

2015-03-01

In humans, tolerance to renal transplants has been associated with alterations in B-cell gene transcription and maintenance of the numbers of circulating transitional B cells. Here, we use a mouse model of transplantation tolerance to investigate the contribution of B cells to allograft survival. We demonstrate that transfer of B cells from mice rendered tolerant to MHC class I mismatched skin grafts can prolong graft survival in a dose-dependent and antigen-specific manner to a degree similar to that afforded by graft-specific regulatory T (Treg) cells. Tolerance in this model was associated with an increase in transitional-2 (T2) B cells. Only T2 B cells from tolerized mice, not naïve T2 nor alloantigen experienced T2, were capable of prolonging skin allograft survival, and suppressing T-cell activation. Tolerized T2 B cells expressed lower levels of CD86, increased TIM-1, and demonstrated a preferential survival in vivo. Furthermore, we demonstrate a synergistic effect between tolerized B cells and graft-specific Treg cells. IL-10 production by T2 B cells did not contribute to tolerance, as shown by transfer of B cells from IL-10(-/-) mice. These results suggest that T2 B cells in tolerant patients may include a population of regulatory B cells that directly inhibit graft rejection. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Depressive symptoms predict head and neck cancer survival: Examining plausible behavioral and biological pathways.

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Zimmaro, Lauren A; Sephton, Sandra E; Siwik, Chelsea J; Phillips, Kala M; Rebholz, Whitney N; Kraemer, Helena C; Giese-Davis, Janine; Wilson, Liz; Bumpous, Jeffrey M; Cash, Elizabeth D

2018-03-01

Head and neck cancers are associated with high rates of depression, which may increase the risk for poorer immediate and long-term outcomes. Here it was hypothesized that greater depressive symptoms would predict earlier mortality, and behavioral (treatment interruption) and biological (treatment response) mediators were examined. Patients (n = 134) reported depressive symptomatology at treatment planning. Clinical data were reviewed at the 2-year follow-up. Greater depressive symptoms were associated with significantly shorter survival (hazard ratio, 0.868; 95% confidence interval [CI], 0.819-0.921; P ratio, 0.865; 95% CI, 0.774-0.966; P = .010), and poorer treatment response (odds ratio, 0.879; 95% CI, 0.803-0.963; P = .005). The poorer treatment response partially explained the depression-survival relation. Other known prognostic indicators did not challenge these results. Depressive symptoms at the time of treatment planning predict overall 2-year mortality. Effects are partly influenced by the treatment response. Depression screening and intervention may be beneficial. Future studies should examine parallel biological pathways linking depression to cancer survival, including endocrine disruption and inflammation. Cancer 2018;124:1053-60. © 2018 American Cancer Society. © 2018 American Cancer Society.

Coconut oil protects cortical neurons from amyloid beta toxicity by enhancing signaling of cell survival pathways.

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Nafar, F; Clarke, J P; Mearow, K M

2017-05-01

Alzheimer's disease is a progressive neurodegenerative disease that has links with other conditions that can often be modified by dietary and life-style interventions. In particular, coconut oil has received attention as having potentially having benefits in lessening the cognitive deficits associated with Alzheimer's disease. In a recent report, we showed that neuron survival in cultures co-treated with coconut oil and Aβ was rescued compared to cultures exposed only to Aβ. Here we investigated treatment with Aβ for 1, 6 or 24 h followed by addition of coconut oil for a further 24 h, or treatment with coconut oil for 24 h followed by Aβ exposure for various periods. Neuronal survival and several cellular parameters (cleaved caspase 3, synaptophysin labeling and ROS) were assessed. In addition, the influence of these treatments on relevant signaling pathways was investigated with Western blotting. In terms of the treatment timing, our data indicated that coconut oil rescues cells pre-exposed to Aβ for 1 or 6 h, but is less effective when the pre-exposure has been 24 h. However, pretreatment with coconut oil prior to Aβ exposure showed the best outcomes. Treatment with octanoic or lauric acid also provided protection against Aβ, but was not as effective as the complete oil. The coconut oil treatment reduced the number of cells with cleaved caspase and ROS labeling, as well as rescuing the loss of synaptophysin labeling observed with Aβ treatment. Treatment with coconut oil, as well as octanoic, decanoic and lauric acids, resulted in a modest increase in ketone bodies compared to controls. The biochemical data suggest that Akt and ERK activation may contribute to the survival promoting influence of coconut oil. This was supported by observations that a PI3-Kinase inhibitor blocked the rescue effect of CoOil on Aβ amyloid toxicity. Further studies into the mechanisms of action of coconut oil and its constituent medium chain fatty acids are warranted

Cell Survival Signaling in Neuroblastoma

Science.gov (United States)

Megison, Michael L.; Gillory, Lauren A.; Beierle, Elizabeth A.

2013-01-01

Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on several facets of cell survival pathways including protein kinases (PI3K, AKT, ALK, and FAK), transcription factors (NF-κB, MYCN and p53), and growth factors (IGF, EGF, PDGF, and VEGF). Modulation of each of these factors decreases the growth or otherwise hinders the malignant potential of neuroblastoma, and many therapeutics targeting these pathways are already in the clinical trial phase of development. Continued research and discovery of effective modulators of these pathways will revolutionize the treatment of neuroblastoma. PMID:22934706

Uric acid, an important antioxidant contributing to survival in termites

Science.gov (United States)

Tasaki, Eisuke; Sakurai, Hiroki; Nitao, Masaru; Matsuura, Kenji; Iuchi, Yoshihito

2017-01-01

Reactive oxygen species (ROS) are generated spontaneously in all organisms and cause oxidative damage to biomolecules when present in excess. Accumulated oxidative damage accelerates aging; enhanced antioxidant capacity may be a positive factor for longevity. Recently, numerous studies of aging and longevity have been performed using short-lived animals, however, longevity mechanisms remain unknown. Here we show that a termite Reticulitermes speratus that is thought to be long-lived eusocial insect than other solitary insects uses large quantities of uric acid as an antioxidant against ROS. We demonstrated that the accumulation of uric acid considerably increases the free radical-scavenging activity and resistance against ultraviolet-induced oxidative stress in laboratory-maintained termites. In addition, we found that externally administered uric acid aided termite survival under highly oxidative conditions. The present data demonstrates that in addition to nutritional and metabolic roles, uric acid is an essential antioxidant for survival and contributes significantly to longevity. Uric acid also plays important roles in primates but causes gout when present in excess in humans. Further longevity studies of long-lived organisms may provide important breakthroughs with human health applications. PMID:28609463

Functional interaction between hMYH and hTRADD in the TNF-α-mediated survival and death pathways of HeLa cells

Energy Technology Data Exchange (ETDEWEB)

Vy Tran, An Hue; Hahm, Soo-Hyun; Han, Se Hee [Department of Advanced Technology Fusion, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701 (Korea, Republic of); Chung, Ji Hyung [Department of Applied Bioscience, College of Life Science, CHA University, Gyeonggi-do 463-836 (Korea, Republic of); Park, Geon Tae [Cornell University, Ithaca, NY 14850 (United States); Han, Ye Sun, E-mail: yshan@konkuk.ac.kr [College of Global Integrated Studies, Division of Interdisciplinary Studies, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701 (Korea, Republic of)

2015-07-15

Highlights: • We determine the interaction between hMYH and hTRADD. • We examine changes in the level of hMYH–hTRADD interaction under TNF-α treatment. • hTRADD–hMYH association is involved in the nuclear translocation of NFκB. • hTRADD–hMYH complex influences the TNFR1–TRADD association. - Abstract: The tumor necrosis factor (TNF) signaling pathway is a classical immune system pathway that plays a key role in regulating cell survival and apoptosis. The TNF receptor-associated death domain (TRADD) protein is recruited to the death domain of TNF receptor 1 (TNFR1), where it interacts with TNF receptor-associated factor 2 (TRAF2) and receptor-interacting protein (RIP) for the induction of apoptosis, necrosis, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and mitogen-activated protein (MAP) kinase activation. In this study, we found that the human MutY homolog (hMYH) interacted with human TRADD (hTRADD) via the C-terminal domain of hMYH. Moreover, under conditions promoting TNF-α-induced cell death or survival in HeLa cells, this interaction was weakened or enhanced, respectively. The interaction between hMYH and hTRADD was important for signaling pathways mediated by TNF-α. Our results also suggested that the hTRADD–hMYH association was involved in the nuclear translocation of NFκB and formation of the TNFR1–TRADD complex. Thus, this study identified a novel mechanism through which the hMYH–hTRADD interaction may affect the TNF-α signaling pathway. Implications: In HeLa cells, the hTRADD–hMYH interaction functioned in both cell survival and apoptosis pathways following TNF-α stimulation.

Endolysosomal pathway activity protects cells from neurotoxic TDP-43

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Christine Leibiger

2018-03-01

Full Text Available The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS and of frontotemporal dementia (FTD. In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP‑43. Using a yeast model for TDP‑43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes markedly contributed to the degradation of TDP‑43. This clearance occurred via TDP‑43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal pathway and autophagy. In line with its dominant role in the clearance of TDP‑43, endosomal-vacuolar pathway activity protected cells from the detrimental effects of TDP‑43. In contrast, enhanced autophagy contributed to TDP‑43 cytotoxicity, despite being involved in TDP‑43 degradation. TDP‑43’s interference with endosomal-vacuolar pathway activity may have two deleterious consequences. First, it interferes with its own degradation via this pathway, resulting in TDP‑43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP‑43-associated diseases.

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

DEFF Research Database (Denmark)

Maddika, S; Ande, SR; Panigrahi, S

2007-01-01

)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted...... approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells....

Scoping calculation for components of the cow-milk dose pathway for evaluating the dose contribution from iodine-131

International Nuclear Information System (INIS)

Ikenberry, T.A.; Napier, B.A.

1992-12-01

A series of scoping calculations have been undertaken to evaluate The absolute and relative contribution of different exposure pathways to doses that may have been received by individuals living in the vicinity of the Hanford site. This scoping calculation (Calculation 001) examined the contributions of the various exposure pathways associated with environmental transport and accumulation of iodine-131 in the pasture-cow-milk pathway. Addressed in this calculation were the contributions to thyroid dose of infants and adult from (1) the ingestion by dairy cattle of various feedstuffs (pasturage, silage, alfalfa hay, and grass hay) in four different feeding regimes; (2) ingestion of soil by dairy cattle; (3) ingestion of stared feed on which airborne iodine-131 had been deposited; and (4) inhalation of airborne iodine-131 by dairy cows

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility.

LENUS (Irish Health Repository)

O'Dushlaine, C

2011-03-01

Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant (P<0.05) to nonsignificant SNPs in a given pathway to identify the \\'enrichment\\' for association signals. We applied this approach to the discovery (the International Schizophrenia Consortium (n=6909)) and validation (Genetic Association Information Network (n=2729)) of schizophrenia genome-wide association study (GWAS) data sets. We investigated each of the 212 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes in the discovery sample. Nominally significant pathways were tested in the validation sample, and five pathways were found to be significant (P=0.03-0.001); only the cell adhesion molecule (CAM) pathway withstood conservative correction for multiple testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium (n=4847)) (P=0.01). At a gene level, CAM genes associated in all three samples (NRXN1 and CNTNAP2), which were previously implicated in specific language disorder, autism and schizophrenia. The CAM pathway functions in neuronal cell adhesion, which is critical for synaptic formation and normal cell signaling. Similar pathways have also emerged from a pathway analysis of autism, suggesting that mechanisms involved in neuronal cell adhesion may contribute broadly to neurodevelopmental psychiatric phenotypes.

Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.

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Lin, Zhiqiang; Zhou, Pingzhu; von Gise, Alexander; Gu, Fei; Ma, Qing; Chen, Jinghai; Guo, Haidong; van Gorp, Pim R R; Wang, Da-Zhi; Pu, William T

2015-01-02

Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart. We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression. Pik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival. © 2014 American Heart Association, Inc.

Deoxycholate, an Endogenous Cytotoxin/Genotoxin, Induces the Autophagic Stress-Survival Pathway: Implications for Colon Carcinogenesis

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Claire M. Payne

2009-01-01

Full Text Available We report that deoxycholate (DOC, a hydrophobic bile acid associated with a high-fat diet, activates the autophagic pathway in non-cancer colon epithelial cells (NCM-460, and that this activation contributes to cell survival. The DOC-induced increase in autophagy was documented by an increase in autophagic vacuoles (detected using transmission electron microscopy, increased levels of LC3-I and LC3-II (western blotting, an increase in acidic vesicles (fluorescence spectroscopy of monodansycadaverine and lysotracker red probes, and increased expression of the autophagic protein, beclin-1 (immunohistochemistry/western blotting. The DOC-induced increase in beclin-1 expression was ROS-dependent. Rapamycin (activator of autophagy pre-treatment of NCM-460 cells significantly (P<.05 decreased, and 3-MA (inhibitor of autophagy significantly (P<.05 increased the cell loss caused by DOC treatment, alone. Rapamycin pre-treatment of the apoptosis-resistant colon cancer cell line, HCT-116RC (developed in our laboratory, resulted in a significant decrease in DOC-induced cell death. Bafilomycin A1 and hydroxychloroquine (inhibitors of the autophagic process increased the DOC-induced percentage of apoptotic cells in HCT-116RC cells. It was concluded that the activation of autophagy by DOC has important implications for colon carcinogenesis and for the treatment of colon cancer in conjunction with commonly used chemotherapeutic agents.

Determination of the contribution of livestock water ingestion to dose from the cow-milk pathway

International Nuclear Information System (INIS)

Ikenberry, T.A.

1992-12-01

As part of the Hanford Environmental Dose Reconstruction (HEDR) Project, a series of calculations has been undertaken to evaluate the absolute and relative contribution of different exposure pathways to thyroid doses that may have been received by individuals living in the vicinity of the Hanford Site. These evaluations include some pathways that were included in the Phase I air-pathway dose evaluations (HEDR staff 1991, page xx), as well as other potential exposure pathways being evaluated for possible inclusion in the future HEDR modeling efforts. This calculation (002) examined the possible doses that may have been received by individuals who drank milk from cows that drank from sources of water (stock tanks and farm ponds) exposed to iodine-131 in the atmosphere during 1945

Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals

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Gupta, Subash C.; Kim, Ji Hye; Prasad, Sahdeo

2010-01-01

Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed “Let food be thy medicine and medicine be thy food.” Exploring the association between diet and health continues today. For example, we now know that as many as 35% of all cancers can be prevented by dietary changes. Carcinogenesis is a multistep process involving the transformation, survival, proliferation, invasion, angiogenesis, and metastasis of the tumor and may take up to 30 years. The pathways associated with this process have been linked to chronic inflammation, a major mediator of tumor progression. The human body consists of about 13 trillion cells, almost all of which are turned over within 100 days, indicating that 70,000 cells undergo apoptosis every minute. Thus, apoptosis/cell death is a normal physiological process, and it is rare that a lack of apoptosis kills the patient. Almost 90% of all deaths due to cancer are linked to metastasis of the tumor. How our diet can prevent cancer is the focus of this review. Specifically, we will discuss how nutraceuticals, such as allicin, apigenin, berberine, butein, caffeic acid, capsaicin, catechin gallate, celastrol, curcumin, epigallocatechin gallate, fisetin, flavopiridol, gambogic acid, genistein, plumbagin, quercetin, resveratrol, sanguinarine, silibinin, sulforaphane, taxol, γ-tocotrienol, and zerumbone, derived from spices, legumes, fruits, nuts, and vegetables, can modulate inflammatory pathways and thus affect the survival, proliferation, invasion, angiogenesis, and metastasis of the tumor. Various cell signaling pathways that are modulated by these agents will also be discussed. PMID:20737283

Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway.

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Liu, Tiantian; Chen, Xiaoxu; Li, Tianjiao; Li, Xueliang; Lyu, Yinghua; Fan, Xiaoteng; Zhang, Pengfei; Zeng, Wenxian

2017-10-01

Spermatogonial stem cells (SSCs) possess the capacity of self-renewal and differentiation, which are the basis of spermatogenesis. In maintenance of SSC homeostasis, intrinsic/extrinsic factors and various signaling pathways tightly control the fate of SSCs. Methyltransferase SETDB1 (Set domain, bifurcated 1) catalyzes histone H3 lysine 9 (H3K9) trimethylation and represses gene expression. SETDB1 is required for maintaining the survival of spermatogonial stem cells in mice. However, the underlying molecular mechanism remains unclear. In the present study, we found that Setdb1 regulates PTEN/AKT/FOXO1 pathway to inhibit SSC apoptosis. Co-immunoprecipitation and reporter gene assay revealed that SETDB1 interacted and coordinated with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decreased in Setdb1-KD group; in contrast, H3K9me3 status on promoters of Bax and Puma remained unchanged. Therefore, SETDB1 was responsible for regulating the transcription activity of genes in the apoptotic pathway at least in part through modulating H3K9me3. This study replenishes the research on the epigenetic regulation of SSC survival, and provides a new insight for the future study of epigenetic regulation of spermatogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

The relative contribution of mannose salvage pathways to glycosylation in PMI-deficient mouse embryonic fibroblast cells.

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Fujita, Naonobu; Tamura, Ayako; Higashidani, Aya; Tonozuka, Takashi; Freeze, Hudson H; Nishikawa, Atsushi

2008-02-01

Mannose for mammalian glycan biosynthesis can be imported directly from the medium, derived from glucose or salvaged from endogenous or external glycans. All pathways must generate mannose 6-phosphate, the activated form of mannose. Imported or salvaged mannose is directly phosphorylated by hexokinase, whereas fructose 6-phosphate from glucose is converted to mannose 6-phosphate by phosphomannose isomerase (PMI). Normally, PMI provides the majority of mannose for glycan synthesis. To assess the contribution of PMI-independent pathways, we used PMI-null fibroblasts to study N-glycosylation of DNase I, a highly sensitive indicator protein. In PMI-null cells, imported mannose and salvaged mannose make a significant contribution to N-glycosylation. When these cells were grown in mannose-free medium along with the mannosidase inhibitor, swainsonine, to block the salvage pathways, N-glycosylation of DNase I was almost completely eliminated. Adding approximately 13 microm mannose to the medium completely restored normal glycosylation. Treatment with bafilomycin A(1), an inhibitor of lysosomal acidification, also markedly reduced N-glycosylation of DNase I, but in this case only 8 microm mannose was required to restore full glycosylation, indicating that a nonlysosomal source of mannose made a significant contribution. Glycosylation levels were greatly also reduced in glycoconjugate-free medium, when endosomal membrane trafficking was blocked by expression of a mutant SKD1. From these data, we conclude that PMI-null cells can salvage mannose from both endogenous and external glycoconjugates via lysosomal and nonlysosomal degradation pathways.

Autocrine prostaglandin E2 signaling promotes promonocytic leukemia cell survival via COX-2 expression and MAPK pathway

Science.gov (United States)

Lee, Jaetae; Lee, Young Sup

2015-01-01

The COX-2/PGE2 pathway has been implicated in the occurrence and progression of cancer. The underlying mechanisms facilitating the production of COX-2 and its mediator, PGE2, in cancer survival remain unknown. Herein, we investigated PGE2-induced COX-2 expression and signaling in HL-60 cells following menadione treatment. Treatment with PGE2 activated anti-apoptotic proteins such as Bcl-2 and Bcl-xL while reducing pro-apoptotic proteins, thereby enhancing cell survival. PGE2 not only induced COX-2 expression, but also prevented casapse-3, PARP, and lamin B cleavage. Silencing and inhibition of COX-2 with siRNA transfection or treatment with indomethacin led to a pronounced reduction of the extracellular levels of PGE2, and restored the menadione-induced cell death. In addition, pretreatment of cells with the MEK inhibitor PD98059 and the PKA inhibitor H89 abrogated the PGE2-induced expression of COX-2, suggesting involvement of the MAPK and PKA pathways. These results demonstrate that PGE2 signaling acts in an autocrine manner, and specific inhibition of PGE2 will provide a novel approach for the treatment of leukemia. [BMB Reports 2015; 48(2): 109-114] PMID:24965577

Genetic variations in radiation and chemotherapy drug action pathways and survival in locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy.

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Huai Liu

Full Text Available BACKGROUND AND PURPOSE: Treatment outcomes vary greatly in patients with nasopharyngeal carcinoma (NPC. The purpose of this study is to evaluate the influence of radiation and chemotherapy drug action pathway gene polymorphisms on the survival of patients with locoregionally advanced NPC treated with cisplatin- and fluorouracil-based chemoradiotherapy. MATERIAL AND METHODS: Four hundred twenty-one consecutive patients with locoregionally advanced NPC were prospectively recruited. We utilized a pathway approach and examined 18 polymorphisms in 13 major genes. Polymorphisms were detected using the LDR-PCR technique. Multifactor dimensionality reduction (MDR analysis was performed to detect potential gene-gene interaction. RESULTS: After adjustment for clinicopathological characteristics, overall survival was significantly decreased in patients with the MPO rs2243828 CT/CC genotype (HR=2.453, 95% CI, 1.687-3.566, P<0.001. The ERCC1 rs3212986 CC (HR=1.711, 95% CI, 1.135-2.579, P=0.010, MDM2 rs2279744 GT/GG (HR=1.743, 95% CI, 1.086-2.798, P=0.021, MPO rs2243828 CT/CC (HR=3.184, 95% CI, 2.261-4.483, P<0.001 and ABCB1 rs2032582 AT/AA (HR=1.997, 95% CI, 1.086-3.670, P=0.026 genotypes were associated with poor progression-free survival. Prognostic score models based on independent prognostic factors successfully classified patients into low-, intermediate-, and high-risk groups. Furthermore, MDR analysis showed no significant interaction between polymorphisms. CONCLUSIONS: Four single nucleotide polymorphisms were associated with survival in patients with locoregionally advanced NPC treated with cisplatin- and fluorouracil-based chemoradiotherapy. Combining clinical prognostic factors with genetic information was valuable in identifying patients with different risk.

Regulatory cross-talks and cascades in rice hormone biosynthesis pathways contribute to stress signaling

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Arindam Deb

2016-08-01

Full Text Available Crosstalk among different hormone signaling pathways play an important role in modulating plant response to both biotic and abiotic stress. Hormone activity is controlled by its bio-availability, which is again influenced by its biosynthesis. Thus independent hormone biosynthesis pathways must be regulated and co-ordinated to mount an integrated response. One of the possibilities is to use cis-regulatory elements to orchestrate expression of hormone biosynthesis genes. Analysis of CREs, associated with differentially expressed hormone biosynthesis related genes in rice leaf under Magnaporthe oryzae attack and drought stress enabled us to obtain insights about cross-talk among hormone biosynthesis pathways at the transcriptional level. We identified some master transcription regulators that co-ordinate different hormone biosynthesis pathways under stress. We found that Abscisic acid and Brassinosteroid regulate Cytokinin conjugation; conversely Brassinosteroid biosynthesis is affected by both Abscisic acid and Cytokinin. Jasmonic acid and Ethylene biosynthesis may be modulated by Abscisic acid through DREB transcription factors. Jasmonic acid or Salicylic acid biosynthesis pathways are co-regulated but they are unlikely to influence each other’s production directly. Thus multiple hormones may modulate hormone biosynthesis pathways through a complex regulatory network, where biosynthesis of one hormone is affected by several other contributing hormones.

Survival advantages conferred to colon cancer cells by E-selectin-induced activation of the PI3K-NFκB survival axis downstream of Death receptor-3

International Nuclear Information System (INIS)

Porquet, Nicolas; Huot, Jacques; Poirier, Andrée; Houle, François; Pin, Anne-Laure; Gout, Stéphanie; Tremblay, Pierre-Luc; Paquet, Éric R; Klinck, Roscoe; Auger, François A

2011-01-01

DR3 that has no trans-membrane domain and no death domain. Colon cancer cells acquire an increased capacity to survive via the activation of the PI3K/NFκB pathway following the stimulation of DR3 by E-selectin. Generation of a DR3 splice variant devoid of death domain can further contribute to protect against apoptosis

Survival advantages conferred to colon cancer cells by E-selectin-induced activation of the PI3K-NFκB survival axis downstream of Death receptor-3

Directory of Open Access Journals (Sweden)

Paquet Éric R

2011-07-01

29 and SW620 express higher levels of a splice variant of DR3 that has no trans-membrane domain and no death domain. Conclusion Colon cancer cells acquire an increased capacity to survive via the activation of the PI3K/NFκB pathway following the stimulation of DR3 by E-selectin. Generation of a DR3 splice variant devoid of death domain can further contribute to protect against apoptosis.

Deoxycholate, an Endogenous Cytotoxin/Geno toxin, Induces the Autophagic Stress-Survival Pathway: Implications for Colon Carcinogenesis

International Nuclear Information System (INIS)

Payne, C.M.; Skillicorn, C.C.; Holubec, H.; Bernstein, C.; Dvorak, K.; Bernstein, H.; Moyer, M.P.; Garewal, H.

2009-01-01

We report that deoxycholate (DOC), a hydrophobic bile acid associated with a high-fat diet, activates the autophagic pathway in non-cancer colon epithelial cells (NCM-460), and that this activation contributes to cell survival. The DOC-induced increase in autophagy was documented by an increase in autophagic vacuoles (detected using transmission electron microscopy, increased levels of LC3-I and LC3-II (western blotting), an increase in acidic vesicles (fluorescence spectroscopy of monodansylcadaverine and lyso tracker red probes), and increased expression of the autophagic protein, beclin-1 (immunohistochemistry/western blotting). The DOC-induced increase in beclin-1 expression was ROS-dependent. Rapa mycin (activator of autophagy) pre-treatment of NCM-460 cells significantly (P<.05) decreased, and 3-MA (inhibitor of autophagy) significantly (P<.05) increased the cell loss caused by DOC treatment, alone. Rapa mycin pre-treatment of the apoptosis-resistant colon cancer cell line, HCT-116RC (developed in our laboratory), resulted in a significant decrease in DOC-induced cell death. Bafilomycin A1 and hydroxychloroquine (inhibitors of the autophagic process) increased the DOC-induced percentage of apoptotic cells in HCT-116RC cells. It was concluded that the activation of autophagy by DOC has important implications for colon carcinogenesis and for the treatment of colon cancer in conjunction with commonly used chemotherapeutic agents.

Decreased function of survival motor neuron protein impairs endocytic pathways.

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Dimitriadi, Maria; Derdowski, Aaron; Kalloo, Geetika; Maginnis, Melissa S; O'Hern, Patrick; Bliska, Bryn; Sorkaç, Altar; Nguyen, Ken C Q; Cook, Steven J; Poulogiannis, George; Atwood, Walter J; Hall, David H; Hart, Anne C

2016-07-26

Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.

Effect of Migration Pathway on Travel Time and Survival of Acoustic-Tagged Juvenile Salmonids in the Columbia River Estuary

Energy Technology Data Exchange (ETDEWEB)

Harnish, Ryan A.; Johnson, Gary E.; McMichael, Geoffrey A.; Hughes, Michael S.; Ebberts, Blaine D.

2012-02-01

Off-channel areas (side channels, tidal flats, sand bars, and shallow-water bays) may serve as important migration corridors through estuarine environments for salmon and steelhead smolts. Relatively large percentages (21-33%) of acoustic-tagged yearling and subyearling Chinook salmon and steelhead smolts were detected migrating through off-channel areas of the Columbia River estuary in 2008. The probability of survival for off-channel migrants (0.78-0.94) was similar to or greater than the survival probability of main channel migrants (0.67-0.93). Median travel times were similar for all species or run types and migration pathways we examined, ranging from 1-2 d. The route used by smolts to migrate through the estuary may affect their vulnerability to predation. Acoustic-tagged steelhead that migrated nearest to avian predator nesting colonies experienced higher predation rates (24%) than those that migrated farthest from the colonies (10%). The use of multiple migration pathways may be advantageous to out-migrating smolts because it helps to buffer against high rates of mortality, which may occur in localized areas, and helps to minimize inter- and intraspecific competition.

Oral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes

International Nuclear Information System (INIS)

Zhang, Min; Chai, Yang D; Brumbaugh, Jeffrey; Liu, Xiaojun; Rabii, Ramin; Feng, Sizhe; Misuno, Kaori; Messadi, Diana; Hu, Shen

2014-01-01

Cancer cells may undergo metabolic adaptations that support their growth as well as drug resistance properties. The purpose of this study is to test if oral cancer cells can overcome the metabolic defects introduced by using small interfering RNA (siRNA) to knock down their expression of important metabolic enzymes. UM1 and UM2 oral cancer cells were transfected with siRNA to transketolase (TKT) or siRNA to adenylate kinase (AK2), and Western blotting was used to confirm the knockdown. Cellular uptake of glucose and glutamine and production of lactate were compared between the cancer cells with either TKT or AK2 knockdown and those transfected with control siRNA. Statistical analysis was performed with student T-test. Despite the defect in the pentose phosphate pathway caused by siRNA knockdown of TKT, the survived UM1 or UM2 cells utilized more glucose and glutamine and secreted a significantly higher amount of lactate than the cells transferred with control siRNA. We also demonstrated that siRNA knockdown of AK2 constrained the proliferation of UM1 and UM2 cells but similarly led to an increased uptake of glucose/glutamine and production of lactate by the UM1 or UM2 cells survived from siRNA silencing of AK2. Our results indicate that the metabolic defects introduced by siRNA silencing of metabolic enzymes TKT or AK2 may be compensated by alternative feedback metabolic mechanisms, suggesting that cancer cells may overcome single defective pathways through secondary metabolic network adaptations. The highly robust nature of oral cancer cell metabolism implies that a systematic medical approach targeting multiple metabolic pathways may be needed to accomplish the continued improvement of cancer treatment

4-Hydroxynonenal Contributes to Angiogenesis through a Redox-Dependent Sphingolipid Pathway: Prevention by Hydralazine Derivatives

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Caroline Camaré

2017-01-01

Full Text Available The neovascularization of atherosclerotic lesions is involved in plaque development and may contribute to intraplaque hemorrhage and plaque fragilization and rupture. Among the various proangiogenic agents involved in the neovascularization process, proatherogenic oxidized LDLs (oxLDLs contribute to the formation of tubes via the generation of sphingosine 1-phosphate (S1P, a major mitogenic and proangiogenic sphingolipid mediator. In this study, we investigated whether 4-hydroxynonenal (4-HNE, an aldehydic lipid oxidation product abundantly present in oxLDLs, contributes to their proangiogenic properties. Immunofluorescence analysis of human atherosclerotic lesions from carotid endarterectomy showed the colocalization of HNE-adducts with CD31, a marker of endothelial cells, suggesting a close relationship between 4-HNE and neovessel formation. In vitro, low 4-HNE concentration (0.5–1 µM elicited the formation of tubes by human microvascular endothelial cells (HMEC-1, whereas higher concentrations were not angiogenic. The formation of tubes by 4-HNE involved the generation of reactive oxygen species and the activation of the sphingolipid pathway, namely, the neutral type 2 sphingomyelinase and sphingosine kinase-1 (nSMase2/SK-1 pathway, indicating a role for S1P in the angiogenic signaling of 4-HNE. Carbonyl scavengers hydralazine and bisvanillyl-hydralazone inhibited the nSMase2/SK1 pathway activation and the formation of tubes on Matrigel® evoked by 4-HNE. Altogether, these results emphasize the role of 4-HNE in the angiogenic effect of oxLDLs and point out the potential interest of pharmacological carbonyl scavengers to prevent the neovascularization process.

Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response.

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Katare, Rajesh; Caporali, Andrea; Emanueli, Costanza; Madeddu, Paolo

2010-10-01

Benfotiamine (BFT) is a transketolase activator that directs glucose to the pentose phosphate pathway. The present study investigated whether BFT improves the recovery after myocardial infarction (MI) and explored underlying mechanisms of protection. Non-diabetic and streptozotocin-induced type 1 diabetic mice were supplemented with BFT (70 mg/kg/day in drinking water) for 4 weeks and then subjected to MI or sham operation. Cardiac function was monitored by echocardiography. At two weeks post-MI, intra-ventricular pressure was measured by Millar tip-catheter and hearts were collected for biochemical, immunohistochemical and expressional analyses. No treatment effect was observed in sham-operated mice. Post-MI mortality was higher in diabetic mice and hemodynamic studies confirmed the worsening effect of diabetes on functional recovery. Furthermore, diabetic mice demonstrated increased cardiomyocyte apoptosis, reduced reparative angiogenesis, larger scars, enhanced oxidative stress, and blunted activation of the pro-survival VEGF receptor-2/Akt/Pim-1 signaling pathway. BFT improved post-MI survival, functional recovery and neovascularization and reduced cardiomyocyte apoptosis and neurohormonal activation in diabetic as well as in non-diabetic mice. In addition, BFT stimulated the activity of pentose phosphate pathway enzymes, leading to reduction of oxidative stress, phosphorylation/activation of VEGF receptor-2 and Akt and increased Pim-1, pBad and Bcl-2 levels. These effects were contrasted on silencing glucose-6-phosphate dehydrogenase, the key enzyme in pentose phosphate pathway, or inhibiting Akt. BFT benefits post-MI recovery through stimulation of pro-survival mechanisms and containment of neurohormonal response. These results may have implications for the treatment of myocardial ischemia. Copyright © 2010 Elsevier Ltd. All rights reserved.

Multinucleation during C. trachomatis infections is caused by the contribution of two effector pathways.

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Heather M Brown

Full Text Available Chlamydia trachomatis is an obligate intracellular bacterial pathogen and the second leading cause of sexually transmitted infections in the US. Infections cause significant morbidity and can lead to serious reproductive sequelae, including an epidemiological link to increased rates of reproductive cancers. One of the overt changes that infected cells exhibit is the development of genomic instability leading to multinucleation. Here we demonstrate that the induction of multinucleation is not conserved equally across chlamydial species; C. trachomatis L2 caused high levels of multinucleation, C. muridarum intermediate levels, and C. caviae had very modest effects on multinucleation. Our data show that at least two effector pathways together cause genomic instability during infection leading to multinucleation. We find that the highly conserved chlamydial protease CPAF is a key effector for one of these pathways. CPAF secretion is required for the loss of centrosome duplication regulation as well as inducing early mitotic exit. The second effector pathway involves the induction of centrosome position errors. This function is not conserved in three chlamydial species tested. Together these two pathways contribute to the induction of high levels of genomic instability and multinucleation seen in C. trachomatis infections.

SIRT1 regulates MAPK pathways in vitiligo skin: insight into the molecular pathways of cell survival

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Becatti, Matteo; Fiorillo, Claudia; Barygina, Victoria; Cecchi, Cristina; Lotti, Torello; Prignano, Francesca; Silvestro, Agrippino; Nassi, Paolo; Taddei, Niccolò

2014-01-01

Vitiligo is an acquired and progressive hypomelanotic disease that manifests as circumscribed depigmented patches on the skin. The aetiology of vitiligo remains unclear, but recent experimental data underline the interactions between melanocytes and other typical skin cells, particularly keratinocytes. Our previous results indicate that keratinocytes from perilesional skin show the features of damaged cells. Sirtuins (silent mating type information regulation 2 homolog) 1, well-known modulators of lifespan in many species, have a role in gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection and healthy ageing. In the literature there is no evidence for SIRT1 signalling in vitiligo and its possible involvement in disease progression. Here, biopsies were taken from the perilesional skin of 16 patients suffering from non-segmental vitiligo and SIRT1 signalling was investigated in these cells. For the first time, a new SIRT1/Akt, also known as Protein Kinase B (PKB)/mitogen-activated protein kinase (MAPK) signalling has been revealed in vitiligo. SIRT1 regulates MAPK pathway via Akt-apoptosis signal-regulating kinase-1 and down-regulates pro-apoptotic molecules, leading to decreased oxidative stress and apoptotic cell death in perilesional vitiligo keratinocytes. We therefore propose SIRT1 activation as a novel way of protecting perilesional vitiligo keratinocytes from damage. PMID:24410795

Association of Sphingosine-1-phosphate (S1P)/S1P Receptor-1 Pathway with Cell Proliferation and Survival in Canine Hemangiosarcoma.

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Rodriguez, A M; Graef, A J; LeVine, D N; Cohen, I R; Modiano, J F; Kim, J-H

2015-01-01

Sphingosine-1-phosphate (S1P) is a key biolipid signaling molecule that regulates cell growth and survival, but it has not been studied in tumors from dogs. S1P/S1P1 signaling will contribute to the progression of hemangiosarcoma (HSA). Thirteen spontaneous HSA tissues, 9 HSA cell lines, 8 nonmalignant tissues, including 6 splenic hematomas and 2 livers with vacuolar degeneration, and 1 endothelial cell line derived from a dog with splenic hematoma were used. This was a retrospective case series and in vitro study. Samples were obtained as part of medically necessary diagnostic procedures. Microarray, qRT-PCR, immunohistochemistry, and immunoblotting were performed to examine S1P1 expression. S1P concentrations were measured by high-performance liquid chromatography/mass spectrometry. S1P signaling was evaluated by intracellular Ca(2+) mobilization; proliferation and survival were evaluated using the MTS assay and Annexin V staining. Canine HSA cells expressed higher levels of S1P1 mRNA than nonmalignant endothelial cells. S1P1 protein was present in HSA tissues and cell lines. HSA cells appeared to produce low levels of S1P, but they selectively consumed S1P from the culture media. Exogenous S1P induced an increase in intracellular calcium as well as increased proliferation and viability of HSA cells. Prolonged treatment with FTY720, an inhibitor of S1P1 , decreased S1P1 protein expression and induced apoptosis of HSA cells. S1P/S1P1 signaling pathway functions to maintain HSA cell viability and proliferation. The data suggest that S1P1 or the S1P pathway in general could be targets for therapeutic intervention for dogs with HSA. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Mechanisms and mediation in survival analysis: towards an integrated analytical framework

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Jonathan Pratschke

2016-02-01

Full Text Available Abstract Background A wide-ranging debate has taken place in recent years on mediation analysis and causal modelling, raising profound theoretical, philosophical and methodological questions. The authors build on the results of these discussions to work towards an integrated approach to the analysis of research questions that situate survival outcomes in relation to complex causal pathways with multiple mediators. The background to this contribution is the increasingly urgent need for policy-relevant research on the nature of inequalities in health and healthcare. Methods The authors begin by summarising debates on causal inference, mediated effects and statistical models, showing that these three strands of research have powerful synergies. They review a range of approaches which seek to extend existing survival models to obtain valid estimates of mediation effects. They then argue for an alternative strategy, which involves integrating survival outcomes within Structural Equation Models via the discrete-time survival model. This approach can provide an integrated framework for studying mediation effects in relation to survival outcomes, an issue of great relevance in applied health research. The authors provide an example of how these techniques can be used to explore whether the social class position of patients has a significant indirect effect on the hazard of death from colon cancer. Results The results suggest that the indirect effects of social class on survival are substantial and negative (-0.23 overall. In addition to the substantial direct effect of this variable (-0.60, its indirect effects account for more than one quarter of the total effect. The two main pathways for this indirect effect, via emergency admission (-0.12, on the one hand, and hospital caseload, on the other, (-0.10 are of similar size. Conclusions The discrete-time survival model provides an attractive way of integrating time-to-event data within the field of

Mechanisms and mediation in survival analysis: towards an integrated analytical framework.

Science.gov (United States)

Pratschke, Jonathan; Haase, Trutz; Comber, Harry; Sharp, Linda; de Camargo Cancela, Marianna; Johnson, Howard

2016-02-29

A wide-ranging debate has taken place in recent years on mediation analysis and causal modelling, raising profound theoretical, philosophical and methodological questions. The authors build on the results of these discussions to work towards an integrated approach to the analysis of research questions that situate survival outcomes in relation to complex causal pathways with multiple mediators. The background to this contribution is the increasingly urgent need for policy-relevant research on the nature of inequalities in health and healthcare. The authors begin by summarising debates on causal inference, mediated effects and statistical models, showing that these three strands of research have powerful synergies. They review a range of approaches which seek to extend existing survival models to obtain valid estimates of mediation effects. They then argue for an alternative strategy, which involves integrating survival outcomes within Structural Equation Models via the discrete-time survival model. This approach can provide an integrated framework for studying mediation effects in relation to survival outcomes, an issue of great relevance in applied health research. The authors provide an example of how these techniques can be used to explore whether the social class position of patients has a significant indirect effect on the hazard of death from colon cancer. The results suggest that the indirect effects of social class on survival are substantial and negative (-0.23 overall). In addition to the substantial direct effect of this variable (-0.60), its indirect effects account for more than one quarter of the total effect. The two main pathways for this indirect effect, via emergency admission (-0.12), on the one hand, and hospital caseload, on the other, (-0.10) are of similar size. The discrete-time survival model provides an attractive way of integrating time-to-event data within the field of Structural Equation Modelling. The authors demonstrate the efficacy

Chronic intermittent fasting improves the survival following large myocardial ischemia by activation of BDNF/VEGF/PI3K signaling pathway.

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Katare, Rajesh G; Kakinuma, Yoshihiko; Arikawa, Mikihiko; Yamasaki, Fumiyasu; Sato, Takayuki

2009-03-01

Chronic heart failure (CHF) is the major cause of death in the developed countries. Calorie restriction is known to improve the recovery in these patients; however, the exact mechanism behind this protective effect is unknown. Here we demonstrate the activation of cell survival PI3kinase/Akt and VEGF pathway as the mechanism behind the protection induced by intermittent fasting in a rat model of established chronic myocardial ischemia (MI). Chronic MI was induced in rats by occlusion of the left coronary artery. Two weeks later, the rats were randomly assigned to a normal feeding group (MI-NF) and an alternate-day feeding group (MI-IF). After 6 weeks of observation, we evaluated the effect of intermittent fasting on cellular and ventricular remodeling and long-term survival after CHF. Compared with the normally fed group, intermittent fasting markedly improved the survival of rats with CHF (88.5% versus 23% survival, Pfasted hearts. Immunohistochemical studies confirmed increased capillary density (Pfasting also upregulated the expression of other anti-apoptotic factors such as Akt and Bcl-2 and reduced the TUNEL positive apoptotic nuclei in the border zone. Chronic intermittent fasting markedly improves the long-term survival after CHF by activation through its pro-angiogenic, anti-apoptotic and anti-remodeling effects.

Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways

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Barreto, Rafael; Mandili, Giorgia; Witzmann, Frank A.; Novelli, Francesco; Zimmers, Teresa A.; Bonetto, Andrea

2016-01-01

Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p < 0.05; −1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08%) and structural (21.25%) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer

Mechanisms and mediation in survival analysis: towards an integrated analytical framework.

LENUS (Irish Health Repository)

Haase, Trutz

2016-02-29

A wide-ranging debate has taken place in recent years on mediation analysis and causal modelling, raising profound theoretical, philosophical and methodological questions. The authors build on the results of these discussions to work towards an integrated approach to the analysis of research questions that situate survival outcomes in relation to complex causal pathways with multiple mediators. The background to this contribution is the increasingly urgent need for policy-relevant research on the nature of inequalities in health and healthcare.

Geographical variations in the use of cancer treatments are associated with survival of lung cancer patients

DEFF Research Database (Denmark)

Møller, Henrik; Coupland, Victoria H; Tataru, Daniela

2018-01-01

INTRODUCTION: Lung cancer outcomes in England are inferior to comparable countries. Patient or disease characteristics, healthcare-seeking behaviour, diagnostic pathways, and oncology service provision may contribute. We aimed to quantify associations between geographic variations in treatment...... and survival of patients in England. METHODS: We retrieved detailed cancer registration data to analyse the variation in survival of 176,225 lung cancer patients, diagnosed 2010-2014. We used Kaplan-Meier analysis and Cox proportional hazards regression to investigate survival in the two-year period following...... diagnosis. RESULTS: Survival improved over the period studied. The use of active treatment varied between geographical areas, with inter-quintile ranges of 9%-17% for surgical resection, 4%-13% for radical radiotherapy, and 22%-35% for chemotherapy. At 2 years, there were 188 potentially avoidable deaths...

Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy.

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Melucci, Elisa; Casini, Beatrice; Ronchetti, Livia; Pizzuti, Laura; Sperati, Francesca; Pallocca, Matteo; De Nicola, Francesca; Goeman, Frauke; Gallo, Enzo; Amoreo, Carla Azzurra; Sergi, Domenico; Terrenato, Irene; Vici, Patrizia; Di Lauro, Luigi; Diodoro, Maria Grazia; Pescarmona, Edoardo; Barba, Maddalena; Mazzotta, Marco; Mottolese, Marcella; Fanciulli, Maurizio; Ciliberto, Gennaro; De Maria, Ruggero; Buglioni, Simonetta; Maugeri-Saccà, Marcello

2018-02-05

An extensive crosstalk co-regulates the Hippo and Wnt pathway. Preclinical studies revealed that the Hippo transducers YAP/TAZ mediate a number of oncogenic functions in gastric cancer (GC). Moreover, comprehensive characterization of GC demonstrated that the Wnt pathway is targeted by oncogenic mutations. On this ground, we hypothesized that YAP/TAZ- and Wnt-related biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. In the present study, we included 86 patients with advanced GC treated with first-line chemotherapy in prospective phase II trials or in routine clinical practice. Tissue samples were immunostained to evaluate the expression of YAP/TAZ. Mutational status of key Wnt pathway genes (CTNNB1, APC and FBXW7) was assessed by targeted DNA next-generation sequencing (NGS). Survival curves were estimated and compared by the Kaplan-Meier product-limit method and the log-rank test, respectively. Variables potentially affecting progression-free survival (PFS) were verified in univariate Cox proportional hazard models. The final multivariate Cox models were obtained with variables testing significant at the univariate analysis, and by adjusting for all plausible predictors of the outcome of interest (PFS). We observed a significant association between TAZ expression and Wnt mutations (Chi-squared p = 0.008). Combined TAZ expression and Wnt mutations (TAZ pos /WNT mut ) was more frequently observed in patients with the shortest progression-free survival (negative outliers) (Fisher p = 0.021). Uni-and multivariate Cox regression analyses revealed that patients whose tumors harbored the TAZ pos /WNT mut signature had an increased risk of disease progression (univariate Cox: HR 2.27, 95% CI 1.27-4.05, p = 0.006; multivariate Cox: HR 2.73, 95% CI 1.41-5.29, p = 0.003). Finally, the TAZ pos /WNT mut signature negatively impacted overall survival. Collectively, our findings indicate that the oncogenic YAP/TAZ-Wnt crosstalk may be

Genetic variants in fanconi anemia pathway genes BRCA2 and FANCA predict melanoma survival.

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Yin, Jieyun; Liu, Hongliang; Liu, Zhensheng; Wang, Li-E; Chen, Wei V; Zhu, Dakai; Amos, Christopher I; Fang, Shenying; Lee, Jeffrey E; Wei, Qingyi

2015-02-01

Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi anemia (FA) pathway involved in DNA crosslink repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2,339 common single-nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 (AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confidence interval (CI)=1.16-2.95, P=0.010), rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.

Dysfunction of different cellular degradation pathways contributes to specific β-amyloid42-induced pathologies.

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Ji, Xuan-Ru; Cheng, Kuan-Chung; Chen, Yu-Ru; Lin, Tzu-Yu; Cheung, Chun Hei Antonio; Wu, Chia-Lin; Chiang, Hsueh-Cheng

2018-03-01

The endosomal-lysosomal system (ELS), autophagy, and ubiquitin-proteasome system (UPS) are cellular degradation pathways that each play a critical role in the removal of misfolded proteins and the prevention of the accumulation of abnormal proteins. Recent studies on Alzheimer's disease (AD) pathogenesis have suggested that accumulation of aggregated β-amyloid (Aβ) peptides in the AD brain results from a dysfunction in these cellular clearance systems. However, the specific roles of these pathways in the removal of Aβ peptides and the pathogenesis underlying AD are unclear. Our in vitro and in vivo genetic approaches revealed that ELS mainly removed monomeric β-amyloid42 (Aβ42), while autophagy and UPS clear oligomeric Aβ42. Although overproduction of phosphatidylinositol 4-phosphate-5 increased Aβ42 clearance, it reduced the life span of Aβ42 transgenic flies. Our behavioral studies further demonstrated impaired autophagy and UPS-enhanced Aβ42-induced learning and memory deficits, but there was no effect on Aβ42-induced reduction in life span. Results from genetic fluorescence imaging showed that these pathways were damaged in the following order: UPS, autophagy, and finally ELS. The results of our study demonstrate that different degradation pathways play distinct roles in the removal of Aβ42 aggregates and in disease progression. These findings also suggest that pharmacologic treatments that are designed to stimulate cellular degradation pathways in patients with AD should be used with caution.-Ji, X.-R., Cheng, K.-C., Chen, Y.-R., Lin, T.-Y., Cheung, C. H. A., Wu, C.-L., Chiang, H.-C. Dysfunction of different cellular degradation pathways contributes to specific β-amyloid42-induced pathologies.

Association study of genetic variants in estrogen metabolic pathway genes and colorectal cancer risk and survival.

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Li, Shuwei; Xie, Lisheng; Du, Mulong; Xu, Kaili; Zhu, Lingjun; Chu, Haiyan; Chen, Jinfei; Wang, Meilin; Zhang, Zhengdong; Gu, Dongying

2018-05-16

Although studies have investigated the association of genetic variants and the abnormal expression of estrogen-related genes with colorectal cancer risk, the evidence remains inconsistent. We clarified the relationship of genetic variants in estrogen metabolic pathway genes with colorectal cancer risk and survival. A case-control study was performed to assess the association of single-nucleotide polymorphisms (SNPs) in ten candidate genes with colorectal cancer risk in a Chinese population. A logistic regression model and Cox regression model were used to calculate SNP effects on colorectal cancer susceptibility and survival, respectively. Expression quantitative trait loci (eQTL) analysis was conducted using the Genotype-Tissue Expression (GTEx) project dataset. The sequence kernel association test (SKAT) was used to perform gene-set analysis. Colorectal cancer risk and rs3760806 in SULT2B1 were significantly associated in both genders [male: OR = 1.38 (1.15-1.66); female: OR = 1.38 (1.13-1.68)]. Two SNPs in SULT1E1 were related to progression-free survival (PFS) [rs1238574: HR = 1.24 (1.02-1.50), P = 2.79 × 10 -2 ; rs3822172: HR = 1.30 (1.07-1.57), P = 8.44 × 10 -3 ] and overall survival (OS) [rs1238574: HR = 1.51 (1.16-1.97), P = 2.30 × 10 -3 ; rs3822172: HR = 1.53 (1.67-2.00), P = 2.03 × 10 -3 ]. Moreover, rs3760806 was an eQTL for SULT2B1 in colon samples (transverse: P = 3.6 × 10 -3 ; sigmoid: P = 1.0 × 10 -3 ). SULT2B1 expression was significantly higher in colorectal tumor tissues than in normal tissues in the Cancer Genome Atlas (TCGA) database (P colorectal cancer susceptibility and survival.

Sensitization of TNF-induced cytotoxicity in lung cancer cells by concurrent suppression of the NF-κB and Akt pathways

International Nuclear Information System (INIS)

Wang Xia; Chen Wenshu; Lin Yong

2007-01-01

Blockage of either nuclear factor-κB (NF-κB) or Akt sensitizes cancer cells to TNF-induced apoptosis. In this study, we investigated the undetermined effect of concurrent blockage of these two survival pathways on TNF-induced cytotoxicity in lung cancer cells. The results show that Akt contributes to TNF-induced NF-κB activation in lung cancer cells through regulating phosphorylation of the p65/RelA subunit of NF-κB. Although individually blocking IKK or Akt partially suppressed TNF-induced NF-κB activation, concurrent suppression of these pathways completely inhibited TNF-induced NF-κB activation and downstream anti-apoptotic gene expression, and synergistically potentiated TNF-induced cytotoxicity. Moreover, suppression of Akt inhibited the Akt-mediated anti-apoptotic pathway through dephosphorylation of BAD. These results indicate that concurrent suppression of NF-κB and Akt synergistically sensitizes TNF-induced cytotoxicity through blockage of distinct survival pathways downstream of NF-κB and Akt, which may be applied in lung cancer therapy

Sub-chronic agmatine treatment modulates hippocampal neuroplasticity and cell survival signaling pathways in mice.

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Freitas, Andiara E; Bettio, Luis E B; Neis, Vivian B; Moretti, Morgana; Ribeiro, Camille M; Lopes, Mark W; Leal, Rodrigo B; Rodrigues, Ana Lúcia S

2014-11-01

Agmatine is an endogenous neuromodulator which, based on animal and human studies, is a putative novel antidepressant drug. In this study, we investigated the ability of sub-chronic (21 days) p.o. agmatine administration to produce an antidepressant-like effect in the tail suspension test and examined the hippocampal cell signaling pathways implicated in such an effect. Agmatine at doses of 0.01 and 0.1 mg/kg (p.o.) produced a significant antidepressant-like effect in the tail suspension test and no effect in the open-field test. Additionally, agmatine (0.001-0.1 mg/kg, p.o.) increased the phosphorylation of protein kinase A substrates (237-258% of control), protein kinase B/Akt (Ser(473)) (116-127% of control), glycogen synthase kinase-3β (Ser(9)) (110-113% of control), extracellular signal-regulated kinases 1/2 (119-137% and 121-138% of control, respectively) and cAMP response elements (Ser(133)) (127-152% of control), and brain-derived-neurotrophic factor (137-175% of control) immunocontent in a dose-dependent manner in the hippocampus. Agmatine (0.001-0.1 mg/kg, p.o.) also reduced the c-jun N-terminal kinase 1/2 phosphorylation (77-71% and 65-51% of control, respectively). Neither protein kinase C nor p38(MAPK) phosphorylation was altered under any experimental conditions. Taken together, the present study extends the available data on the mechanisms that underlie the antidepressant action of agmatine by showing an antidepressant-like effect following sub-chronic administration. In addition, our results are the first to demonstrate the ability of agmatine to elicit the activation of cellular signaling pathways associated with neuroplasticity/cell survival and the inhibition of signaling pathways associated with cell death in the hippocampus. Copyright © 2014 Elsevier Ltd. All rights reserved.

Geographical variations in the use of cancer treatments are associated with survival of lung cancer patients

DEFF Research Database (Denmark)

Møller, Henrik; Coupland, Victoria H; Tataru, Daniela

2018-01-01

INTRODUCTION: Lung cancer outcomes in England are inferior to comparable countries. Patient or disease characteristics, healthcare-seeking behaviour, diagnostic pathways, and oncology service provision may contribute. We aimed to quantify associations between geographic variations in treatment...... and survival of patients in England. METHODS: We retrieved detailed cancer registration data to analyse the variation in survival of 176,225 lung cancer patients, diagnosed 2010-2014. We used Kaplan-Meier analysis and Cox proportional hazards regression to investigate survival in the two-year period following...... to statistical adjustments for age, sex, socio-economic status, performance status and co-morbidity. CONCLUSION: The extent of use of different treatment modalities varies between geographical areas in England. These variations are not attributable to measurable patient and tumour characteristics, and more...

Contribution of the Exposure Pathways After a Severe Accident

Energy Technology Data Exchange (ETDEWEB)

Lee, Joeun; Hwang, Wontae; Han, Moonhee [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Jae, Moosung [Hanyang University, Seoul (Korea, Republic of)

2016-10-15

A radiological dose assessment calculates the amount of radiation energy absorbed by a potentially exposed individual as a result of a specific exposure. Public can be exposure from several exposure pathways. External doses occur when the body is exposed to radioactive material outside the body. When making the emergency preparedness for severe accident from NPPs, therefore, we need to have comprehension about those exposure pathways. Thus, in this study, an evaluation of external and internal dose from radioactive materials during severe accident was performed to find out exposure pathway from which the dose has the highest value for several radionuclides. The basic study to make out the relation between exposure pathways and dose from them was performed. In the emergency phase, the most affecting nuclide type on public was noble gas, especially {sup 133}Xe, and the dominant exposure pathway was could shine. Also, in the long term-phase, the most affecting nuclide type on public was fission product, especially {sup 90}Sr, and the dominant exposure pathway was water ingestion. The information of the dose composition from exposure pathway obtained in this study might be basic data for making emergency preparedness plan for severe accident. In the future, assessment of the source term is expected to enhance the reliability of dose assessment during severe accident.

Metagenomic Analysis of Hot Springs in Central India Reveals Hydrocarbon Degrading Thermophiles and Pathways Essential for Survival in Extreme Environments

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Saxena, Rituja; Dhakan, Darshan B.; Mittal, Parul; Waiker, Prashant; Chowdhury, Anirban; Ghatak, Arundhuti; Sharma, Vineet K.

2017-01-01

Extreme ecosystems such as hot springs are of great interest as a source of novel extremophilic species, enzymes, metabolic functions for survival and biotechnological products. India harbors hundreds of hot springs, the majority of which are not yet explored and require comprehensive studies to unravel their unknown and untapped phylogenetic and functional diversity. The aim of this study was to perform a large-scale metagenomic analysis of three major hot springs located in central India namely, Badi Anhoni, Chhoti Anhoni, and Tattapani at two geographically distinct regions (Anhoni and Tattapani), to uncover the resident microbial community and their metabolic traits. Samples were collected from seven distinct sites of the three hot spring locations with temperature ranging from 43.5 to 98°C. The 16S rRNA gene amplicon sequencing of V3 hypervariable region and shotgun metagenome sequencing uncovered a unique taxonomic and metabolic diversity of the resident thermophilic microbial community in these hot springs. Genes associated with hydrocarbon degradation pathways, such as benzoate, xylene, toluene, and benzene were observed to be abundant in the Anhoni hot springs (43.5–55°C), dominated by Pseudomonas stutzeri and Acidovorax sp., suggesting the presence of chemoorganotrophic thermophilic community with the ability to utilize complex hydrocarbons as a source of energy. A high abundance of genes belonging to methane metabolism pathway was observed at Chhoti Anhoni hot spring, where methane is reported to constitute >80% of all the emitted gases, which was marked by the high abundance of Methylococcus capsulatus. The Tattapani hot spring, with a high-temperature range (61.5–98°C), displayed a lower microbial diversity and was primarily dominated by a nitrate-reducing archaeal species Pyrobaculum aerophilum. A higher abundance of cell metabolism pathways essential for the microbial survival in extreme conditions was observed at Tattapani. Taken together

Surviving mousepox infection requires the complement system.

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Elizabeth A Moulton

2008-12-01

Full Text Available Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host's immune response have co-evolved. Using this model, our study investigated the role of the complement system during a poxvirus infection. By multiple inoculation routes, ectromelia virus caused increased mortality by 7 to 10 days post-infection in C57BL/6 mice that lack C3, the central component of the complement cascade. In C3(-/- mice, ectromelia virus disseminated earlier to target organs and generated higher peak titers compared to the congenic controls. Also, increased hepatic inflammation and necrosis correlated with these higher tissue titers and likely contributed to the morbidity in the C3(-/- mice. In vitro, the complement system in naïve C57BL/6 mouse sera neutralized ectromelia virus, primarily through the recognition of the virion by natural antibody and activation of the classical and alternative pathways. Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo. The increased mortality of C4(-/- or Factor B(-/- mice also indicates that these two pathways of complement activation are required for survival. In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection.

Gene Expression, Bacteria Viability and Survivability Following Spray Drying of Mycobacterium smegmatis

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Elizabeth Hunter Lauten

2010-04-01

Full Text Available We find that Mycobacterium smegmatis survives spray drying and retains cell viability in accelerated temperature stress (40 °C conditions with a success rate that increases with increasing thermal, osmotic, and nutrient-restriction stresses applied to the mycobacterium prior to spray drying. M.smegmatis that are spray dried during log growth phase, where they suffer little or no nutrient-reduction stress, survive for less than 7 days in the dry powder state at accelerated temperature stress conditions, whereas M. smegmatis that are spray dried during stationary phase, where cells do suffer nutrient reduction, survive for up to 14 days. M. smegmatis that are spray dried from stationary phase, subjected to accelerated temperature stress conditions, regrown to stationary phase, spray dried again, and resubmitted to this same process four consecutive times, display, on the fourth spray drying iteration, an approximate ten-fold increase in stability during accelerated temperature stress testing, surviving up to 105 days. Microarray tests revealed significant differences in genetic expression of M. smegmatis between log phase and stationary phase conditions, between naïve (non spray-dried and multiply cycled dried M. smegmatis (in log and stationary phase, and between M. smegmatis in the dry powder state following a single spray drying operation and after four consecutive spray drying operations. These differences, and other phenotypical differences, point to the carotenoid biosynthetic pathway as a probable pathway contributing to bacteria survival in the spray-dried state and suggests strategies for spray drying that may lead to significantly greater room-temperature stability of mycobacteria, including mycobacterium bovis bacille Calmette-Guerin (BCG, the current TB vaccine.

Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 genes involved in the double-strand break repair pathway predict glioblastoma survival.

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Liu, Yanhong; Shete, Sanjay; Etzel, Carol J; Scheurer, Michael; Alexiou, George; Armstrong, Georgina; Tsavachidis, Spyros; Liang, Fu-Wen; Gilbert, Mark; Aldape, Ken; Armstrong, Terri; Houlston, Richard; Hosking, Fay; Robertson, Lindsay; Xiao, Yuanyuan; Wiencke, John; Wrensch, Margaret; Andersson, Ulrika; Melin, Beatrice S; Bondy, Melissa

2010-05-10

Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment. Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; or= 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs. We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients >or= 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years). Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.

Inhibition of tumor vasculogenic mimicry and prolongation of host survival in highly aggressive gallbladder cancers by norcantharidin via blocking the ephrin type a receptor 2/focal adhesion kinase/paxillin signaling pathway.

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Hui Wang

Full Text Available Vasculogenic mimicry (VM is a newly-defined tumor microcirculation pattern in highly aggressive malignant tumors. We recently reported tumor growth and VM formation of gallbladder cancers through the contribution of the ephrin type a receptor 2 (EphA2/focal adhesion kinase (FAK/Paxillin signaling pathways. In this study, we further investigated the anti-VM activity of norcantharidin (NCTD as a VM inhibitor for gallbladder cancers and the underlying mechanisms. In vivo and in vitro experiments to determine the effects of NCTD on tumor growth, host survival, VM formation of GBC-SD nude mouse xenografts, and vasculogenic-like networks, malignant phenotypes i.e., proliferation, apoptosis, invasion and migration of GBC-SD cells. Expression of VM signaling-related markers EphA2, FAK and Paxillin in vivo and in vitro were examined by immunofluorescence, western blotting and real-time polymerase chain reaction (RT-PCR, respectively. The results showed that after treatment with NCTD, GBC-SD cells were unable to form VM structures when injecting into nude mouse, growth of the xenograft was inhibited and these observations were confirmed by facts that VM formation by three-dimensional (3-D matrix, proliferation, apoptosis, invasion, migration of GBC-SD cells were affected; and survival time of the xenograft mice was prolonged. Furthermore, expression of EphA2, FAK and Paxillin proteins/mRNAs of the xenografts was downregulated. Thus, we concluded that NCTD has potential anti-VM activity against human gallbladder cancers; one of the underlying mechanisms may be via blocking the EphA2/FAK/Paxillin signaling pathway.

Adrenaline in pro-oxidant conditions elicits intracellular survival pathways in isolated rat cardiomyocytes

International Nuclear Information System (INIS)

Costa, Vera Marisa; Silva, Renata; Ferreira, Rita; Amado, Francisco; Carvalho, Felix; Bastos, Maria Lourdes de; Albuquerque Carvalho, Rui; Carvalho, Marcia; Remiao, Fernando

2009-01-01

In several pathologic conditions, like cardiac ischemia/reperfusion, the sustained elevation of plasma and interstitial catecholamine levels, namely adrenaline (ADR), and the generation of reactive oxygen species (ROS) are hallmarks. The present work aimed to investigate in cardiomyocytes which intracellular signalling pathways are altered by ADR redox ability. To mimic pathologic conditions, freshly isolated calcium tolerant cardiomyocytes from adult rat were incubated with ADR alone or in the presence of a system capable of generating ROS [(xanthine with xanthine oxidase) (X/XO)]. ADR elicited a pro-oxidant signal with generation of reactive species, which was largely magnified by the ROS generating system. However, no change in cardiomyocytes viability was observed. The pro-oxidant signal promoted the translocation to the nucleus of the transcription factors, Heat shock factor-1 (HSF-1) and Nuclear factor-κB (NF-κB). In addition, proteasome activity was compromised in the experimental groups where the generation of reactive species occurred. The decrease in the proteasome activity of the ADR group resulted from its redox sensitivity, since the activity was recovered by adding the ROS scavenger, tiron. Proteasome inhibition seemed to elicit an increase in HSP70 levels. Furthermore, retention of mitochondrial cytochrome c and inhibition of caspase 3 activity were observed by X/XO incubation in presence or absence of ADR. In conclusion, in spite of all the insults inflicted to the cardiomyocytes, they were capable to activate intracellular responses that enabled their survival. These mechanisms, namely the pathways altered by catecholamine proteasome inhibition, should be further characterized, as they could be of relevance in the ischemia preconditioning and the reperfusion injury

Decreased expression of MEG3 contributes to retinoblastoma progression and affects retinoblastoma cell growth by regulating the activity of Wnt/β-catenin pathway.

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Gao, Yali; Lu, Xiaohe

2016-02-01

The aberrant expression of MEG3 has been found in some types of cancers; however, little is known concerning the function of MEG3 in retinoblastoma. To elucidate the roles of MEG3 in retinoblastoma, MEG3 expression was quantified in 63 retinoblastoma samples and corresponding nontumor tissues in this work. Moreover, retinoblastoma cell lines were transfected with pcDNA3.1-MEG3 or si-MEG3, after which proliferation, apoptosis, and expression of β-catenin were assayed. TOP-Flash reporter assay was also used to investigate the activity of the Wnt/β-catenin pathway. The results showed that MEG3 was downregulated in retinoblastoma tissues, and the level of MEG3 was negatively associated with IIRC stages and nodal or distant metastasis. More importantly, Kaplan-Meier survival analysis demonstrated that patients with low MEG3 expression had poorer survival and multivariate Cox regression analysis revealed that MEG3 was an independent prognostic factor in retinoblastoma patients. We also observed that MEG3 expression can be modulated by DNA methylation by using 5-aza-CdR treatment. In addition, overexpression of MEG3 suppressed proliferation, promoted apoptosis, and influences the activity of the Wnt/β-catenin pathway in retinoblastoma cell lines. Furthermore, we found that Wnt/β-catenin pathway activator rescued the anticancer effect of MEG3 in retinoblastoma. In conclusion, our study for the first time demonstrated that MEG3 was a tumor suppressor by negatively regulating the activity of the Wnt/β-catenin pathway in the progression of retinoblastoma and might serve as a prognostic biomarker and molecular therapeutic target.

Multiple Gene-Environment Interactions on the Angiogenesis Gene-Pathway Impact Rectal Cancer Risk and Survival

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Noha Sharafeldin

2017-09-01

Full Text Available Characterization of gene-environment interactions (GEIs in cancer is limited. We aimed at identifying GEIs in rectal cancer focusing on a relevant biologic process involving the angiogenesis pathway and relevant environmental exposures: cigarette smoking, alcohol consumption, and animal protein intake. We analyzed data from 747 rectal cancer cases and 956 controls from the Diet, Activity and Lifestyle as a Risk Factor for Rectal Cancer study. We applied a 3-step analysis approach: first, we searched for interactions among single nucleotide polymorphisms on the pathway genes; second, we searched for interactions among the genes, both steps using Logic regression; third, we examined the GEIs significant at the 5% level using logistic regression for cancer risk and Cox proportional hazards models for survival. Permutation-based test was used for multiple testing adjustment. We identified 8 significant GEIs associated with risk among 6 genes adjusting for multiple testing: TNF (OR = 1.85, 95% CI: 1.10, 3.11, TLR4 (OR = 2.34, 95% CI: 1.38, 3.98, and EGR2 (OR = 2.23, 95% CI: 1.04, 4.78 with smoking; IGF1R (OR = 1.69, 95% CI: 1.04, 2.72, TLR4 (OR = 2.10, 95% CI: 1.22, 3.60 and EGR2 (OR = 2.12, 95% CI: 1.01, 4.46 with alcohol; and PDGFB (OR = 1.75, 95% CI: 1.04, 2.92 and MMP1 (OR = 2.44, 95% CI: 1.24, 4.81 with protein. Five GEIs were associated with survival at the 5% significance level but not after multiple testing adjustment: CXCR1 (HR = 2.06, 95% CI: 1.13, 3.75 with smoking; and KDR (HR = 4.36, 95% CI: 1.62, 11.73, TLR2 (HR = 9.06, 95% CI: 1.14, 72.11, EGR2 (HR = 2.45, 95% CI: 1.42, 4.22, and EGFR (HR = 6.33, 95% CI: 1.95, 20.54 with protein. GEIs between angiogenesis genes and smoking, alcohol, and animal protein impact rectal cancer risk. Our results support the importance of considering the biologic hypothesis to characterize GEIs associated with cancer outcomes.

Upregulated miR-132 in Lgr5+ gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway.

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Zhang, Lanfang; Guo, Xiaohe; Zhang, Dezhong; Fan, Yingying; Qin, Lei; Dong, Shuping; Zhang, Lanfang

2017-09-01

Cisplatin resistance has long been a major problem that restricts its use. A novel paradigm in tumor biology suggests that gastric tumor chemo-resistance is driven by gastric cancer stem cell-like (GCSCs). Growing evidence has indicated that microRNAs (miRNAs) contributes to chemo-resistance in gastric cancer (GC). Here, Lgr5 + cells derived from gastric cancer cell lines displayed stem cell-like features. Flow cytometry demonstrated the presence of a variable fraction of Lgr5 in 19 out of 20 GC specimens. By comparing the miRNA expression profiles of Lgr5 + GCSCs and Lrg5 - cells, we established the upregulation of miR-132 in Lgr5 + GCSCs. The enhanced miR-132 expression correlated chemo-resistance in GC patients. Kaplan-Meier survival curve showed that patients with low miR-132 expression survived obviously longer. Functional assays results indicated that miR-132 promoted cisplatin resistance in Lgr5 + GCSCs in vitro and in vivo. Further dual-luciferase reporter gene assays revealed that SIRT1 was the direct target of miR-132. The expression of miR-132 was inversely correlated with SIRT1 in gastric cancer specimens. Furthermore, through PCR array we discovered ABCG2 was one of the downstream targets of SIRT1. Overexpression of SIRT1 down-regulated ABCG2 expression by promoting the de-acetylation of the transcription factor CREB. CREB was further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Thus, we concluded that miR-132 regulated SIRT1/CREB/ABCG2 signaling pathway contributing to the cisplatin resistance and might serve as a novel therapeutic target against gastric cancer. © 2017 Wiley Periodicals, Inc.

EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

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Honami Takada

Full Text Available Epstein-Barr virus (EBV has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV. However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.

The cytotoxic type 3 secretion system 1 of Vibrio rewires host gene expression to subvert cell death and activate cell survival pathways.

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De Nisco, Nicole J; Kanchwala, Mohammed; Li, Peng; Fernandez, Jessie; Xing, Chao; Orth, Kim

2017-05-16

Bacterial effectors potently manipulate host signaling pathways. The marine bacterium Vibrio parahaemolyticus ( V. para ) delivers effectors into host cells through two type 3 secretion systems (T3SSs). T3SS1 is vital for V. para survival in the environment, whereas T3SS2 causes acute gastroenteritis in human hosts. Although the natural host is undefined, T3SS1 effectors attack highly conserved cellular processes and pathways to orchestrate nonapoptotic cell death. To understand how the concerted action of T3SS1 effectors globally affects host cell signaling, we compared gene expression changes over time in primary fibroblasts infected with V. para that have a functional T3SS1 (T3SS1 + ) to those in cells infected with V. para lacking T3SS1 (T3SS1 - ). Overall, the host transcriptional response to both T3SS1 + and T3SS1 - V. para was rapid, robust, and temporally dynamic. T3SS1 rewired host gene expression by specifically altering the expression of 398 genes. Although T3SS1 effectors targeted host cells at the posttranslational level to cause cytotoxicity, V. para T3SS1 also precipitated a host transcriptional response that initially activated cell survival and repressed cell death networks. The increased expression of several key prosurvival transcripts mediated by T3SS1 depended on a host signaling pathway that is silenced posttranslationally later in infection. Together, our analysis reveals a complex interplay between the roles of T3SS1 as both a transcriptional and posttranslational manipulator of host cell signaling. Copyright © 2017, American Association for the Advancement of Science.

Spectral evidence for multi-pathway contribution to the upconversion pathway in NaYF4:Yb3+,Er3+ phosphors.

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Cho, Youngho; Song, Si Won; Lim, Soo Yeong; Kim, Jae Hun; Park, Chan Ryang; Kim, Hyung Min

2017-03-08

Although upconversion phosphors have been widely used in nanomedicine, laser engineering, bioimaging, and solar cell technology, the upconversion luminescence mechanism of the phosphors has been fiercely debated. A comprehensive understanding of upconversion photophysics has been significantly impeded because the number of photons incorporated in the process in different competitive pathways could not be resolved. Few convincing results to estimate the contribution of each of the two-, three-, and four-photon channels of near-infrared (NIR) energy have been reported in yielding upconverted visible luminescence. In this study, we present the energy upconversion process occurring in NaYF 4 :Yb 3+ ,Er 3+ phosphors as a function of excitation frequency and power density. We investigated the upconversion mechanism of lanthanide phosphors by comparing UV/VIS one-photon excitation spectra and NIR multi-photon spectra. A detailed analysis of minor transitions in one-photon spectra and luminescence decay enables us to assign electronic origins of individual bands in multi-photon upconversion luminescence and provides characteristic transitions representing the corresponding upconversion channel. Furthermore, we estimated the quantitative contribution of multiple channels with respect to irradiation power and excitation energy.

Contribution of a caffeine-sensitive recombinational repair pathway to survival and mutagenesis in UV-irradiated Schizosaccharomyces pombe

International Nuclear Information System (INIS)

Gentner, N.E.; Werner, M.M.; Hannan, M.A.; Nasim, A.

1978-01-01

Cells of wild-type Schizosacharomyces pombe exposed to UV radiation in either G1 or G2 phase show enhanced inactivation of colony-forming ability if plated in the presence of caffeine. This UV-sensitization by caffeine is abolished in both G1 an G2 phase cells by the radlmutation; since both caffeine and the radl mutation markedly reduce recombinational events, this suggests that a recombinational repair process is active in cells irradiated either in G1 or G2 phase. Caffeine-sensitive repair begins immediately and is completed before resumption of DNA synthesis. Caffeine-sensitive repair of UV-damage in G1 cells displays a considerable lag and then occurs concomitantly with DNA synthesis. UV-induced mutagenesis was examined in wild-type and rad mutants using a forward mutation system. Rad mutants which show higher UV-induced mutation rates than wild-type retain the recombinational mechanism. In contrast, rad strains which are relatively UV-immutable compared to wild-type do not possess the caffeine-sensitive UV-repair process. The recombinational process therefore may be the major pathway responsible for UV-induced mutation. (orig./AJ) [de

Regulation of Schistosoma mansoni development and reproduction by the mitogen-activated protein kinase signaling pathway.

Science.gov (United States)

Andrade, Luiza Freire de; Mourão, Marina de Moraes; Geraldo, Juliana Assis; Coelho, Fernanda Sales; Silva, Larissa Lopes; Neves, Renata Heisler; Volpini, Angela; Machado-Silva, José Roberto; Araujo, Neusa; Nacif-Pimenta, Rafael; Caffrey, Conor R; Oliveira, Guilherme

2014-06-01

Protein kinases are proven targets for drug development with an increasing number of eukaryotic Protein Kinase (ePK) inhibitors now approved as drugs. Mitogen-activated protein kinase (MAPK) family members connect cell-surface receptors to regulatory targets within cells and influence a number of tissue-specific biological activities such as cell proliferation, differentiation and survival. However, the contributions of members of the MAPK pathway to schistosome development and survival are unclear. We employed RNA interference (RNAi) to elucidate the functional roles of five S. mansoni genes (SmCaMK2, SmJNK, SmERK1, SmERK2 and SmRas) involved in MAPK signaling pathway. Mice were injected with post-infective larvae (schistosomula) subsequent to RNAi and the development of adult worms observed. The data demonstrate that SmJNK participates in parasite maturation and survival of the parasites, whereas SmERK are involved in egg production as infected mice had significantly lower egg burdens with female worms presenting underdeveloped ovaries. Furthermore, it was shown that the c-fos transcription factor was overexpressed in parasites submitted to RNAi of SmERK1, SmJNK and SmCaMK2 indicating its putative involvement in gene regulation in this parasite's MAPK signaling cascade. We conclude that MAPKs proteins play important roles in the parasite in vivo survival, being essential for normal development and successful survival and reproduction of the schistosome parasite. Moreover SmERK and SmJNK are potential targets for drug development.

Exendin-4 improved rat cortical neuron survival under oxygen/glucose deprivation through PKA pathway.

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Wang, M-D; Huang, Y; Zhang, G-P; Mao, L; Xia, Y-P; Mei, Y-W; Hu, B

2012-12-13

Previous studies demonstrated that exendin-4 (Ex-4) may possess neurotrophic and neuroprotective functions in ischemia insults, but its mechanism remained unknown. Here, by using real-time PCR and ELISA, we identified the distribution of active GLP-1Rs in the rat primary cortical neurons. After establishment of an in vitro ischemia model by oxygen/glucose deprivation (OGD), neurons were treated with various dosages of Ex-4. The MTT assay showed that the relative survival rate increased with the dosage of Ex-4 ranging from 0.2 to 0.8 μg/ml (Pglucose-regulated proteins 78 (GRP78) and reduced C/EBP-homologous protein (CHOP). Western blot analysis demonstrated that, after neurons were treated with Ex-4, GRP78 was up-regulated over time (Pneurons, down-regulated the expression of B-cell lymphoma 2 (Bcl-2) and up-regulated the Bax expression 3h after ODG (Pneurons against OGD by modulating the unfolded protein response (UPR) through the PKA pathway and may serve as a novel therapeutic agent for stroke. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Streptococcus mutans autolysin AtlA is a fibronectin-binding protein and contributes to bacterial survival in the bloodstream and virulence for infective endocarditis.

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Jung, Chiau-Jing; Zheng, Quan-Hau; Shieh, Ya-Hsiung; Lin, Chi-Shuan; Chia, Jean-San

2009-11-01

Streptococcus mutans, a commensal of the human oral cavity, can survive in the bloodstream and cause infective endocarditis (IE). However, the virulence factors associated with this manifestation of disease are not known. Here, we demonstrate that AtlA, an autolysin of S. mutans is a newly identified fibronectin (Fn) binding protein and contributes to bacterial resistance to phagocytosis and survival in the bloodstream. Interestingly, prior exposure to plasma at low concentrations was sufficient to enhance bacterial survival in the circulation. Calcium ions at physiological plasma concentrations induced maturation of AtlA from the 104-90 kDa isoform resulting in increased Fn binding and resistance to phagocytosis. An isogenic mutant strain defective in AtlA expression exhibited reduced survival and virulence when tested in a rat model of IE compared with the wild-type and complemented strains. The data presented suggest that plasma components utilized by S. mutans enhanced survival in the circulation and AtlA is a virulence factor associated with infective endocarditis.

Deprivation of L-Arginine Induces Oxidative Stress Mediated Apoptosis in Leishmania donovani Promastigotes: Contribution of the Polyamine Pathway

Science.gov (United States)

Mandal, Abhishek; Das, Sushmita; Roy, Saptarshi; Ghosh, Ayan Kumar; Sardar, Abul Hasan; Verma, Sudha; Saini, Savita; Singh, Ruby; Abhishek, Kumar; Kumar, Ajay; Mandal, Chitra; Das, Pradeep

2016-01-01

The growth and survival of intracellular parasites depends on the availability of extracellular nutrients. Deprivation of nutrients viz glucose or amino acid alters redox balance in mammalian cells as well as some lower organisms. To further understand the relationship, the mechanistic role of L-arginine in regulation of redox mediated survival of Leishmania donovani promastigotes was investigated. L-arginine deprivation from the culture medium was found to inhibit cell growth, reduce proliferation and increase L-arginine uptake. Relative expression of enzymes, involved in L-arginine metabolism, which leads to polyamine and trypanothione biosynthesis, were downregulated causing decreased production of polyamines in L-arginine deprived parasites and cell death. The resultant increase in reactive oxygen species (ROS), due to L-arginine deprivation, correlated with increased NADP+/NADPH ratio, decreased superoxide dismutase (SOD) level, increased lipid peroxidation and reduced thiol content. A deficiency of L-arginine triggered phosphatidyl serine externalization, a change in mitochondrial membrane potential, release of intracellular calcium and cytochrome-c. This finally led to DNA damage in Leishmania promastigotes. In summary, the growth and survival of Leishmania depends on the availability of extracellular L-arginine. In its absence the parasite undergoes ROS mediated, caspase-independent apoptosis-like cell death. Therefore, L-arginine metabolism pathway could be a probable target for controlling the growth of Leishmania parasites and disease pathogenesis. PMID:26808657

GCN5 regulates the activation of PI3K/Akt survival pathway in B cells exposed to oxidative stress via controlling gene expressions of Syk and Btk.

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Kikuchi, Hidehiko; Kuribayashi, Futoshi; Takami, Yasunari; Imajoh-Ohmi, Shinobu; Nakayama, Tatsuo

2011-02-25

Histone acetyltransferase(s) (HATs) are involved in the acetylation of core histones, which is an important event for transcription regulation through alterations in the chromatin structure in eukaryotes. General control non-depressible 5 (GCN5) was first identified as a global coactivator and transcription-related HAT. Here we report that GCN5 regulates the activation of phosphatidylinositol 3-kinase (PI3K)/acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) survival pathway in B cells exposed to oxidative stress via controlling gene expressions of spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk). The GCN5-deficiency remarkably caused apoptotic cell death by treatment with exogenous hydrogen peroxide (H(2)O(2)) in chicken DT40 cells. In GCN5-deficient DT40 cells, gene expressions of Syk and Btk, which are involved in activation of PI3K/Akt survival pathway in DT40 cells exposed to exogenous H(2)O(2), were remarkably decreased compared with those in wild type DT40 cells. In addition, phosphorylation of Akt in H(2)O(2)-treated GCN5-deficient cells was remarkably suppressed as compared to that of DT40. Chromatin immunoprecipitation assay revealed that GCN5 binds to proximal 5'-upstream regions of Syk and Btk genes in vivo. These results suggest that GCN5 takes part in transcriptional regulations of the Syk and Btk genes, and plays a key role in epigenetic regulation of PI3K/Akt survival pathway in B cells exposed to reactive oxygen species such as H(2)O(2). Copyright © 2011 Elsevier Inc. All rights reserved.

DNA Methylation Targets Influenced by Bisphenol A and/or Genistein Are Associated with Survival Outcomes in Breast Cancer Patients

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Jadhav, Rohit R.; Santucci-Pereira, Julia; Wang, Yao V.; Liu, Joseph; Nguyen, Theresa D.; Wang, Jun; Jenkins, Sarah; Russo, Jose; Huang, Tim H.-M.; Jin, Victor X.; Lamartiniere, Coral A.

2017-01-01

Early postnatal exposures to Bisphenol A (BPA) and genistein (GEN) have been reported to predispose for and against mammary cancer, respectively, in adult rats. Since the changes in cancer susceptibility occurs in the absence of the original chemical exposure, we have investigated the potential of epigenetics to account for these changes. DNA methylation studies reveal that prepubertal BPA exposure alters signaling pathways that contribute to carcinogenesis. Prepubertal exposure to GEN and BPA + GEN revealed pathways involved in maintenance of cellular function, indicating that the presence of GEN either reduces or counters some of the alterations caused by the carcinogenic properties of BPA. We subsequently evaluated the potential of epigenetic changes in the rat mammary tissues to predict survival in breast cancer patients via the Cancer Genomic Atlas (TCGA). We identified 12 genes that showed strong predictive values for long-term survival in estrogen receptor positive patients. Importantly, two genes associated with improved long term survival, HPSE and RPS9, were identified to be hypomethylated in mammary glands of rats exposed prepuberally to GEN or to GEN + BPA respectively, reinforcing the suggested cancer suppressive properties of GEN. PMID:28505145

Par3L enhances colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway

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Li, Taiyuan; Liu, Dongning; Lei, Xiong; Jiang, Qunguang

2017-01-01

Partitioning defective 3-like protein (Par3L) is a recently identified cell polarity protein that plays an important role in mammary stem cell maintenance. Previously, we showed that high expression of Par3L is associated with poor survival in malignant colorectal cancer (CRC), but the underlying mechanism remained unknown. To this end, we established a Par3L knockout colorectal cancer cell line using the CRISPR/Cas system. Interestingly, reduced proliferation, enhanced cell death and caspase-3 activation were observed in Par3L knockout (KO) cells as compared with wildtype (WT) cells. Consistent with previous studies, we showed that Par3L interacts with a tumor suppressor protein liver kinase B1 (Lkb1). Moreover, Par3L depletion resulted in abnormal activation of Lkb1/AMPK signaling cascade. Knockdown of Lkb1 in these cells could significantly reduce AMPK activity and partially rescue cell death caused by Par3L knockdown. Furthermore, we showed that Par3L KO cells were more sensitive to chemotherapies and irradiation. Together, these results suggest that Par3L is essential for colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway, and is a putative therapeutic target for CRC. - Highlights: • Par3L knockout using the CRISPR/Cas system induces apoptosis in colorectal cancer cells. • Par3L interacts with Lkb1 and regulates the activity of AMPK signaling cascade. • Par3L knockout cells are more sensitive to treatment of different chemotherapy drugs and irradiation.

The Ras GTPase-activating protein Rasal3 supports survival of naive T cells.

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Ryunosuke Muro

Full Text Available The Ras-mitogen-activated protein kinase (MAPK pathway is crucial for T cell receptor (TCR signaling in the development and function of T cells. The significance of various modulators of the Ras-MAPK pathway in T cells, however, remains to be fully understood. Ras-activating protein-like 3 (Rasal3 is an uncharacterized member of the SynGAP family that contains a conserved Ras GTPase-activating protein (GAP domain, and is predominantly expressed in the T cell lineage. In the current study, we investigated the function and physiological roles of Rasal3. Our results showed that Rasal3 possesses RasGAP activity, but not Rap1GAP activity, and represses TCR-stimulated ERK phosphorylation in a T cell line. In systemic Rasal3-deficient mice, T cell development in the thymus including positive selection, negative selection, and β-selection was unaffected. However, the number of naive, but not effector memory CD4 and CD8 T cell in the periphery was significantly reduced in Rasal3-deficient mice, and associated with a marked increase in apoptosis of these cells. Indeed, survival of Rasal3 deficient naive CD4 T cells in vivo by adoptive transfer was significantly impaired, whereas IL-7-dependent survival of naive CD4 T cells in vitro was unaltered. Collectively, Rasal3 is required for in vivo survival of peripheral naive T cells, contributing to the maintenance of optimal T cell numbers.

The decrease of mineralcorticoid receptor drives angiogenic pathways in colorectal cancer.

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Laura Tiberio

Full Text Available Angiogenesis plays a crucial role in tumor growth and progression. Low expression of mineralocorticoid receptor (MR in several malignant tumors correlates with disease recurrence and overall survival. Previous studies have shown that MR expression is decreased in colorectal cancer (CRC. Here we hypothesize that decreased MR expression can contribute to angiogenesis and poor patient survival in colorectal malignancies. In a cohort of CRC patients, we analyzed tumor MR expression, its correlation with tumor microvascular density and its impact on survival. Subsequently, we interrogated the role of MR in angiogenesis in an in vitro model, based on the colon cancer cell line HCT116, ingenierized to re-express a physiologically controlled MR. In CRC, decreased MR expression was associated with increased microvascular density and poor patient survival. In pchMR transfected HCT116, aldosterone or natural serum steroids largely inhibited mRNA expression levels of both VEGFA and its receptor 2/KDR. In CRC, MR activation may significantly decrease angiogenesis by directly inhibiting dysregulated VEGFA and hypoxia-induced VEGFA mRNA expression. In addition, MR activation attenuates the expression of the VEGF receptor 2/KDR, possibly dampening the activation of a VEGFA/KDR dependent signaling pathway important for the survival of tumor cells under hypoxic conditions.

Degradation of clofibric acid in UV/chlorine disinfection process: kinetics, reactive species contribution and pathways.

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Tang, Yuqing; Shi, Xueting; Liu, Yongze; Feng, Li; Zhang, Liqiu

2018-02-01

As a potential endocrine disruptor, clofibric acid (CA) was investigated in this study for its degradation kinetics and pathways in UV/chlorine process. The results showed that CA in both UV photolysis and UV/chlorine processes could be degraded via pseudo-first-order kinetics, while it almost could not be degraded in the dark chlorination process. The observed rate constant ( k obs ) in UV photolysis was 0.0078 min -1, and increased to 0.0107 min -1 combining with 0.1 mM chlorine. The k obs increased to 0.0447 min -1 with further increasing the chlorine dosage from 0.1 to 1.0 mM, and reached a plateau at higher dosage (greater than 1.0 mM). The higher k obs was obtained at acid solution rather than basic solution. Moreover, the calculated contributions of radical species to k obs indicated that the HO• contributed significantly to CA degradation in acidic conditions, while the reactive chlorine species and UV direct photolysis dominated in neutral and basic solution. The degradation of CA was slightly inhibited in the presence of [Formula: see text] (1 ∼ 50 mM), barely affected by the presence of Cl - (1 ∼ 200 mM) and greatly suppressed by humic acid (0 ∼ 5 mg l -1 ). Thirteen main degradation intermediates and three degradation pathways of CA were identified during UV/chlorine process.

IL22/IL-22R pathway induces cell survival in human glioblastoma cells.

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Hussein Akil

Full Text Available Interleukin-22 (IL-22 is a member of the IL-10 cytokine family that binds to a heterodimeric receptor consisting of IL-22 receptor 1 (IL-22R1 and IL-10R2. IL-22R expression was initially characterized on epithelial cells, and plays an essential role in a number of inflammatory diseases. Recently, a functional receptor was detected on cancer cells such as hepatocarcinoma and lung carcinoma, but its presence was not reported in glioblastoma (GBM. Two GBM cell lines and 10 primary cell lines established from patients undergoing surgery for malignant GBM were used to investigate the expression of IL-22 and IL-22R by using quantitative RT-PCR, western blotting and confocal microscopy studies. The role of IL-22 in proliferation and survival of GBM cell lines was investigated in vitro by BrdU and ELISA cell death assays. We report herein that the two subunits of the IL-22R complex are expressed on human GBM cells. Their activation, depending on exogenous IL-22, induced antiapoptotic effect and cell proliferation. IL-22 treatment of GBM cells resulted in increased levels of phosphorylated Akt, STAT3 signaling protein and its downstream antiapoptotic protein Bcl-xL and decreased level of phosphorylated ERK1/2. In addition, IL-22R subunits were expressed in all the 10 tested primary cell lines established from GBM tumors. Our results showed that IL-22R is expressed on GBM established and primary cell lines. Depending on STAT3, ERK1/2 and PI3K/Akt pathways, IL-22 induced GBM cell survival. These data are consistent with a potential role of IL-22R in tumorigenesis of GBM. Since endogenous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells.

Clathrin-independent pathways do not contribute significantly to endocytic flux.

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Bitsikas, Vassilis; Corrêa, Ivan R; Nichols, Benjamin J

2014-09-17

Several different endocytic pathways have been proposed to function in mammalian cells. Clathrin-coated pits are well defined, but the identity, mechanism and function of alternative pathways have been controversial. Here we apply universal chemical labelling of plasma membrane proteins to define all primary endocytic vesicles, and labelling of specific proteins with a reducible SNAP-tag substrate. These approaches provide high temporal resolution and stringent discrimination between surface-connected and intracellular membranes. We find that at least 95% of the earliest detectable endocytic vesicles arise from clathrin-coated pits. GPI-anchored proteins, candidate cargoes for alternate pathways, are also found to enter the cell predominantly via coated pits. Experiments employing a mutated clathrin adaptor reveal distinct mechanisms for sorting into coated pits, and thereby explain differential effects on the uptake of transferrin and GPI-anchored proteins. These data call for a revision of models for the activity and diversity of endocytic pathways in mammalian cells.

Proliferation and survival molecules implicated in the inhibition of BRAF pathway in thyroid cancer cells harbouring different genetic mutations

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Preto, Ana; Soares, Paula; Sobrinho-Simões, Manuel; Gonçalves, Joana; Rebocho, Ana P; Figueiredo, Joana; Meireles, Ana M; Rocha, Ana S; Vasconcelos, Helena M; Seca, Hugo; Seruca, Raquel

2009-01-01

Thyroid carcinomas show a high prevalence of mutations in the oncogene BRAF which are inversely associated with RAS or RET/PTC oncogenic activation. The possibility of using inhibitors on the BRAF pathway as became an interesting therapeutic approach. In thyroid cancer cells the target molecules, implicated on the cellular effects, mediated by inhibition of BRAF are not well established. In order to fill this lack of knowledge we studied the proliferation and survival pathways and associated molecules induced by BRAF inhibition in thyroid carcinoma cell lines harbouring distinct genetic backgrounds. Suppression of BRAF pathway in thyroid cancer cell lines (8505C, TPC1 and C643) was achieved using RNA interference (RNAi) for BRAF and the kinase inhibitor, sorafenib. Proliferation analysis was performed by BrdU incorporation and apoptosis was accessed by TUNEL assay. Levels of protein expression were analysed by western-blot. Both BRAF RNAi and sorafenib inhibited proliferation in all the cell lines independently of the genetic background, mostly in cells with BRAF V600E mutation. In BRAF V600E mutated cells inhibition of BRAF pathway lead to a decrease in ERK1/2 phosphorylation and cyclin D1 levels and an increase in p27 Kip1 . Specific inhibition of BRAF by RNAi in cells with BRAF V600E mutation had no effect on apoptosis. In the case of sorafenib treatment, cells harbouring BRAF V600E mutation showed increase levels of apoptosis due to a balance of the anti-apoptotic proteins Mcl-1 and Bcl-2. Our results in thyroid cancer cells, namely those harbouring BRAF V600E mutation showed that BRAF signalling pathway provides important proliferation signals. We have shown that in thyroid cancer cells sorafenib induces apoptosis by affecting Mcl-1 and Bcl-2 in BRAF V600E mutated cells which was independent of BRAF. These results suggest that sorafenib may prove useful in the treatment of thyroid carcinomas, particularly those refractory to conventional treatment and

The intersection between DNA damage response and cell death pathways.

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Nowsheen, S; Yang, E S

2012-10-01

Apoptosis is a finely regulated process that serves to determine the fate of cells in response to various stresses. One such stress is DNA damage, which not only can signal repair processes but is also intimately involved in regulating cell fate. In this review we examine the relationship between the DNA damage/repair response in cell survival and apoptosis following insults to the DNA. Elucidating these pathways and the crosstalk between them is of great importance, as they eventually contribute to the etiology of human disease such as cancer and may play key roles in determining therapeutic response. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

Integrated microRNA and mRNA signatures associated with survival in triple negative breast cancer.

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Cascione, Luciano; Gasparini, Pierluigi; Lovat, Francesca; Carasi, Stefania; Pulvirenti, Alfredo; Ferro, Alfredo; Alder, Hansjuerg; He, Gang; Vecchione, Andrea; Croce, Carlo M; Shapiro, Charles L; Huebner, Kay

2013-01-01

Triple negative breast cancer (TNBC) is a heterogeneous disease at the molecular, pathologic and clinical levels. To stratify TNBCs, we determined microRNA (miRNA) expression profiles, as well as expression profiles of a cancer-focused mRNA panel, in tumor, adjacent non-tumor (normal) and lymph node metastatic lesion (mets) tissues, from 173 women with TNBCs; we linked specific miRNA signatures to patient survival and used miRNA/mRNA anti-correlations to identify clinically and genetically different TNBC subclasses. We also assessed miRNA signatures as potential regulators of TNBC subclass-specific gene expression networks defined by expression of canonical signal pathways.Tissue specific miRNAs and mRNAs were identified for normal vs tumor vs mets comparisons. miRNA signatures correlated with prognosis were identified and predicted anti-correlated targets within the mRNA profile were defined. Two miRNA signatures (miR-16, 155, 125b, 374a and miR-16, 125b, 374a, 374b, 421, 655, 497) predictive of overall survival (P = 0.05) and distant-disease free survival (P = 0.009), respectively, were identified for patients 50 yrs of age or younger. By multivariate analysis the risk signatures were independent predictors for overall survival and distant-disease free survival. mRNA expression profiling, using the cancer-focused mRNA panel, resulted in clustering of TNBCs into 4 molecular subclasses with different expression signatures anti-correlated with the prognostic miRNAs. Our findings suggest that miRNAs play a key role in triple negative breast cancer through their ability to regulate fundamental pathways such as: cellular growth and proliferation, cellular movement and migration, Extra Cellular Matrix degradation. The results define miRNA expression signatures that characterize and contribute to the phenotypic diversity of TNBC and its metastasis.

Probiotic-fermented purple sweet potato yogurt activates compensatory IGF‑IR/PI3K/Akt survival pathways and attenuates cardiac apoptosis in the hearts of spontaneously hypertensive rats.

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Lin, Pei-Pei; Hsieh, You-Miin; Kuo, Wei-Wen; Lin, Yueh-Min; Yeh, Yu-Lan; Lin, Chien-Chung; Tsai, Fuu-Jen; Tsai, Chang-Hai; Huang, Chih-Yang; Tsai, Cheng-Chih

2013-12-01

Apoptosis is recognized as a predictor of adverse outcomes in subjects with cardiac diseases. The aim of this study was to explore the effects of probiotic-fermented purple sweet potato yogurt (PSPY) with high γ-aminobutyric acid (GABA) content on cardiac apoptosis in spontaneously hypertensive rat (SHR) hearts. The rats were orally adminsitered with 2 different concentrations of PSPY (10 and 100%) or captopril, 15.6 mg/kg, body weight (BW)/day. The control group was administered distilled water. DAPI and TUNEL staining were used to detect the numbers of apoptotic cells. A decrease in the number of TUNEL-positive cardiac myocytes was observed in the SHR-PSPY (10 and 100%) groups. In addition, the levels of key components of the Fas receptor- and mitochondrial-dependent apoptotic pathways were determined by western blot analysis. The results revealed that the levels of the key components of the Fas receptor- and mitochondrial-dependent apoptotic pathway were significantly decreased in the SHR-captopril, and 10 and 100% PSPY groups. Additionally, the levels of phosphorylated insulin-like growth factor‑I receptor (p-IGF‑IR) were increased in SHR hearts from the SHR-control group; however, no recovery in the levels of downstream signaling components was observed. In addition, the levels of components of the compensatory IGF-IR-dependent survival pathway (p-PI3K and p-Akt) were all highly enhanced in the left ventricles in the hearts form the SHR-10 and 100% PSPY groups. Therefore, the oral administration of PSPY may attenuate cardiomyocyte apoptosis in SHR hearts by activating IGF‑IR-dependent survival signaling pathways.

Neonatal maternal separation up-regulates protein signalling for cell survival in rat hypothalamus.

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Irles, Claudine; Nava-Kopp, Alicia T; Morán, Julio; Zhang, Limei

2014-05-01

We have previously reported that in response to early life stress, such as maternal hyperthyroidism and maternal separation (MS), the rat hypothalamic vasopressinergic system becomes up-regulated, showing enlarged nuclear volume and cell number, with stress hyperresponsivity and high anxiety during adulthood. The detailed signaling pathways involving cell death/survival, modified by adverse experiences in this developmental window remains unknown. Here, we report the effects of MS on cellular density and time-dependent fluctuations of the expression of pro- and anti-apoptotic factors during the development of the hypothalamus. Neonatal male rats were exposed to 3 h-daily MS from postnatal days 2 to 15 (PND 2-15). Cellular density was assessed in the hypothalamus at PND 21 using methylene blue staining, and neuronal nuclear specific protein and glial fibrillary acidic protein immunostaining at PND 36. Expression of factors related to apoptosis and cell survival in the hypothalamus was examined at PND 1, 3, 6, 9, 12, 15, 20 and 43 by Western blot. Rats subjected to MS exhibited greater cell-density and increased neuronal density in all hypothalamic regions assessed. The time course of protein expression in the postnatal brain showed: (1) decreased expression of active caspase 3; (2) increased Bcl-2/Bax ratio; (3) increased activation of ERK1/2, Akt and inactivation of Bad; PND 15 and PND 20 were the most prominent time-points. These data indicate that MS can induce hypothalamic structural reorganization by promoting survival, suppressing cell death pathways, increasing cellular density which may alter the contribution of these modified regions to homeostasis.

Newborn survival in Bangladesh: a decade of change and future implications.

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Rubayet, Sayed; Shahidullah, Mohammad; Hossain, Altaf; Corbett, Erica; Moran, Allisyn C; Mannan, Imteaz; Matin, Ziaul; Wall, Stephen N; Pfitzer, Anne; Mannan, Ishtiaq; Syed, Uzma

2012-07-01

Remarkable progress over the last decade has put Bangladesh on track for Millennium Development Goal (MDG) 4 for child survival and achieved a 40% decline in maternal mortality. However, since neonatal deaths make up 57% of under-five mortality in the country, increased scale up and equity in programmes for neonatal survival are critical to sustain progress. We examined change for newborn survival from 2000 to 2010 considering mortality, coverage and funding indicators, as well as contextual factors. The national neonatal mortality rate has undergone an annual decline of 4.0% since 2000, reflecting greater progress than both the regional and global averages, but the mortality reduction for children 1-59 months was double this rate, at 8.6%. Examining policy and programme change, and national and donor funding for health, we identified various factors which contributed to an environment favourable to newborn survival. Locally-generated evidence combined with re-packaged global evidence, notably The Lancet Neonatal Series, has played a role, although pathways between research and policies and programme change are often complex. Several high-profile champions have had major influence. Attention for community initiatives and considerable donor funding also appear to have contributed. There have been some increases in coverage of key interventions, such as skilled attendance at birth and postnatal care, however these are low and reach less than one-third of families. Major reductions in total fertility, some change in gross national income and other contextual factors are likely to also have had an influence in mortality reduction. However, other factors such as socio-economic and geographic inequalities, frequent changes in government and pluralistic implementation structures have provided challenges. As coverage of health services increases, a notable gap remains in quality of facility-based care. Future gains for newborn survival in Bangladesh rest upon increased

The thrombopoietin/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO

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Chou, Fu-Sheng; Griesinger, Andrea; Wunderlich, Mark; Lin, Shan; Link, Kevin A.; Shrestha, Mahesh; Goyama, Susumu; Mizukawa, Benjamin; Shen, Shuhong; Marcucci, Guido

2012-01-01

AML1-ETO (AE) is a fusion product of translocation (8;21) that accounts for 40% of M2 type acute myeloid leukemia (AML). In addition to its role in promoting preleukemic hematopoietic cell self-renewal, AE represses DNA repair genes, which leads to DNA damage and increased mutation frequency. Although this latter function may promote leukemogenesis, concurrent p53 activation also leads to an increased baseline apoptotic rate. It is unclear how AE expression is able to counterbalance this intrinsic apoptotic conditioning by p53 to promote survival and self-renewal. In this report, we show that Bcl-xL is up-regulated in AE cells and plays an essential role in their survival and self-renewal. Further investigation revealed that Bcl-xL expression is regulated by thrombopoietin (THPO)/MPL-signaling induced by AE expression. THPO/MPL-signaling also controls cell cycle reentry and mediates AE-induced self-renewal. Analysis of primary AML patient samples revealed a correlation between MPL and Bcl-xL expression specifically in t(8;21) blasts. Taken together, we propose that survival signaling through Bcl-xL is a critical and intrinsic component of a broader self-renewal signaling pathway downstream of AML1-ETO–induced MPL. PMID:22337712

Autophagy/Xenophagy as a survival strategy of cancer cells. The role of Cathepsins

International Nuclear Information System (INIS)

Malorni, W.; Matarrese, P.; Ascione, B.; Ciarlo, L.; Zakeri, Z.

2009-01-01

Macroautophagy, often referred as to autophagy (self-cannibalism), designates the genetically determined process by which portions of the cytoplasm, organelles and long-lived proteins are engulfed in double-membraned vacuoles (autophagosomes) and sent for lysosomal degradation. Basal levels of autophagy contribute to the maintenance of intracellular homoeostasis by ensuring the turnover of supernumerary, aged and/or damaged components. Under conditions of starvation, the autophagic pathway operates to supply cells with metabolic substrates, and thus represents an important pro-survival mechanism. In cultured cells, the withdrawal of growth factors, known to represent an experimental condition triggering autophagy, can also enhance xeno-cannibalism (xenophagy; xeno is from ancient greek=foreign)

Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic adenocarcinoma.

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Katarzyna A Ellsworth

Full Text Available FKBP51, (FKBP5, is a negative regulator of Akt. Variability in FKBP5 expression level is a major factor contributing to variation in response to chemotherapeutic agents including gemcitabine, a first line treatment for pancreatic cancer. Genetic variation in FKBP5 could influence its function and, ultimately, treatment response of pancreatic cancer.We set out to comprehensively study the role of genetic variation in FKBP5 identified by Next Generation DNA resequencing on response to gemcitabine treatment of pancreatic cancer by utilizing both tumor and germline DNA samples from 43 pancreatic cancer patients, including 19 paired normal-tumor samples. Next, genotype-phenotype association studies were performed with overall survival as well as with FKBP5 gene expression in tumor using the same samples in which resequencing had been performed, followed by functional genomics studies.In-depth resequencing identified 404 FKBP5 single nucleotide polymorphisms (SNPs in normal and tumor DNA. SNPs with the strongest associations with survival or FKBP5 expression were subjected to functional genomic study. Electromobility shift assay showed that the rs73748206 "A(T" SNP altered DNA-protein binding patterns, consistent with significantly increased reporter gene activity, possibly through its increased binding to Glucocorticoid Receptor (GR. The effect of rs73748206 was confirmed on the basis of its association with FKBP5 expression by affecting the binding to GR in lymphoblastoid cell lines derived from the same patients for whom DNA was used for resequencing.This comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response.

PPARγ agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria.

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Lena Serghides

2014-03-01

Full Text Available Cerebral malaria (CM is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ adjunctive therapy administered to mice at the onset of CM signs, was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase and the neurotrophic factors brain derived neurotrophic factor (BDNF and nerve growth factor (NGF in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM.

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells.

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Lim, Yi Chieh; Roberts, Tara L; Day, Bryan W; Stringer, Brett W; Kozlov, Sergei; Fazry, Shazrul; Bruce, Zara C; Ensbey, Kathleen S; Walker, David G; Boyd, Andrew W; Lavin, Martin F

2014-12-01

Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non-homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia-telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA-dependent protein kinase inhibitor (DNA-PKi) to inhibit NHEJ. Pre-treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR-mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA-PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival. Copyright © 2014. Published by Elsevier B.V.

Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway.

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Zhang, B; Zhang, B; Chen, X; Bae, S; Singh, K; Washington, M K; Datta, P K

2014-02-18

Higher frequency of Smad4 inactivation or loss of expression is observed in metastasis of colorectal cancer (CRC) leading to unfavourable survival and contributes to chemoresistance. However, the molecular mechanism of how Smad4 regulates chemosensitivity of CRC is unknown. We evaluated how the loss of Smad4 in CRC enhanced chemoresistance to 5-fluorouracil (5-FU) using two CRC cell lines in vitro and in vivo. Immunoblotting with cell and tumour lysates and immunohistochemical analyses with tissue microarray were performed. Knockdown or loss of Smad4 induced tumorigenicity, migration, invasion, angiogenesis, metastasis, and 5-FU resistance. Smad4 expression in mouse tumours regulated cell-cycle regulatory proteins leading to Rb phosphorylation. Loss of Smad4 activated Akt pathway that resulted in upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-w, and Survivin. Suppression of phosphatidylinositol-3-kinase (PI3K)/Akt pathway by LY294002 restored chemosensitivity of Smad4-deficient cells to 5-FU. Vascular endothelial growth factor-induced angiogenesis in Smad4-deficient cells might also lead to chemoresistance. Low levels of Smad4 expression in CRC tissues correlated with higher levels of Bcl-2 and Bcl-w and with poor overall survival as observed in immunohistochemical staining of tissue microarrays. Loss of Smad4 in CRC patients induces resistance to 5-FU-based therapy through activation of Akt pathway and inhibitors of this pathway may sensitise these patients to 5-FU.

Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro: Possible involvement of inhibition of survival signal transduction pathways

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Akimoto, Tetsuo; Nonaka, Tetsuo; Ishikawa, Hitoshi; Sakurai, Hideyuki; Saitoh, Jun-ichi; Takahashi, Takeo; Mitsuhashi, Norio

2001-01-01

Purpose: The effect of genistein, a tyrosine kinase inhibitor, on radiosensitivity was examined, especially focusing on 'survival signal transduction pathways'. Methods and Materials: Two human esophageal squamous cell cancer cell lines, TE-1 (p53, mutant) and TE-2 (p53, wild), were used. Radiosensitivity was determined by clonogenic assay, and activation of survival signals was examined by Western blot. Results: Genistein (30 μM) greatly enhanced radiosensitivity in these cell lines by suppressing radiation-induced activation of survival signals, p42/p44 extracellular signal-regulated kinase and AKT/PKB. Significant increase in the percentage of apoptotic cells and increased poly[ADP-ribose] polymerase cleavage were observed in TE-2, but not in TE-1 even after combination of genistein with irradiation. In terms of changes in expression of p53-related proteins, increase in expression of Bax and decrease in that of Bcl-2 were observed in TE-2 but not in TE-1, suggesting that the main mode of cell death induced by genistein in a cell line with wild type p53 differed from that with mutant p53. Conclusions: This study suggested that survival signals, including p42/p44 ERK and AKT/PKB, may be involved in determining radiosensitivity, and genistein would be a potent therapeutic agent that has an enhancing effect on radiation

Riboflavin Provisioning Underlies Wolbachia's Fitness Contribution to Its Insect Host.

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Moriyama, Minoru; Nikoh, Naruo; Hosokawa, Takahiro; Fukatsu, Takema

2015-11-10

Endosymbiotic bacteria of the genus Wolbachia represent the most successful symbiotic bacteria in the terrestrial ecosystem. The success of Wolbachia has been ascribed to its remarkable phenotypic effects on host reproduction, such as cytoplasmic incompatibility, whereby maternally inherited bacteria can spread in their host populations at the expense of their host's fitness. Meanwhile, recent theoretical as well as empirical studies have unveiled that weak and/or conditional positive fitness effects may significantly facilitate invasion and spread of Wolbachia infections in host populations. Here, we report a previously unrecognized nutritional aspect, the provision of riboflavin (vitamin B2), that potentially underpins the Wolbachia-mediated fitness benefit to insect hosts. A comparative genomic survey for synthetic capability of B vitamins revealed that only the synthesis pathway for riboflavin is highly conserved among diverse insect-associated Wolbachia strains, while the synthesis pathways for other B vitamins were either incomplete or absent. Molecular phylogenetic and genomic analyses of riboflavin synthesis genes from diverse Wolbachia strains revealed that, in general, their phylogenetic relationships are concordant with Wolbachia's genomic phylogeny, suggesting that the riboflavin synthesis genes have been stably maintained in the course of Wolbachia evolution. In rearing experiments with bedbugs (Cimex lectularius) on blood meals in which B vitamin contents were manipulated, we demonstrated that Wolbachia's riboflavin provisioning significantly contributes to growth, survival, and reproduction of the insect host. These results provide a physiological basis upon which Wolbachia-mediated positive fitness consequences are manifested and shed new light on the ecological and evolutionary relevance of Wolbachia infections. Conventionally, Wolbachia has been regarded as a parasitic bacterial endosymbiont that manipulates the host insect's reproduction in a

Analysis of the role of betL in contributing to the growth and survival of Listeria monocytogenes LO28.

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Sleator, R D; Gahan CGM; O'Driscoll, B; Hill, C

2000-09-25

Survival of the food-borne pathogen Listeria monocytogenes in environments of elevated osmolarity and reduced temperature is attributed, at least in part, to the accumulation of the trimethylammonium compound glycine betaine. Previously we identified betL, a gene encoding the secondary glycine betaine transporter BetL, which we linked to the salt tolerance of Listeria. In this report, we demonstrate that betL, preceded by a consensus sigmaB-dependent promoter, is regulated by osmotic up-shock, at least in part at the level of transcription. Using allelic exchange mutagenesis we constructed an in-frame deletion in betL, and used this mutant to determine the role of BetL in contributing to the growth and survival of L. monocytogenes, both in a high risk food (Camembert cheese) and animal model. Our results indicate that while BetL plays an important role in glycine betaine mediated osmoprotection, mutating the gene does not significantly effect either the cryotolerance or virulence of the organism.

TRAF1 Coordinates Polyubiquitin Signaling to Enhance Epstein-Barr Virus LMP1-Mediated Growth and Survival Pathway Activation.

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Hannah Greenfeld

2015-05-01

Full Text Available The Epstein-Barr virus (EBV encoded oncoprotein Latent Membrane Protein 1 (LMP1 signals through two C-terminal tail domains to drive cell growth, survival and transformation. The LMP1 membrane-proximal TES1/CTAR1 domain recruits TRAFs to activate MAP kinase, non-canonical and canonical NF-kB pathways, and is critical for EBV-mediated B-cell transformation. TRAF1 is amongst the most highly TES1-induced target genes and is abundantly expressed in EBV-associated lymphoproliferative disorders. We found that TRAF1 expression enhanced LMP1 TES1 domain-mediated activation of the p38, JNK, ERK and canonical NF-kB pathways, but not non-canonical NF-kB pathway activity. To gain insights into how TRAF1 amplifies LMP1 TES1 MAP kinase and canonical NF-kB pathways, we performed proteomic analysis of TRAF1 complexes immuno-purified from cells uninduced or induced for LMP1 TES1 signaling. Unexpectedly, we found that LMP1 TES1 domain signaling induced an association between TRAF1 and the linear ubiquitin chain assembly complex (LUBAC, and stimulated linear (M1-linked polyubiquitin chain attachment to TRAF1 complexes. LMP1 or TRAF1 complexes isolated from EBV-transformed lymphoblastoid B cell lines (LCLs were highly modified by M1-linked polyubiqutin chains. The M1-ubiquitin binding proteins IKK-gamma/NEMO, A20 and ABIN1 each associate with TRAF1 in cells that express LMP1. TRAF2, but not the cIAP1 or cIAP2 ubiquitin ligases, plays a key role in LUBAC recruitment and M1-chain attachment to TRAF1 complexes, implicating the TRAF1:TRAF2 heterotrimer in LMP1 TES1-dependent LUBAC activation. Depletion of either TRAF1, or the LUBAC ubiquitin E3 ligase subunit HOIP, markedly impaired LCL growth. Likewise, LMP1 or TRAF1 complexes purified from LCLs were decorated by lysine 63 (K63-linked polyubiqutin chains. LMP1 TES1 signaling induced K63-polyubiquitin chain attachment to TRAF1 complexes, and TRAF2 was identified as K63-Ub chain target. Co-localization of M1- and K63

Pathway Relevance Ranking for Tumor Samples through Network-Based Data Integration.

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Lieven P C Verbeke

Full Text Available The study of cancer, a highly heterogeneous disease with different causes and clinical outcomes, requires a multi-angle approach and the collection of large multi-omics datasets that, ideally, should be analyzed simultaneously. We present a new pathway relevance ranking method that is able to prioritize pathways according to the information contained in any combination of tumor related omics datasets. Key to the method is the conversion of all available data into a single comprehensive network representation containing not only genes but also individual patient samples. Additionally, all data are linked through a network of previously identified molecular interactions. We demonstrate the performance of the new method by applying it to breast and ovarian cancer datasets from The Cancer Genome Atlas. By integrating gene expression, copy number, mutation and methylation data, the method's potential to identify key pathways involved in breast cancer development shared by different molecular subtypes is illustrated. Interestingly, certain pathways were ranked equally important for different subtypes, even when the underlying (epi-genetic disturbances were diverse. Next to prioritizing universally high-scoring pathways, the pathway ranking method was able to identify subtype-specific pathways. Often the score of a pathway could not be motivated by a single mutation, copy number or methylation alteration, but rather by a combination of genetic and epi-genetic disturbances, stressing the need for a network-based data integration approach. The analysis of ovarian tumors, as a function of survival-based subtypes, demonstrated the method's ability to correctly identify key pathways, irrespective of tumor subtype. A differential analysis of survival-based subtypes revealed several pathways with higher importance for the bad-outcome patient group than for the good-outcome patient group. Many of the pathways exhibiting higher importance for the bad

Contribution of screening and survival differences to racial disparities in colorectal cancer rates

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Lansdorp-Vogelaar, Iris; Kuntz, Karen M.; Knudsen, Amy B.; van Ballegooijen, Marjolein; Zauber, Ann G.; Jemal, Ahmedin

2012-01-01

Background Considerable disparities exist in colorectal cancer (CRC) incidence and mortality rates between blacks and whites in the US. We estimated how much of these disparities could be explained by differences in CRC screening and stage-specific relative CRC survival. Methods We used the MISCAN-Colon microsimulation model to estimate CRC incidence and mortality rates in blacks aged 50 years and older from 1975 to 2007 assuming they had: 1) the same trends in screening rates as whites instead of observed screening rates (incidence and mortality); and 2) the same trends in stage-specific relative CRC survival rates as whites instead of observed (mortality only); and 3) a combination of both. The racial disparities in CRC incidence and mortality rates attributable to differences in screening and/or stage-specific relative CRC survival were then calculated by comparing rates from these scenarios to the observed black rates. Results Differences in screening account for 42% of disparity in CRC incidence and 19% of disparity in CRC mortality between blacks and whites. 36% of the disparity in CRC mortality could be attributed to differences in stage-specific relative CRC survival. Together screening and survival explained a little over 50% of the disparity in CRC mortality between blacks and whites. Conclusion Differences in screening and relative CRC survival are responsible for a considerable proportion of the observed disparities in CRC incidence and mortality rates between blacks and whites. Impact Enabling blacks to achieve equal access to care as whites could substantially reduce the racial disparities in CRC burden. PMID:22514249

Correlation of the L-Arginine Pathway with Thrombo-Inflammation May Contribute to the Outcome of Acute Ischemic Stroke

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Molnar, Tihamer; Pusch, Gabriella; Nagy, Lajos

2016-01-01

BACKGROUND: Immune responses contribute to secondary injury after acute ischemic stroke (AIS), and metabolites of the L-arginine pathway are associated with stroke outcome. Here, we analyzed the relationship of the L-arginine pathway with thrombo-inflammatory biomarkers in AIS and their additive...... and independent associations to outcome. METHODS: Serial changes in P-selectin, tPA, MCP-1, sCD40L, IL-6, IL-8, L-arginine, and asymmetric and symmetric dimethylarginine (ADMA, SDMA) were investigated in 55 patients with AIS and without infection within 6 and 72 hours after stroke onset. Outcomes were assessed...... as National Institutes of Health Stroke Scale (NIHSS) worsening by 24 hours, poststroke infection, and death by 1 month. RESULTS: Serum levels of L-arginine showed negative correlation, whereas ADMA and SDMA showed positive correlation with thrombo-inflammatory biomarkers in the hyperacute phase. Most...

Survival in common cancers defined by risk and survival of family members

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Jianguang Ji

2011-10-01

Full Text Available Studies on survival between familial and sporadic cancers have been inconclusive and only recent data on a limited number of cancers are available on the concordance of survival between family members. In this review, we address these questions by evaluating the published and unpublished data from the nation-wide Swedish Family-Cancer Database and a total of 13 cancer sites were assessed. Using sporadic cancer as reference, HRs were close to 1.0 for most of the familial cancers in both the offspring and parental generations, which suggested that survival in patients with familial and sporadic cancers was equal, with an exception for ovarian cancer with a worse prognosis. Compared to offspring whose parents had a poor survival, those with a good parental survival had a decreased risk of death for most cancers and HR was significantly decreased for cancers in the breast, prostate, bladder, and kidney. For colorectal and nervous system cancers, favorable survival between the generations showed a borderline significance. These data are consistent in showing that both good and poor survival in certain cancers aggregate in families. Genetic factors are likely to contribute to the results. These observations call for intensified efforts to consider heritability in survival as one mechanism regulating prognosis in cancer patients.

Targeting the AKT/GSK3β/Cyclin D1/Cdk4 Survival Signaling Pathway for Eradication of Tumor Radioresistance Acquired by Fractionated Radiotherapy

International Nuclear Information System (INIS)

Shimura, Tsutomu; Kakuda, Satoshi; Ochiai, Yasushi; Kuwahara, Yoshikazu; Takai, Yoshihiro; Fukumoto, Manabu

2011-01-01

Purpose: Radioresistance is a major cause of treatment failure of radiotherapy (RT) in human cancer. We have recently revealed that acquired radioresistance of tumor cells induced by fractionated radiation is attributable to cyclin D1 overexpression as a consequence of the downregulation of GSK3β-dependent cyclin D1 proteolysis mediated by a constitutively activated serine-threonine kinase, AKT. This prompted us to hypothesize that targeting the AKT/GSK3β/cyclin D1 pathway may improve fractionated RT by suppressing acquired radioresistance of tumor cells. Methods and Materials: Two human tumor cell lines with acquired radioresistance were exposed to X-rays after incubation with either an AKT inhibitor, AKT/PKB signaling inhibitor-2 (API-2), or a Cdk4 inhibitor (Cdk4-I). Cells were then subjected to immunoblotting, clonogenic survival assay, cell growth analysis, and cell death analysis with TUNEL and annexin V staining. In vivo radiosensitivity was assessed by growth of human tumors xenografted into nude mice. Results: Treatment with API-2 resulted in downregulation of cyclin D1 expression in cells with acquired radioresistance. Cellular radioresistance disappeared completely both in vitro and in vivo with accompanying apoptosis when treated with API-2. Furthermore, inhibition of cyclin D1/Cdk4 by Cdk4-I was sufficient for abolishing radioresistance. Treatment with either API-2 or Cdk4-I was also effective in suppressing resistance to cis-platinum (II)-diamine-dichloride in the cells with acquired radioresistance. Interestingly, the radiosensitizing effect of API-2 was canceled by overexpression of cyclin D1 whereas Cdk4-I was still able to sensitize cells with cyclin D1 overexpression. Conclusion: Cyclin D1/Cdk4 is a critical target of the AKT survival signaling pathway responsible for tumor radioresistance. Targeting the AKT/GSK3β/cyclin D1/Cdk4 pathway would provide a novel approach to improve fractionated RT and would have an impact on tumor eradication in

Deubiquitinase inhibitor b-AP15 activates endoplasmic reticulum (ER) stress and inhibits Wnt/Notch1 signaling pathway leading to the reduction of cell survival in hepatocellular carcinoma cells.

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Ding, Youming; Chen, Xiaoyan; Wang, Bin; Yu, Bin; Ge, Jianhui

2018-04-15

b-AP15, a potent and selective inhibitor of the ubiquitin-specific peptidase 14 (USP14), displays in vitro and in vivo antitumor abilities on some types of cancer cells. However, the mechanism underlying its action is not well elucidated. The purposes of the present study are to observe the potential impacts of b-AP15 on cell survival of hepatocellular carcinoma cells and to investigate whether and how this compound inhibits some survival-promoting signaling pathways. We found that b-AP15 significantly decreased cell viability and increased cell apoptosis in a dose-dependent manner in hepatocellular carcinoma cells, along with the perturbation of cell cycle and the decreased expressions of cell cycle-related proteins. We also demonstrated that the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were enhanced by b-AP15 supplementation. The inhibition of ER stress/UPR only partly attenuated the cytotoxicity of b-AP15 on hepatocellular carcinoma cells. In addition, b-AP15 treatment inhibited Wnt/β-catenin and Notch1 signaling pathways, and suppressed phosphorylation of STAT3, Akt, and Erk1/2, which were not restored by the inhibition of ER stress/UPR. Furthermore, the expression levels of signaling molecules in Notch1 were reduced by specific inhibitor of Wnt/β-catenin pathway. Notably, either Wnt or Notch1 signaling inhibitor mitigated phosphorylation of STAT3, Akt, and Erk1/2, and mimicked the cytotoxicity of b-AP15 on hepatocellular carcinoma cells. These results clearly indicate that b-AP15 induced cytotoxic response to hepatocellular carcinoma cells by augmenting ER stress/UPR and inhibiting Wnt/Notch1 signaling pathways. This new finding provides a novel mechanism by which b-AP15 produces its antitumor therapeutic effects. Copyright © 2018 Elsevier B.V. All rights reserved.

Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics

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Krakstad Camilla

2010-06-01

Full Text Available Abstract Glioblastoma multiforme (GBM is the most common primary brain tumour in adults and one of the most aggressive cancers in man. Despite technological advances in surgical management, combined regimens of radiotherapy with new generation chemotherapy, the median survival for these patients is 14.6 months. This is largely due to a highly deregulated tumour genome with opportunistic deletion of tumour suppressor genes, amplification and/or mutational hyper-activation of receptor tyrosine kinase receptors. The net result of these genetic changes is augmented survival pathways and systematic defects in the apoptosis signalling machinery. The only randomised, controlled phase II trial conducted targeting the epidermal growth factor receptor (EGFR signalling with the small molecule inhibitor, erlotinib, has showed no therapeutic benefit. Survival signalling and apoptosis resistance in GBMs can be viewed as two sides of the same coin. Targeting increased survival is unlikely to be efficacious without at the same time targeting apoptosis resistance. We have critically reviewed the literature regarding survival and apoptosis signalling in GBM, and highlighted experimental, preclinical and recent clinical trials attempting to target these pathways. Combined therapies simultaneously targeting apoptosis and survival signalling defects might shift the balance from tumour growth stasis to cytotoxic therapeutic responses that might be associated with greater therapeutic benefits.

Boosted TCA cycle enhances survival of zebrafish to Vibrio alginolyticus infection.

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Yang, Man-Jun; Cheng, Zhi-Xue; Jiang, Ming; Zeng, Zao-Hai; Peng, Bo; Peng, Xuan-Xian; Li, Hui

2018-01-01

Vibrio alginolyticus is a waterborne pathogen that infects a wide variety of hosts including fish and human, and the outbreak of this pathogen can cause a huge economic loss in aquaculture. Thus, enhancing host's capability to survive from V. alginolyticus infection is key to fighting infection and this remains still unexplored. In the present study, we established a V. alginolyticus-zebrafish interaction model by which we explored how zebrafish survived from V. alginolyticus infection. We used GC-MS based metabolomic approaches to characterize differential metabolomes between survival and dying zebrafish upon infection. Pattern recognition analysis identified the TCA cycle as the most impacted pathway. The metabolites in the TCA cycle were decreased in the dying host, whereas the metabolites were increased in the survival host. Furthermore, the enzymatic activities of the TCA cycle including pyruvate dehydrogenase (PDH), α-ketoglutaric dehydrogenase (KGDH) and succinate dehydrogenase (SDH) also supported this conclusion. Among the increased metabolites in the TCA cycle, malic acid was the most crucial biomarker for fish survival. Indeed, exogenous malate promoted zebrafish survival in a dose-dependent manner. The corresponding activities of KGDH and SDH were also increased. These results indicate that the TCA cycle is a key pathway responsible for the survival or death in response to infection caused by V. alginolyticus, and highlight the way on development of metabolic modulation to control the infection.

Stem cell death and survival in heart regeneration and repair.

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Abdelwahid, Eltyeb; Kalvelyte, Audrone; Stulpinas, Aurimas; de Carvalho, Katherine Athayde Teixeira; Guarita-Souza, Luiz Cesar; Foldes, Gabor

2016-03-01

Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.

Structure of Pigment Metabolic Pathways and Their Contributions to White Tepal Color Formation of Chinese Narcissus tazetta var. chinensis cv Jinzhanyintai.

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Ren, Yujun; Yang, Jingwen; Lu, Bingguo; Jiang, Yaping; Chen, Haiyang; Hong, Yuwei; Wu, Binghua; Miao, Ying

2017-09-08

Chinese narcissus ( Narcissus tazetta var. chinensis ) is one of the ten traditional flowers in China and a famous bulb flower in the world flower market. However, only white color tepals are formed in mature flowers of the cultivated varieties, which constrains their applicable occasions. Unfortunately, for lack of genome information of narcissus species, the explanation of tepal color formation of Chinese narcissus is still not clear. Concerning no genome information, the application of transcriptome profile to dissect biological phenomena in plants was reported to be effective. As known, pigments are metabolites of related metabolic pathways, which dominantly decide flower color. In this study, transcriptome profile and pigment metabolite analysis methods were used in the most widely cultivated Chinese narcissus "Jinzhanyintai" to discover the structure of pigment metabolic pathways and their contributions to white tepal color formation during flower development and pigmentation processes. By using comparative KEGG pathway enrichment analysis, three pathways related to flavonoid, carotenoid and chlorophyll pigment metabolism showed significant variations. The structure of flavonoids metabolic pathway was depicted, but, due to the lack of F3'5'H gene; the decreased expression of C4H , CHS and ANS genes; and the high expression of FLS gene, the effect of this pathway to synthesize functional anthocyanins in tepals was weak. Similarly, the expression of DXS , MCT and PSY genes in carotenoids synthesis sub-pathway was decreased, while CCD1 / CCD4 genes in carotenoids degradation sub-pathway was increased; therefore, the effect of carotenoids metabolic pathway to synthesize adequate color pigments in tepals is restricted. Interestingly, genes in chlorophyll synthesis sub-pathway displayed uniform down-regulated expression, while genes in heme formation and chlorophyll breakdown sub-pathways displayed up-regulated expression, which also indicates negative regulation

Modulation of neurotrophic signaling pathways by polyphenols

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Moosavi F

2015-12-01

Full Text Available Fatemeh Moosavi,1,2 Razieh Hosseini,1,2 Luciano Saso,3 Omidreza Firuzi1 1Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 2Department of Pharmacology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran; 3Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Rome, Italy Abstract: Polyphenols are an important class of phytochemicals, and several lines of evidence have demonstrated their beneficial effects in the context of a number of pathologies including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. In this report, we review the studies on the effects of polyphenols on neuronal survival, growth, proliferation and differentiation, and the signaling pathways involved in these neurotrophic actions. Several polyphenols including flavonoids such as baicalein, daidzein, luteolin, and nobiletin as well as nonflavonoid polyphenols such as auraptene, carnosic acid, curcuminoids, and hydroxycinnamic acid derivatives including caffeic acid phentyl ester enhance neuronal survival and promote neurite outgrowth in vitro, a hallmark of neuronal differentiation. Assessment of underlying mechanisms, especially in PC12 neuronal-like cells, reveals that direct agonistic effect on tropomyosin receptor kinase (Trk receptors, the main receptors of neurotrophic factors including nerve growth factor (NGF and brain-derived neurotrophic factor (BDNF explains the action of few polyphenols such as 7,8-dihydroxyflavone. However, several other polyphenolic compounds activate extracellular signal-regulated kinase (ERK and phosphoinositide 3-kinase (PI3K/Akt pathways. Increased expression of neurotrophic factors in vitro and in vivo is the mechanism of neurotrophic action of flavonoids such as scutellarin, daidzein, genistein, and fisetin, while compounds like apigenin and ferulic acid increase cyclic adenosine monophosphate

Targeting Apoptosis Signaling Pathways for Anticancer Therapy

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Fulda, Simone, E-mail: simone.fulda@kgu.de [Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt (Germany)

2011-08-29

Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

Targeting Apoptosis Signaling Pathways for Anticancer Therapy

International Nuclear Information System (INIS)

Fulda, Simone

2011-01-01

Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

Stress-triggered signaling affecting survival or suicide of Streptococcus pneumoniae.

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Cortes, Paulo R; Piñas, Germán E; Cian, Melina B; Yandar, Nubia; Echenique, Jose

2015-01-01

Streptococcus pneumoniae is a major human pathogen that can survive to stress conditions, such as the acidic environment of inflammatory foci, and tolerates lethal pH through a mechanism known as the acid tolerance response. We previously described that S. pneumoniae activates acidic-stress induced lysis in response to acidified environments, favoring the release of cell wall compounds, DNA and virulence factors. Here, we demonstrate that F(0)F(1)-ATPase is involved in the response to acidic stress. Chemical inhibitors (DCCD, optochin) of this proton pump repressed the ATR induction, but caused an increased ASIL. Confirming these findings, mutants of the subunit c of this enzyme showed the same phenotypes as inhibitors. Importantly, we demonstrated that F(0)F(1)-ATPase and ATR are necessary for the intracellular survival of the pneumococcus in macrophages. Alternatively, a screening of two-component system (TCS) mutants showed that ATR and survival in pneumocytes were controlled in contrasting ways by ComDE and CiaRH, which had been involved in the ASIL mechanism. Briefly, CiaRH was essential for ATR (ComE represses activation) whereas ComE was necessary for ASIL (CiaRH protects against induction). They did not regulate F0F1-ATPase expression, but control LytA expression on the pneumococcal surface. These results suggest that both TCSs and F(0)F(1)-ATPase control a stress response and decide between a survival or a suicide mechanism by independent pathways, either in vitro or in pneumocyte cultures. This biological model contributes to the current knowledge about bacterial response under stress conditions in host tissues, where pathogens need to survive in order to establish infections. Copyright © 2014 Elsevier GmbH. All rights reserved.

Analyzing the genes related to Alzheimer's disease via a network and pathway-based approach.

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Hu, Yan-Shi; Xin, Juncai; Hu, Ying; Zhang, Lei; Wang, Ju

2017-04-27

Our understanding of the molecular mechanisms underlying Alzheimer's disease (AD) remains incomplete. Previous studies have revealed that genetic factors provide a significant contribution to the pathogenesis and development of AD. In the past years, numerous genes implicated in this disease have been identified via genetic association studies on candidate genes or at the genome-wide level. However, in many cases, the roles of these genes and their interactions in AD are still unclear. A comprehensive and systematic analysis focusing on the biological function and interactions of these genes in the context of AD will therefore provide valuable insights to understand the molecular features of the disease. In this study, we collected genes potentially associated with AD by screening publications on genetic association studies deposited in PubMed. The major biological themes linked with these genes were then revealed by function and biochemical pathway enrichment analysis, and the relation between the pathways was explored by pathway crosstalk analysis. Furthermore, the network features of these AD-related genes were analyzed in the context of human interactome and an AD-specific network was inferred using the Steiner minimal tree algorithm. We compiled 430 human genes reported to be associated with AD from 823 publications. Biological theme analysis indicated that the biological processes and biochemical pathways related to neurodevelopment, metabolism, cell growth and/or survival, and immunology were enriched in these genes. Pathway crosstalk analysis then revealed that the significantly enriched pathways could be grouped into three interlinked modules-neuronal and metabolic module, cell growth/survival and neuroendocrine pathway module, and immune response-related module-indicating an AD-specific immune-endocrine-neuronal regulatory network. Furthermore, an AD-specific protein network was inferred and novel genes potentially associated with AD were identified. By

The p75NTR mediates a bifurcated signal transduction cascade through the NFκB and JNK pathways to inhibit cell survival

International Nuclear Information System (INIS)

Allen, Jeffrey; Khwaja, Fatima; Byers, Stephen; Djakiew, Daniel

2005-01-01

p75 NTR is most abundantly expressed in the nervous system, but is also widely expressed in many other organs and tissues where it primarily functions as a negative regulator of cell survival. In the prostate, p75 NTR functions as an inhibitory protein capable of slowing proliferation and inducing apoptosis. It has been shown that p75 NTR is expressed in the normal prostate, progressively lost from malignant tumor cells in vivo, and largely absent from prostate cancer cell lines derived from metastases. Although the role of p75 NTR in prostate cancer has been well established, the signal transduction pathway that mediates its inhibitory activity has only been partially elucidated. This study demonstrates that exogenous expression of p75 NTR down-regulates, in a dose-dependent manner, a bifurcated signaling cascade that results in reduced expression of potent transcription effectors. This two-arm signal transduction cascade was directly linked to the upstream receptor by using dominant-negative deletion constructs of p75 NTR that rescued tumor cells from p75 NTR -induced loss of survival and promotion of apoptosis. Furthermore, the dominant negatives rescued alterations in the levels of signal transduction intermediates. Conversely, the use of kinase-inactive intermediates that are downstream of the receptor further reduced expression of involved transcription effectors and reduced survival of the cells. These results provide a definitive link between the proximate p75 NTR and signal transduction intermediates leading to the transcription effectors NFκB and JNK, with associated growth suppression and induction of apoptosis

Unconventional Pathways of Secretion Contribute to Inflammation

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Michael J. D. Daniels

2017-01-01

Full Text Available In the conventional pathway of protein secretion, leader sequence-containing proteins leave the cell following processing through the endoplasmic reticulum (ER and Golgi body. However, leaderless proteins also enter the extracellular space through mechanisms collectively known as unconventional secretion. Unconventionally secreted proteins often have vital roles in cell and organism function such as inflammation. Amongst the best-studied inflammatory unconventionally secreted proteins are interleukin (IL-1β, IL-1α, IL-33 and high-mobility group box 1 (HMGB1. In this review we discuss the current understanding of the unconventional secretion of these proteins and highlight future areas of research such as the role of nuclear localisation.

Gluconeogenesis in Leishmania mexicana: contribution of glycerol kinase, phosphoenolpyruvate carboxykinase, and pyruvate phosphate dikinase.

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Rodriguez-Contreras, Dayana; Hamilton, Nicklas

2014-11-21

Gluconeogenesis is an active pathway in Leishmania amastigotes and is essential for their survival within the mammalian cells. However, our knowledge about this pathway in trypanosomatids is very limited. We investigated the role of glycerol kinase (GK), phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate phosphate dikinase (PPDK) in gluconeogenesis by generating the respective Leishmania mexicana Δgk, Δpepck, and Δppdk null mutants. Our results demonstrated that indeed GK, PEPCK, and PPDK are key players in the gluconeogenesis pathway in Leishmania, although stage-specific differences in their contribution to this pathway were found. GK participates in the entry of glycerol in promastigotes and amastigotes; PEPCK participates in the entry of aspartate in promastigotes, and PPDK is involved in the entry of alanine in amastigotes. Furthermore, the majority of alanine enters into the pathway via decarboxylation of pyruvate in promastigotes, whereas pathway redundancy is suggested for the entry of aspartate in amastigotes. Interestingly, we also found that l-lactate, an abundant glucogenic precursor in mammals, was used by Leishmania amastigotes to synthesize mannogen, entering the pathway through PPDK. On the basis of these new results, we propose a revision in the current model of gluconeogenesis in Leishmania, emphasizing the differences between amastigotes and promastigotes. This work underlines the importance of studying the trypanosomatid intracellular life cycle stages to gain a better understanding of the pathologies caused in humans. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Apoptotic pathways of epothilone BMS 310705.

Science.gov (United States)

Uyar, Denise; Takigawa, Nagio; Mekhail, Tarek; Grabowski, Dale; Markman, Maurie; Lee, Francis; Canetta, Renzo; Peck, Ron; Bukowski, Ronald; Ganapathi, Ram

2003-10-01

BMS 310705 is a novel water-soluble analog of epothilone B currently in phase I clinical evaluation in the treatment of malignancies such as ovarian, renal, bladder, and lung carcinoma. Using an early passage cell culture model derived from the ascites of a patient clinically refractory to platinum/paclitaxel therapy, we evaluated the pathway of caspase-mediated apoptosis. Cells were treated for 1 h and subsequently evaluated for apoptosis, survival, and caspase activity. Apoptosis was determined by fluorescent microscopy. Caspase-3, -8, and -9 activities were determined by fluorometry using target tetrapeptide substrates. Mitochondrial release of cytochrome c was determined by immunoblot analysis. After treatment with BMS 310705, apoptosis was confirmed in >25% of cells at 24 h. Survival was significantly lower (P < 0.02) in cells treated with 0.05 micro M BMS 310705 vs paclitaxel. Analysis revealed an increase of caspase-9 and -3 activity; no caspase -8 activity was observed. Release of cytochrome c was detected at 12 h following treatment. SN-38 and topotecan failed to induce apoptosis. BMS 310705 induces significant apoptosis, decreases survival, and utilizes the mitochondrial-mediated pathway for apoptosis in this model.

Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

DEFF Research Database (Denmark)

Zub, Kamila Anna; Sousa, Mirta Mittelstedt Leal de; Sarno, Antonio

2015-01-01

of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further...... and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels...

Activation of the Canonical Wnt/β-Catenin Signalling Pathway is Rare in Canine Malignant Melanoma Tissue and Cell Lines

Science.gov (United States)

Chon, E.; Thompson, V.; Schmid, S.; Stein, T. J.

2012-01-01

Summary Canine malignant melanoma is a highly aggressive tumour associated with a poor overall survival rate due to both local disease recurrence and its highly metastatic nature. Similar to advanced melanoma in man, canine oral melanoma is poorly responsive to conventional anti-cancer therapies. The lack of sustainable disease control warrants investigation of novel therapies, preferably targeting features specific to the tumour and different from normal cells. The Wnt signalling pathway is known to contribute to melanocytic lineage development in vertebrates and perturbation of the Wnt/β-catenin pathway has been implicated in numerous cancer types. Alterations of the Wnt/β-catenin pathway are suggested to occur in a subset of human melanomas, although the precise role of the Wnt/β-catenin pathway in melanoma is yet to be defined. This study investigates the activation status of the canonical Wnt/β-catenin pathway in canine malignant melanoma and its potential as a therapeutic target for treating this disease. The data indicate canonical Wnt/β-catenin pathway activation is a rare event in canine oral malignant melanoma tissue and canine malignant melanoma cell lines. PMID:22901430

Survival and SOS response induction in ultraviolet B irradiated Escherichia coli cells with defective repair mechanisms.

Science.gov (United States)

Prada Medina, Cesar Augusto; Aristizabal Tessmer, Elke Tatjana; Quintero Ruiz, Nathalia; Serment-Guerrero, Jorge; Fuentes, Jorge Luis

2016-06-01

Purpose In this paper, the contribution of different genes involved in DNA repair for both survival and SOS induction in Escherichia coli mutants exposed to ultraviolet B radiation (UVB, [wavelength range 280-315 nm]) was evaluated. Materials and methods E. coli strains defective in uvrA, oxyR, recO, recN, recJ, exoX, recB, recD or xonA genes were used to determine cell survival. All strains also had the genetic sulA::lacZ fusion, which allowed for the quantification of SOS induction through the SOS Chromotest. Results Five gene products were particularly important for survival, as follows: UvrA > RecB > RecO > RecJ > XonA. Strains defective in uvrA and recJ genes showed elevated SOS induction compared with the wild type, which remained stable for up to 240 min after UVB-irradiation. In addition, E. coli strains carrying the recO or recN mutation showed no SOS induction. Conclusions The nucleotide excision and DNA recombination pathways were equally used to repair UVB-induced DNA damage in E. coli cells. The sulA gene was not turned off in strains defective in UvrA and RecJ. RecO protein was essential for processing DNA damage prior to SOS induction. In this study, the roles of DNA repair proteins and their contributions to the mechanisms that induce SOS genes in E. coli are proposed.

Aberrant Signaling Pathways in Glioma

International Nuclear Information System (INIS)

Nakada, Mitsutoshi; Kita, Daisuke; Watanabe, Takuya; Hayashi, Yutaka; Teng, Lei; Pyko, Ilya V.; Hamada, Jun-Ichiro

2011-01-01

Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12–15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies

Novel radiosensitizers for locally advanced epithelial tumors: inhibition of the PI3K/Akt survival pathway in tumor cells and in tumor-associated endothelial cells as a novel treatment strategy?

International Nuclear Information System (INIS)

Riesterer, Oliver; Tenzer, Angela; Zingg, Daniel; Hofstetter, Barbara; Vuong, Van; Pruschy, Martin; Bodis, Stephan

2004-01-01

In locally advanced epithelial malignancies, local control can be achieved with high doses of radiotherapy (RT). Concurrent chemoradiotherapy can improve tumor control in selected solid epithelial adult tumors; however, treatment-related toxicity is of major concern and the therapeutic window often small. Therefore, novel pharmacologic radiosensitizers with a tumor-specific molecular target and a broad therapeutic window are attractive. Because of clonal heterogeneity and the high mutation rate of these tumors, combined treatment with single molecular target radiosensitizers and RT are unlikely to improve sustained local tumor control substantially. Therefore, radiosensitizers modulating entire tumor cell survival pathways in epithelial tumors are of potential clinical use. We discuss the preclinical efficacy and the mechanism of three different, potential radiosensitizers targeting the PTEN/PI3K/Akt survival pathway. These compounds were initially thought to act as single-target agents against growth factor receptors (PKI 166 and PTK 787) or protein kinase C isoforms (PKC 412). We describe an additional target for these compounds. PKI 166 (an epidermal growth factor [EGF] receptor inhibitor) and PKC 412, target the PTEN/PI3K/Akt pathway mainly in tumor cells, and PTK 787 (a vascular endothelial growth factor [VEGF] receptor inhibitor) in endothelial cells. Even for these broader range molecular radiosensitizers, the benefit could be restricted to human epithelial tumor cell clones with a distinct molecular profile. Therefore, these potential radiosensitizers have to be carefully tested in specific model systems before introduction in early clinical trials

Gene expression profiling of canine osteosarcoma reveals genes associated with short and long survival times

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Rao Nagesha AS

2009-09-01

Full Text Available Abstract Background Gene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart with respect to histology, high metastatic rate and poor long-term survival. This study investigates the prognostic gene profile among thirty-two primary canine OS using canine specific cDNA microarrays representing 20,313 genes to identify genes and cellular signaling pathways associated with survival. This, the first report of its kind in dogs with OS, also demonstrates the advantages of cross-species comparison with human OS. Results The 32 tumors were classified into two prognostic groups based on survival time (ST. They were defined as short survivors (dogs with poor prognosis: surviving fewer than 6 months and long survivors (dogs with better prognosis: surviving 6 months or longer. Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors. The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis. Several deregulated pathways identified in the present study, including Wnt signaling, Integrin signaling and Chemokine/cytokine signaling are comparable to the pathway analysis conducted on human OS gene profiles, emphasizing the value of the dog as an excellent model for humans. Conclusion A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy. The similarities between human and canine OS makes the

The influence of the CHIEF pathway on colorectal cancer-specific mortality.

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Martha L Slattery

Full Text Available Many components of the CHIEF (Convergence of Hormones, Inflammation, and Energy Related Factors pathway could influence survival given their involvement in cell growth, apoptosis, angiogenesis, and tumor invasion stimulation. We used ARTP (Adaptive Rank Truncation Product to test if genes in the pathway were associated with colorectal cancer-specific mortality. Colon cancer (n = 1555 and rectal cancer (n = 754 cases were followed over five years. Age, center, stage at diagnosis, and tumor molecular phenotype were considered when calculating ARTP p values. A polygenic risk score was used to summarize the magnitude of risk associated with this pathway. The JAK/STAT/SOC was significant for colon cancer survival (PARTP = 0.035. Fifteen genes (DUSP2, INFGR1, IL6, IRF2, JAK2, MAP3K10, MMP1, NFkB1A, NOS2A, PIK3CA, SEPX1, SMAD3, TLR2, TYK2, and VDR were associated with colon cancer mortality (PARTP < 0.05; JAK2 (PARTP  = 0.0086, PIK3CA (PARTP = 0.0098, and SMAD3 (PARTP = 0.0059 had the strongest associations. Over 40 SNPs were significantly associated with survival within the 15 significant genes (PARTP < 0.05. SMAD3 had the strongest association with survival (HRGG 2.46 95% CI 1.44,4.21 PTtrnd = 0.0002. Seven genes (IL2RA, IL8RA, IL8RB, IRF2, RAF1, RUNX3, and SEPX1 were significantly associated with rectal cancer (PARTP < 0.05. The HR for colorectal cancer-specific mortality among colon cancer cases in the upper at-risk alleles group was 11.81 (95% CI 7.07, 19. 74 and was 10.99 (95% CI 5.30, 22.78 for rectal cancer. These results suggest that several genes in the CHIEF pathway are important for colorectal cancer survival; the risk associated with the pathway merits validation in other studies.

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

Science.gov (United States)

2009-01-01

Background During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On

In vivo relevance for photoprotection by the vitamin D rapid response pathway.

Science.gov (United States)

Dixon, K M; Deo, S S; Norman, A W; Bishop, J E; Halliday, G M; Reeve, V E; Mason, R S

2007-03-01

Vitamin D is produced by exposure of 7-dehydrocholesterol in the skin to UV irradiation (UVR) and further converted in the skin to the biologically active metabolite, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and other compounds. UVR also results in DNA damage producing cyclobutane pyrimidine dimers (CPD). We previously reported that 1,25(OH)(2)D(3) at picomolar concentrations, protects human skin cells from UVR-induced apoptosis, and decreases CPD in surviving cells. 1,25(OH)(2)D(3) has been shown to generate biological responses via two pathways-the classical steroid receptor/genomic pathway or a rapid, non-genomic pathway mediated by a putative membrane receptor. Whether the rapid response pathway is physiologically relevant is unclear. A cis-locked, rapid-acting agonist 1,25(OH)(2)lumisterol(3) (JN), entirely mimicked the actions of 1,25(OH)(2)D(3) to reduce fibroblast and keratinocyte loss and CPD damage after UVR. The effects of 1,25(OH)(2)D(3) were abolished by a rapid-acting antagonist, but not by a genomic antagonist. Skh:hr1 mice exposed to three times the minimal erythemal dose of solar-simulated UVR and treated topically with 1,25(OH)(2)D(3) or JN immediately after UVR showed reduction in UVR-induced UVR-induced sunburn cells (pphotoprotective effects via the rapid pathway and raise the possibility that other D compounds produced in skin may contribute to the photoprotective effects.

Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway.

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Timothy G Lesnick

2008-01-01

Full Text Available We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs within axon guidance pathway genes were highly predictive of Parkinson disease (PD susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD.Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS; and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92x10(-60, survival free of ALS (hazards ratio = 149.80, p = 1.25x10(-74, and age at onset of ALS (R(2 = 0.86, p = 5.96x10(-66. We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively.Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.

Cancer Stem Cells, EMT, and Developmental Pathway Activation in Pancreatic Tumors

International Nuclear Information System (INIS)

Hindriksen, Sanne; Bijlsma, Maarten F.

2012-01-01

Pancreatic cancer is a disease with remarkably poor patient survival rates. The frequent presence of metastases and profound chemoresistance pose a severe problem for the treatment of these tumors. Moreover, cross-talk between the tumor and the local micro-environment contributes to tumorigenicity, metastasis and chemoresistance. Compared to bulk tumor cells, cancer stem cells (CSC) have reduced sensitivity to chemotherapy. CSC are tumor cells with stem-like features that possess the ability to self-renew, but can also give rise to more differentiated progeny. CSC can be identified based on increased in vitro spheroid- or colony formation, enhanced in vivo tumor initiating potential, or expression of cell surface markers. Since CSC are thought to be required for the maintenance of a tumor cell population, these cells could possibly serve as a therapeutic target. There appears to be a causal relationship between CSC and epithelial-to-mesenchymal transition (EMT) in pancreatic tumors. The occurrence of EMT in pancreatic cancer cells is often accompanied by re-activation of developmental pathways, such as the Hedgehog, WNT, NOTCH, and Nodal/Activin pathways. Therapeutics based on CSC markers, EMT, developmental pathways, or tumor micro-environment could potentially be used to target pancreatic CSC. This may lead to a reduction of tumor growth, metastatic events, and chemoresistance in pancreatic cancer

HIF-1α pathway: role, regulation and intervention for cancer therapy

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Georgina N. Masoud

2015-09-01

Full Text Available Hypoxia-inducible factor-1 (HIF-1 has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1α pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1α pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1α in cancer, and recent therapeutic approaches targeting this important pathway.

Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway

International Nuclear Information System (INIS)

Zhan, Meixiao; Sun, Xiaohan; Liu, Jinxiao; Li, Yan; Li, Yong; He, Xu; Zhou, Zizhang; Lu, Ligong

2017-01-01

The ubiquitin-specific protease Usp7 plays roles in multiple cellular processes through deubiquitinating and stabilizing numerous substrates, including P53, Pten and Gli. Aberrant Usp7 activity has been implicated in many disorders and tumorigenesis, making it as a potential target for therapeutic intervention. Although it is clear that Usp7 is involved in many types of cancer, its role in regulating medulloblastoma (MB) is still unknown. In this study, we show that knockdown of Usp7 inhibits the proliferation and migration of MB cells, while Usp7 overexpression exerts an opposite effect. Furthermore, we establish Usp7 knockout MB cell line using the CRISPR/Cas9 system and further confirm that Usp7 knockout also blocks MB cell proliferation and metastasis. In addition, we reveal that knockdown of Usp7 compromises Shh pathway activity and decrease Gli protein levels, while P53 level and P53 target gene expression have no obvious changes. Finally, we find that Usp7 inhibitors apparently inhibit MB cell viability and migration. Taken together, our findings suggest that Usp7 is important for MB cell proliferation and metastasis by activating Shh pathway, and is a putative therapeutic target for MBs. - Highlights: • Loss of usp7 blocks the proliferation and metastasis of MB cells. • Usp7 regulates MB cell growth and migration through stimulating Shh pathway. • Usp7 inhibitors hamper MB cell proliferation and migration. • Usp7 inhibitors could attenuate Shh pathway activity.

Pathway-based Analysis of the Hidden Genetic Heterogeneities in Cancers

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Xiaolei Zhao

2014-02-01

Full Text Available Many cancers apparently showing similar phenotypes are actually distinct at the molecular level, leading to very different responses to the same treatment. It has been recently demonstrated that pathway-based approaches are robust and reliable for genetic analysis of cancers. Nevertheless, it remains unclear whether such function-based approaches are useful in deciphering molecular heterogeneities in cancers. Therefore, we aimed to test this possibility in the present study. First, we used a NCI60 dataset to validate the ability of pathways to correctly partition samples. Next, we applied the proposed method to identify the hidden subtypes in diffuse large B-cell lymphoma (DLBCL. Finally, the clinical significance of the identified subtypes was verified using survival analysis. For the NCI60 dataset, we achieved highly accurate partitions that best fit the clinical cancer phenotypes. Subsequently, for a DLBCL dataset, we identified three hidden subtypes that showed very different 10-year overall survival rates (90%, 46% and 20% and were highly significantly (P = 0.008 correlated with the clinical survival rate. This study demonstrated that the pathway-based approach is promising for unveiling genetic heterogeneities in complex human diseases.

Increased survival with enzalutamide in prostate cancer after chemotherapy

NARCIS (Netherlands)

H.I. Scher (Howard I.); K. Fizazi (Karim); F. Saad (Fred); M.-E. Taplin (Mary-Ellen); C.N. Sternberg (Cora); K. Miller (Kurt); R. de Wit (Ronald); P.F.A. Mulders (P. F A); K.N. Chi (Kim Nguyen); N.D. Shore (Neal); A.J. Armstrong (Andrew); T.W. Flaig (Thomas); A. Flechon (Aude); P. Mainwaring (Paul); M. Fleming; J.D. Hainsworth (John); M. Hirmand (Mohammad); B. Selby (Bryan); L. Seely (Lynn); J.S. de Bono (Johann)

2012-01-01

textabstractBACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after

The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma.

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Steven N Steinway

Full Text Available c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF, plays a critical role in tumor growth, invasion, and metastasis. Hepatocellular carcinoma (HCC patients with activated HGF/c-Met signaling have a significantly worse prognosis. Targeted therapies using c-Met tyrosine kinase inhibitors are currently in clinical trials for HCC, although receptor tyrosine kinase inhibition in other cancers has demonstrated early success. Unfortunately, therapeutic effect is frequently not durable due to acquired resistance.We utilized the human MHCC97-H c-Met positive (c-Met+ HCC cell line to explore the compensatory survival mechanisms that are acquired after c-Met inhibition. MHCC97-H cells with stable c-Met knockdown (MHCC97-H c-Met KD cells were generated using a c-Met shRNA vector with puromycin selection and stably transfected scrambled shRNA as a control. Gene expression profiling was conducted, and protein expression was analyzed to characterize MHCC97-H cells after blockade of the c-Met oncogene. A high-throughput siRNA screen was performed to find putative compensatory survival proteins, which could drive HCC growth in the absence of c-Met. Findings from this screen were validated through subsequent analyses.We have previously demonstrated that treatment of MHCC97-H cells with a c-Met inhibitor, PHA665752, results in stasis of tumor growth in vivo. MHCC97-H c-Met KD cells demonstrate slower growth kinetics, similar to c-Met inhibitor treated tumors. Using gene expression profiling and siRNA screening against 873 kinases and phosphatases, we identified ErbB3 and TGF-α as compensatory survival factors that are upregulated after c-Met inhibition. Suppressing these factors in c-Met KD MHCC97-H cells suppresses tumor growth in vitro. In addition, we found that the PI3K/Akt signaling pathway serves as a negative feedback signal responsible for the ErbB3 upregulation after c-Met inhibition. Furthermore, in vitro studies demonstrate that

Molecular Pathways

Science.gov (United States)

Lok, Benjamin H.; Powell, Simon N.

2012-01-01

The Rad52 protein was largely ignored in humans and other mammals when the mouse knockout revealed a largely “no-effect” phenotype. However, using synthetic lethal approaches to investigate context dependent function, new studies have shown that Rad52 plays a key survival role in cells lacking the function of the BRCA1-BRCA2 pathway of homologous recombination. Biochemical studies also showed significant differences between yeast and human Rad52, in which yeast Rad52 can promote strand invasion of RPA-coated single-stranded DNA in the presence of Rad51, but human Rad52 cannot. This results in the paradox of how is human Rad52 providing Rad51 function: presumably there is something missing in the biochemical assays that exists in-vivo, but the nature of this missing factor is currently unknown. Recent studies have suggested that Rad52 provides back-up Rad51 function for all members of the BRCA1-BRCA2 pathway, suggesting that Rad52 may be a target for therapy in BRCA pathway deficient cancers. Screening for ways to inhibit Rad52 would potentially provide a complementary strategy for targeting BRCA-deficient cancers in addition to PARP inhibitors. PMID:23071261

Homologous recombination contributes to the repair of DNA double-strand breaks induced by high-energy iron ions

Energy Technology Data Exchange (ETDEWEB)

Zafar, Faria; Seidler, Sara B.; Kronenberg, Amy; Schild, David; Wiese, Claudia

2010-06-29

To test the contribution of homologous recombinational repair (HRR) in repairing DNA damaged sites induced by high-energy iron ions, we used: (1) HRR-deficient rodent cells carrying a deletion in the RAD51D gene and (2) syngeneic human cells impaired for HRR by RAD51D or RAD51 knockdown using RNA interference. We show that in response to iron ions, HRR contributes to cell survival in rodent cells, and that HRR-deficiency abrogates RAD51 foci formation. Complementation of the HRR defect by human RAD51D rescues both enhanced cytotoxicity and RAD51 foci formation. For human cells irradiated with iron ions, cell survival is decreased, and, in p53 mutant cells, the levels of mutagenesis are increased when HRR is impaired. Human cells synchronized in S phase exhibit more pronounced resistance to iron ions as compared with cells in G1 phase, and this increase in radioresistance is diminished by RAD51 knockdown. These results implicate a role for RAD51-mediated DNA repair (i.e. HRR) in removing a fraction of clustered lesions induced by charged particle irradiation. Our results are the first to directly show the requirement for an intact HRR pathway in human cells in ensuring DNA repair and cell survival in response to high-energy high LET radiation.

Homologous recombination contributes to the repair of DNA double-strand breaks induced by high-energy iron ions

International Nuclear Information System (INIS)

Zafar, Faria; Seidler, Sara B.; Kronenberg, Amy; Schild, David; Wiese, Claudia

2010-01-01

To test the contribution of homologous recombinational repair (HRR) in repairing DNA damaged sites induced by high-energy iron ions, we used: (1) HRR-deficient rodent cells carrying a deletion in the RAD51D gene and (2) syngeneic human cells impaired for HRR by RAD51D or RAD51 knockdown using RNA interference. We show that in response to iron ions, HRR contributes to cell survival in rodent cells, and that HRR-deficiency abrogates RAD51 foci formation. Complementation of the HRR defect by human RAD51D rescues both enhanced cytotoxicity and RAD51 foci formation. For human cells irradiated with iron ions, cell survival is decreased, and, in p53 mutant cells, the levels of mutagenesis are increased when HRR is impaired. Human cells synchronized in S phase exhibit more pronounced resistance to iron ions as compared with cells in G1 phase, and this increase in radioresistance is diminished by RAD51 knockdown. These results implicate a role for RAD51-mediated DNA repair (i.e. HRR) in removing a fraction of clustered lesions induced by charged particle irradiation. Our results are the first to directly show the requirement for an intact HRR pathway in human cells in ensuring DNA repair and cell survival in response to high-energy high LET radiation.

Increased survival with enzalutamide in prostate cancer after chemotherapy

NARCIS (Netherlands)

Scher, H.I.; Fizazi, K.; Saad, F.; Taplin, M.E.; Sternberg, C.N.; Miller, K.; de Wit, R.; Mulders, P.F.A.; Chi, K.N.; Shore, N.D.; Armstrong, A.J.; Flaig, T.W.; Flechon, A.; Mainwaring, P.; Fleming, M.; Hainsworth, J.D.; Hirmand, M.; Selby, B.; Seely, L.; Bono, J. De; Investigators, A.

2012-01-01

BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. METHODS:

Neuronal survival in the brain: neuron type-specific mechanisms

DEFF Research Database (Denmark)

Pfisterer, Ulrich Gottfried; Khodosevich, Konstantin

2017-01-01

Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial...... numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether...... for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various...

Customer service skills for survival.

Science.gov (United States)

McAtee, L F

1999-11-01

As APICS practitioners, we all must share a common goal. How can we contribute to our company's success? Success can be measured in positive terms of market share, growth, profitability, return on investment, or some combination thereof. Each company must establish its own definition of success. For the purposes of this article, success will be equated to one word that we can all readily identify with: survival. What skills do we need to survive in the marketplace of the next millennium?

The Wnt Signaling Pathway Is Differentially Expressed during the Bovine Herpesvirus 1 Latency-Reactivation Cycle: Evidence That Two Protein Kinases Associated with Neuronal Survival, Akt3 and BMPR2, Are Expressed at Higher Levels during Latency.

Science.gov (United States)

Workman, Aspen; Zhu, Liqian; Keel, Brittney N; Smith, Timothy P L; Jones, Clinton

2018-04-01

Sensory neurons in trigeminal ganglia (TG) of calves latently infected with bovine herpesvirus 1 (BoHV-1) abundantly express latency-related (LR) gene products, including a protein (ORF2) and two micro-RNAs. Recent studies in mouse neuroblastoma cells (Neuro-2A) demonstrated ORF2 interacts with β-catenin and a β-catenin coactivator, high-mobility group AT-hook 1 (HMGA1) protein, which correlates with increased β-catenin-dependent transcription and cell survival. β-Catenin and HMGA1 are readily detected in a subset of latently infected TG neurons but not TG neurons from uninfected calves or reactivation from latency. Consequently, we hypothesized that the Wnt/β-catenin signaling pathway is differentially expressed during the latency and reactivation cycle and an active Wnt pathway promotes latency. RNA-sequencing studies revealed that 102 genes associated with the Wnt/β-catenin signaling pathway were differentially expressed in TG during the latency-reactivation cycle in calves. Wnt agonists were generally expressed at higher levels during latency, but these levels decreased during dexamethasone-induced reactivation. The Wnt agonist bone morphogenetic protein receptor 2 (BMPR2) was intriguing because it encodes a serine/threonine receptor kinase that promotes neuronal differentiation and inhibits cell death. Another differentially expressed gene encodes a protein kinase (Akt3), which is significant because Akt activity enhances cell survival and is linked to herpes simplex virus 1 latency and neuronal survival. Additional studies demonstrated ORF2 increased Akt3 steady-state protein levels and interacted with Akt3 in transfected Neuro-2A cells, which correlated with Akt3 activation. Conversely, expression of Wnt antagonists increased during reactivation from latency. Collectively, these studies suggest Wnt signaling cooperates with LR gene products, in particular ORF2, to promote latency. IMPORTANCE Lifelong BoHV-1 latency primarily occurs in sensory neurons

Pathway cross-talk network analysis identifies critical pathways in neonatal sepsis.

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Meng, Yu-Xiu; Liu, Quan-Hong; Chen, Deng-Hong; Meng, Ying

2017-06-01

Despite advances in neonatal care, sepsis remains a major cause of morbidity and mortality in neonates worldwide. Pathway cross-talk analysis might contribute to the inference of the driving forces in bacterial sepsis and facilitate a better understanding of underlying pathogenesis of neonatal sepsis. This study aimed to explore the critical pathways associated with the progression of neonatal sepsis by the pathway cross-talk analysis. By integrating neonatal transcriptome data with known pathway data and protein-protein interaction data, we systematically uncovered the disease pathway cross-talks and constructed a disease pathway cross-talk network for neonatal sepsis. Then, attract method was employed to explore the dysregulated pathways associated with neonatal sepsis. To determine the critical pathways in neonatal sepsis, rank product (RP) algorithm, centrality analysis and impact factor (IF) were introduced sequentially, which synthetically considered the differential expression of genes and pathways, pathways cross-talks and pathway parameters in the network. The dysregulated pathways with the highest IF values as well as RPpathways in neonatal sepsis. By integrating three kinds of data, only 6919 common genes were included to perform the pathway cross-talk analysis. By statistic analysis, a total of 1249 significant pathway cross-talks were selected to construct the pathway cross-talk network. Moreover, 47 dys-regulated pathways were identified via attract method, 20 pathways were identified under RPpathways with the highest IF were also screened from the pathway cross-talk network. Among them, we selected 8 common pathways, i.e. critical pathways. In this study, we systematically tracked 8 critical pathways involved in neonatal sepsis by integrating attract method and pathway cross-talk network. These pathways might be responsible for the host response in infection, and of great value for advancing diagnosis and therapy of neonatal sepsis. Copyright © 2017

Transcriptomes and pathways associated with infectivity, survival and immunogenicity in Brugia malayi L3

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Spiro David

2009-06-01

the enhanced immunogenicity of L3ir. Gene Ontology and KEGG analyses revealed altered pathways between L3 types. Energy and "immune pathways" are up-regulated and may be needed for L3i invasion and survival, while growth and development are priorities for L3c. This study has improved our understanding of molecules involved in parasite invasion and immune evasion, potential targets of protective immunity, and molecules required for parasite growth and development.

A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection

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Pluchino Stefano

2011-07-01

Full Text Available Abstract Background Dopamine-synthesizing (dopaminergic, DA neurons in the ventral midbrain (VM constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. Results In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+ neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd

Anisotropic Covalency Contributions to Superexchange Pathways in Type One Copper Active Sites

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2015-01-01

Type one (T1) Cu sites deliver electrons to catalytic Cu active sites: the mononuclear type two (T2) Cu site in nitrite reductases (NiRs) and the trinuclear Cu cluster in the multicopper oxidases (MCOs). The T1 Cu and the remote catalytic sites are connected via a Cys-His intramolecular electron-transfer (ET) bridge, which contains two potential ET pathways: P1 through the protein backbone and P2 through the H-bond between the Cys and the His. The high covalency of the T1 Cu–S(Cys) bond is shown here to activate the T1 Cu site for hole superexchange via occupied valence orbitals of the bridge. This covalency-activated electronic coupling (HDA) facilitates long-range ET through both pathways. These pathways can be selectively activated depending on the geometric and electronic structure of the T1 Cu site and thus the anisotropic covalency of the T1 Cu–S(Cys) bond. In NiRs, blue (π-type) T1 sites utilize P1 and green (σ-type) T1 sites utilize P2, with P2 being more efficient. Comparing the MCOs to NiRs, the second-sphere environment changes the conformation of the Cys-His pathway, which selectively activates HDA for superexchange by blue π sites for efficient turnover in catalysis. These studies show that a given protein bridge, here Cys-His, provides different superexchange pathways and electronic couplings depending on the anisotropic covalencies of the donor and acceptor metal sites. PMID:25310460

Modeling of DNA damage-cluster, cell-cycle and repair pathway dependent radiosensitivity after low- and high-LET irradiation

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Guenther, Paul

2017-01-01

This work focuses on modeling of the effects of ionizing radiation on cells, primarily on, the influence of the DNA repair pathway availability and the radiation quality on the cell-survival probability. The availability of DNA repair pathways depends on the replication state and defects of the DNA repair pathways. The radiation quality manifests itself in the microscopic ionization pattern. The Giant LOop Binary LEsion (GLOBLE) model and the Local Effect Model (LEM) describe the cell-survival after photon and ion irradiation, respectively. Both models assume that cell survival can be modeled based on the spatial distribution of Double-Strand Breaks (DSB) of the DNA (damage pattern), within a higher order chromatin structure. Single DSB are referred to as isolated DSB (iDSB) and two or more DSB in close proximity (within 540 nm) are called complex DSB (cDSB). In order to predict the cell-survival, the GLOBLE-Model considers different iDSB repair-pathways and their availability. One central assumption of the LEM is that the same damage patterns imply same effects, regardless of the radiation quality. In order to predict the damage pattern the microscopic local dose distribution of ions, described by the amorphous track structure, is evaluated. The cell survival after ion irradiation is predicted from a comparison with corresponding damage patterns after photon irradiation. The cell-survival curves after high dose photon irradiation cannot be predicted from the Linear Quadratic (LQ) Model due to their transition towards a linear dose dependence. This work uses the GLOBLE-Model to introduce a novel mechanistic approach, which allows the threshold dose to be predicted for the transition from a linear quadratic dose dependence, of survival curves at low doses, to a linear dose dependence at high doses. Furthermore, a method is presented, which allows LEM to predict the survival of synchronous cells after ion irradiation based on the cell survival after photon

Management of optic pathway and chiasmatic-hypothalamic gliomas in children with radiation therapy

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Erkal, Haldun Suekrue; Serin, Meltem; Cakmak, Ahmet

1997-01-01

Background and purpose: Optic pathway and chiasmatic-hypothalamic gliomas are rare childhood tumors. This study presents the experience in management of these tumors with radiation therapy. Materials and methods: Thirty-three children with the diagnosis of optic pathway and chiasmatic-hypothalamic gliomas were treated with radiation therapy from 1973 through 1994 in the Department of Radiation Oncology at Ankara University Faculty of Medicine. Twenty-four children had optic pathway gliomas and nine had chiasmatic-hypothalamic gliomas. Evidence of neurofibromatosis was present in six children. Subtotal resection was performed in 22 children and a biopsy in seven. The most common prescription for total tumor dose was 50 Gy, delivered in 2 Gy daily fractions. Follow-up ranged from 0.5 to 16.1 years (mean, 13.6 years). Results: Overall, progression-free and cause-specific survival probabilities for the entire group were 93%, 82% and 93%, respectively, at 5 years and 79%, 77% and 88%, respectively, at 10 years. Differences in overall, progression-free and cause-specific survival probabilities between optic pathway and chiasmatic-hypothalamic gliomas were not statistically significant. Absence of evidence of neurofibromatosis correlated with significantly better progression-free and cause-specific survival probabilities. Conclusion: Radiation therapy is effective in stabilization or improvement of vision and prevention of tumor progression in both optic pathway and chiasmatic-hypothalamic gliomas

The TOR signaling pathway regulates vegetative development and virulence in Fusarium graminearum.

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Yu, Fangwei; Gu, Qin; Yun, Yingzi; Yin, Yanni; Xu, Jin-Rong; Shim, Won-Bo; Ma, Zhonghua

2014-07-01

The target of rapamycin (TOR) signaling pathway plays critical roles in controlling cell growth in a variety of eukaryotes. However, the contribution of this pathway in regulating virulence of plant pathogenic fungi is unknown. We identified and characterized nine genes encoding components of the TOR pathway in Fusarium graminearum. Biological, genetic and biochemical functions of each component were investigated. The FgFkbp12-rapamycin complex binds to the FgTor kinase. The type 2A phosphatases FgPp2A, FgSit4 and FgPpg1 were found to interact with FgTap42, a downstream component of FgTor. Among these, we determined that FgPp2A is likely to be essential for F. graminearum survival, and FgSit4 and FgPpg1 play important roles in cell wall integrity by positively regulating the phosphorylation of FgMgv1, a key MAP kinase in the cell wall integrity pathway. In addition, the FgPpg1 interacting protein, FgTip41, is involved in regulating mycelial growth and virulence. Notably, FgTip41 does not interact with FgTap42 but with FgPpg1, suggesting the existence of FgTap42:FgPpg1:FgTip41 heterotrimer in F. graminearum, a complex not observed in the yeast model. Collectively, we defined a genetic regulatory framework that elucidates how the TOR pathway regulates virulence and vegetative development in F. graminearum. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

Activation of the polyol pathway may contribute to increased risk of radiocontrast agent nephrotoxicity in diabetes

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Kaplan, D.L.; Mann, P.L.; Zager, P.G.; Smith, M.A.

1991-01-01

The incidence of radiocontrast (RC) agent nephrotoxicity is higher in diabetic than non-diabetic patients. RC nephropathy involves both glomerular and tubular cells. The authors postulate that activation of the polyol pathway contributes to the increased susceptibility of diabetics to RC nephrotoxicity. Mesangial cells modulate GFR by altering the capillary surface area available for filtration. Toxic insult to mesangial cells can impair glomerular function. The present study was performed to determine if mesangial cells isolated from galactose fed rats, the classic model for studying the effects of polyol accumulation, demonstrate increased susceptibility to RC toxicity. A cellular model was developed to study the effects of RC agents on mesangial cells isolated from rats maintained on diets of 50% galactose (MCG) and 50% dextrin (MCD). MCG's and MCD's were plated in 96 well trays at a density of 6.25 x 10 4 cells/ml. Cells were exposed to Hypaque 90 at concentrations of 10 mM to 1 uM for 1, 2, 4 and 24 hrs. Cell viability was determined by fluorescein diacetate/propidium iodide staining. 3H-thymidine incorporation was used to determine cell proliferation rates. Hypaque 90 produced no direct cytotoxicity at any time points or concentrations tested. An increase in cell proliferation was observed 1 hr after exposure to 1 uM to 1mM Hypaque. Higher concentrations blunted cell proliferation rates. Hypaque 90 produced no direct cytotoxicity at any time points or concentrations tested. An increase in cell proliferation was observed 1 hr after exposure to 1 uM to 1mM Hypaque. Higher concentrations blunted cell proliferation. No significant effects on 3H-thymidine incorporation were observed at later time points. The effects on 3H-thymidine incorporation were more pronounced in MCG's than MCD's. Activation of the polyol pathway amplifies the proliferative response of MC to RC agents. This activation may contribute to the risk of RC nephropathy in diabetics

Genetic Ancestry Is not Associated with Breast Cancer Recurrence or Survival in U.S. Latina Women Enrolled in the Kaiser Permanente Pathways Study.

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Engmann, Natalie J; Ergas, Isaac J; Yao, Song; Kwan, Marilyn L; Roh, Janise M; Ambrosone, Christine B; Kushi, Lawrence H; Fejerman, Laura

2017-09-01

Background: The U.S. Hispanic/Latino population is heterogeneous both socioculturally and by the proportion of European, Indigenous American, and African ancestry of the regions from which individuals originate. A previous study reported that genetic ancestry was associated with breast cancer survival among Latinas, independent of sociodemographic and tumor characteristics, suggesting that a genetic factor associated with ancestry may affect breast cancer survival. Methods: We evaluated the association of genetic ancestry with breast cancer outcomes among 506 Latina women with invasive breast cancer in the Pathways Study, a cohort study within Kaiser Permanente, an integrated health care delivery system. Proportional hazards models were used to assess the effect of ancestry on breast cancer recurrence (53 events), breast cancer-specific mortality (31 events) and all-cause mortality (54 events), with a mean follow-up time of 6 years. Results: Indigenous American ancestry was not associated with breast cancer recurrence [HR = 1.00 per 10% increase; 95% confidence interval (CI), 0.86-1.16], breast cancer mortality (HR = 0.95; 95% CI, 0.77-1.17), or all-cause mortality (HR = 0.93; 95% CI, 0.80-1.08). Adjustment for sociodemographic variables, tumor characteristics, and treatment did not alter the associations. Conclusions: Our results suggest that previously reported differences in breast cancer survival by genetic ancestry may be overcome by improving health care access and/or quality. Impact: Improving health care access and quality may reduce breast cancer disparities among U.S. Latinas. Cancer Epidemiol Biomarkers Prev; 26(9); 1466-9. ©2017 AACR . ©2017 American Association for Cancer Research.

Imaging rapid redistribution of sensory-evoked depolarization through existing cortical pathways after targeted stroke in mice.

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Sigler, Albrecht; Mohajerani, Majid H; Murphy, Timothy H

2009-07-14

Evidence suggests that recovery from stroke damage results from the production of new synaptic pathways within surviving brain regions over weeks. To address whether brain function might redistribute more rapidly through preexisting pathways, we examined patterns of sensory-evoked depolarization in mouse somatosensory cortex within hours after targeted stroke to a subset of the forelimb sensory map. Brain activity was mapped with voltage-sensitive dye imaging allowing millisecond time resolution over 9 mm(2) of brain. Before targeted stroke, we report rapid activation of the forelimb area within 10 ms of contralateral forelimb stimulation and more delayed activation of related areas of cortex such as the hindlimb sensory and motor cortices. After stroke to a subset of the forelimb somatosensory cortex map, function was lost in ischemic areas within the forelimb map center, but maintained in regions 200-500 microm blood flow deficits indicating the size of a perfused, but nonfunctional, penumbra. In many cases, stroke led to only partial loss of the forelimb map, indicating that a subset of a somatosensory domain can function on its own. Within the forelimb map spared by stroke, forelimb-stimulated responses became delayed in kinetics, and their center of activity shifted into adjacent hindlimb and posterior-lateral sensory areas. We conclude that the focus of forelimb-specific somatosensory cortex activity can be rapidly redistributed after ischemic damage. Given that redistribution occurs within an hour, the effect is likely to involve surviving accessory pathways and could potentially contribute to rapid behavioral compensation or direct future circuit rewiring.

Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway.

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Kambe, Taiho; Matsunaga, Mayu; Takeda, Taka-Aki

2017-10-19

More than one-third of newly synthesized proteins are targeted to the early secretory pathway, which is comprised of the endoplasmic reticulum (ER), Golgi apparatus, and other intermediate compartments. The early secretory pathway plays a key role in controlling the folding, assembly, maturation, modification, trafficking, and degradation of such proteins. A considerable proportion of the secretome requires zinc as an essential factor for its structural and catalytic functions, and recent findings reveal that zinc plays a pivotal role in the function of the early secretory pathway. Hence, a disruption of zinc homeostasis and metabolism involving the early secretory pathway will lead to pathway dysregulation, resulting in various defects, including an exacerbation of homeostatic ER stress. The accumulated evidence indicates that specific members of the family of Zn transporters (ZNTs) and Zrt- and Irt-like proteins (ZIPs), which operate in the early secretory pathway, play indispensable roles in maintaining zinc homeostasis by regulating the influx and efflux of zinc. In this review, the biological functions of these transporters are discussed, focusing on recent aspects of their roles. In particular, we discuss in depth how specific ZNT transporters are employed in the activation of zinc-requiring ectoenzymes. The means by which early secretory pathway functions are controlled by zinc, mediated by specific ZNT and ZIP transporters, are also subjects of this review.

Crocin prevents retinal ischaemia/reperfusion injury-induced apoptosis in retinal ganglion cells through the PI3K/AKT signalling pathway.

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Qi, Yun; Chen, Li; Zhang, Lei; Liu, Wen-Bo; Chen, Xiao-Yan; Yang, Xin-Guang

2013-02-01

Crocin is a pharmacologically active component of Crocus sativus L. (saffron) and has been reported to be useful in the treatment of neuronal damage. In the present study, we investigated the neuroprotective effect of crocin on retinal ganglion cells (RGCs) after retinal ischaemia/reperfusion (IR) injury, and our results show that crocin acts through the PI3K/AKT signalling pathway. Retinal IR injury was induced by raising the intraocular pressure of Sprague-Dawley rats to 110 mmHg for 60 min. The neuroprotective effect of crocin was determined by quantifying the surviving RGCs and apoptotic RGCs following IR injury by means of retrograde labelling and TUNEL staining, respectively. The phosphorylated AKT protein level was determined by western blot and immunohistochemical analysis. To determine the extent to which the PI3K/AKT pathway contributes to the neuroprotective effect of crocin, experiments were also performed using the PI3K inhibitor LY294002. Compared with the IR + vehicle group, crocin (50 mg/kg) treatment enhanced RGC survival by approximately 36% and decreased RGC apoptosis by 44% after retinal IR injury. Western blot and immunohistochemical analysis demonstrated that the PI3K/AKT pathway was activated by crocin in the ganglion cell layer after retinal IR injury. Intravitreal injection of LY294002 blocked the neuroprotective effect of crocin on IR-induced RGC death. In conclusion, crocin prevents retinal IR-induced apoptosis of RGCs by activating the PI3K/AKT signalling pathway. Copyright © 2012 Elsevier Ltd. All rights reserved.

Ehrlichia chaffeensis TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival

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Taslima T. Lina

2016-07-01

Full Text Available Ehrlichia chaffeensis preferentially targets mononuclear phagocytes and survives through a strategy of subverting innate immune defenses, but the mechanisms are unknown. We have shown E. chaffeensis type 1 secreted tandem repeat protein (TRP effectors are involved in diverse molecular pathogen-host interactions, such as the TRP120 interaction with the Notch receptor-cleaving metalloprotease ADAM17. In the present study, we demonstrate E. chaffeensis, via the TRP120 effector, activates the canonical Notch signaling pathway to promote intracellular survival. We found that nuclear translocation of the transcriptionally active Notch intracellular domain (NICD occurs in response to E. chaffeensis or recombinant TRP120, resulting in upregulation of Notch signaling pathway components and target genes notch1, adam17, hes, and hey. Significant differences in canonical Notch signaling gene expression levels (>40% were observed during early and late stages of infection, indicating activation of the Notch pathway. We linked Notch pathway activation specifically to the TRP120 effector, which directly interacts with the Notch metalloprotease ADAM17. Using pharmacological inhibitors and small interfering RNAs (siRNAs against γ-secretase enzyme, Notch transcription factor complex, Notch1, and ADAM17, we demonstrated that Notch signaling is required for ehrlichial survival. We studied the downstream effects and found that E. chaffeensis TRP120-mediated activation of the Notch pathway causes inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2 and p38 mitogen-activated protein kinase (MAPK pathways required for PU.1 and subsequent Toll-like receptor 2/4 (TLR2/4 expression. This investigation reveals a novel mechanism whereby E. chaffeensis exploits the Notch pathway to evade the host innate immune response for intracellular survival.

Apoptosis and inactivation of the PI3-kinase pathway by tetrocarcin A in breast cancers

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Nakajima, Hiroo; Sakaguchi, Koichi; Fujiwara, Ikuya; Mizuta, Mitsuhiko; Tsuruga, Mie; Magae, Junji; Mizuta, Naruhiko

2007-01-01

A survival kinase, Akt, is a downstream factor in the phosphatidylinositide-3'-kinase-dependent pathway, which mediates many biological responses including glucose uptake, protein synthesis and the regulation of proliferation and apoptosis, which is assumed to contribute to acquisition of malignant properties of human cancers. Here we find that an anti-tumor antibiotic, tetrocarcin A, directly induces apoptosis of human breast cancer cells. The apoptosis is accompanied by the activation of a proteolytic cascade of caspases including caspase-3 and -9, and concomitantly decreases phosphorylation of Akt, PDK1, and PTEN, a tumor suppressor that regulates the activity of Akt through the dephosphorylation of polyphosphoinositides. Tetrocarcin A affected neither expression of Akt, PDK1, or PTEN, nor did it affect the expression of Bcl family members including Bcl-2, Bcl-X L , and Bax. These results suggest that tetrocarcin A could be a potent chemotherapeutic agent for human breast cancer targeting the phosphatidylinositide-3'-kinase/Akt signaling pathway

Tumour cell dormancy as a contributor to the reduced survival of GBM patients who received standard therapy.

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Tong, Luqing; Yi, Li; Liu, Peidong; Abeysekera, Iruni Roshanie; Hai, Long; Li, Tao; Tao, Zhennan; Ma, Haiwen; Xie, Yang; Huang, Yubao; Yu, Shengping; Li, Jiabo; Yuan, Feng; Yang, Xuejun

2018-07-01

Glioblastoma multiforme (GBM) is a fatal cancer with varying life expectancy, even for patients undergoing the same standard therapy. Identification of differentially expressed genes in GBM patients with different survival rates may benefit the development of effective therapeutic strategies. In the present study, key pathways and genes correlated with survival in GBM patients were screened with bioinformatic analysis. Included in the study were 136 eligible patients who had undertaken surgical resection of GBM followed by temozolomide (TMZ) chemoradiation and long-term therapy with TMZ. A total of 383 differentially expressed genes (DEGs) related to GBM survival were identified. Gene Ontology and pathway enrichment analysis as well as hub gene screening and module analysis were performed. As expected, angiogenesis and migration of GBM cells were closely correlated with a poor prognosis. Importantly, the results also indicated that cell dormancy was an essential contributor to the reduced survival of GBM patients. Given the lack of specific targeted genes and pathways known to be involved in tumour cell dormancy, we proposed enriched candidate genes related to the negative regulation of cell proliferation, signalling pathways regulating pluripotency of stem cells and neuroactive ligand-receptor interaction, and 3 hub genes (FTH1, GRM1 and DDIT3). Maintaining persistent cell dormancy or preventing tumour cells from entering dormancy during chemoradiation should be a promising therapeutic strategy.

Rac1 selective activation improves retina ganglion cell survival and regeneration.

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Erika Lorenzetto

Full Text Available In adult mammals, after optic nerve injury, retinal ganglion cells (RGCs do not regenerate their axons and most of them die by apoptosis within a few days. Recently, several strategies that activate neuronal intracellular pathways were proposed to prevent such degenerative processes. The rho-related small GTPase Rac1 is part of a complex, still not fully understood, intracellular signaling network, mediating in neurons many effects, including axon growth and cell survival. However, its role in neuronal survival and regeneration in vivo has not yet been properly investigated. To address this point we intravitreally injected selective cell-penetrating Rac1 mutants after optic nerve crush and studied the effect on RGC survival and axonal regeneration. We injected two well-characterized L61 constitutively active Tat-Rac1 fusion protein mutants, in which a second F37A or Y40C mutation confers selectivity in downstream signaling pathways. Results showed that, 15 days after crush, both mutants were able to improve survival and to prevent dendrite degeneration, while the one harboring the F37A mutation also improved axonal regeneration. The treatment with F37A mutant for one month did not improve the axonal elongation respect to 15 days. Furthermore, we found an increase of Pak1 T212 phosphorylation and ERK1/2 expression in RGCs after F37A treatment, whereas ERK1/2 was more activated in glial cells after Y40C administration. Our data suggest that the selective activation of distinct Rac1-dependent pathways could represent a therapeutic strategy to counteract neuronal degenerative processes in the retina.

MO-DE-207B-03: Improved Cancer Classification Using Patient-Specific Biological Pathway Information Via Gene Expression Data

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Young, M; Craft, D [Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)

2016-06-15

Purpose: To develop an efficient, pathway-based classification system using network biology statistics to assist in patient-specific response predictions to radiation and drug therapies across multiple cancer types. Methods: We developed PICS (Pathway Informed Classification System), a novel two-step cancer classification algorithm. In PICS, a matrix m of mRNA expression values for a patient cohort is collapsed into a matrix p of biological pathways. The entries of p, which we term pathway scores, are obtained from either principal component analysis (PCA), normal tissue centroid (NTC), or gene expression deviation (GED). The pathway score matrix is clustered using both k-means and hierarchical clustering, and a clustering is judged by how well it groups patients into distinct survival classes. The most effective pathway scoring/clustering combination, per clustering p-value, thus generates various ‘signatures’ for conventional and functional cancer classification. Results: PICS successfully regularized large dimension gene data, separated normal and cancerous tissues, and clustered a large patient cohort spanning six cancer types. Furthermore, PICS clustered patient cohorts into distinct, statistically-significant survival groups. For a suboptimally-debulked ovarian cancer set, the pathway-classified Kaplan-Meier survival curve (p = .00127) showed significant improvement over that of a prior gene expression-classified study (p = .0179). For a pancreatic cancer set, the pathway-classified Kaplan-Meier survival curve (p = .00141) showed significant improvement over that of a prior gene expression-classified study (p = .04). Pathway-based classification confirmed biomarkers for the pyrimidine, WNT-signaling, glycerophosphoglycerol, beta-alanine, and panthothenic acid pathways for ovarian cancer. Despite its robust nature, PICS requires significantly less run time than current pathway scoring methods. Conclusion: This work validates the PICS method to improve

KNK437, abrogates hypoxia-induced radioresistance by dual targeting of the AKT and HIF-1α survival pathways

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Oommen, Deepu; Prise, Kevin M.

2012-01-01

Highlights: ► KNK437, a benzylidene lactam compound, is a novel radiosensitizer. ► KNK437 inhibits AKT signaling and abrogates the accumulation of HIF-1α under hypoxia. ► KNK437 abrogates hypoxia induced resistance to radiation. -- Abstract: KNK437 is a benzylidene lactam compound known to inhibit stress-induced synthesis of heat shock proteins (HSPs). HSPs promote radioresistance and play a major role in stabilizing hypoxia inducible factor-1α (HIF-1α). HIF-1α is widely responsible for tumor resistance to radiation under hypoxic conditions. We hypothesized that KNK437 sensitizes cancer cells to radiation and overrides hypoxia-induced radioresistance via destabilizing HIF-1α. Treatment of human cancer cells MDA-MB-231 and T98G with KNK437 sensitized them to ionizing radiation (IR). Surprisingly, IR did not induce HSPs in these cell lines. As hypothesized, KNK437 abrogated the accumulation of HIF-1α in hypoxic cells. However, there was no induction of HSPs under hypoxic conditions. Moreover, the proteosome inhibitor MG132 did not restore HIF-1α levels in KNK437-treated cells. This suggested that the absence of HIF-1α in hypoxic cells was not due to the enhanced protein degradation. HIF-1α is mainly regulated at the level of post-transcription and AKT is known to modulate the translation of HIF-1α mRNA. Interestingly, pre-treatment of cells with KNK437 inhibited AKT signaling. Furthermore, down regulation of AKT by siRNA abrogated HIF-1α levels under hypoxia. Interestingly, KNK437 reduced cell survival in hypoxic conditions and inhibited hypoxia-induced resistance to radiation. Taken together, these data suggest that KNK437 is an effective radiosensitizer that targets multiple pro-survival stress response pathways.

NF-kappaB signaling: a tale of two pathways in skeletal myogenesis.

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Bakkar, Nadine; Guttridge, Denis C

2010-04-01

NF-kappaB is a ubiquitiously expressed transcription factor that plays vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. Activation of NF-kappaB is controlled by an IkappaB kinase (IKK) complex that can direct either canonical (classical) NF-kappaB signaling by degrading the IkappaB inhibitor and releasing p65/p50 dimers to the nucleus, or causes p100 processing and nuclear translocation of RelB/p52 via a noncanonical (alternative) pathway. Under physiological conditions, NF-kappaB activity is transiently regulated, whereas constitutive activation of this transcription factor typically in the classical pathway is associated with a multitude of disease conditions, including those related to skeletal muscle. How NF-kappaB functions in muscle diseases is currently under intense investigation. Insight into this role of NF-kappaB may be gained by understanding at a more basic level how this transcription factor contributes to skeletal muscle cell differentiation. Recent data from knockout mice support that the classical NF-kappaB pathway functions as an inhibitor of skeletal myogenesis and muscle regeneration acting through multiple mechanisms. In contrast, alternative NF-kappaB signaling does not appear to be required for myofiber conversion, but instead functions in myotube homeostasis by regulating mitochondrial biogenesis. Additional knowledge of these signaling pathways in skeletal myogenesis should aid in the development of specific inhibitors that may be useful in treatments of muscle disorders.

Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles.

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Arsen Arakelyan

Full Text Available Autoinflammatory and autoimmune disorders are characterized by aberrant changes in innate and adaptive immunity that may lead from an initial inflammatory state to an organ specific damage. These disorders possess heterogeneity in terms of affected organs and clinical phenotypes. However, despite the differences in etiology and phenotypic variations, they share genetic associations, treatment responses and clinical manifestations. The mechanisms involved in their initiation and development remain poorly understood, however the existence of some clear similarities between autoimmune and autoinflammatory disorders indicates variable degrees of interaction between immune-related mechanisms.Our study aims at contributing to a holistic, pathway-centered view on the inflammatory condition of autoimmune and autoinflammatory diseases. We have evaluated similarities and specificities of pathway activity changes in twelve autoimmune and autoinflammatory disorders by performing meta-analysis of publicly available gene expression datasets generated from peripheral blood mononuclear cells, using a bioinformatics pipeline that integrates Self Organizing Maps and Pathway Signal Flow algorithms along with KEGG pathway topologies.The results reveal that clinically divergent disease groups share common pathway perturbation profiles. We identified pathways, similarly perturbed in all the studied diseases, such as PI3K-Akt, Toll-like receptor, and NF-kappa B signaling, that serve as integrators of signals guiding immune cell polarization, migration, growth, survival and differentiation. Further, two clusters of diseases were identified based on specifically dysregulated pathways: one gathering mostly autoimmune and the other mainly autoinflammatory diseases. Cluster separation was driven not only by apparent involvement of pathways implicated in adaptive immunity in one case, and inflammation in the other, but also by processes not explicitly related to immune

Thrombin has biphasic effects on the nitric oxide-cGMP pathway in endothelial cells and contributes to experimental pulmonary hypertension.

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Katrin F Nickel

Full Text Available BACKGROUND: A potential role for coagulation factors in pulmonary arterial hypertension has been recently described, but the mechanism of action is currently not known. Here, we investigated the interactions between thrombin and the nitric oxide-cGMP pathway in pulmonary endothelial cells and experimental pulmonary hypertension. PRINCIPAL FINDINGS: Chronic treatment with the selective thrombin inhibitor melagatran (0.9 mg/kg daily via implanted minipumps reduced right ventricular hypertrophy in the rat monocrotaline model of experimental pulmonary hypertension. In vitro, thrombin was found to have biphasic effects on key regulators of the nitric oxide-cGMP pathway in endothelial cells (HUVECs. Acute thrombin stimulation led to increased expression of the cGMP-elevating factors endothelial nitric oxide synthase (eNOS and soluble guanylate cyclase (sGC subunits, leading to increased cGMP levels. By contrast, prolonged exposition of pulmonary endothelial cells to thrombin revealed a characteristic pattern of differential expression of the key regulators of the nitric oxide-cGMP pathway, in which specifically the factors contributing to cGMP elevation (eNOS and sGC were reduced and the cGMP-hydrolyzing PDE5 was elevated (qPCR and Western blot. In line with the differential expression of key regulators of the nitric oxide-cGMP pathway, a reduction of cGMP by prolonged thrombin stimulation was found. The effects of prolonged thrombin exposure were confirmed in endothelial cells of pulmonary origin (HPAECs and HPMECs. Similar effects could be induced by activation of protease-activated receptor-1 (PAR-1. CONCLUSION: These findings suggest a link between thrombin generation and cGMP depletion in lung endothelial cells through negative regulation of the nitric oxide-cGMP pathway, possibly mediated via PAR-1, which could be of relevance in pulmonary arterial hypertension.

Importance of Mediator complex in the regulation and integration of diverse signaling pathways in plants

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Subhasis eSamanta

2015-09-01

Full Text Available Basic transcriptional machinery in eukaryotes is assisted by a number of cofactors, which either increase or decrease the rate of transcription. Mediator complex is one such cofactor, and recently has drawn a lot of interest because of its integrative power to converge different signaling pathways before channelling the transcription instructions to the RNA polymerase II machinery. Like yeast and metazoans, plants do possess the Mediator complex across the kingdom, and its isolation and subunit analyses have been reported from the model plant, Arabidopsis. Genetic and molecular analyses have unravelled important regulatory roles of Mediator subunits at every stage of plant life cycle starting from flowering to embryo and organ development, to even size determination. It also contributes immensely to the survival of plants against different environmental vagaries by the timely activation of its resistance mechanisms. Here, we have provided an overview of plant Mediator complex starting from its discovery to regulation of stoichiometry of its subunits. We have also reviewed involvement of different Mediator subunits in different processes and pathways including defense response pathways evoked by diverse biotic cues. Wherever possible, attempts have been made to provide mechanistic insight of Mediator’s involvement in these processes.

Importance of Mediator complex in the regulation and integration of diverse signaling pathways in plants.

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Samanta, Subhasis; Thakur, Jitendra K

2015-01-01

Basic transcriptional machinery in eukaryotes is assisted by a number of cofactors, which either increase or decrease the rate of transcription. Mediator complex is one such cofactor, and recently has drawn a lot of interest because of its integrative power to converge different signaling pathways before channeling the transcription instructions to the RNA polymerase II machinery. Like yeast and metazoans, plants do possess the Mediator complex across the kingdom, and its isolation and subunit analyses have been reported from the model plant, Arabidopsis. Genetic, and molecular analyses have unraveled important regulatory roles of Mediator subunits at every stage of plant life cycle starting from flowering to embryo and organ development, to even size determination. It also contributes immensely to the survival of plants against different environmental vagaries by the timely activation of its resistance mechanisms. Here, we have provided an overview of plant Mediator complex starting from its discovery to regulation of stoichiometry of its subunits. We have also reviewed involvement of different Mediator subunits in different processes and pathways including defense response pathways evoked by diverse biotic cues. Wherever possible, attempts have been made to provide mechanistic insight of Mediator's involvement in these processes.

Cyclophilin B Supports Myc and Mutant p53 Dependent Survival of Glioblastoma Multiforme Cells

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Choi, Jae Won; Schroeder, Mark A.; Sarkaria, Jann N.; Bram, Richard J.

2014-01-01

Glioblastoma multiforme (GBM) is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in GBM cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human GBM cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of GBM cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-MAPK pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1 and JAK/STAT3 signaling. Elevated reactive oxygen species, ER expansion and abnormal unfolded protein responses in CypB-depleted GBM cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of GBM tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for GBM therapy. PMID:24272483

Statistical models and methods for reliability and survival analysis

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Couallier, Vincent; Huber-Carol, Catherine; Mesbah, Mounir; Huber -Carol, Catherine; Limnios, Nikolaos; Gerville-Reache, Leo

2013-01-01

Statistical Models and Methods for Reliability and Survival Analysis brings together contributions by specialists in statistical theory as they discuss their applications providing up-to-date developments in methods used in survival analysis, statistical goodness of fit, stochastic processes for system reliability, amongst others. Many of these are related to the work of Professor M. Nikulin in statistics over the past 30 years. The authors gather together various contributions with a broad array of techniques and results, divided into three parts - Statistical Models and Methods, Statistical

The arginine-ornithine antiporter ArcD contributes to biological fitness of Streptococcus suis

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Marcus eFulde

2014-08-01

Full Text Available The arginine-ornithine antiporter (ArcD is part of the Arginine Deiminase System (ADS, a catabolic, energy-providing pathway found in a variety of different bacterial species, including the porcine zoonotic pathogen Streptococcus suis. The ADS has recently been shown to play a role in the pathogenicity of S. suis, in particular in its survival in host cells. The contribution of arginine and arginine transport mediated by ArcD, however, has yet to be clarified. In the present study, we showed by experiments using [U-13C6]arginine as a tracer molecule that S. suis is auxotrophic for arginine and that bacterial growth depends on the uptake of extracellular arginine. To further study the role of ArcD in arginine metabolism, we generated an arcD-specific mutant strain and characterized its growth compared to the wild-type (WT strain, a virulent serotype 2 strain. The mutant strain showed a markedly reduced growth rate in chemically defined media supplemented with arginine when compared to the WT strain, indicating that ArcD promotes arginine uptake. To further evaluate the in vivo relevance of ArcD, we studied the intracellular bacterial survival of the arcD mutant strain in an epithelial cell culture infection model. The mutant strain was substantially attenuated, and its reduced intracellular survival rate correlated with a lower ability to neutralize the acidified environment. Based on these results, we propose that ArcD, by its function as an arginine-ornithine antiporter, is important for supplying arginine as substrate of the ADS and, thereby, contributes to biological fitness and virulence of S. suis in the host.

Survival Processing and the Stroop Task

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Stephanie A. Kazanas; Kendra M. Van Valkenburg; Jeanette Altarriba

2015-01-01

This study was designed to investigate the impact of survival processing with a novel task for this paradigm: the Stroop color-naming task. As the literature is mixed with regard to task generalizability, with survival processing promoting better memory for words, but not better memory for faces or paired associates, these types of task investigations are important to a growing field of research. Using the Stroop task provides a unique contribution, as identifying items by color is an importa...

PERSPECTIVE: Electrical activity enhances neuronal survival and regeneration

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Corredor, Raul G.; Goldberg, Jeffrey L.

2009-10-01

The failure of regeneration in the central nervous system (CNS) remains an enormous scientific and clinical challenge. After injury or in degenerative diseases, neurons in the adult mammalian CNS fail to regrow their axons and reconnect with their normal targets, and furthermore the neurons frequently die and are not normally replaced. While significant progress has been made in understanding the molecular basis for this lack of regenerative ability, a second approach has gained momentum: replacing lost neurons or lost connections with artificial electrical circuits that interface with the nervous system. In the visual system, gene therapy-based 'optogenetics' prostheses represent a competing technology. Now, the two approaches are converging, as recent data suggest that electrical activity itself, via the molecular signaling pathways such activity stimulates, is sufficient to induce neuronal survival and regeneration, particularly in retinal ganglion cells. Here, we review these data, discuss the effects of electrical activity on neurons' molecular signaling pathways and propose specific mechanisms by which exogenous electrical activity may be acting to enhance survival and regeneration.

Nitric oxide induces thioredoxin-1 nuclear translocation: Possible association with the p21Ras survival pathway

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Arai, Roberto J.; Masutani, H.; Yodoi, J.; Debbas, V.; Laurindo, Francisco R.; Stern, A.; Monteiro, Hugo P.

2006-01-01

One of the major redox-regulating molecules with thiol reducing activity is thioredoxin-1 (TRX-1). TRX-1 is a multifunctional protein that exists in the extracellular millieu, cytoplasm, and nucleus, and has a distinct role in each environment. It is well known that TRX-1 promptly migrates to the nuclear compartment in cells exposed to oxidants. However, the intracellular location of TRX-1 in cells exposed to nitrosothiols has not been investigated. Here, we demonstrated that the exposure of HeLa cells to increasing concentrations of the nitrosothiol S-nitroso-N-acetylpenicillamine (SNAP) promoted TRX-1 nuclear accumulation. The SNAP-induced TRX-1 translocation to the nucleus was inhibited by FPTIII, a selective inhibitor of p21Ras. Furthermore, TRX-1 migration was attenuated in cells stably transfected with NO insensitive p21Ras (p21 RasC118S ). Downstream to p21Ras, the MAP Kinases ERK1/2 were activated by SNAP under conditions that promote TRX-1 nuclear translocation. Inhibition of MEK prevented SNAP-stimulated ERK1/2 activation and TRX-1 nuclear migration. In addition, cells treated with p21Ras or MEK inhibitor showed increased susceptibility to cell death induced by SNAP. In conclusion, our observations suggest that the nuclear translocation of TRX-1 is induced by SNAP involving p21Ras survival pathway

Both the Jasmonic Acid and the Salicylic Acid Pathways Contribute to Resistance to the Biotrophic Clubroot Agent Plasmodiophora brassicae in Arabidopsis.

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Lemarié, Séverine; Robert-Seilaniantz, Alexandre; Lariagon, Christine; Lemoine, Jocelyne; Marnet, Nathalie; Jubault, Mélanie; Manzanares-Dauleux, Maria J; Gravot, Antoine

2015-11-01

The role of salicylic acid (SA) and jasmonic acid (JA) signaling in resistance to root pathogens has been poorly documented. We assessed the contribution of SA and JA to basal and partial resistance of Arabidopsis to the biotrophic clubroot agent Plasmodiophora brassicae. SA and JA levels as well as the expression of the SA-responsive genes PR2 and PR5 and the JA-responsive genes ARGAH2 and THI2.1 were monitored in infected roots of the accessions Col-0 (susceptible) and Bur-0 (partially resistant). SA signaling was activated in Bur-0 but not in Col-0. The JA pathway was weakly activated in Bur-0 but was strongly induced in Col-0. The contribution of both pathways to clubroot resistance was then assessed using exogenous phytohormone application and mutants affected in SA or JA signaling. Exogenous SA treatment decreased clubroot symptoms in the two Arabidopsis accessions, whereas JA treatment reduced clubroot symptoms only in Col-0. The cpr5-2 mutant, in which SA responses are constitutively induced, was more resistant to clubroot than the corresponding wild type, and the JA signaling-deficient mutant jar1 was more susceptible. Finally, we showed that the JA-mediated induction of NATA1 drove N(δ)-acetylornithine biosynthesis in infected Col-0 roots. The 35S::NATA1 and nata1 lines displayed reduced or enhanced clubroot symptoms, respectively, thus suggesting that in Col-0 this pathway was involved in the JA-mediated basal clubroot resistance. Overall, our data support the idea that, depending on the Arabidopsis accession, both SA and JA signaling can play a role in partial inhibition of clubroot development in compatible interactions with P. brassicae. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Contributions of citrate in redox potential maintenance and ATP production: metabolic pathways and their regulation in Lactobacillus panis PM1.

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Kang, Tae Sun; Korber, Darren R; Tanaka, Takuji

2013-10-01

Lactobacillus panis PM1 belongs to the group III heterofermentative lactobacilli and can utilize various NADH-reoxidizing routes (e.g., citrate, glycerol, and oxygen) according to environmental conditions. In this study, we investigated the ability of L. panis PM1 to produce succinate, acetate, and lactate via citrate utilization. Possible pathways, as well as regulation, for citrate metabolism were examined on the basis of the genome sequence data and metabolic profiles of L. panis PM1. The presence of citrate led to the up-regulation, at the transcriptional level, of the genes encoding for citrate lyase, malate dehydrogenase, and malic enzyme of the citrate pathways by 10- to 120-fold. The transcriptional regulator of the dha operon coding for glycerol dehydratase of L. panis PM1 repressed the expression of the citrate lyase gene (10-fold). Metabolite analyses indicated that the transcriptional enhancement by citrate stimulated succinate yield. Citrate metabolism contributed to energy production by providing a major alternate pathway for NAD(+) regeneration and allowed acetyl phosphate to yield acetate/ATP instead of ethanol/NAD(+). Additionally, a branching pathway from oxaloacetate to pyruvate increased the pool of lactate, which was then used to produce ATP during stationary phase. However, the redirection of NADH-to-citrate utilization resulted in stress caused by end-products (i.e., succinate and acetate). This stress reduced succinate production by up to 50 % but did not cause significant changes at transcriptional level. Overall, citrate utilization was beneficial for the growth of L. panis PM1 by providing a NAD(+) regeneration route and producing extra ATP.

Combining Pathway Identification and Breast Cancer Survival Prediction via Screening-Network Methods

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Antonella Iuliano

2018-06-01

Full Text Available Breast cancer is one of the most common invasive tumors causing high mortality among women. It is characterized by high heterogeneity regarding its biological and clinical characteristics. Several high-throughput assays have been used to collect genome-wide information for many patients in large collaborative studies. This knowledge has improved our understanding of its biology and led to new methods of diagnosing and treating the disease. In particular, system biology has become a valid approach to obtain better insights into breast cancer biological mechanisms. A crucial component of current research lies in identifying novel biomarkers that can be predictive for breast cancer patient prognosis on the basis of the molecular signature of the tumor sample. However, the high dimension and low sample size of data greatly increase the difficulty of cancer survival analysis demanding for the development of ad-hoc statistical methods. In this work, we propose novel screening-network methods that predict patient survival outcome by screening key survival-related genes and we assess the capability of the proposed approaches using METABRIC dataset. In particular, we first identify a subset of genes by using variable screening techniques on gene expression data. Then, we perform Cox regression analysis by incorporating network information associated with the selected subset of genes. The novelty of this work consists in the improved prediction of survival responses due to the different types of screenings (i.e., a biomedical-driven, data-driven and a combination of the two before building the network-penalized model. Indeed, the combination of the two screening approaches allows us to use the available biological knowledge on breast cancer and complement it with additional information emerging from the data used for the analysis. Moreover, we also illustrate how to extend the proposed approaches to integrate an additional omic layer, such as copy number

Biliverdin reductase/bilirubin mediates the anti-apoptotic effect of hypoxia in pulmonary arterial smooth muscle cells through ERK1/2 pathway

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Song, Shasha; Wang, Shuang; Ma, Jun; Yao, Lan; Xing, Hao; Zhang, Lei; Liao, Lin; Zhu, Daling

2013-01-01

Inhibition of pulmonary arterial smooth muscle cell (PASMC) apoptosis induced by hypoxia plays an important role in pulmonary arterial remodeling leading to aggravate hypoxic pulmonary arterial hypertension. However, the mechanisms of hypoxia acting on PASMC apoptosis remain exclusive. Biliverdin reductase (BVR) has many essential biologic roles in physiological and pathological processes. Nevertheless, it is unclear whether the hypoxia-induced inhibition on PASMC apoptosis is mediated by BVR. In the present work, we found BVR majorly localized in PASMCs and was up-regulated in levels of protein and mRNA by hypoxia. Then we studied the contribution of BVR to anti-apoptotic response of hypoxia in PASMCs. Our results showed that siBVR, blocking generation of bilirubin, reversed the effect of hypoxia on enhancing cell survival and apoptotic protein (Bcl-2, procasepase-9, procasepase-3) expression, preventing nuclear shrinkage, DNA fragmentation and mitochondrial depolarization in starved PASMCs, which were recovered by exogenous bilirubin. Moreover, the inhibitory effect of bilirubin on PASMC apoptosis under hypoxic condition was blocked by the inhibitor of ERK1/2 pathway. Taken together, our data indicate that BVR contributes to the inhibitory process of hypoxia on PASMC apoptosis, which is mediated by bilirubin through ERK1/2 pathway. Highlights: • BVR expresses in PASMC and is up-regulated by hypoxia in protein and mRNA levels. • BVR/bilirubin contribute to the inhibitive process of hypoxia on PASMC apoptosis. • Bilirubin protects PASMC from apoptosis under hypoxia via ERK1/2 pathway

Biliverdin reductase/bilirubin mediates the anti-apoptotic effect of hypoxia in pulmonary arterial smooth muscle cells through ERK1/2 pathway

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Song, Shasha [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Wang, Shuang [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China); Ma, Jun; Yao, Lan; Xing, Hao; Zhang, Lei; Liao, Lin [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Zhu, Daling, E-mail: dalingz@yahoo.com [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China)

2013-08-01

Inhibition of pulmonary arterial smooth muscle cell (PASMC) apoptosis induced by hypoxia plays an important role in pulmonary arterial remodeling leading to aggravate hypoxic pulmonary arterial hypertension. However, the mechanisms of hypoxia acting on PASMC apoptosis remain exclusive. Biliverdin reductase (BVR) has many essential biologic roles in physiological and pathological processes. Nevertheless, it is unclear whether the hypoxia-induced inhibition on PASMC apoptosis is mediated by BVR. In the present work, we found BVR majorly localized in PASMCs and was up-regulated in levels of protein and mRNA by hypoxia. Then we studied the contribution of BVR to anti-apoptotic response of hypoxia in PASMCs. Our results showed that siBVR, blocking generation of bilirubin, reversed the effect of hypoxia on enhancing cell survival and apoptotic protein (Bcl-2, procasepase-9, procasepase-3) expression, preventing nuclear shrinkage, DNA fragmentation and mitochondrial depolarization in starved PASMCs, which were recovered by exogenous bilirubin. Moreover, the inhibitory effect of bilirubin on PASMC apoptosis under hypoxic condition was blocked by the inhibitor of ERK1/2 pathway. Taken together, our data indicate that BVR contributes to the inhibitory process of hypoxia on PASMC apoptosis, which is mediated by bilirubin through ERK1/2 pathway. Highlights: • BVR expresses in PASMC and is up-regulated by hypoxia in protein and mRNA levels. • BVR/bilirubin contribute to the inhibitive process of hypoxia on PASMC apoptosis. • Bilirubin protects PASMC from apoptosis under hypoxia via ERK1/2 pathway.

Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation.

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Gallon, Lorenzo; Mathew, James M; Bontha, Sai Vineela; Dumur, Catherine I; Dalal, Pranav; Nadimpalli, Lakshmi; Maluf, Daniel G; Shetty, Aneesha A; Ildstad, Suzanne T; Leventhal, Joseph R; Mas, Valeria R

2018-02-01

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways. Copyright © 2018 by the

Calcineurin Targets Involved in Stress Survival and Fungal Virulence.

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Hee-Soo Park

2016-09-01

Full Text Available Calcineurin governs stress survival, sexual differentiation, and virulence of the human fungal pathogen Cryptococcus neoformans. Calcineurin is activated by increased Ca2+ levels caused by stress, and transduces signals by dephosphorylating protein substrates. Herein, we identified and characterized calcineurin substrates in C. neoformans by employing phosphoproteomic TiO2 enrichment and quantitative mass spectrometry. The identified targets include the transactivator Crz1 as well as novel substrates whose functions are linked to P-bodies/stress granules (PBs/SGs and mRNA translation and decay, such as Pbp1 and Puf4. We show that Crz1 is a bona fide calcineurin substrate, and Crz1 localization and transcriptional activity are controlled by calcineurin. We previously demonstrated that thermal and other stresses trigger calcineurin localization to PBs/SGs. Several calcineurin targets localized to PBs/SGs, including Puf4 and Pbp1, contribute to stress resistance and virulence individually or in conjunction with Crz1. Moreover, Pbp1 is also required for sexual development. Genetic epistasis analysis revealed that Crz1 and the novel targets Lhp1, Puf4, and Pbp1 function in a branched calcineurin pathway that orchestrates stress survival and virulence. These findings support a model whereby calcineurin controls stress and virulence, at the transcriptional level via Crz1, and post-transcriptionally by localizing to PBs/SGs and acting on targets involved in mRNA metabolism. The calcineurin targets identified in this study share little overlap with known calcineurin substrates, with the exception of Crz1. In particular, the mRNA binding proteins and PBs/SGs residents comprise a cohort of novel calcineurin targets that have not been previously linked to calcineurin in mammals or in Saccharomyces cerevisiae. This study suggests either extensive evolutionary rewiring of the calcineurin pathway, or alternatively that these novel calcineurin targets have yet

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases*

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Song, Xiao; Ding, Yanping; Liu, Gang; Yang, Xiao; Zhao, Ruifang; Zhang, Yinlong; Zhao, Xiao; Anderson, Gregory J.; Nie, Guangjun

2016-01-01

Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signal-regulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment. PMID:26895960

Comprehensive suppression of all apoptosis-induced proliferation pathways as a proposed approach to colorectal cancer prevention and therapy.

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Michael Bordonaro

Full Text Available Mutations in the WNT/beta-catenin pathway are present in the majority of all sporadic colorectal cancers (CRCs, and histone deacetylase inhibitors induce apoptosis in CRC cells with such mutations. This apoptosis is counteracted by (1 the signaling heterogeneity of CRC cell populations, and (2 the survival pathways induced by mitogens secreted from apoptotic cells. The phenomena of signaling heterogeneity and apoptosis-induced survival constitute the immediate mechanisms of resistance to histone deacetylase inhibitors, and probably other chemotherapeutic agents. We explored the strategy of augmenting CRC cell death by inhibiting all survival pathways induced by the pro-apoptotic agent LBH589, a histone deacetylase inhibitor: AKT, JAK/STAT, and ERK signaling. The apoptosis-enhancing ability of a cocktail of synthetic inhibitors of proliferation was compared to the effects of the natural product propolis. We utilized colorectal adenoma, drug-sensitive and drug-resistant colorectal carcinoma cells to evaluate the apoptotic potential of the combination treatments. The results suggest that an effective approach to CRC combination therapy is to combine apoptosis-inducing drugs (e.g., histone deacetylase inhibitors, such as LBH589 with agents that suppress all compensatory survival pathways induced during apoptosis (such as the cocktail of inhibitors of apoptosis-associated proliferation. The same paradigm can be applied to a CRC prevention approach, as the apoptotic effect of butyrate, a diet-derived histone deacetylase inhibitor, is augmented by other dietary agents that modulate survival pathways (e.g., propolis and coffee extract. Thus, dietary supplements composed by fermentable fiber, propolis, and coffee extract may effectively counteract neoplastic growth in the colon.

Edaravone Improves Septic Cardiac Function by Inducing an HIF-1α/HO-1 Pathway

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Chao He

2018-01-01

Full Text Available Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia-inducible factor- (HIF- 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO- 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp. before CLP and intraperitoneal injection of the HIF-1α antagonist, ME (15 mg/kg, after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1α, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1α by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1α/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction.

Pathway enrichment analysis approach based on topological structure and updated annotation of pathway.

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Yang, Qian; Wang, Shuyuan; Dai, Enyu; Zhou, Shunheng; Liu, Dianming; Liu, Haizhou; Meng, Qianqian; Jiang, Bin; Jiang, Wei

2017-08-16

Pathway enrichment analysis has been widely used to identify cancer risk pathways, and contributes to elucidating the mechanism of tumorigenesis. However, most of the existing approaches use the outdated pathway information and neglect the complex gene interactions in pathway. Here, we first reviewed the existing widely used pathway enrichment analysis approaches briefly, and then, we proposed a novel topology-based pathway enrichment analysis (TPEA) method, which integrated topological properties and global upstream/downstream positions of genes in pathways. We compared TPEA with four widely used pathway enrichment analysis tools, including database for annotation, visualization and integrated discovery (DAVID), gene set enrichment analysis (GSEA), centrality-based pathway enrichment (CePa) and signaling pathway impact analysis (SPIA), through analyzing six gene expression profiles of three tumor types (colorectal cancer, thyroid cancer and endometrial cancer). As a result, we identified several well-known cancer risk pathways that could not be obtained by the existing tools, and the results of TPEA were more stable than that of the other tools in analyzing different data sets of the same cancer. Ultimately, we developed an R package to implement TPEA, which could online update KEGG pathway information and is available at the Comprehensive R Archive Network (CRAN): https://cran.r-project.org/web/packages/TPEA/. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prediction of novel target genes and pathways involved in irinotecan-resistant colorectal cancer.

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Precious Takondwa Makondi

Full Text Available Acquired drug resistance to the chemotherapeutic drug irinotecan (the active metabolite of which is SN-38 is one of the significant obstacles in the treatment of advanced colorectal cancer (CRC. The molecular mechanism or targets mediating irinotecan resistance are still unclear. It is urgent to find the irinotecan response biomarkers to improve CRC patients' therapy.Genetic Omnibus Database GSE42387 which contained the gene expression profiles of parental and irinotecan-resistant HCT-116 cell lines was used. Differentially expressed genes (DEGs between parental and irinotecan-resistant cells, protein-protein interactions (PPIs, gene ontologies (GOs and pathway analysis were performed to identify the overall biological changes. The most common DEGs in the PPIs, GOs and pathways were identified and were validated clinically by their ability to predict overall survival and disease free survival. The gene-gene expression correlation and gene-resistance correlation was also evaluated in CRC patients using The Cancer Genomic Atlas data (TCGA.The 135 DEGs were identified of which 36 were upregulated and 99 were down regulated. After mapping the PPI networks, the GOs and the pathways, nine genes (GNAS, PRKACB, MECOM, PLA2G4C, BMP6, BDNF, DLG4, FGF2 and FGF9 were found to be commonly enriched. Signal transduction was the most significant GO and MAPK pathway was the most significant pathway. The five genes (FGF2, FGF9, PRKACB, MECOM and PLA2G4C in the MAPK pathway were all contained in the signal transduction and the levels of those genes were upregulated. The FGF2, FGF9 and MECOM expression were highly associated with CRC patients' survival rate but not PRKACB and PLA2G4C. In addition, FGF9 was also associated with irinotecan resistance and poor disease free survival. FGF2, FGF9 and PRKACB were positively correlated with each other while MECOM correlated positively with FGF9 and PLA2G4C, and correlated negatively with FGF2 and PRKACB after doing gene

TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin

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Moruno Manchon, Jose Felix; Uzor, Ndidi-Ese; Kesler, Shelli R.; Wefel, Jeffrey S.; Townley, Debra M.; Nagaraja, Archana Sidalaghatta; Pradeep, Sunila; Mangala, Lingegowda S.; Sood, Anil K.; Tsvetkov, Andrey S.

2016-01-01

Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin. PMID:27992857

Inherited Variants in Wnt Pathway Genes Influence Outcomes of Prostate Cancer Patients Receiving Androgen Deprivation Therapy

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Jiun-Hung Geng

2016-11-01

Full Text Available Aberrant Wnt signaling has been associated with many types of cancer. However, the association of inherited Wnt pathway variants with clinical outcomes in prostate cancer patients receiving androgen deprivation therapy (ADT has not been determined. Here, we comprehensively studied the contribution of common single nucleotide polymorphisms (SNPs in Wnt pathway genes to the clinical outcomes of 465 advanced prostate cancer patients treated with ADT. Two SNPs, adenomatous polyposis coli (APC rs2707765 and rs497844, were significantly (p ≤ 0.009 and q ≤ 0.043 associated with both prostate cancer progression and all-cause mortality, even after multivariate analyses and multiple testing correction. Patients with a greater number of favorable alleles had a longer time to disease progression and better overall survival during ADT (p for trend ≤ 0.003. Additional, cDNA array and in silico analyses of prostate cancer tissue suggested that rs2707765 affects APC expression, which in turn is correlated with tumor aggressiveness and patient prognosis. This study identifies the influence of inherited variants in the Wnt pathway on the efficacy of ADT and highlights a preclinical rationale for using APC as a prognostic marker in advanced prostate cancer.

EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

International Nuclear Information System (INIS)

Huang, Er-Wen; Xue, Sheng-Jiang; Li, Xiao-Yan; Xu, Suo-Wen; Cheng, Jian-Ding; Zheng, Jin-Xiang; Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong; Li, Jie; Liu, Chao

2014-01-01

Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma

EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

Energy Technology Data Exchange (ETDEWEB)

Huang, Er-Wen [Guangzhou Institute of Forensic Science, Guangzhou (China); Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Xue, Sheng-Jiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Li, Xiao-Yan [Department of Pharmacy, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Xu, Suo-Wen [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Cheng, Jian-Ding; Zheng, Jin-Xiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong [Guangzhou Institute of Forensic Science, Guangzhou (China); Li, Jie, E-mail: mdlijie@sina.com [Department of Anaesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Liu, Chao, E-mail: liuchaogaj@21cn.com [Guangzhou Institute of Forensic Science, Guangzhou (China)

2014-05-02

Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.

Molecular and Microenvironmental Determinants of Glioma Stem-Like Cell Survival and Invasion

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Alison Roos

2017-06-01

Full Text Available Glioblastoma multiforme (GBM is the most frequent primary brain tumor in adults with a 5-year survival rate of 5% despite intensive research efforts. The poor prognosis is due, in part, to aggressive invasion into the surrounding brain parenchyma. Invasion is a complex process mediated by cell-intrinsic pathways, extrinsic microenvironmental cues, and biophysical cues from the peritumoral stromal matrix. Recent data have attributed GBM invasion to the glioma stem-like cell (GSC subpopulation. GSCs are slowly dividing, highly invasive, therapy resistant, and are considered to give rise to tumor recurrence. GSCs are localized in a heterogeneous cellular niche, and cross talk between stromal cells and GSCs cultivates a fertile environment that promotes GSC invasion. Pro-migratory soluble factors from endothelial cells, astrocytes, macrophages, microglia, and non-stem-like tumor cells can stimulate peritumoral invasion of GSCs. Therefore, therapeutic efforts designed to target the invasive GSCs may enhance patient survival. In this review, we summarize the current understanding of extrinsic pathways and major stromal and immune players facilitating GSC maintenance and survival.

Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells

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Patzelt, Thomas; Keppler, Selina J.; Gorka, Oliver; Thoene, Silvia; Wartewig, Tim; Reth, Michael; Förster, Irmgard; Lang, Roland; Buchner, Maike; Ruland, Jürgen

2018-01-01

The transcription factor Foxp1 is critical for early B cell development. Despite frequent deregulation of Foxp1 in B cell lymphoma, the physiological functions of Foxp1 in mature B cells remain unknown. Here, we used conditional gene targeting in the B cell lineage and report that Foxp1 disruption in developing and mature B cells results in reduced numbers and frequencies of follicular and B-1 B cells and in impaired antibody production upon T cell-independent immunization in vivo. Moreover, Foxp1-deficient B cells are impaired in survival even though they exhibit an increased capacity to proliferate. Transcriptional analysis identified defective expression of the prosurvival Bcl-2 family gene Bcl2l1 encoding Bcl-xl in Foxp1-deficient B cells, and we identified Foxp1 binding in the regulatory region of Bcl2l1. Transgenic overexpression of Bcl2 rescued the survival defect in Foxp1-deficient mature B cells in vivo and restored peripheral B cell numbers. Thus, our results identify Foxp1 as a physiological regulator of mature B cell survival mediated in part via the control of Bcl-xl expression and imply that this pathway might contribute to the pathogenic function of aberrant Foxp1 expression in lymphoma. PMID:29507226

Rac1 is essential for basement membrane-dependent epiblast survival

DEFF Research Database (Denmark)

He, Xiaowen; Liu, Jie; Qi, Yanmei

2010-01-01

During murine peri-implantation development, the egg cylinder forms from a solid cell mass by the apoptotic removal of inner cells that do not contact the basement membrane (BM) and the selective survival of the epiblast epithelium, which does. The signaling pathways that mediate this fundamental...

Molecular strategies of the Caenorhabditis elegans dauer larva to survive extreme desiccation.

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Cihan Erkut

Full Text Available Massive water loss is a serious challenge for terrestrial animals, which usually has fatal consequences. However, some organisms have developed means to survive this stress by entering an ametabolic state called anhydrobiosis. The molecular and cellular mechanisms underlying this phenomenon are poorly understood. We recently showed that Caenorhabditis elegans dauer larva, an arrested stage specialized for survival in adverse conditions, is resistant to severe desiccation. However, this requires a preconditioning step at a mild desiccative environment to prepare the organism for harsher desiccation conditions. A systems approach was used to identify factors that are activated during this preconditioning. Using microarray analysis, proteomics, and bioinformatics, genes, proteins, and biochemical pathways that are upregulated during this process were identified. These pathways were validated via reverse genetics by testing the desiccation tolerances of mutants. These data show that the desiccation response is activated by hygrosensation (sensing the desiccative environment via head neurons. This leads to elimination of reactive oxygen species and xenobiotics, expression of heat shock and intrinsically disordered proteins, polyamine utilization, and induction of fatty acid desaturation pathway. Remarkably, this response is specific and involves a small number of functional pathways, which represent the generic toolkit for anhydrobiosis in plants and animals.

The survival advantage of olfaction in a competitive environment.

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Asahina, Kenta; Pavlenkovich, Viktoryia; Vosshall, Leslie B

2008-08-05

Olfaction is generally assumed to be critical for survival because this sense allows animals to detect food and pheromonal cues. Although the ability to sense sex pheromones [1, 2, 3] is likely to be important for insects, the contribution of general odor detection to survival is unknown. We investigated the extent to which the olfactory system confers a survival advantage on Drosophila larvae foraging for food under conditions of limited resources and competition from other larvae.

Survival Processing and the Stroop Task

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Stephanie A. Kazanas

2015-11-01

Full Text Available This study was designed to investigate the impact of survival processing with a novel task for this paradigm: the Stroop color-naming task. As the literature is mixed with regard to task generalizability, with survival processing promoting better memory for words, but not better memory for faces or paired associates, these types of task investigations are important to a growing field of research. Using the Stroop task provides a unique contribution, as identifying items by color is an important evolutionary adaptation and not specific to humans as is the case with word recall. Our results indicate that survival processing, with its accompanying survival-relevance rating task, remains the best mnemonic strategy for word memory. However, our results also indicate that presenting the survival passage does not motivate better color-naming performance than color-naming alone. In addition, survival processing led to a larger amount of Stroop interference, though not significantly larger than the other conditions. Together, these findings suggest that considering one’s survival when performing memory and attention-based tasks does not enhance cognitive performance generally, although greater allocation of attentional resources to color-incongruent concrete objects could be considered adaptive. These findings support the notion that engaging in deeper processing via survival-relevance ratings may preserve these words across a variety of experimental manipulations.

Candida glabrata tryptophan-based pigment production via the Ehrlich pathway.

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Brunke, Sascha; Seider, Katja; Almeida, Ricardo Sergio; Heyken, Antje; Fleck, Christian Benjamin; Brock, Matthias; Barz, Dagmar; Rupp, Steffen; Hube, Bernhard

2010-04-01

Pigments contribute to the pathogenicity of many fungi, mainly by protecting fungal cells from host defence activities. Here, we have dissected the biosynthetic pathway of a tryptophan-derived pigment of the human pathogen Candida glabrata, identified key genes involved in pigment production and have begun to elucidate the possible biological function of the pigment. Using transcriptional analyses and a transposon insertion library, we have identified genes associated with pigment production. Targeted deletion mutants revealed that the pigment is a by-product of the Ehrlich pathway of tryptophan degradation: a mutant lacking a tryptophan-upregulated aromatic aminotransferase (Aro8) displayed significantly reduced pigmentation and a recombinantly expressed version of this protein was sufficient for pigment production in vitro. Pigment production is tightly regulated as the synthesis is affected by the presence of alternative nitrogen sources, carbon sources, cyclic AMP and oxygen. Growth of C. glabrata on pigment inducing medium leads to an increased resistance to hydrogen peroxide, an effect which was not observed with a mutant defective in pigmentation. Furthermore, pigmented yeast cells had a higher survival rate when exposed to human neutrophils and caused increased damage in a monolayer model of human epithelia, indicating a possible role of pigmentation during interactions with host cells.

Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases.

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Song, Xiao; Ding, Yanping; Liu, Gang; Yang, Xiao; Zhao, Ruifang; Zhang, Yinlong; Zhao, Xiao; Anderson, Gregory J; Nie, Guangjun

2016-04-15

Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signal-regulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Nerve Growth Factor in Cancer Cell Death and Survival

International Nuclear Information System (INIS)

Molloy, Niamh H.; Read, Danielle E.; Gorman, Adrienne M.

2011-01-01

One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75 NTR , a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75 NTR . For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75 NTR . This latter signaling through p75 NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75 NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer

Working Conditions and Factory Survival: Evidence from Better Factories Cambodia

OpenAIRE

Robertson, Raymond; Brown, Drusilla; Dehejia, Rajeev

2016-01-01

A large and growing literature has identified several conditions, including exporting, that contribute to plant survival. A prevailing sentiment suggests that anti-sweatshop activity against plants in developing countries adds the risk of making survival more difficult by imposing external constraints that may interfere with optimizing behavior. Using a relatively new plant-level panel dataset from Cambodia, this paper applies survival analysis to estimate the relationship between changes in ...

Neurotrophin receptors expression and JNK pathway activation in human astrocytomas

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Maraziotis Theodore

2007-10-01

Full Text Available Abstract Background Neurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane – receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC and p75NTR neurotrophin receptor. Trk receptors promote cell survival and differentiation while p75NTR induces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75NTR -induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75NTR, and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue. Methods Formalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75NTR and phosphorylated forms of JNK (pJNK and c-Jun (pc-Jun were used. The labeling index (LI, defined as the percentage of positive (labeled cells out of the total number of tumor cells counted, was determined. Results Moderate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75NTR receptor expression was found in a small percentage of tumor cells (~1% in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK and c-Jun (pc-Jun were

PRAP1 is a novel executor of p53-dependent mechanisms in cell survival after DNA damage.

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Huang, B H; Zhuo, J L; Leung, C H W; Lu, G D; Liu, J J; Yap, C T; Hooi, S C

2012-12-13

p53 has a crucial role in governing cellular mechanisms in response to a broad range of genotoxic stresses. During DNA damage, p53 can either promote cell survival by activating senescence or cell-cycle arrest and DNA repair to maintain genomic integrity for cell survival or direct cells to undergo apoptosis to eliminate extensively damaged cells. The ability of p53 to execute these two opposing cell fates depends on distinct signaling pathways downstream of p53. In this study, we showed that under DNA damage conditions induced by chemotherapeutic drugs, gamma irradiation and hydrogen peroxide, p53 upregulates a novel protein, proline-rich acidic protein 1 (PRAP1). We identified functional p53-response elements within intron 1 of PRAP1 gene and showed that these regions interact directly with p53 using ChIP assays, indicating that PRAP1 is a novel p53 target gene. The induction of PRAP1 expression by p53 may promote resistance of cancer cells to chemotherapeutic drugs such as 5-fluorouracil (5-FU), as knockdown of PRAP1 increases apoptosis in cancer cells after 5-FU treatment. PRAP1 appears to protect cells from apoptosis by inducing cell-cycle arrest, suggesting that the induction of PRAP1 expression by p53 in response to DNA-damaging agents contributes to cancer cell survival. Our findings provide a greater insight into the mechanisms underlying the pro-survival role of p53 in response to cytotoxic treatments.

Transcriptional repressor role of PocR on the 1,3-propanediol biosynthetic pathway by Lactobacillus panis PM1.

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Kang, Tae Sun; Korber, Darren R; Tanaka, Takuji

2014-06-01

The regulatory role of a transcriptional regulator (PocR) in the 1,3-propanediol biosynthetic pathway of Lactobacillus panis PM1 contributes to the optimization of 1,3-propanediol production by this strain, which potentially will lead to 1,3-propanediol manufacturing efficiencies. Lactobacillus panis PM1 can utilize a 1,3-propanediol (1,3-PDO) biosynthetic pathway, consisting of diol dehydratase (PduCDE) and 1,3-PDO dehydrogenase, as a NADH recycling system, to survive under various environmental conditions. In this study, we identified a key transcriptional repressor (PocR) which was annotated as a transcriptional factor of AraC family as part of the 1,3-PDO biosynthetic pathway of L. panis PM1. The over-expression of the PocR gene resulted in the significant repression (81 %) of pduC (PduCDE large subunit) transcription, and subsequently, the decreased activity of PduCDE by 22 %. As a result of the regulation of PduCDE, production of both 3-hydroxypropionaldehyde and 1,3-PDO in the PocR over-expressing strain were significantly decreased by 40 % relative to the control strain. These results clearly demonstrate the transcriptional repressor role of PocR in the 1,3-PDO biosynthetic pathway.

Contribution of the D-Serine-dependent pathway to the cellular mechanisms underlying cognitive aging

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Emilie Rouaud

2010-02-01

Full Text Available An association between age-related memory impairments and changes in functional plasticity in the aging brain has been under intense study within the last decade. In this article, we show that an impaired activation of the strychnine-insensitive glycine site of N-Methyl-D-Aspartate receptors (NMDA-R by its agonist D-serine contributes to deficits of synaptic plasticity in the hippocampus of memory-impaired aged rats. Supplementation with exogenous D-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation. Endogenous levels of D-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid. On the contrary, the affinity of D-serine binding to NMDA-R is not affected by aging. These results point to a critical role for the D-serine-dependent pathway in the functional alterations of the brain underlying memory impairment and provide key information in the search for new therapeutic strategies for the treatment of memory deficits in the elderly.

ATM-Dependent Phosphorylation of MEF2D Promotes Neuronal Survival after DNA Damage

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Chan, Shing Fai; Sances, Sam; Brill, Laurence M.; Okamoto, Shu-ichi; Zaidi, Rameez; McKercher, Scott R.; Akhtar, Mohd W.; Nakanishi, Nobuki

2014-01-01

Mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a kinase critical for the normal DNA damage response, cause the neurodegenerative disorder ataxia-telangiectasia (AT). The substrates of ATM in the brain are poorly understood. Here we demonstrate that ATM phosphorylates and activates the transcription factor myocyte enhancer factor 2D (MEF2D), which plays a critical role in promoting survival of cerebellar granule cells. ATM associates with MEF2D after DNA damage and phosphorylates the transcription factor at four ATM consensus sites. Knockdown of endogenous MEF2D with a short-hairpin RNA (shRNA) increases sensitivity to etoposide-induced DNA damage and neuronal cell death. Interestingly, substitution of endogenous MEF2D with an shRNA-resistant phosphomimetic MEF2D mutant protects cerebellar granule cells from cell death after DNA damage, whereas an shRNA-resistant nonphosphorylatable MEF2D mutant does not. In vivo, cerebella in Mef2d knock-out mice manifest increased susceptibility to DNA damage. Together, our results show that MEF2D is a substrate for phosphorylation by ATM, thus promoting survival in response to DNA damage. Moreover, dysregulation of the ATM–MEF2D pathway may contribute to neurodegeneration in AT. PMID:24672010

Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival

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Hsieh Fu-Chuan

2008-10-01

Full Text Available Abstract Background Constitutive activation of signal transducer and activator of transcription 3 (Stat3 signaling pathway plays an important role in several human cancers. Activation of Stat3 is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization. It remains unclear whether oncogenic Stat3 signaling pathway is involved in the oncogenesis of bladder cancer. Results We found that elevated Stat3 phosphorylation in 19 of 100 (19% bladder cancer tissues as well as bladder cancer cell lines, WH, UMUC-3 and 253J. To explore whether Stat3 activation is associated with cell growth and survival of bladder cancer, we targeted the Stat3 signaling pathway in bladder cancer cells using an adenovirus-mediated dominant-negative Stat3 (Y705F and a small molecule compound, STA-21. Both prohibited cell growth and induction of apoptosis in these bladder cancer cell lines but not in normal bladder smooth muscle cell (BdSMC. The survival inhibition might be mediated through apoptotic caspase 3, 8 and 9 pathways. Moreover, down-regulation of anti-apoptotic genes (Bcl-2, Bcl-xL and survivin and a cell cycle regulating gene (cyclin D1 was associated with the cell growth inhibition and apoptosis. Conclusion These results indicated that activation of Stat3 is crucial for bladder cancer cell growth and survival. Therefore, interference of Stat3 signaling pathway emerges as a potential therapeutic approach for bladder cancer.

Cyclophilin B supports Myc and mutant p53-dependent survival of glioblastoma multiforme cells.

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Choi, Jae Won; Schroeder, Mark A; Sarkaria, Jann N; Bram, Richard J

2014-01-15

Glioblastoma multiforme is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here, we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in glioblastoma multiforme cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human glioblastoma multiforme cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of glioblastoma multiforme cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS-mitogen-activated protein kinase pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1, and Janus-activated kinase/STAT3 signaling. Elevated reactive oxygen species, ER expansion, and abnormal unfolded protein responses in CypB-depleted glioblastoma multiforme cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of glioblastoma multiforme tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for glioblastoma multiforme therapy.

Drug synergy drives conserved pathways to increase fission yeast lifespan.

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Xinhe Huang

Full Text Available Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker's yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to mammals. Pathways include the target of rapamycin complex 1 (TORC1 protein kinase, the protein kinase A (PKA and a stress response pathway, which in fission yeasts contains the Sty1 protein kinase, an ortholog of the mammalian p38 MAP kinase, a type of Stress Activated Protein Kinase (SAPK. These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival. The molecular mechanisms for fine-tuning are probably species-specific, but since they are driven by conserved nutrient and stress sensing pathways, the drug combination may enhance survival in other organisms.

Promoting long-term survival of insulin-producing cell grafts that differentiate from adipose tissue-derived stem cells to cure type 1 diabetes.

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Shuzi Zhang

Full Text Available BACKGROUND: Insulin-producing cell clusters (IPCCs have recently been generated in vitro from adipose tissue-derived stem cells (ASCs to circumvent islet shortage. However, it is unknown how long they can survive upon transplantation, whether they are eventually rejected by recipients, and how their long-term survival can be induced to permanently cure type 1 diabetes. IPCC graft survival is critical for their clinical application and this issue must be systematically addressed prior to their in-depth clinical trials. METHODOLOGY/PRINCIPAL FINDINGS: Here we found that IPCC grafts that differentiated from murine ASCs in vitro, unlike their freshly isolated islet counterparts, did not survive long-term in syngeneic mice, suggesting that ASC-derived IPCCs have intrinsic survival disadvantage over freshly isolated islets. Indeed, β cells retrieved from IPCC syngrafts underwent faster apoptosis than their islet counterparts. However, blocking both Fas and TNF receptor death pathways inhibited their apoptosis and restored their long-term survival in syngeneic recipients. Furthermore, blocking CD40-CD154 costimulation and Fas/TNF signaling induced long-term IPCC allograft survival in overwhelming majority of recipients. Importantly, Fas-deficient IPCC allografts exhibited certain immune privilege and enjoyed long-term survival in diabetic NOD mice in the presence of CD28/CD40 joint blockade while their islet counterparts failed to do so. CONCLUSIONS/SIGNIFICANCE: Long-term survival of ASC-derived IPCC syngeneic grafts requires blocking Fas and TNF death pathways, whereas blocking both death pathways and CD28/CD40 costimulation is needed for long-term IPCC allograft survival in diabetic NOD mice. Our studies have important clinical implications for treating type 1 diabetes via ASC-derived IPCC transplantation.

Ras and Rheb Signaling in Survival and Cell Death

International Nuclear Information System (INIS)

Ehrkamp, Anja; Herrmann, Christian; Stoll, Raphael; Heumann, Rolf

2013-01-01

One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively

Ras and Rheb Signaling in Survival and Cell Death

Energy Technology Data Exchange (ETDEWEB)

Ehrkamp, Anja [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany); Herrmann, Christian [Department of Physical Chemistry1, Protein Interaction, Ruhr University of Bochum, 44780 Bochum (Germany); Stoll, Raphael [Biomolecular NMR, Ruhr University of Bochum, 44780 Bochum (Germany); Heumann, Rolf, E-mail: rolf.heumann@rub.de [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany)

2013-05-28

One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively.

Contribution of screening and survival differences to racial disparities in colorectal cancer rates

NARCIS (Netherlands)

I. Lansdorp-Vogelaar (Iris); K.M. Kuntz (Karen); A.B. Knudsen (Amy); M. van Ballegooijen (Marjolein); A. Zauber (Ann); A. Jemal (Ahmedin)

2012-01-01

textabstractBackground: Considerable disparities exist in colorectal cancer (CRC) incidence and mortality rates between blacks and whites in the United States. We estimated how much of these disparities could be explained by differences in CRC screening and stage-specific relative CRC survival.

Nerve Growth Factor in Cancer Cell Death and Survival

Energy Technology Data Exchange (ETDEWEB)

Molloy, Niamh H.; Read, Danielle E.; Gorman, Adrienne M., E-mail: adrienne.gorman@nuigalway.ie [Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway (Ireland)

2011-02-01

One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75{sup NTR}, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75{sup NTR}. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75{sup NTR}. This latter signaling through p75{sup NTR} promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75{sup NTR} mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer.

MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2

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Murphy Derek M

2010-04-01

Full Text Available Abstract Background Neuroblastoma is a paediatric cancer of the sympathetic nervous system. The single most important genetic indicator of poor clinical outcome is amplification of the MYCN transcription factor. One of many down-stream MYCN targets is miR-184, which is either directly or indirectly repressed by this transcription factor, possibly due to its pro-apoptotic effects when ectopically over-expressed in neuroblastoma cells. The purpose of this study was to elucidate the molecular mechanism by which miR-184 conveys pro-apoptotic effects. Results We demonstrate that the knock-down of endogenous miR-184 has the opposite effect of ectopic up-regulation, leading to enhanced neuroblastoma cell numbers. As a mechanism of how miR-184 causes apoptosis when over-expressed, and increased cell numbers when inhibited, we demonstrate direct targeting and degradation of AKT2, a major downstream effector of the phosphatidylinositol 3-kinase (PI3K pathway, one of the most potent pro-survival pathways in cancer. The pro-apoptotic effects of miR-184 ectopic over-expression in neuroblastoma cell lines is reproduced by siRNA inhibition of AKT2, while a positive effect on cell numbers similar to that obtained by the knock-down of endogenous miR-184 can be achieved by ectopic up-regulation of AKT2. Moreover, co-transfection of miR-184 with an AKT2 expression vector lacking the miR-184 target site in the 3'UTR rescues cells from the pro-apoptotic effects of miR-184. Conclusions MYCN contributes to tumorigenesis, in part, by repressing miR-184, leading to increased levels of AKT2, a direct target of miR-184. Thus, two important genes with positive effects on cell growth and survival, MYCN and AKT2, can be linked into a common genetic pathway through the actions of miR-184. As an inhibitor of AKT2, miR-184 could be of potential benefit in miRNA mediated therapeutics of MYCN amplified neuroblastoma and other forms of cancer.

Public health surveillance of cancer survival in the United States and worldwide: The contribution of the CONCORD programme.

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Allemani, Claudia; Coleman, Michel P

2017-12-15

CONCORD is a programme for the global surveillance of cancer survival. In 2015, the second cycle of the program (CONCORD-2) established long-term surveillance of cancer survival worldwide, for the first time, in the largest cancer survival study published to date. CONCORD-2 provided cancer survival trends for 25,676,887 patients diagnosed during the 15-year period between 1995 and 2009 with 1 of 10 common cancers that collectively represented 63% of the global cancer burden in 2009. Herein, the authors summarize the past, describe the present, and outline the future of the CONCORD programme. They discuss the difference between population-based studies and clinical trials, and review the importance of international comparisons of population-based cancer survival. This study will focus on the United States. The authors explain why population-based survival estimates are crucial for driving effective cancer control strategies to reduce the wide and persistent disparities in cancer survival between white and black patients, which are likely to be attributable to differences in access to early diagnosis and optimal treatment. Cancer 2017;123:4977-81. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Research advances in sorafenib-induced apoptotic signaling pathways in liver cancer cells

Directory of Open Access Journals (Sweden)

ZHANG Chaoya

2016-04-01

Full Text Available Currently, sorafenib is the multi-target inhibitor for the treatment of advanced primary liver cancer, and can effectively prolong the progression-free survival and overall survival in patients with advanced primary liver cancer. The application of sorafenib in the targeted therapy for liver cancer has become a hot topic. Major targets or signaling pathways include Raf/Mek/Erk, Jak/Stat, PI3K/Akt/mTOR, VEGFR and PDGFR, STAT, microRNA, Wnt/β-catenin, autolysosome, and tumor-related proteins, and sorafenib can regulate the proliferation, differentiation, metastasis, and apoptosis of liver cancer cells through these targets. This article reviews the current research on the action of sorafenib on these targets or signaling pathways to provide useful references for further clinical research on sorafenib.

Mechanisms of ROS modulated cell survival during carcinogenesis.

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Clerkin, J S; Naughton, R; Quiney, C; Cotter, T G

2008-07-18

There is increasing evidence within the literature that the decreased susceptibility of tumour cells to stimuli that induce apoptosis can be linked to their inherently increased redox potential. The review primarily focuses on the PI3-kinase/Akt pathway, and the multiple points along this signalling pathway that may be redox regulated. The PI3-kinase/Akt pathway can influence a cells' sensitivity to death inducing signals, through direct manipulation of apoptosis regulating molecules or by regulating the activity of key transcription factors. Proteins involved in the control of apoptosis that are directly regulated by the PI3-kinase/Akt pathway include caspase-9, Bad and the transcription factor GSK-3beta. Lately, it is becoming increasingly obvious that phosphatases are a major counter balance to the PI3-kinase/Akt pathway. Phosphatases such as PP2A and PP1alpha can dephosphorylate signalling molecules within the PI3-kinase/Akt pathway, blocking their activity. It is the balance between the kinase activity and the phosphatase activity that determines the presence and strength of the PI3-kinase/Akt signal. This is why any protein modifications that hinder dephosphorylation can increase the tumours survival advantage. One such modification is the oxidation of the sulphydryl group in key cysteine residues present within the active site of the phosphatases. This highlights the link between the increased redox stress in tumours with the PI3-kinase/Akt pathway. This review will discuss the various sources of reactive oxygen species within a tumour and the effect of these radicals on the PI3-kinase/Akt pathway.

Enhanced B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation contributes to ABCC1-mediated chemoresistance and glutathione-mediated survival in acquired topoisomerase II poison-resistant cancer cells.

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Chen, Huang-Hui; Chang, Hsin-Huei; Chang, Jang-Yang; Tang, Ya-Chu; Cheng, Yung-Chi; Lin, Li-Mei; Cheng, Shu-Ying; Huang, Chih-Hsiang; Sun, Man-Wu; Chen, Chiung-Tong; Kuo, Ching-Chuan

2017-12-01

Nuclear factor erythroid-2-related factor 2 (NRF2) mainly regulates transcriptional activation through antioxidant-responsive elements (AREs) present in the promoters of NRF2 target genes. Recently, we found that NRF2 was overexpressed in a KB-derived drug-resistant cancer cell panel. In this panel, KB-7D cells, which show acquired resistance to topoisomerase II (Top II) poisons, exhibited the highest NRF2 activation. To investigate whether NRF2 directly contributed to acquired resistance against Top II poisons, we manipulated NRF2 by genetic and pharmacological approaches. The result demonstrated that silencing of NRF2 by RNA interference increased the sensitivity and treatment with NRF2 activator decreased the sensitivity of KB and KB-7D cells toward Top II poisons. Further, increased B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation activated NRF2 signaling in KB-7D cells. Moreover, increased binding of NRF2 to an ARE in the promoter of ATP-binding cassette subfamily C member 1 (ABCC1) directly contributed to Top II poison resistance. In addition, activation of NRF2 increased glutathione level and antioxidant capacity in KB-7D cells compared with that in KB cells; moreover, high glutathione level provided survival advantage to KB-7D cells. Our study is the first to show that aberrant NRF2 activation is via increased B-Raf-mediated NRF2 gene transcription and HATs-mediated NRF2 protein acetylation, which increases the acquired resistance and promote the survival of Top II poison-resistant cancer cells. Importantly, NRF2 downstream effectors ABCC1 and glutathione directly contribute to acquired resistance and survival, respectively. These results suggest that blockade of NRF2 signaling may enhance therapeutic efficacy and reduce the survival of Top II poison-refractory tumors in clinical. Copyright © 2017 Elsevier Inc. All rights reserved.

Predictive Modelling Risk Calculators and the Non Dialysis Pathway.

Science.gov (United States)

Robins, Jennifer; Katz, Ivor

2013-04-16

This guideline will review the current prediction models and survival/mortality scores available for decision making in patients with advanced kidney disease who are being considered for a non-dialysis treatment pathway. Risk prediction is gaining increasing attention with emerging literature suggesting improved patient outcomes through individualised risk prediction (1). Predictive models help inform the nephrologist and the renal palliative care specialists in their discussions with patients and families about suitability or otherwise of dialysis. Clinical decision making in the care of end stage kidney disease (ESKD) patients on a non-dialysis treatment pathway is currently governed by several observational trials (3). Despite the paucity of evidence based medicine in this field, it is becoming evident that the survival advantages associated with renal replacement therapy in these often elderly patients with multiple co-morbidities and limited functional status may be negated by loss of quality of life (7) (6), further functional decline (5, 8), increased complications and hospitalisations. This article is protected by copyright. All rights reserved.

PEGylated liposome IHL-305 markedly improved the survival of ovarian cancer peritoneal metastasis in mouse

International Nuclear Information System (INIS)

Konishi, Hiroaki; Takagi, Akimitsu; Kurita, Akinobu; Kaneda, Norimasa; Matsuzaki, Takeshi

2012-01-01

Advanced ovarian cancer is characterized by peritoneal metastasis and the accumulation of ascites. Peritoneal metastasis of ovarian cancer is a major cause of the negative treatment outcome, as these metastases are resistant to most chemotherapy regimens. The aim of this study was to clarify aggressive pathology of peritoneal metastasis and examine the therapeutic efficacy of a liposomal agent in the model. A human cancer cell line ES-2 of ovarian clear cell carcinoma, known as a chemotherapy-resistant cancer, was cultured in nonadherent plate to form spheroid and single cell suspension was transplanted into mouse peritoneal cavity. The epidermal growth factor receptor (EGFR) pathways in the cellular aggregates were analyzed both spheroid and ascites. The pharmacokinetics and therapeutic efficacy of CPT-11 (45 mg/kg) and IHL-305 (45 mg/kg), an irinotecan-encapsulated liposome, were examined by intravenous administration. Established peritoneal metastasis model showed an accumulation of ascites. The activation of EGFR and Akt was demonstrated in cellular aggregates both in the spheroid and ascites. In ascites samples, the area under the curve of SN-38, the activated form of CPT-11, was 3.8 times higher from IHL-305-treated mice than from CPT-11-treated mice. IHL-305 prolonged the survival time and decreased the accumulation of ascites and tumor metastasis. The median survival time were 22, 37 and 54 days in the control, CPT-11-treated, and IHL-305-treated mice, respectively. EGFR/Akt pathway contributes to the aggressive progression in ES-2 peritoneal metastasis model and effective delivery into ascites of IHL-305 was thought to useful treatment for ovarian cancer with peritoneal metastasis

Long-term survival of hydrated resting eggs from Brachionus plicatilis.

Science.gov (United States)

Clark, Melody S; Denekamp, Nadav Y; Thorne, Michael A S; Reinhardt, Richard; Drungowski, Mario; Albrecht, Marcus W; Klages, Sven; Beck, Alfred; Kube, Michael; Lubzens, Esther

2012-01-01

Several organisms display dormancy and developmental arrest at embryonic stages. Long-term survival in the dormant form is usually associated with desiccation, orthodox plant seeds and Artemia cysts being well documented examples. Several aquatic invertebrates display dormancy during embryonic development and survive for tens or even hundreds of years in a hydrated form, raising the question of whether survival in the non-desiccated form of embryonic development depends on pathways similar to those occurring in desiccation tolerant forms. To address this question, Illumina short read sequencing was used to generate transcription profiles from the resting and amictic eggs of an aquatic invertebrate, the rotifer, Brachionus plicatilis. These two types of egg have very different life histories, with the dormant or diapausing resting eggs, the result of the sexual cycle and amictic eggs, the non-dormant products of the asexual cycle. Significant transcriptional differences were found between the two types of egg, with amictic eggs rich in genes involved in the morphological development into a juvenile rotifer. In contrast, representatives of classical "stress" proteins: a small heat shock protein, ferritin and Late Embryogenesis Abundant (LEA) proteins were identified in resting eggs. More importantly however, was the identification of transcripts for messenger ribonucleoprotein particles which stabilise RNA. These inhibit translation and provide a valuable source of useful RNAs which can be rapidly activated on the exit from dormancy. Apoptotic genes were also present. Although apoptosis is inconsistent with maintenance of prolonged dormancy, an altered apoptotic pathway has been proposed for Artemia, and this may be the case with the rotifer. These data represent the first transcriptional profiling of molecular processes associated with dormancy in a non-desiccated form and indicate important similarities in the molecular pathways activated in resting eggs compared

Long-term survival of hydrated resting eggs from Brachionus plicatilis.

Directory of Open Access Journals (Sweden)

Melody S Clark

Full Text Available Several organisms display dormancy and developmental arrest at embryonic stages. Long-term survival in the dormant form is usually associated with desiccation, orthodox plant seeds and Artemia cysts being well documented examples. Several aquatic invertebrates display dormancy during embryonic development and survive for tens or even hundreds of years in a hydrated form, raising the question of whether survival in the non-desiccated form of embryonic development depends on pathways similar to those occurring in desiccation tolerant forms.To address this question, Illumina short read sequencing was used to generate transcription profiles from the resting and amictic eggs of an aquatic invertebrate, the rotifer, Brachionus plicatilis. These two types of egg have very different life histories, with the dormant or diapausing resting eggs, the result of the sexual cycle and amictic eggs, the non-dormant products of the asexual cycle. Significant transcriptional differences were found between the two types of egg, with amictic eggs rich in genes involved in the morphological development into a juvenile rotifer. In contrast, representatives of classical "stress" proteins: a small heat shock protein, ferritin and Late Embryogenesis Abundant (LEA proteins were identified in resting eggs. More importantly however, was the identification of transcripts for messenger ribonucleoprotein particles which stabilise RNA. These inhibit translation and provide a valuable source of useful RNAs which can be rapidly activated on the exit from dormancy. Apoptotic genes were also present. Although apoptosis is inconsistent with maintenance of prolonged dormancy, an altered apoptotic pathway has been proposed for Artemia, and this may be the case with the rotifer.These data represent the first transcriptional profiling of molecular processes associated with dormancy in a non-desiccated form and indicate important similarities in the molecular pathways activated in

Pathway-focused PCR array profiling of enriched populations of laser capture microdissected hippocampal cells after traumatic brain injury.

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Deborah R Boone

Full Text Available Cognitive deficits in survivors of traumatic brain injury (TBI are associated with irreversible neurodegeneration in brain regions such as the hippocampus. Comparative gene expression analysis of dying and surviving neurons could provide insight into potential therapeutic targets. We used two pathway-specific PCR arrays (RT2 Profiler Apoptosis and Neurotrophins & Receptors PCR arrays to identify and validate TBI-induced gene expression in dying (Fluoro-Jade-positive or surviving (Fluoro-Jade-negative pyramidal neurons obtained by laser capture microdissection (LCM. In the Apoptosis PCR array, dying neurons showed significant increases in expression of genes associated with cell death, inflammation, and endoplasmic reticulum (ER stress compared with adjacent, surviving neurons. Pro-survival genes with pleiotropic functions were also significantly increased in dying neurons compared to surviving neurons, suggesting that even irreversibly injured neurons are able to mount a protective response. In the Neurotrophins & Receptors PCR array, which consists of genes that are normally expected to be expressed in both groups of hippocampal neurons, only a few genes were expressed at significantly different levels between dying and surviving neurons. Immunohistochemical analysis of selected, differentially expressed proteins supported the gene expression data. This is the first demonstration of pathway-focused PCR array profiling of identified populations of dying and surviving neurons in the brain after TBI. Combining precise laser microdissection of identifiable cells with pathway-focused PCR array analysis is a practical, low-cost alternative to microarrays that provided insight into neuroprotective signals that could be therapeutically targeted to ameliorate TBI-induced neurodegeneration.

Alterations in tumor necrosis factor signaling pathways are associated with cytotoxicity and resistance to taxanes: a study in isogenic resistant tumor cells

Science.gov (United States)

2012-01-01

in the expression of TNF-α-related genes consistent with reduced TNF-induced cytotoxicity and activation of NF-κB survival pathways. Conclusions We report for the first time that taxanes can promote dose-dependent sTNF-α production in tumor cells at clinically relevant concentrations, which can contribute to their cytotoxicity. Defects in the TNF cytotoxicity pathway or activation of TNF-dependent NF-κB survival genes may, in contrast, contribute to taxane resistance in tumor cells. These findings may be of strong clinical significance. PMID:22225778

Interference of silibinin with IGF-1R signalling pathways protects human epidermoid carcinoma A431 cells from UVB-induced apoptosis

International Nuclear Information System (INIS)

Liu, Weiwei; Otkur, Wuxiyar; Li, Lingzhi; Wang, Qiong; He, Hao; Zang, Linghe; Hayashi, Toshihiko; Tashiro, Shin-ichi; Onodera, Satoshi; Xia, Mingyu; Ikejima, Takashi

2013-01-01

Highlights: ► Silibinin protects A431 cells from UVB irradiation-induced apoptosis. ► Up-regulation of the IGF-1R-JNK/ERK pathways by UVB induces cell apoptosis. ► Silibinin inhibits IGF-1R pathways to repress caspase-8-mediated apoptosis. -- Abstract: Ultraviolet B (UVB) from sunlight is a major cause of cutaneous lesion. Silibinin, a traditional hepatic protectant, elicits protective effects against UVB-induced cellular damage. In A431 cells, the insulin-like growth factor-1 receptor (IGF-1R) was markedly up-regulated by UVB irradiation. The activation of the IGF-1R signalling pathways contributed to apoptosis of the cells rather than rescuing the cells from death. Up-regulated IGF-1R stimulated downstream mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinases (JNK) and extracellular signal-regulated protein kinases 1/2 (ERK1/2). The subsequent activation of caspase-8 and caspase-3 led to apoptosis. The activation of IGF-1R signalling pathways is the cause of A431 cell death. The pharmacological inhibitors and the small interfering RNA (siRNA) targeting IGF-1R suppressed the downstream activation of JNK/ERK-caspases to help the survival of the UVB-irradiated A431 cells. Indeed, silibinin treatment suppressed the IGF-1R-JNK/ERK pathways and thus protected the cells from UVB-induced apoptosis

Neuronal apoptotic signaling pathways probed and intervened by synthetically and modularly modified (SMM) chemokines.

Science.gov (United States)

Choi, Won-Tak; Kaul, Marcus; Kumar, Santosh; Wang, Jun; Kumar, I M Krishna; Dong, Chang-Zhi; An, Jing; Lipton, Stuart A; Huang, Ziwei

2007-03-09

As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1alpha or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120(IIIB), and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

Relative contribution of rat cytochrome P450 isoforms to the metabolism of caffeine: the pathway and concentration dependence.

Science.gov (United States)

Kot, Marta; Daniel, Władysława A

2008-04-01

The aim of the present study was to estimate the relative contribution of rat P450 isoforms to the metabolism of caffeine and to assess the usefulness of caffeine as a marker substance for estimating the activity of P450 in rat liver and its potential for pharmacokinetic interactions in pharmacological experiments. The results obtained using rat cDNA-expressed P450s indicated that 8-hydroxylation was the main oxidation pathway of caffeine (70%) in the rat. CYP1A2 was found to be a key enzyme catalyzing 8-hydroxylation (72%) and substantially contributing to 3-N-demethylation (47%) and 1-N-demethylation (37.5%) at a caffeine concentration of 0.1mM (relevant to "the maximum therapeutic concentration in humans"). Furthermore, CYP2C11 considerably contributed to 3-N-demethylation (31%). The CYP2C subfamily (66%) - mainly CYP2C6 (27%) and CYP2C11 (29%) - played a major role in catalyzing 7-N-demethylation. At higher substrate concentrations, the contribution of CYP1A2 to the metabolism of caffeine decreased in favor of CYP2C11 (N-demethylations) and CYP3A2 (mainly 8-hydroxylation). The obtained results were confirmed with liver microsomes (inhibition and correlation studies). Therefore, caffeine may be used as a marker substance for assessing the activity of CYP1A2 in rats, using 8-hydroxylation (but not 3-N-demethylation-like in humans); moreover, caffeine may also be used to simultaneously, preliminarily estimate the activity of CYP2C using 7-N-demethylation as a marker reaction. Hence caffeine pharmacokinetics in rats may be changed by drugs affecting the activity of CYP1A2 and/or CYP2C, e.g. by some antidepressants.

The contribution of Nth and Nei DNA glycosylases to mutagenesis in Mycobacterium smegmatis.

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Moolla, Nabiela; Goosens, Vivianne J; Kana, Bavesh D; Gordhan, Bhavna G

2014-01-01

The increased prevalence of drug resistant strains of Mycobacterium tuberculosis (Mtb) indicates that significant mutagenesis occurs during tuberculosis disease in humans. DNA damage by host-derived reactive oxygen/nitrogen species is hypothesized to be critical for the mutagenic process in Mtb thus, highlighting an important role for DNA repair enzymes in maintenance of genome fidelity. Formamidopyrimidine (Fpg/MutM/Fapy) and EndonucleaseVIII (Nei) constitute the Fpg/Nei family of DNA glycosylases and together with EndonucleaseIII (Nth) are central to the base excision repair pathway in bacteria. In this study we assess the contribution of Nei and Nth DNA repair enzymes in Mycobacterium smegmatis (Msm), which retains a single nth homologue and duplications of the Fpg (fpg1 and fpg2) and Nei (nei1 and nei2) homologues. Using an Escherichia coli nth deletion mutant, we confirm the functionality of the mycobacterial nth gene in the base excision repair pathway. Msm mutants lacking nei1, nei2 and nth individually or in combination did not display aberrant growth in broth culture. Deletion of nth individually results in increased UV-induced mutagenesis and combinatorial deletion with the nei homologues results in reduced survival under oxidative stress conditions and an increase in spontaneous mutagenesis to rifampicin. Deletion of nth together with the fpg homolgues did not result in any growth/survival defects or changes in mutation rate. Furthermore, no differential emergence of the common rifampicin resistance conferring genotypes were noted. Collectively, these data confirm a role for Nth in base excision repair in mycobacteria and further highlight a novel interplay between the Nth and Nei homologues in spontaneous mutagenesis. Copyright © 2013 Elsevier B.V. All rights reserved.

Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD).

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Nguyen, Michael; Roth, Andrew; Kyzar, Evan J; Poudel, Manoj K; Wong, Keith; Stewart, Adam Michael; Kalueff, Allan V

2014-01-01

Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca(2+) signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells

Directory of Open Access Journals (Sweden)

Joseph L. Regan

2017-12-01

Full Text Available Summary: Colon cancer is a heterogeneous tumor driven by a subpopulation of cancer stem cells (CSCs. To study CSCs in colon cancer, we used limiting dilution spheroid and serial xenotransplantation assays to functionally define the frequency of CSCs in a panel of patient-derived cancer organoids. These studies demonstrated cancer organoids to be enriched for CSCs, which varied in frequency between tumors. Whole-transcriptome analysis identified WNT and Hedgehog signaling components to be enhanced in CSC-enriched tumors and in aldehyde dehydrogenase (ALDH-positive CSCs. Canonical GLI-dependent Hedgehog signaling is a negative regulator of WNT signaling in normal intestine and intestinal tumors. Here, we show that Hedgehog signaling in colon CSCs is autocrine SHH-dependent, non-canonical PTCH1 dependent, and GLI independent. In addition, using small-molecule inhibitors and RNAi against SHH-palmitoylating Hedgehog acyltransferase (HHAT, we demonstrate that non-canonical Hedgehog signaling is a positive regulator of WNT signaling and required for colon CSC survival. : Colon cancer is a heterogeneous tumor driven by a subpopulation(s of therapy-resistant cancer stem cells (CSCs. Regan et al. use 3D culture models to demonstrate that CSC survival is regulated by non-canonical, SHH-dependent, PTCH1-dependent Hedgehog signaling, which acts as a positive regulator of WNT signaling to block CSC differentiation. Keywords: WNT pathway, non-canonical Hedgehog signaling, cancer stem cell, colon cancer, cancer organoid, PTCH1, HHAT, SHH

Prognostic value of hedgehog signaling pathway in digestive system cancers: A systematic review and meta-analysis.

Science.gov (United States)

Wang, Yihan; Peng, Qian; Jia, Hongyuan; Du, Xiao

2016-01-01

The Hedgehog (Hh) signaling pathway has recently been reported to be associated with the prognosis of digestive system cancers. However, the results are inconsistent. This study aimed to investigate the association between Hh pathway components and survival outcomes in patients with digestive system cancers. We conducted a comprehensive retrieval in PubMed, EMBASE and Cochrane library for relevant literatures until May 1st, 2015. The pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) with 95% confidence intervals (CIs) were calculated to clarify the prognostic value of Hh pathway components, including Shh, Gli1, Gli2, Smo and Ptch1. A total of 16 eligible articles with 3222 patients were included in the meta-analysis. Pooled HR suggested that over-expression of Shh and Gli1 were both associated with poor OS (HR = 1.87, 95% CI: 1.14-3.07 and HR = 1.96, 95% CI: 1.66-2.32, respectively) and DFS (HR = 2.37, 95% CI: 1.19-4.72 and HR = 2.18, 95% CI: 1.61-2.96, respectively). In addition, over-expression of Smo was associated with poor DFS (HR = 1.38, 95% CI: 1.08-1.75). This study reveals that over-expressed Hh pathway components, including Shh, Gli1 and Smo, are associated with poor prognosis in digestive system cancer patients. Hh signaling pathway may become a potential therapeutic target in digestive system cancers.

A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

International Nuclear Information System (INIS)

Latham, Antony M.; Odell, Adam F.; Mughal, Nadeem A.; Issitt, Theo; Ulyatt, Clare; Walker, John H.; Homer-Vanniasinkam, Shervanthi; Ponnambalam, Sreenivasan

2012-01-01

Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: ► Endothelial cells mount a stress response under conditions of low serum. ► Endothelial VEGFR levels are

Carnitine protects the nematode Caenorhabditis elegans from glucose-induced reduction of survival depending on the nuclear hormone receptor DAF-12

International Nuclear Information System (INIS)

Deusing, Dorothé Jenni; Beyrer, Melanie; Fitzenberger, Elena; Wenzel, Uwe

2015-01-01

Besides its function in transport of fatty acids into mitochondria in order to provide substrates for β-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 μM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA-interference for sir-2.1, a candidate genes mediating the effects of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for γ-butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors. - Highlights: • Carnitine protects from glucose-induced reduction of stress-resistance. • Carnitine acts via the PPAR homolog DAF-12 on glucose toxicity. • Carnitine protects from glucose toxicity independent of protein degradation

Carnitine protects the nematode Caenorhabditis elegans from glucose-induced reduction of survival depending on the nuclear hormone receptor DAF-12

Energy Technology Data Exchange (ETDEWEB)

Deusing, Dorothé Jenni, E-mail: Dorothe.J.Deusing@ernaehrung.uni-giessen.de; Beyrer, Melanie, E-mail: m.beyrer@web.de; Fitzenberger, Elena, E-mail: Elena.Fitzenberger@ernaehrung.uni-giessen.de; Wenzel, Uwe, E-mail: uwe.wenzel@ernaehrung.uni-giessen.de

2015-05-08

Besides its function in transport of fatty acids into mitochondria in order to provide substrates for β-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 μM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA-interference for sir-2.1, a candidate genes mediating the effects of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for γ-butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors. - Highlights: • Carnitine protects from glucose-induced reduction of stress-resistance. • Carnitine acts via the PPAR homolog DAF-12 on glucose toxicity. • Carnitine protects from glucose toxicity independent of protein degradation.

Obesity adversely affects survival in pancreatic cancer patients.

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McWilliams, Robert R; Matsumoto, Martha E; Burch, Patrick A; Kim, George P; Halfdanarson, Thorvardur R; de Andrade, Mariza; Reid-Lombardo, Kaye; Bamlet, William R

2010-11-01

Higher body-mass index (BMI) has been implicated as a risk factor for developing pancreatic cancer, but its effect on survival has not been thoroughly investigated. The authors assessed the association of BMI with survival in a sample of pancreatic cancer patients and used epidemiologic and clinical information to understand the contribution of diabetes and hyperglycemia. A survival analysis using Cox proportional hazards by usual adult BMI was performed on 1861 unselected patients with pancreatic adenocarcinoma; analyses were adjusted for covariates that included clinical stage, age, and sex. Secondary analyses incorporated self-reported diabetes and fasting blood glucose in the survival model. BMI as a continuous variable was inversely associated with survival from pancreatic adenocarcinoma (hazard ratio [HR], 1.019 for each increased unit of BMI [kg/m2], PFasting blood glucose and diabetes did not affect the results. Higher BMI is associated with decreased survival in pancreatic cancer. Although the mechanism of this association remains undetermined, diabetes and hyperglycemia do not appear to account for the observed association. Copyright © 2010 American Cancer Society.

Inactivation of CDK/pRb pathway normalizes survival pattern of lymphoblasts expressing the FTLD-progranulin mutation c.709-1G>A.

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Carolina Alquezar

Full Text Available BACKGROUND: Mutations in the progranulin (PGRN gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP, although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. METHODOLOGY/PRINCIPAL FINDINGS: We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. CONCLUSION/SIGNIFICANCE: The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDP.

Activation of IRE1α-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma

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Jin, Chun; Jin, Zhao; Chen, Nian-zhao; Lu, Min; Liu, Chang-bao; Hu, Wan-Le; Zheng, Chen-guo

2016-01-01

Cell proliferation and tumor metastasis are considered as the main reasons for death in colorectal carcinoma (CRC). IRE1α-XBP1 pathway is the most conserved UPR pathways, which are activated during ER stress caused by the accumulation of unfolded or misfolded protein in the lumen of ER. Here, we demonstrated the critical role of IRE1α-XBP1 pathway and underlying molecular mechanism in cell proliferation and tumor metastasis in CRC. By the use of tissue microarray analysis of samples from 119 patients with CRC, IRE1α was determined to be an independent predictor of overall survival as higher expression of IRE1α in CRC patients showed lower survival rates (p = 0.0041). RNA interference and ectopic expression of IRE1α were applied to determine the molecular effects of IRE1α in CRC cells. The silencing of IRE1α inhibited the proliferation and blocked the invasion of CRC cells in vitro, while ectopic expression of IRE1α in turn promoted cell proliferation and invasion. IRE1α-XBP1 pathway regulated the mitosis of CRC cells through the directly binding of XBP1s to Cyclin D1 promoter to activate Cyclin D1 expression. Our results reveal that IRE1α-XBP1 pathway plays an important role in tumor progression and epithelial-to-mesenchymal transition (EMT), and IRE1α could be employed as a novel prognostic marker and a promising therapeutic target for CRC. - Highlights: • IRE1 was determined to be an independent predictor of overall survival in CRC patient. • IRE1-XBP1 pathway promoted CRC cell proliferation through regulating Cyclin D1 expression. • IRE1-XBP1 pathway played important role in EMT of CRC cells.

Activation of IRE1α-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma

Energy Technology Data Exchange (ETDEWEB)

Jin, Chun [Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000 (China); Jin, Zhao [Department of Coloproctology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou 325000 (China); Chen, Nian-zhao [Department of Medicine, The Chinese Medicine Hospital of Wenzhou, Wenzhou 325000 (China); Lu, Min; Liu, Chang-bao; Hu, Wan-Le [Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000 (China); Zheng, Chen-guo, E-mail: zhengchenguo80@163.com [Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000 (China)

2016-01-29

Cell proliferation and tumor metastasis are considered as the main reasons for death in colorectal carcinoma (CRC). IRE1α-XBP1 pathway is the most conserved UPR pathways, which are activated during ER stress caused by the accumulation of unfolded or misfolded protein in the lumen of ER. Here, we demonstrated the critical role of IRE1α-XBP1 pathway and underlying molecular mechanism in cell proliferation and tumor metastasis in CRC. By the use of tissue microarray analysis of samples from 119 patients with CRC, IRE1α was determined to be an independent predictor of overall survival as higher expression of IRE1α in CRC patients showed lower survival rates (p = 0.0041). RNA interference and ectopic expression of IRE1α were applied to determine the molecular effects of IRE1α in CRC cells. The silencing of IRE1α inhibited the proliferation and blocked the invasion of CRC cells in vitro, while ectopic expression of IRE1α in turn promoted cell proliferation and invasion. IRE1α-XBP1 pathway regulated the mitosis of CRC cells through the directly binding of XBP1s to Cyclin D1 promoter to activate Cyclin D1 expression. Our results reveal that IRE1α-XBP1 pathway plays an important role in tumor progression and epithelial-to-mesenchymal transition (EMT), and IRE1α could be employed as a novel prognostic marker and a promising therapeutic target for CRC. - Highlights: • IRE1 was determined to be an independent predictor of overall survival in CRC patient. • IRE1-XBP1 pathway promoted CRC cell proliferation through regulating Cyclin D1 expression. • IRE1-XBP1 pathway played important role in EMT of CRC cells.

Targeting chondrosarcoma and osteosarcoma cell metabolism : the IGF pathway and beyond

NARCIS (Netherlands)

Peterse, E.F.P.

2018-01-01

Thesis explored potential new therapeutic strategies by identifying cellular pathways that are essential for chondrosarcoma and osteosarcoma cell survival. Although clinical trials with IGF1R inhibitors have disappointing results in osteosarcoma, this thesis strengthens the view that the IGF

Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes.

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Katare, Rajesh; Oikawa, Atsuhiko; Cesselli, Daniela; Beltrami, Antonio P; Avolio, Elisa; Muthukrishnan, Deepti; Munasinghe, Pujika Emani; Angelini, Gianni; Emanueli, Costanza; Madeddu, Paolo

2013-01-01

Diabetes impinges upon mechanisms of cardiovascular repair. However, the biochemical adaptation of cardiac stem cells to sustained hyperglycaemia remains largely unknown. Here, we investigate the molecular targets of high glucose-induced damage in cardiac progenitor cells (CPCs) from murine and human hearts and attempt safeguarding CPC viability and function through reactivation of the pentose phosphate pathway. Type-1 diabetes was induced by streptozotocin. CPC abundance was determined by flow cytometry. Proliferating CPCs were identified in situ by immunostaining for the proliferation marker Ki67. Diabetic hearts showed marked reduction in CPC abundance and proliferation when compared with controls. Moreover, Sca-1(pos) CPCs isolated from hearts of diabetic mice displayed reduced activity of key enzymes of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD), and transketolase, increased levels of superoxide and advanced glucose end-products (AGE), and inhibition of the Akt/Pim-1/Bcl-2 signalling pathway. Similarly, culture of murine CPCs or human CD105(pos) progenitor cells in high glucose inhibits the pentose phosphate and pro-survival signalling pathways, leading to the activation of apoptosis. In vivo and in vitro supplementation with benfotiamine reactivates the pentose phosphate pathway and rescues CPC availability and function. This benefit is abrogated by either G6PD silencing by small interfering RNA (siRNA) or Akt inhibition by dominant-negative Akt. We provide new evidence of the negative impact of diabetes and high glucose on mechanisms controlling CPC redox state and survival. Boosting the pentose phosphate pathway might represent a novel mechanistic target for protection of CPC integrity.

Neurotrophin receptors expression and JNK pathway activation in human astrocytomas

International Nuclear Information System (INIS)

Assimakopoulou, Martha; Kondyli, Maria; Gatzounis, George; Maraziotis, Theodore; Varakis, John

2007-01-01

Neurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane – receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC) and p75 NTR neurotrophin receptor. Trk receptors promote cell survival and differentiation while p75 NTR induces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75 NTR -induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75 NTR , and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue. Formalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV) were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75 NTR and phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were used. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined. Moderate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75 NTR receptor expression was found in a small percentage of tumor cells (~1%) in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were significantly co-expressed in a tumor

cAMP/PKA signaling pathway contributes to neuronal apoptosis via regulating IDE expression in a mixed model of type 2 diabetes and Alzheimer's disease.

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Li, Huajie; Yang, Song; Wu, Jian; Ji, Lei; Zhu, Linfeng; Cao, Liping; Huang, Jinzhong; Jiang, Qingqing; Wei, Jiang; Liu, Meng; Mao, Keshi; Wei, Ning; Xie, Wei; Yang, Zhilong

2018-02-01

Type 2 diabetes (T2D) may play a relevant role in the development of Alzheimer's disease (AD), however, the underlying mechanism was not clear yet. We developed an animal model presenting both AD and T2D, morris water maze (MWM) test and recognition task were performed to trace the cognitive function. Fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) were determined to trace the metabolism evolution. TUNEL assay and apoptosis-related protein levels were analyzed for the detection of neuronal apoptosis. Cyclic adenosine monophosphate (cAMP) agonist bucladesine or protein kinase (PKA) inhibitor H-89 were used to determine the effects of cAMP/PKA signaling pathway on IDE expression and neuronal apoptosis. The results showed that T2D contributes to the AD progress by accelerating and worsening spatial memory and recognition dysfunctions. Metabolic parameters and glucose tolerance were significantly changed in the presence of the AD and T2D. The significantly induced neuronal apoptosis and increased pro-apoptotic proteins in mice with AD and T2D were also observed. We showed the decreased expression level of IDE and the activating of cAMP/PKA signaling pathway in AD and T2D mice. Further studies indicated that cAMP agonist decreased the expression level of IDE and induced the neuronal apoptosis in mice with AD and T2D; whereas PKA inhibitor H-89 treatment showed the completely opposite results. Our study indicated that, in the T2D and AD mice, cAMP/PKA signaling pathway and IDE may participate in the contribute role of T2D in accelerating the pathological process of AD via causing the accumulation of Aβ and neuronal apoptosis. © 2017 Wiley Periodicals, Inc.

Tax Protein-induced Expression of Antiapoptotic Bfl-1 Protein Contributes to Survival of Human T-cell Leukemia Virus Type 1 (HTLV-1)-infected T-cells*♦

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Macaire, Héloïse; Riquet, Aurélien; Moncollin, Vincent; Biémont-Trescol, Marie-Claude; Duc Dodon, Madeleine; Hermine, Olivier; Debaud, Anne-Laure; Mahieux, Renaud; Mesnard, Jean-Michel; Pierre, Marlène; Gazzolo, Louis; Bonnefoy, Nathalie; Valentin, Hélène

2012-01-01

Human T lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL). ATLL is a severe malignancy with no effective treatment. HTLV-1 regulatory proteins Tax and HTLV-1 basic leucine zipper factor (HBZ) play a major role in ATLL development, by interfering with cellular functions such as CD4+ T-cell survival. In this study, we observed that the expression of Bfl-1, an antiapoptotic protein of the Bcl-2 family, is restricted to HTLV-1-infected T-cell lines and to T-cells expressing both Tax and HBZ proteins. We showed that Tax-induced bfl-1 transcription through the canonical NF-κB pathway. Moreover, we demonstrated that Tax cooperated with c-Jun or JunD, but not JunB, transcription factors of the AP-1 family to stimulate bfl-1 gene activation. By contrast, HBZ inhibited c-Jun-induced bfl-1 gene activation, whereas it increased JunD-induced bfl-1 gene activation. We identified one NF-κB, targeted by RelA, c-Rel, RelB, p105/p50, and p100/p52, and two AP-1, targeted by both c-Jun and JunD, binding sites in the bfl-1 promoter of T-cells expressing both Tax and HBZ. Analyzing the potential role of antiapoptotic Bcl-2 proteins in HTLV-1-infected T-cell survival, we demonstrated that these cells are differentially sensitive to silencing of Bfl-1, Bcl-xL, and Bcl-2. Indeed, both Bfl-1 and Bcl-xL knockdowns decreased the survival of HTLV-1-infected T-cell lines, although no cell death was observed after Bcl-2 knockdown. Furthermore, we demonstrated that Bfl-1 knockdown sensitizes HTLV-1-infected T-cells to ABT-737 or etoposide treatment. Our results directly implicate Bfl-1 and Bcl-xL in HTLV-1-infected T-cell survival and suggest that both Bfl-1 and Bcl-xL represent potential therapeutic targets for ATLL treatment. PMID:22553204

Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways.

Science.gov (United States)

Lalli, Matthew A; Jang, Jiwon; Park, Joo-Hye C; Wang, Yidi; Guzman, Elmer; Zhou, Hongjun; Audouard, Morgane; Bridges, Daniel; Tovar, Kenneth R; Papuc, Sorina M; Tutulan-Cunita, Andreea C; Huang, Yadong; Budisteanu, Magdalena; Arghir, Aurora; Kosik, Kenneth S

2016-04-01

Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphoma

Directory of Open Access Journals (Sweden)

Hannah ePhipps-Yonas

2013-12-01

Full Text Available The MHC class II-restricted antigen processing pathway presents antigenic peptides acquired in the endocytic route for the activation of CD4+ T cells. Multiple cancers express MHC class II, which may influence the anti-tumor immune response and patient outcome. Low MHC class II expression is associated with poor survival in diffuse large B-cell lymphoma (DLBCL, the most common form of aggressive non-Hodgkin lymphoma. Therefore, we investigated whether gamma-interferon-inducible lysosomal thiol reductase (GILT, an upstream component of the MHC class II-restricted antigen processing pathway that is not regulated by the transcription factor class II transactivator, may be important in DLBCL biology. GILT reduces protein disulfide bonds in the endocytic compartment, exposing additional epitopes for MHC class II binding and facilitating antigen presentation. In each of four independent gene expression profiling cohorts with a total of 585 DLBCL patients, low GILT expression was significantly associated with poor overall survival. In contrast, low expression of a classical MHC class II gene, HLA-DRA, was associated with poor survival in one of four cohorts. The association of low GILT expression with poor survival was independent of established clinical and molecular prognostic factors, the International Prognostic Index and the cell of origin classification, respectively. Immunohistochemical analysis of GILT expression in 96 DLBCL cases demonstrated variation in GILT protein expression within tumor cells which correlated strongly with GILT mRNA expression. These studies identify a novel association between GILT expression and clinical outcome in lymphoma. Our findings underscore the role of antigen processing in DLBCL and suggest that molecules targeting this pathway warrant investigation as potential therapeutics.

Contributions of vital rates to growth of a protected population of American black bears

Science.gov (United States)

Mitchell, M.S.; Pacifici, L.B.; Grand, J.B.; Powell, R.A.

2009-01-01

Analyses of large, long-lived animals suggest that adult survival generally has the potential to contribute more than reproduction to population growth rate (??), but because survival varies little, high variability in reproduction can have a greater influence. This pattern has been documented for several species of large mammals, but few studies have evaluated such contributions of vital rates to ?? for American black bears (Ursus americanus). We used variance-based perturbation analyses (life table response experiments, LTRE) and analytical sensitivity and elasticity analyses to examine the actual and potential contributions of variation of vital rates to variation in growth rate (??) of a population of black bears inhabiting the Pisgah Bear Sanctuary in the southern Appalachian Mountains of North Carolina, using a 22-year dataset. We found that recruitment varied more than other vital rates; LTRE analyses conducted over several time intervals thus indicated that recruitment generally contributed at least as much as juvenile and adult survival to observed variation in ??, even though the latter 2 vital rates had the greater potential to affect ??. Our findings are consistent with predictions from studies on polar bears (U. maritimus) and grizzly bears (U. arctos), but contrast with the few existing studies on black bears in ways that suggest levels of protection from human-caused mortality might explain whether adult survival or recruitment contribute most to variation in ?? for this species. We hypothesize that ?? is most strongly influenced by recruitment in protected populations where adult survival is relatively high and constant, whereas adult survival will most influence ?? for unprotected populations. ?? 2009 International Association for Bear Research and Management.

Role of Aspirin in Breast Cancer Survival.

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Chen, Wendy Y; Holmes, Michelle D

2017-07-01

Chemotherapy and hormonal therapy have significantly decreased breast cancer mortality, although with considerable side effects and financial costs. In the USA, over three million women are living after a breast cancer diagnosis and are eager for new treatments that are low in toxicity and cost. Multiple observational studies have reported improved breast cancer survival with regular aspirin use. Furthermore, pooled data from five large randomized trials of aspirin for cardiovascular disease showed that subjects on aspirin had decreased risk of cancer mortality and decreased risk of metastatic cancer. Although the potential mechanism for aspirin preventing breast cancer is not known, possible pathways may involve platelets, inflammation, cyclooxygenase (COX) 2, hormones, or PI3 kinase. This review article summarizes the current epidemiologic and clinical trial evidence as well as possible underlying mechanisms that justify current phase III randomized trials of aspirin to improve breast cancer survival.

Altered Leukocyte Sphingolipid Pathway in Breast Cancer

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Larissa P. Maia

2017-11-01

Full Text Available Sphingolipid metabolism pathway is essential in membrane homeostasis, and its dysfunction has been associated with favorable tumor microenvironment, disease progression, and chemotherapy resistance. Its major components have key functions on survival and proliferation, with opposing effects. We have profiled the components of the sphingolipid pathway on leukocytes of breast cancer (BC patients undergoing chemotherapy treatment and without, including the five sphingosine 1-phosphate (S1P receptors, the major functional genes, and cytokines, in order to better understand the S1P signaling in the immune cells of these patients. To the best of our knowledge, this is the first characterization of the sphingolipid pathway in whole blood of BC patients. Skewed gene profiles favoring high SPHK1 expression toward S1P production during BC development was observed, which was reversed by chemotherapy treatment, and reached similar levels to those found in healthy donors. Such levels were also correlated with high levels of TNF-α. Our data revealed an important role of the sphingolipid pathway in immune cells in BC with skewed signaling of S1P receptors, which favored cancer development even under chemotherapy, and may probably be a trigger of cancer resistance. Thus, these molecules must be considered as a target pathway for combined BC therapeutics.

Allorecognition pathways in transplant rejection and tolerance.

Science.gov (United States)

Ali, Jason M; Bolton, Eleanor M; Bradley, J Andrew; Pettigrew, Gavin J

2013-10-27

With the advent of cellular therapies, it has become clear that the success of future therapies in prolonging allograft survival will require an intimate understanding of the allorecognition pathways and effector mechanisms that are responsible for chronic rejection and late graft loss.Here, we consider current understanding of T-cell allorecognition pathways and discuss the most likely mechanisms by which these pathways collaborate with other effector mechanisms to cause allograft rejection. We also consider how this knowledge may inform development of future strategies to prevent allograft rejection.Although both direct and indirect pathway CD4 T cells appear active immediately after transplantation, it has emerged that indirect pathway CD4 T cells are likely to be the dominant alloreactive T-cell population late after transplantation. Their ability to provide help for generating long-lived alloantibody is likely one of the main mechanisms responsible for the progression of allograft vasculopathy and chronic rejection.Recent work has suggested that regulatory T cells may be an effective cellular therapy in transplantation. Given the above, adoptive therapy with CD4 regulatory T cells with indirect allospecificity is a rational first choice in attempting to attenuate the development and progression of chronic rejection; those with additional properties that enable inhibition of germinal center alloantibody responses hold particular appeal.

Lymphatic drainage pathways from the cervix uteri: implications for radical hysterectomy?

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Kraima, A C; Derks, M; Smit, N N; Van Munsteren, J C; Van der Velden, J; Kenter, G G; DeRuiter, M C

2014-01-01

Radical hysterectomy with pelvic lymphadenectomy is the treatment of choice for early-stage cervical cancer. Wertheim's original technique has been often modified, mainly in the extent of parametrectomy. Okabayashi's technique is considered as the most radical variant regarding removal of the ventral parametrium and paracolpal tissues. Surgical outcome concerning recurrence and survival is good, but morbidity is high due to autonomic nerve damage. While the autonomic network has been studied extensively, the lymphatic system is less understood. This study describes the lymphatic drainage pathways of the cervix uteri and specifically the presence of lymphatics in the vesico-uterine ligament (VUL). A developmental series of 10 human female fetal pelves was studied. Paraffin embedded blocks were sliced in transverse sections of 8 or 10 μm. Analysis was performed by staining with antibodies against LYVE-1 (lymphatic endothelium), S100 (Schwann cells), alpha-Smooth Muscle Actin (smooth muscle cells) and CD68 (macrophages). The results were three-dimensionally represented. Two major pathways drained the cervix uteri: a supra-ureteral pathway, running in the cardinal ligament superior to the ureter, and a dorsal pathway, running in the utero-sacral ligament towards the rectal pillars. No lymph vessels draining the cervix uteri were detected in the VUL. In the paracolpal parametrium lymph vessels draining the upper vagina fused with those from the bladder. The VUL does not contain lymphatics from the cervix uteri. Hence, the favorable survival outcomes of the Okabayashi technique cannot be explained by radical removal of lymphatic pathways in the ventrocaudal parametrium. © 2013.

HDAC inhibitors: modulating leukocyte differentiation, survival, proliferation and inflammation.

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Sweet, Matthew J; Shakespear, Melanie R; Kamal, Nabilah A; Fairlie, David P

2012-01-01

Therapeutic effects of histone deacetylase (HDAC) inhibitors in cancer models were first linked to their ability to cause growth arrest and apoptosis of tumor cells. It is now clear that these agents also have pleiotropic effects on angiogenesis and the immune system, and some of these properties are likely to contribute to their anti-cancer activities. It is also emerging that inhibitors of specific HDACs affect the differentiation, survival and/or proliferation of distinct immune cell populations. This is true for innate immune cells such as macrophages, as well as cells of the acquired immune system, for example, T-regulatory cells. These effects may contribute to therapeutic profiles in some autoimmune and chronic inflammatory disease models. Here, we review our current understanding of how classical HDACs (HDACs 1-11) and their inhibitors impact on differentiation, survival and proliferation of distinct leukocyte populations, as well as the likely relevance of these effects to autoimmune and inflammatory disease processes. The ability of HDAC inhibitors to modulate leukocyte survival may have implications for the rationale of developing selective inhibitors as anti-inflammatory drugs.

Role of care pathways in interprofessional teamwork.

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Scaria, Minimol Kulakkottu

2016-08-24

Cohesive interprofessional teamwork is essential to successful healthcare services. Interprofessional teamwork is the means by which different healthcare professionals - with diverse knowledge, skills and talents - collaborate to achieve a common goal. Several interventions are available to improve teamwork in the healthcare setting. This article explores the role of care pathways in improving interprofessional teamwork. Care pathways enhance teamwork by promoting coordination, collaboration, communication and decision making to achieve optimal healthcare outcomes. They result in improved staff knowledge, communication, documentation and interprofessional relations. Care pathways also contribute to patient-centred care and increase patient satisfaction.

PERK Signal-Modulated Protein Translation Promotes the Survivability of Dengue 2 Virus-Infected Mosquito Cells and Extends Viral Replication.

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Hou, Jiun-Nan; Chen, Tien-Huang; Chiang, Yi-Hsuan; Peng, Jing-Yun; Yang, Tsong-Han; Cheng, Chih-Chieh; Sofiyatun, Eny; Chiu, Cheng-Hsun; Chiang-Ni, Chuan; Chen, Wei-June

2017-09-20

Survival of mosquitoes from dengue virus (DENV) infection is a prerequisite of viral transmission to the host. This study aimed to see how mosquito cells can survive the infection during prosperous replication of the virus. In C6/36 cells, global protein translation was shut down after infection by DENV type 2 (DENV2). However, it returned to a normal level when infected cells were treated with an inhibitor of the protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway. Based on a 7-Methylguanosine 5'-triphosphate (m7GTP) pull-down assay, the eukaryotic translation initiation factor 4F (eIF4F) complex was also identified in DENV2-infected cells. This suggests that most mosquito proteins are synthesized via canonical cap-dependent translation. When the PERK signal pathway was inhibited, both accumulation of reactive oxygen species and changes in the mitochondrial membrane potential increased. This suggested that ER stress response was alleviated through the PERK-mediated shutdown of global proteins in DENV2-infected C6/36 cells. In the meantime, the activities of caspases-9 and -3 and the apoptosis-related cell death rate increased in C6/36 cells with PERK inhibition. This reflected that the PERK-signaling pathway is involved in determining cell survival, presumably by reducing DENV2-induced ER stress. Looking at the PERK downstream target, α-subunit of eukaryotic initiation factor 2 (eIF2α), an increased phosphorylation status was only shown in infected C6/36 cells. This indicated that recruitment of ribosome binding to the mRNA 5'-cap structure could have been impaired in cap-dependent translation. It turned out that shutdown of cellular protein translation resulted in a pro-survival effect on mosquito cells in response to DENV2 infection. As synthesis of viral proteins was not affected by the PERK signal pathway, an alternate mode other than cap-dependent translation may be utilized. This finding provides insights into elucidating how the PERK signal

AKT signaling mediates IGF-I survival actions on otic neural progenitors.

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Maria R Aburto

Full Text Available BACKGROUND: Otic neurons and sensory cells derive from common progenitors whose transition into mature cells requires the coordination of cell survival, proliferation and differentiation programmes. Neurotrophic support and survival of post-mitotic otic neurons have been intensively studied, but the bases underlying the regulation of programmed cell death in immature proliferative otic neuroblasts remains poorly understood. The protein kinase AKT acts as a node, playing a critical role in controlling cell survival and cell cycle progression. AKT is activated by trophic factors, including insulin-like growth factor I (IGF-I, through the generation of the lipidic second messenger phosphatidylinositol 3-phosphate by phosphatidylinositol 3-kinase (PI3K. Here we have investigated the role of IGF-dependent activation of the PI3K-AKT pathway in maintenance of otic neuroblasts. METHODOLOGY/PRINCIPAL FINDINGS: By using a combination of organotypic cultures of chicken (Gallus gallus otic vesicles and acoustic-vestibular ganglia, Western blotting, immunohistochemistry and in situ hybridization, we show that IGF-I-activation of AKT protects neural progenitors from programmed cell death. IGF-I maintains otic neuroblasts in an undifferentiated and proliferative state, which is characterised by the upregulation of the forkhead box M1 (FoxM1 transcription factor. By contrast, our results indicate that post-mitotic p27(Kip-positive neurons become IGF-I independent as they extend their neuronal processes. Neurons gradually reduce their expression of the Igf1r, while they increase that of the neurotrophin receptor, TrkC. CONCLUSIONS/SIGNIFICANCE: Proliferative otic neuroblasts are dependent on the activation of the PI3K-AKT pathway by IGF-I for survival during the otic neuronal progenitor phase of early inner ear development.

USP21 regulates Hippo pathway activity by mediating MARK protein turnover

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Nguyen, Thanh Hung; Kugler, Jan-Michael; Loya, Anand Chainsukh

2017-01-01

observed in cancer and often correlates with worse survival. The activity and stability of Hippo pathway components, including YAP/TAZ, AMOT and LATS1/2, are regulated by ubiquitin-mediated protein degradation. Aberrant expression of ubiquitin ligase complexes that regulate the turnover of Hippo components...

Mediation analysis of the relationship between institutional research activity and patient survival

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Rochon, Justine; du Bois, Andreas; Lange, Theis

2014-01-01

BACKGROUND: Recent studies have suggested that patients treated in research-active institutions have better outcomes than patients treated in research-inactive institutions. However, little attention has been paid to explaining such effects, probably because techniques for mediation analysis...... existing so far have not been applicable to survival data. METHODS: We investigated the underlying mechanisms using a recently developed method for mediation analysis of survival data. Our analysis of the effect of research activity on patient survival was based on 352 patients who had been diagnosed...... mediated through either optimal surgery or chemotherapy. Taken together, about 26% of the beneficial effect of research activity was mediated through the proposed pathways. CONCLUSIONS: Mediation analysis allows proceeding from the question "Does it work?" to the question "How does it work?" In particular...

Toward a quantitative understanding of the Wnt/ β -catenin pathway through simulation and experiment

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Lloyd-Lewis, Bethan; Fletcher, Alexander G.; Dale, Trevor C.; Byrne, Helen M.

2013-01-01

Wnt signaling regulates cell survival, proliferation, and differentiation throughout development and is aberrantly regulated in cancer. The pathway is activated when Wnt ligands bind to specific receptors on the cell surface, resulting

Differences in cancer awareness and beliefs between Australia, Canada, Denmark, Norway, Sweden and the UK (the International Cancer Benchmarking Partnership): do they contribute to differences in cancer survival?

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Forbes, L J L; Simon, A E; Warburton, F; Boniface, D; Brain, K E; Dessaix, A; Donnelly, C; Haynes, K; Hvidberg, L; Lagerlund, M; Lockwood, G; Tishelman, C; Vedsted, P; Vigmostad, M N; Ramirez, A J; Wardle, J

2013-01-01

Background: There are wide international differences in 1-year cancer survival. The UK and Denmark perform poorly compared with other high-income countries with similar health care systems: Australia, Canada and Sweden have good cancer survival rates, Norway intermediate survival rates. The objective of this study was to examine the pattern of differences in cancer awareness and beliefs across these countries to identify where these might contribute to the pattern of survival. Methods: We carried out a population-based telephone interview survey of 19 079 men and women aged ⩾50 years in Australia, Canada, Denmark, Norway, Sweden and the UK using the Awareness and Beliefs about Cancer measure. Results: Awareness that the risk of cancer increased with age was lower in the UK (14%), Canada (13%) and Australia (16%) but was higher in Denmark (25%), Norway (29%) and Sweden (38%). Symptom awareness was no lower in the UK and Denmark than other countries. Perceived barriers to symptomatic presentation were highest in the UK, in particular being worried about wasting the doctor's time (UK 34% Canada 21% Australia 14% Denmark 12% Norway 11% Sweden 9%). Conclusion: The UK had low awareness of age-related risk and the highest perceived barriers to symptomatic presentation, but symptom awareness in the UK did not differ from other countries. Denmark had higher awareness of age-related risk and few perceived barriers to symptomatic presentation. This suggests that other factors must be involved in explaining Denmark's poor survival rates. In the UK, interventions that address barriers to prompt presentation in primary care should be developed and evaluated. PMID:23370208

Gender and survival in patients with heart failure

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Martínez-Sellés, Manuel; Doughty, Robert N; Poppe, Katrina

2012-01-01

The aim of this study was to investigate the relationship between gender and survival of patients with heart failure, using data from both randomized trials and observational studies, and the relative contribution of age, left ventricular systolic function, aetiology, and diabetes to differences...

The interplay of CD150 and CD180 receptor pathways contribute to the pathobiology of chronic lymphocytic leukemia B cells by selective inhibition of Akt and MAPK signaling.

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Inna Gordiienko

Full Text Available Cell surface expression of CD150 and CD180 receptors in chronic lymphocytic leukemia (CLL associates with mutational IGHV status and favourable prognosis. Here we show a direct correlation between cell surface expression and colocalization of these receptors on CLL B cells. In the absence of CD150 and CD180 on the cell surface both receptors were expressed in the cytoplasm. The CD150 receptor was colocalized with markers of the endoplasmic reticulum, the Golgi apparatus and early endosomes. In contrast, CD180 was detected preferentially in early endosomes. Analysis of CD150 isoforms differential expression revealed that regardless of CD150 cell surface expression the mCD150 isoform with two ITSM signaling motifs was a predominant CD150 isoform in CLL B cells. The majority of CLL cases had significantly elevated expression level of the soluble sCD150, moreover CLL B cells secrete this isoform. CD150 or CD180 crosslinking on CLL B cells alone led to activation of Akt, mTORC1, ERK1/2, p38MAPK and JNK1/2 networks. Both CD150 and CD180 target the translation machinery through mTOR independent as well as mTOR dependent pathways. Moreover, both these receptors transmit pro-survival signals via Akt-mediated inhibition of GSK3β and FOXO1/FOXO3a. Unexpectedly, coligation CD150 and CD180 receptors on CLL B cells led to mutual inhibition of the Akt and MAPK pathways. While CD150 and CD180 coligation resulted in reduced phosphorylation of Akt, ERK1/2, c-Jun, RSK, p70S6K, S6RP, and 4E-BP; it led to complete blocking of mTOR and p38MAPK phosphorylation. At the same time coligation of CD150 and CD40 receptors did not result in Akt and MAPK inhibition. This suggests that combination of signals via CD150 and CD180 leads to blocking of pro-survival pathways that may be a restraining factor for neoplastic CLL B cells propagation in more than 50% of CLL cases where these receptors are coexpressed.

Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

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Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Aftab, Blake T. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Rudin, Charles M. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hales, Russell K., E-mail: rhales1@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

2013-05-01

Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

Cell Signaling and Differential Protein Expression in Neuronal Differentiation of Bone Marrow Mesenchymal Stem Cells with Hypermethylated Salvador/Warts/Hippo (SWH Pathway Genes.

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Hui-Hung Tzeng

Full Text Available Human mesenchymal stem cells (MSCs modified by targeting DNA hypermethylation of genes in the Salvador/Warts/Hippo pathway were induced to differentiate into neuronal cells in vitro. The differentiated cells secreted a significant level of brain-derived neurotrophy factor (BDNF and the expression of BDNF receptor tyrosine receptor kinase B (TrkB correlated well with the secretion of BDNF. In the differentiating cells, CREB was active after the binding of growth factors to induce phosphorylation of ERK in the MAPK/ERK pathway. Downstream of phosphorylated CREB led to the functional maturation of differentiated cells and secretion of BDNF, which contributed to the sustained expression of pERK and pCREB. In summary, both PI3K/Akt and MAPK/ERK signaling pathways play important roles in the neuronal differentiation of MSCs. The main function of the PI3K/Akt pathway is to maintain cell survival during neural differentiation; whereas the role of the MAPK/ERK pathway is probably to promote the maturation of differentiated MSCs. Further, cellular levels of protein kinase C epsilon type (PKC-ε and kinesin heavy chain (KIF5B increased with time of induction, whereas the level of NME/NM23 nucleoside diphosphate kinase 1 (Nm23-H1 decreased during the time course of differentiation. The correlation between PKC-ε and TrkB suggested that there is cross-talk between PKC-ε and the PI3K/Akt signaling pathway.

Veratridine increases the survival of retinal ganglion cells in vitro

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S.P.F. Pereira

1997-12-01

Full Text Available Neuronal cell death is an important phenomenon involving many biochemical pathways. This degenerative event has been studied to understand how the cells activate the mechanisms that lead to self-destruction. Target cells and afferent cells play a relevant role in the regulation of natural cell death. We studied the effect of veratridine (1.5, 3.0, 4.5 and 6.0 µM on the survival of neonatal rat retinal ganglion cells in vitro. Veratridine (3.0 µM, a well-known depolarizing agent that opens the Na+ channel, promoted a two-fold increase in the survival of retinal ganglion cells kept in culture for 48 h. This effect was dose-dependent and was blocked by 1.0 µM tetrodotoxin (a classical voltage-dependent Na+ channel blocker and 30.0 µM flunarizine (a Na+ and Ca2+ channel blocker. These results indicate that electrical activity is also important for the maintenance of retinal ganglion cell survival in vitro

Activation of the TXNIP/NLRP3 inflammasome pathway contributes to inflammation in diabetic retinopathy: a novel inhibitory effect of minocycline.

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Chen, Wei; Zhao, Minjie; Zhao, Shuzhi; Lu, Qianyi; Ni, Lisha; Zou, Chen; Lu, Li; Xu, Xun; Guan, Huaijin; Zheng, Zhi; Qiu, Qinghua

2017-02-01

Chronic low-grade inflammation occurs in diabetic retinopathy (DR), but the underlying mechanism(s) remains (remain) unclear. NLRP3 inflammasome activation is involved in several other inflammatory diseases. Thus, we investigated the role of the NLRP3 inflammasome signaling pathway in the pathogenesis of DR. Diabetes was induced in rats by streptozotocin treatment for 8 weeks. They were treated with NLRP3 shRNA or minocycline during the last 4 weeks. High glucose-exposed human retinal microvascular endothelial cells (HRMECs) were co-incubated with antioxidants or subjected to TXNIP or NLRP3 shRNA interference. In high glucose-exposed HRMECs and retinas of diabetic rats, mRNA and protein expression of NLRP3, ASC, and proinflammatory cytokines were induced significantly by hyperglycemia. Upregulated interleukin (IL)-1β maturation, IL-18 secretion, and caspase-1 cleavage were also observed with increased cell apoptosis and retinal vascular permeability, compared with the control group. NLRP3 silencing blocked these effects in the rat model and HRMECs, confirming that inflammasome activation contributed to inflammation in DR. TXNIP expression was increased by reactive oxygen species (ROS) overproduction in animal and cell models, whereas antioxidant addition or TXNIP silencing blocked IL-1β and IL-18 secretion in high glucose-exposed HRMECs, indicating that the ROS-TXNIP pathway mediates NLRP3 inflammasome activation. Minocycline significantly downregulated ROS generation and reduced TXNIP expression, subsequently inhibited NLRP3 activation, and further decreased inflammatory factors, which were associated with a decrease in retinal vascular permeability and cell apoptosis. Together, our data suggest that the TXNIP/NLRP3 pathway is a potential therapeutic target for the treatment of DR, and the use of minocycline specifically for such therapy may be a new avenue of investigation in inflammatory disease.

Methylprednisolone promotes recovery of neurological function after spinal cord injury: association with Wnt/β-catenin signaling pathway activation

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Lu, Gong-biao; Niu, Fu-wen; Zhang, Ying-chun; Du, Lin; Liang, Zhi-yuan; Gao, Yuan; Yan, Ting-zhen; Nie, Zhi-kui; Gao, Kai

2016-01-01

Some studies have indicated that the Wnt/β-catenin signaling pathway is activated following spinal cord injury, and expression levels of specific proteins, including low-density lipoprotein receptor related protein-6 phosphorylation, β-catenin, and glycogen synthase kinase-3β, are significantly altered. We hypothesized that methylprednisolone treatment contributes to functional recovery after spinal cord injury by inhibiting apoptosis and activating the Wnt/β-catenin signaling pathway. In the current study, 30 mg/kg methylprednisolone was injected into rats with spinal cord injury immediately post-injury and at 1 and 2 days post-injury. Basso, Beattie, and Bresnahan scores showed that methylprednisolone treatment significantly promoted locomotor functional recovery between 2 and 6 weeks post-injury. The number of surviving motor neurons increased, whereas the lesion size significantly decreased following methylprednisolone treatment at 7 days post-injury. Additionally, caspase-3, caspase-9, and Bax protein expression levels and the number of apoptotic cells were reduced at 3 and 7 days post-injury, while Bcl-2 levels at 7 days post-injury were higher in methylprednisolone-treated rats compared with saline-treated rats. At 3 and 7 days post-injury, methylprednisolone up-regulated expression and activation of the Wnt/β-catenin signaling pathway, including low-density lipoprotein receptor related protein-6 phosphorylation, β-catenin, and glycogen synthase kinase-3β phosphorylation. These results indicate that methylprednisolone-induced neuroprotection may correlate with activation of the Wnt/β-catenin signaling pathway. PMID:28123427

period-Regulated Feeding Behavior and TOR Signaling Modulate Survival of Infection.

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Allen, Victoria W; O'Connor, Reed M; Ulgherait, Matthew; Zhou, Clarice G; Stone, Elizabeth F; Hill, Vanessa M; Murphy, Keith R; Canman, Julie C; Ja, William W; Shirasu-Hiza, Mimi M

2016-01-25

Most metazoans undergo dynamic, circadian-regulated changes in behavior and physiology. Currently, it is unknown how circadian-regulated behavior impacts immunity against infection. Two broad categories of defense against bacterial infection are resistance, control of microbial growth, and tolerance, control of the pathogenic effects of infection. Our study of behaviorally arrhythmic Drosophila circadian period mutants identified a novel link between nutrient intake and tolerance of infection with B. cepacia, a bacterial pathogen of rising importance in hospital-acquired infections. We found that infection tolerance in wild-type animals is stimulated by acute exposure to dietary glucose and amino acids. Glucose-stimulated tolerance was induced by feeding or direct injection; injections revealed a narrow window for glucose-stimulated tolerance. In contrast, amino acids stimulated tolerance only when ingested. We investigated the role of a known amino-acid-sensing pathway, the TOR (Target of Rapamycin) pathway, in immunity. TORC1 is circadian regulated and inhibition of TORC1 decreased resistance, as in vertebrates. Surprisingly, inhibition of the less well-characterized TOR complex 2 (TORC2) dramatically increased survival, through both resistance and tolerance mechanisms. This work suggests that dietary intake on the day of infection by B. cepacia can make a significant difference in long-term survival. We further demonstrate that TOR signaling mediates both resistance and tolerance of infection and identify TORC2 as a novel potential therapeutic target for increasing survival of infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival

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Yunjong Lee

2017-01-01

Full Text Available Mutations in PTEN-induced putative kinase 1 (PINK1 and parkin cause autosomal-recessive Parkinson’s disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746 that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α promoter activity. Here, we show that PARIS links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity, as well as repression of PGC-1α promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Altogether, these results uncover a function of PINK1 to direct parkin-PARIS-regulated PGC-1α expression and dopaminergic neuronal survival.

Reverse survival method of fertility estimation: An evaluation

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Thomas Spoorenberg

2014-07-01

Full Text Available Background: For the most part, demographers have relied on the ever-growing body of sample surveys collecting full birth history to derive total fertility estimates in less statistically developed countries. Yet alternative methods of fertility estimation can return very consistent total fertility estimates by using only basic demographic information. Objective: This paper evaluates the consistency and sensitivity of the reverse survival method -- a fertility estimation method based on population data by age and sex collected in one census or a single-round survey. Methods: A simulated population was first projected over 15 years using a set of fertility and mortality age and sex patterns. The projected population was then reverse survived using the Excel template FE_reverse_4.xlsx, provided with Timæus and Moultrie (2012. Reverse survival fertility estimates were then compared for consistency to the total fertility rates used to project the population. The sensitivity was assessed by introducing a series of distortions in the projection of the population and comparing the difference implied in the resulting fertility estimates. Results: The reverse survival method produces total fertility estimates that are very consistent and hardly affected by erroneous assumptions on the age distribution of fertility or by the use of incorrect mortality levels, trends, and age patterns. The quality of the age and sex population data that is 'reverse survived' determines the consistency of the estimates. The contribution of the method for the estimation of past and present trends in total fertility is illustrated through its application to the population data of five countries characterized by distinct fertility levels and data quality issues. Conclusions: Notwithstanding its simplicity, the reverse survival method of fertility estimation has seldom been applied. The method can be applied to a large body of existing and easily available population data

The Survival Advantage: Underlying Mechanisms and Extant Limitations

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Stephanie A. Kazanas

2015-04-01

Full Text Available Recently, researchers have begun to investigate the function of memory in our evolutionary history. According to Nairne and colleagues (e.g., Nairne, Pandeirada, and Thompson, 2008; Nairne, Thompson, and Pandeirada, 2007, the best mnemonic strategy for learning lists of unrelated words may be one that addresses the same problems that our Pleistocene ancestors faced: fitness-relevant problems including securing food and water, as well as protecting themselves from predators. Survival processing has been shown to promote better recall and recognition memory than many well-known mnemonic strategies (e.g., pleasantness ratings, imagery, generation, etc.. However, the survival advantage does not extend to all types of stimuli and tasks. The current review presents research that has replicated Nairne et al.'s (2007 original findings, in addition to the research designs that fail to replicate the survival advantage. In other words, there are specific manipulations in which survival processing does not appear to benefit memory any more than other strategies. Potential mechanisms for the survival advantage are described, with an emphasis on those that are the most plausible. These proximate mechanisms outline the memory processes that may contribute to the advantage, although the ultimate mechanism may be the congruity between the survival scenario and Pleistocene problem-solving.

Lysosomal cysteine peptidases - Molecules signaling tumor cell death and survival.

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Pišlar, Anja; Perišić Nanut, Milica; Kos, Janko

2015-12-01

Lysosomal cysteine peptidases - cysteine cathepsins - are general intracellular protein-degrading enzymes that control also a variety of specific physiological processes. They can trigger irreversible events leading to signal transduction and activation of signaling pathways, resulting in cell survival and proliferation or cell death. In cancer cells, lysosomal cysteine peptidases are involved in multiple processes during malignant progression. Their translocation from the endosomal/lysosomal pathway to nucleus, cytoplasm, plasma membrane and extracellular space enables the activation and remodeling of a variety of tumor promoting proteins. Thus, lysosomal cysteine peptidases interfere with cytokine/chemokine signaling, regulate cell adhesion and migration and endocytosis, are involved in the antitumor immune response and apoptosis, and promote cell invasion, angiogenesis and metastasis. Further, lysosomal cysteine peptidases modify growth factors and receptors involved in tyrosine kinase dependent pathways such as MAPK, Akt and JNK, thus representing key signaling tools for the activation of tumor cell growth and proliferation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Intrinsic JNK-MAPK pathway involvement requires daf-16-mediated immune response during Shigella flexneri infection in C. elegans.

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Marudhupandiyan, Shanmugam; Balamurugan, Krishnaswamy

2017-06-01

The c-Jun N-terminal kinase-mitogen-activated protein kinase (JNK-MAPK) pathway assists in modulating signals for growth, survival, and metabolism, thereby coordinating many cellular events during normal and stress conditions. To understand the role of the JNK-MAPK pathway during bacterial infection, an in vivo model organism Caenorhabditis elegans was used. In order to check the involvement of the JNK-MAPK pathway, the survival rate of C. elegans wild type (WT), and JNK-MAPK pathway mutant worms' upon exposure to selective Gram-positive and Gram-negative pathogenic bacteria, was studied. Among the pathogens, Shigella flexneri M9OT was found to efficiently colonize inside the WT and JNK-MAPK pathway mutant worms. qPCR studies had suggested that the above pathway-specific genes kgb-2 and jnk-1 were prominently responsible for the immune response elicited by the host during the M9OT infection. In addition, daf-16, which is a major transcription factor of the insulin/insulin growth factor-1 signaling (IIS) pathway, was also found to be involved during the host response. Crosstalk between IIS and JNK-MAPK pathways has probably been involved in the activation of the host immune system, which consequently leads to lifespan extension. Furthermore, it is also observed that daf-16 activation by JNK-MAPK pathway leads to antimicrobial response, by activating lys-7 expression. These findings suggest that JNK-MAPK is not the sole pathway that enhances the immunity of the host. Nonetheless, the IIS pathway bridges the JNK-MAPK pathway that influences in protecting the host in counter to the M9OT infection.

Vitamin K2 regression aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats.

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Jiang, Xiaoyu; Tao, Huiren; Qiu, Cuiting; Ma, Xiaolei; Li, Shan; Guo, Xian; Lv, Anlin; Li, Huan

2016-09-05

The aim of this study was to investigate the effect of vitamin K2 on aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats. A calcification model was established by administering 3mg/g warfarin to rats. Rats were divided into 9 groups: control group (0W, 4W, 6W and 12W groups), 4W calcification group, 6W calcification group, 12W calcification group, 6W calcification+6W normal group and 6W calcification+6W vitamin K2 group. Alizarin red S staining measured aortic calcium depositions; alkaline phosphatase activity in serum was measured by a kit; apoptosis was evaluated by TUNEL assay; protein expression levels of Gas6, Axl, phosphorylated Akt (p-Akt), and Bcl-2 were determined by western blotting. The calcium content, calcium depositions, ALP activity and apoptosis were significantly higher in the calcification groups than control group. Gas6, Axl, p-Akt and Bcl-2 expression was lower in the calcification group than control group. 100μg/g vitamin K2 treatment decreased calcium depositions, ALP activity and apoptosis significantly, but increased Gas6, Axl, p-Akt and Bcl-2 expression. 100μg/g vitamin K2 reversed 44% calcification. Pearson correlation analysis showed a positive correlation between formation calcification and apoptosis (R(2)=0.8853, PK2 can inhibit warfarin-induced aortic calcification and apoptosis. The regression of aortic calcification by vitamin K2 involved the Gas6/Axl axis. This data may provide a theoretical basis for future clinical treatments for aortic calcification. Copyright © 2016 Elsevier B.V. All rights reserved.

Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells.

Science.gov (United States)

Benoit, G R; Flexor, M; Besançon, F; Altucci, L; Rossin, A; Hillion, J; Balajthy, Z; Legres, L; Ségal-Bendirdjian, E; Gronemeyer, H; Lanotte, M

2001-07-01

On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.

Frontline Science: HMGB1 induces neutrophil dysfunction in experimental sepsis and in patients who survive septic shock.

Science.gov (United States)

Grégoire, Murielle; Tadié, Jean-Marc; Uhel, Fabrice; Gacouin, Arnaud; Piau, Caroline; Bone, Nathaniel; Le Tulzo, Yves; Abraham, Edward; Tarte, Karin; Zmijewski, Jaroslaw W

2017-06-01

Sepsis is accompanied by the initial activation of proinflammatory pathways and long-lasting immunosuppression that appears to contribute to late-occurring mortality. Although high-mobility group box 1 (HMGB1) is involved in many aspects of inflammation, its role in sepsis-induced immune suppression remains unclear. In this study, we examined HMGB1's contribution to neutrophil NADPH oxidase activity dysfunction and associated neutrophil-dependent bacterial clearance in mice subjected to sepsis and in patients who survive septic shock. Using a murine model of polymicrobial septic peritonitis, we demonstrated that treatment with anti-HMGB1 Ab significantly diminished sepsis-induced dysfunction of neutrophil NADPH oxidase activity. In a subsequent set of experiments, we found that blocking HMGB1 preserved the ability of neutrophils from patients recovering from septic shock to activate NADPH oxidase. Taken together, our data suggest that HMGB1 accumulation in the late phase of sepsis plays a specific role in the development of postsepsis immunosuppression and specifically affects neutrophil-dependent antibacterial defense mechanisms. Thus, blocking HMGB1 may be a promising therapeutic intervention to diminish the adverse effects of sepsis-induced immunosuppression. © Society for Leukocyte Biology.

SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

DEFF Research Database (Denmark)

Jamshidi, Maral; Fagerholm, Rainer; Khan, Sofia

2015-01-01

of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare...

Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

International Nuclear Information System (INIS)

Jhanwar-Uniyal, Meena; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj

2015-01-01

Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM

Glioblastoma: Molecular Pathways, Stem Cells and Therapeutic Targets

Energy Technology Data Exchange (ETDEWEB)

Jhanwar-Uniyal, Meena, E-mail: meena_jhanwar@nymc.edu; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj [Department of Neurosurgery, New York Medical College, Valhalla, NY 10595 (United States)

2015-03-25

Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM.

YAP and the Hippo pathway in pediatric cancer.

Science.gov (United States)

Ahmed, Atif A; Mohamed, Abdalla D; Gener, Melissa; Li, Weijie; Taboada, Eugenio

2017-01-01

The Hippo pathway is an important signaling pathway that controls cell proliferation and apoptosis. It is evolutionarily conserved in mammals and is stimulated by cell-cell contact, inhibiting cell proliferation in response to increased cell density. During early embryonic development, the Hippo signaling pathway regulates organ development and size, and its functions result in the coordinated balance between proliferation, apoptosis, and differentiation. Its principal effectors, YAP and TAZ, regulate signaling by the embryonic stem cells and determine cell fate and histogenesis. Dysfunction of this pathway contributes to cancer development in adults and children. Emerging studies have shed light on the upregulation of Hippo pathway members in several pediatric cancers and may offer prognostic information on rhabdomyosarcoma, osteosarcoma, Wilms tumor, neuroblastoma, medulloblastoma, and other brain gliomas. We review the results of such published studies and highlight the potential clinical application of this pathway in pediatric oncologic and pathologic studies. These studies support targeting this pathway as a novel treatment strategy.

Three Models of Anthrax Toxin Effects on the MAP-Kinase Pathway and Macrophage Survival

Science.gov (United States)

2008-03-01

2005). Apic, Gordana, Tijana Ignjatovic, Scott Boyer , and Robert B. Russell. “Illuminating drug discovery with biological pathways,” FEBS Letters...Molecular Biology Reviews, 68(2): 320–344 (June 2004). Sauro, Herbert M. and Boris N. Kholodenko. “Quantitative analysis of signaling networks

Carbonaceous Survivability on Impact

Science.gov (United States)

Bunch, T. E.; Becker, Luann; Morrison, David (Technical Monitor)

1994-01-01

In order to gain knowledge about the potential contributions of comets and cosmic dust to the origin of life on Earth, we need to explore the survivability of their potential organic compounds on impact and the formation of secondary products that may have arisen from the chaotic events sustained by the carriers as they fell to Earth. We have performed a series of hypervelocity impact experiments using carbon-bearing impactors (diamond, graphite, kerogens, PAH crystals, and Murchison and Nogoya meteorites) into Al plate targets at velocities - 6 km/s. Estimated peak shock pressures probably did not exceed 120 GPa and peak shock temperatures were probably less than 4000 K for times of nano- to microsecs. Nominal crater dia. are less than one mm. The most significant results of these experiments are the preservation of the higher mass PAHs (e. g., pyrene relative to napthalene) and the formation of additional alkylated PAHs. We have also examined the residues of polystyrene projectiles impacted by a microparticle accelerator into targets at velocities up to 15 km/s. This talk will discuss the results of these experiments and their implications with respect to the survival of carbonaceous deliverables to early Earth. The prospects of survivability of organic molecules on "intact" capture of cosmic dust in space via soft: and hard cosmic dust collectors will also be discussed.

Oncogenic functions of the cancer-testis antigen SSX on the proliferation, survival, and signaling pathways of cancer cells.

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Padraig D'Arcy

Full Text Available SSX is a transcription factor with elusive oncogenic functions expressed in a variety of human tumors of epithelial and mesenchymal origin. It has raised substantial interest as a target for cancer therapy since it elicits humoral responses and displays restricted expression to cancer, spermatogonia and mesenchymal stem cells. Here, we investigated the oncogenic properties of SSX by employing a RNA interference to knock-down the endogenous expression of SSX in melanoma and osteosarcoma cell lines. Depletion of SSX expression resulted in reduced proliferation with cells accumulating in the G1 phase of the cell cycle. We found that the growth promoting and survival properties of SSX are mediated in part though modulation of MAPK/Erk and Wnt signaling pathways, since SSX silencing inhibited Erk-mediated signaling and transcription of cMYC and Akt-1. We also found that SSX forms a transient complex with β-catenin at the G1-S phase boundary resulting in the altered expression of β-catenin target genes such as E-cadherin, snail-2 and vimentin, involved in epithelial-mesenchymal transitions. Importantly the silencing of SSX expression in in vivo significantly impaired the growth of melanoma tumor xenografts. Tumor biopsies from SSX silenced tumors displayed reduced cyclin A staining, indicative of low proliferation and predominantly cycloplasmic β-catenin compared to SSX expressing tumors. The present study demonstrates a previously unknown function of SSX, that as an oncogene and as a tumor target for the development of novel anti-cancer drugs.

Females increase reproductive investment in response to helper-mediated improvements in allo-feeding, nest survival, nestling provisioning and post-fledging survival in the Karoo scrub-robin Cercotrichas coryphaeus

Science.gov (United States)

Lloyd, P.; Andrew, Taylor W.; du Plessis, Morné A.; Martin, T.E.

2009-01-01

In many cooperatively-breeding species, the presence of one or more helpers improves the reproductive performance of the breeding pair receiving help. Helper contributions can take many different forms, including allo-feeding, offspring provisioning, and offspring guarding or defence. Yet, most studies have focussed on single forms of helper contribution, particularly offspring provisioning, and few have evaluated the relative importance of a broader range of helper contributions to group reproductive performance. We examined helper contributions to multiple components of breeding performance in the Karoo scrub-robin Cercotrichas coryphaeus, a facultative cooperative breeder. We also tested a prediction of increased female investment in reproduction when helpers improve conditions for rearing young. Helpers assisted the breeding male in allo-feeding the incubating female, increasing allo-feeding rates. Greater allo-feeding correlated with greater female nest attentiveness during incubation. Nest predation was substantially lower among pairs breeding with a helper, resulting in a 74% increase in the probability of nest survival. Helper contributions to offspring provisioning increased nestling feeding rates, resulting in a reduced incidence of nestling starvation and increased nestling mass. Nestling mass had a strong, positive effect on post-fledging survival. Controlling for female age and habitat effects, annual production of fledged young was 130% greater among pairs breeding with a helper, and was influenced most strongly by helper correlates with nest survival, despite important helper effects on offspring provisioning. Females breeding with a helper increased clutch size, supporting the prediction of increased female investment in reproduction in response to helper benefits. ?? 2009 J. Avian Biol.

Phosphodiesterase type 4 inhibitor rolipram improves survival of spiral ganglion neurons in vitro.

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Katharina Kranz

Full Text Available Sensorineural deafness is caused by damage of hair cells followed by degeneration of the spiral ganglion neurons and can be moderated by cochlear implants. However, the benefit of the cochlear implant depends on the excitability of the spiral ganglion neurons. Therefore, current research focuses on the identification of agents that will preserve their degeneration. In this project we investigated the neuroprotective effect of Rolipram as a promising agent to improve the viability of the auditory neurons. It is a pharmaceutical agent that acts by selective inhibition of the phosphodiesterase 4 leading to an increase in cyclic AMP. Different studies reported a neuroprotective effect of Rolipram. However, its significance for the survival of SGN has not been reported so far. Thus, we isolated spiral ganglion cells of neonatal rats for cultivation with different Rolipram concentrations and determined the neuronal survival rate. Furthermore, we examined immunocytologically distinct proteins that might be involved in the neuroprotective signalling pathway of Rolipram and determined endogenous BDNF by ELISA. When applied at a concentration of 0.1 nM, Rolipram improved the survival of SGN in vitro. According to previous studies, our immunocytological data showed that Rolipram application induces the phosphorylation and thereby activation of the transcription factor CREB. This activation can be mediated by the cAMP-PKA-signalling pathway as well as via ERK as a part of the MAP-kinase pathway. However, only in cultures pre-treated with BDNF, an endogenous increase of BDNF was detected. We conclude that Rolipram has the potential to improve the vitality of neonatal auditory nerve cells in vitro. Further investigations are necessary to prove the effect of Rolipram in vivo in the adult organism after lesion of the hair cells and insertion of cochlear implants.

Stem cell factor expression after renal ischemia promotes tubular epithelial survival.

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Geurt Stokman

Full Text Available BACKGROUND: Renal ischemia leads to apoptosis of tubular epithelial cells and results in decreased renal function. Tissue repair involves re-epithelialization of the tubular basement membrane. Survival of the tubular epithelium following ischemia is therefore important in the successful regeneration of renal tissue. The cytokine stem cell factor (SCF has been shown to protect the tubular epithelium against apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: In a mouse model for renal ischemia/reperfusion injury, we studied how expression of c-KIT on tubular epithelium and its ligand SCF protect cells against apoptosis. Administration of SCF specific antisense oligonucleotides significantly decreased specific staining of SCF following ischemia. Reduced SCF expression resulted in impaired renal function, increased tubular damage and increased tubular epithelial apoptosis, independent of inflammation. In an in vitro hypoxia model, stimulation of tubular epithelial cells with SCF activated survival signaling and decreased apoptosis. CONCLUSIONS/SIGNIFICANCE: Our data indicate an important role for c-KIT and SCF in mediating tubular epithelial cell survival via an autocrine pathway.

An enhanced functional interrogation/manipulation of intracellular signaling pathways with the peptide 'stapling' technology.

Science.gov (United States)

He, Y; Chen, D; Zheng, W

2015-11-12

Specific protein-protein interactions (PPIs) constitute a key underlying mechanism for the presence of a multitude of intracellular signaling pathways, which are essential for the survival of normal and cancer cells. Specific molecular blockers for a crucial PPI would therefore be invaluable tools for an enhanced functional interrogation of the signaling pathway harboring this particular PPI. On the other hand, if a particular PPI is essential for the survival of cancer cells but is absent in or dispensable for the survival of normal cells, its specific molecular blockers could potentially be developed into effective anticancer therapeutics. Due to the flat and extended PPI interface, it would be conceivably difficult for small molecules to achieve an effective blockade, a problem which could be potentially circumvented with peptides or proteins. However, the well-documented proteolytic instability and cellular impermeability of peptides and proteins in general would make their developing into effective intracellular PPI blockers quite a challenge. With the advent of the peptide 'stapling' technology which was demonstrated to be able to stabilize the α-helical conformation of a peptide via bridging two neighboring amino-acid side chains with a 'molecular staple', a linear parent peptide could be transformed into a stronger PPI blocker with enhanced proteolytic stability and cellular permeability. This review will furnish an account on the peptide 'stapling' technology and its exploitation in efforts to achieve an enhanced functional interrogation or manipulation of intracellular signaling pathways especially those that are cancer relevant.

Complexity for survival of livings

Energy Technology Data Exchange (ETDEWEB)

Zak, Michail [Jet Propulsion Laboratory, California Institute of Technology, Advance Computing Algorithms and IVHM Group, Pasadena, CA 91109 (United States)]. E-mail: Michail.Zak@jpl.nasa.gov

2007-05-15

A connection between survivability of livings and complexity of their behavior is established. New physical paradigms-exchange of information via reflections, and chain of abstractions-explaining and describing progressive evolution of complexity in living (active) systems are introduced. A biological origin of these paradigms is associated with a recently discovered mirror neuron that is able to learn by imitation. As a result, an active element possesses the self-nonself images and interacts with them creating the world of mental dynamics. Three fundamental types of complexity of mental dynamics that contribute to survivability are identified. Mathematical model of the corresponding active systems is described by coupled motor-mental dynamics represented by Langevin and Fokker-Planck equations, respectively, while the progressive evolution of complexity is provided by nonlinear evolution of probability density. Application of the proposed formalism to modeling common-sense-based decision-making process is discussed.

Complexity for survival of livings

International Nuclear Information System (INIS)

Zak, Michail

2007-01-01

A connection between survivability of livings and complexity of their behavior is established. New physical paradigms-exchange of information via reflections, and chain of abstractions-explaining and describing progressive evolution of complexity in living (active) systems are introduced. A biological origin of these paradigms is associated with a recently discovered mirror neuron that is able to learn by imitation. As a result, an active element possesses the self-nonself images and interacts with them creating the world of mental dynamics. Three fundamental types of complexity of mental dynamics that contribute to survivability are identified. Mathematical model of the corresponding active systems is described by coupled motor-mental dynamics represented by Langevin and Fokker-Planck equations, respectively, while the progressive evolution of complexity is provided by nonlinear evolution of probability density. Application of the proposed formalism to modeling common-sense-based decision-making process is discussed

Cardiomyocyte Survival Pathways

NARCIS (Netherlands)

Lips, Daniel Jozef

2004-01-01

In the present thesis, the link between the genotype of the mouse and the concurrent phenotype is investigated employing sophisticated molecular and cellular techniques combined with in vivo cardiac performance measurements. In chapter 1 we focus on the characteristics of cardiac remodeling

C-Jun N-terminal kinase signalling pathway in response to cisplatin.

Science.gov (United States)

Yan, Dong; An, GuangYu; Kuo, Macus Tien

2016-11-01

Cisplatin (cis diamminedichloroplatinum II, cDDP) is one of the most effective cancer chemotherapeutic agents and is used in the treatment of many types of human malignancies. However, inherent tumour resistance is a major barrier to effective cisplatin therapy. So far, the mechanism of cDDP resistance has not been well defined. In general, cisplatin is considered to be a cytotoxic drug, for damaging DNA and inhibiting DNA synthesis, resulting in apoptosis via the mitochondrial death pathway or plasma membrane disruption. cDDP-induced DNA damage triggers signalling pathways that will eventually decide between cell life and death. As a member of the mitogen-activated protein kinases family, c-Jun N-terminal kinase (JNK) is a signalling pathway in response to extracellular stimuli, especially drug treatment, to modify the activity of numerous proteins locating in the mitochondria or the nucleus. Recent studies suggest that JNK signalling pathway plays a major role in deciding the fate of the cell and inducing resistance to cDDP-induced apoptosis in human tumours. c-Jun N-terminal kinase regulates several important cellular functions including cell proliferation, differentiation, survival and apoptosis while activating and inhibiting substrates for phosphorylation transcription factors (c-Jun, ATF2: Activating transcription factor 2, p53 and so on), which subsequently induce pro-apoptosis and pro-survival factors expression. Therefore, it is suggested that JNK signal pathway is a double-edged sword in cDDP treatment, simultaneously being a significant pro-apoptosis factor but also being associated with increased resistance to cisplatin-based chemotherapy. This review focuses on current knowledge concerning the role of JNK in cell response to cDDP, as well as their role in cisplatin resistance. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Isotype-specific inhibition of the phosphatidylinositol-3-kinase pathway in hematologic malignancies

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Castillo JJ

2014-02-01

Full Text Available Jorge J Castillo,1 Meera Iyengar,2 Benjamin Kuritzky,2 Kenneth D Bishop2 1Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, 2Division of Hematology and Oncology, Rhode Island Hospital, Providence, RI, USA Abstract: In the last decade, the advent of biological targeted therapies has revolutionized the management of several types of cancer, especially in the realm of hematologic malignancies. One of these pathways, and the center of this review, is the phosphatidylinositol-3-kinase (PI3K pathway. The PI3K pathway seems to play an important role in the pathogenesis and survival advantage in hematologic malignancies, such as leukemia, lymphoma, and myeloma. The objectives of the present review, hence, are to describe the current knowledge on the PI3K pathway and its isoforms, and to summarize preclinical and clinical studies using PI3K inhibitors, focusing on the advances made in hematologic malignancies. Keywords: phosphatidylinositol-3-kinase pathway, inhibitors, leukemia, lymphoma, myeloma

Relative contribution of decreased productivity and survival to recent changes in the demographic trend of the Rivière George Caribou Herd

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M. Crête

1996-01-01

Full Text Available The Rivière George caribou herd (RGCH was numerically low during the middle part of the century but apparently erupted in the sixties and the seventies. Puberty was early and pregnancy rate was high among RGCH females from 1973 until the mid-eighties when fecundity decreased significantly, in particular among sub-adults; productivity remained low in 1992. Autumn calf:female ratios reflected this trend in pregnancy, exceeding 50 calves: 100 cows between 1973 and 1983, but dropping thereafter progressively to a low of 24 in 1992. In 1993, this ratio rebounded back to 42. Annual adult survival rate of radio-collared females was high (0.95 at the beginning of the monitoring in 1984, but exhibited a variable but declining trend until 1992. Simulations were conducted to estimate the demographic trend of the RGCH between 1984 and 1992, using annual survival rates of radio-collared animals and annual autumn calffemale ratios to estimate calf production. Age structure played a minor role in estimating the finite rate of increase (Lamda. According to the simulations, the RGCH increased in size until 1987, and showed a slight decrease thereafter. The herd should have decreased by 12-15% between 1988 and 1993, according to the simulations. Productivity first caused a decline in Lamda, but in recent years decreased survival contributed slightly more than productivity to the reduction in Lamda. Estimation of the herd size by means of aerial censuses in 1976, 1984, 1988 and 1993 suggested a similar pattern in demographic trend, differences being statistically meaningless. We speculated on the future of the RGCH, that could have erupted after many decades of unfavourable weather. The herd will exhibit a rapid descent to low numbers if wolves show a numerical response to current caribou abundance, or if lichen availability on the winter range decreases due to competition with the adjacent and increasing Rivière aux Feuilles herd; otherwise it will exhibit

Interaction between Galectin-9/TIM-3 pathway and follicular helper CD4+ T cells contributes to viral persistence in chronic hepatitis C.

Science.gov (United States)

Zhuo, Ya; Zhang, Yi-Fu; Wu, Hong-Jie; Qin, Lei; Wang, Yan-Ping; Liu, A-Min; Wang, Xin-Hong

2017-10-01

Both Galectin 9 (Gal-9)/T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) pathway and follicular helper CD4 + T (Tfh) cells play important roles in persistent hepatitis C virus (HCV) infection. Thus, we aimed to investigate the regulatory role of interaction between Gal-9/TIM-3 pathway and Tfh cells in chronic hepatitis C. A total of 44 chronic hepatitis C patients and 19 normal controls (NCs) were enrolled in this study. Purified CD4 + T cells were cultured by TIM-3 Fc protein, recombinant Gal-9, or IL-21 for 48h. TIM-3 expression, Tfh proportion, and IL-21 production was measured, respectively. The immunomodulatory role of Gal-9/TIM-3 and IL-21 was also investigated in HCV cell culture system in vitro. We found that the percentage corresponding to both TIM-3-positive and CXCR5 + ICOS + Tfh cells within CD4 + T cells, which correlated with HCV RNA replication, was significantly elevated in patients with chronic hepatitis C in comparison with those in NCs. Moreover, blockade of Gal-9/TIM-3 pathway by TIM-3 Fc protein increased Tfh cells proportion, IL-21 mRNA and protein expression within purified CD4 + T cells, while activation of Gal-9/TIM-3 signaling by Gal-9 stimulation decreased IL-21 production in both patients with chronic HCV infection and healthy individuals. Meanwhile, high concentrations (100 and 200ng/mL) of IL-21 stimulation also elevated TIM-3 expression on CD4 + T cells in chronic hepatitis C. Furthermore, TIM-3 blockage and IL-21 stimulation suppressed mRNA expressions of HCV-induced antiviral proteins (myxovirus resistance A and oligoadenylate synthetase) in Huh7.5 cells without affecting viral replication in HCV cell culture system. The interaction between Gal-9/TIM-3 pathway and Tfh cells contributed to viral persistent in chronic HCV infection, which might be pivotal for development of new therapeutic approaches for chronic hepatitis C. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Exogenous Modulation of Retinoic Acid Signaling Affects Adult RGC Survival in the Frog Visual System after Optic Nerve Injury.

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Mildred V Duprey-Díaz

Full Text Available After lesions to the mammalian optic nerve, the great majority of retinal ganglion cells (RGCs die before their axons have even had a chance to regenerate. Frog RGCs, on the other hand, suffer only an approximately 50% cell loss, and we have previously investigated the mechanisms by which the application of growth factors can increase their survival rate. Retinoic acid (RA is a vitamin A-derived lipophilic molecule that plays major roles during development of the nervous system. The RA signaling pathway is also present in parts of the adult nervous system, and components of it are upregulated after injury in peripheral nerves but not in the CNS. Here we investigate whether RA signaling affects long-term RGC survival at 6 weeks after axotomy. Intraocular injection of all-trans retinoic acid (ATRA, the retinoic acid receptor (RAR type-α agonist AM80, the RARβ agonist CD2314, or the RARγ agonist CD1530, returned axotomized RGC numbers to almost normal levels. On the other hand, inhibition of RA synthesis with disulfiram, or of RAR receptors with the pan-RAR antagonist Ro-41-5253, or the RARβ antagonist LE135E, greatly reduced the survival of the axotomized neurons. Axotomy elicited a strong activation of the MAPK, STAT3 and AKT pathways; this activation was prevented by disulfiram or by RAR antagonists. Finally, addition of exogenous ATRA stimulated the activation of the first two of these pathways. Future experiments will investigate whether these strong survival-promoting effects of RA are mediated via the upregulation of neurotrophins.

Determination of key radionuclides and parameters related to dose from the Columbia River pathway

International Nuclear Information System (INIS)

Napier, B.A.

1993-03-01

A series of scoping calculations has been undertaken to evaluate the absolute and relative contributions of different radionuclides and exposure pathways to doses that may have been received by individuals living in the vicinity of the Hanford Site. These scoping calculations may include some radionuclides and pathways that were included in the Phase 1 Columbia River pathway dose evaluations, as well as other potential exposure pathways being evaluated for possible inclusion in future Hanford Environmental Dose Reconstruction Project (HEDR) modeling efforts. This scoping calculation (Calculation 009) examines the contributions of numerous radionuclides to dose via environmental exposures and accumulation in water, fish, and other aquatic biota. Addressed in these calculations are the contributions to effective dose from (1) external exposure to contaminated river water, ( 2) ingestion of contaminated drinking water, and (3) ingestion of contaminated resident Columbia River fish. Additional information on contamination of anadromous fish and waterfowl is provided

The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival.

Science.gov (United States)

Moulin, Pauline; Patron, Kévin; Cano, Camille; Zorgani, Mohamed Amine; Camiade, Emilie; Borezée-Durant, Elise; Rosenau, Agnès; Mereghetti, Laurent; Hiron, Aurélia

2016-12-15

The Lmb protein of Streptococcus agalactiae is described as an adhesin that binds laminin, a component of the human extracellular matrix. In this study, we revealed a new role for this protein in zinc uptake. We also identified two Lmb homologs, AdcA and AdcAII, redundant binding proteins that combine with the AdcCB translocon to form a zinc-ABC transporter. Expression of this transporter is controlled by the zinc concentration in the medium through the zinc-dependent regulator AdcR. Triple deletion of lmb, adcA, and adcAII, or that of the adcCB genes, impaired growth and cell separation in a zinc-restricted environment. Moreover, we found that this Adc zinc-ABC transporter promotes S. agalactiae growth and survival in some human biological fluids, suggesting that it contributes to the infection process. These results indicated that zinc has biologically vital functions in S. agalactiae and that, under the conditions tested, the Adc/Lmb transporter constitutes the main zinc acquisition system of the bacterium. A zinc transporter, composed of three redundant binding proteins (Lmb, AdcA, and AdcAII), was characterized in Streptococcus agalactiae This system was shown to be essential for bacterial growth and morphology in zinc-restricted environments, including human biological fluids. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

BRAFV600E Negatively Regulates the AKT Pathway in Melanoma Cell Lines

OpenAIRE

Chen, Brenden; Tardell, Christine; Higgins, Brian; Packman, Kathryn; Boylan, John F.; Niu, Huifeng

2012-01-01

Cross-feedback activation of MAPK and AKT pathways is implicated as a resistance mechanism for cancer therapeutic agents targeting either RAF/MEK or PI3K/AKT/mTOR. It is thus important to have a better understanding of the molecular resistance mechanisms to improve patient survival benefit from these agents. Here we show that BRAFV600E is a negative regulator of the AKT pathway. Expression of BRAFV600E in NIH3T3 cells significantly suppresses MEK inhibitor (RG7167) or mTORC1 inhibitor (rapamy...

Lymphotoxin organizes contributions to host defense and metabolic illness from innate lymphoid cells.

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Upadhyay, Vaibhav; Fu, Yang-Xin

2014-04-01

The lymphotoxin (LT)-pathway is a unique constituent branch of the Tumor Necrosis Superfamily (TNFSF). Use of LT is a critical mechanism by which fetal innate lymphoid cells regulate lymphoid organogenesis. Within recent years, adult innate lymphoid cells have been discovered to utilize this same pathway to regulate IL-22 and IL-23 production for host defense. Notably, genetic studies have linked polymorphisms in the genes encoding LTα to several phenotypes contributing to metabolic syndrome. The role of the LT-pathway may lay the foundation for a bridge between host immune response, microbiota, and metabolic syndrome. The contribution of the LT-pathway to innate lymphoid cell function and metabolic syndrome will be visited in this review. Copyright © 2013 Elsevier Ltd. All rights reserved.

The exploration of contrasting pathways in Triple Negative Breast Cancer (TNBC).

Science.gov (United States)

Narrandes, Shavira; Huang, Shujun; Murphy, Leigh; Xu, Wayne

2018-01-04

Triple Negative Breast Cancers (TNBCs) lack the appropriate targets for currently used breast cancer therapies, conferring an aggressive phenotype, more frequent relapse and poorer survival rates. The biological heterogeneity of TNBC complicates the clinical treatment further. We have explored and compared the biological pathways in TNBC and other subtypes of breast cancers, using an in silico approach and the hypothesis that two opposing effects (Yin and Yang) pathways in cancer cells determine the fate of cancer cells. Identifying breast subgroup specific components of these opposing pathways may aid in selecting potential therapeutic targets as well as further classifying the heterogeneous TNBC subtype. Gene expression and patient clinical data from The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used for this study. Gene Set Enrichment Analysis (GSEA) was used to identify the more active pathways in cancer (Yin) than in normal and the more active pathways in normal (Yang) than in cancer. The clustering analysis was performed to compare pathways of TNBC with other types of breast cancers. The association of pathway classified TNBC sub-groups to clinical outcomes was tested using Cox regression model. Among 4729 curated canonical pathways in GSEA database, 133 Yin pathways (FDR pathways (p-value pathway while PPARα is the top Yang pathway in TNBC. The TNBC and other types of breast cancers showed different pathways enrichment significance profiles. Using top Yin and Yang pathways as classifier, the TNBC can be further subtyped into six sub-groups each having different clinical outcomes. We first reported that the FOMX1 pathway is the most upregulated and the PPARα pathway is the most downregulated pathway in TNBC. These two pathways could be simultaneously targeted in further studies. Also the pathway classifier we performed in this study provided insight into the TNBC heterogeneity.

Protein degradation pathways in Parkinson's disease: curse or blessing.

Science.gov (United States)

Ebrahimi-Fakhari, Darius; Wahlster, Lara; McLean, Pamela J

2012-08-01

Protein misfolding, aggregation and deposition are common disease mechanisms in many neurodegenerative diseases including Parkinson's disease (PD). Accumulation of damaged or abnormally modified proteins may lead to perturbed cellular function and eventually to cell death. Thus, neurons rely on elaborated pathways of protein quality control and removal to maintain intracellular protein homeostasis. Molecular chaperones, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are critical pathways that mediate the refolding or removal of abnormal proteins. The successive failure of these protein degradation pathways, as a cause or consequence of early pathological alterations in vulnerable neurons at risk, may present a key step in the pathological cascade that leads to spreading neurodegeneration. A growing number of studies in disease models and patients have implicated dysfunction of the UPS and ALP in the pathogenesis of Parkinson's disease and related disorders. Deciphering the exact mechanism by which the different proteolytic systems contribute to the elimination of pathogenic proteins, like α-synuclein, is therefore of paramount importance. We herein review the role of protein degradation pathways in Parkinson's disease and elaborate on the different contributions of the UPS and the ALP to the clearance of altered proteins. We examine the interplay between different degradation pathways and provide a model for the role of the UPS and ALP in the evolution and progression of α-synuclein pathology. With regards to exciting recent studies we also discuss the putative potential of using protein degradation pathways as novel therapeutic targets in Parkinson's disease.

Tracking plasma cell differentiation and survival.

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Roth, Katrin; Oehme, Laura; Zehentmeier, Sandra; Zhang, Yang; Niesner, Raluca; Hauser, Anja E

2014-01-01

Plasma cells play a crucial role for the humoral immune response as they represent the body's factories for antibody production. The differentiation from a B cell into a plasma cell is controlled by a complex transcriptional network and happens within secondary lymphoid organs. Based on their lifetime, two types of antibody secreting cells can be distinguished: Short-lived plasma cells are located in extrafollicular sites of secondary lymphoid organs such as lymph node medullary cords and the splenic red pulp. A fraction of plasmablasts migrate from secondary lymphoid organs to the bone marrow where they can become long-lived plasma cells. Bone marrow plasma cells reside in special microanatomical environments termed survival niches, which provide factors promoting their longevity. Reticular stromal cells producing the chemokine CXCL12, which is known to attract plasmablasts to the bone marrow but also to promote plasma cell survival, play a crucial role in the maintenance of these niches. In addition, hematopoietic cells are contributing to the niches by providing other soluble survival factors. Here, we review the current knowledge on the factors involved in plasma cell differentiation, their localization and migration. We also give an overview on what is known regarding the maintenance of long lived plasma cells in survival niches of the bone marrow. © 2013 International Society for Advancement of Cytometry.

Identifying alternate pathways for climate change to impact inland recreational fishers

Science.gov (United States)

Hunt, Len M.; Fenichel, Eli P.; Fulton, David C.; Mendelsohn, Robert; Smith, Jordan W.; Tunney, Tyler D.; Lynch, Abigail J.; Paukert, Craig P.; Whitney, James E.

2016-01-01

Fisheries and human dimensions literature suggests that climate change influences inland recreational fishers in North America through three major pathways. The most widely recognized pathway suggests that climate change impacts habitat and fish populations (e.g., water temperature impacting fish survival) and cascades to impact fishers. Climate change also impacts recreational fishers by influencing environmental conditions that directly affect fishers (e.g., increased temperatures in northern climates resulting in extended open water fishing seasons and increased fishing effort). The final pathway occurs from climate change mitigation and adaptation efforts (e.g., refined energy policies result in higher fuel costs, making distant trips more expensive). To address limitations of past research (e.g., assessing climate change impacts for only one pathway at a time and not accounting for climate variability, extreme weather events, or heterogeneity among fishers), we encourage researchers to refocus their efforts to understand and document climate change impacts to inland fishers.

Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment.

Science.gov (United States)

Hawk, Mark A; Schafer, Zachary T

2018-01-16

Non-transformed cells that become detached from the extracellular matrix (ECM) undergo dysregulation of redox homeostasis and cell death. In contrast, cancer cells often acquire the ability to mitigate programmed cell death pathways and recalibrate the redox balance to survive after ECM detachment, facilitating metastatic dissemination. Accordingly, recent studies of the mechanisms by which cancer cells overcome ECM detachment-induced metabolic alterations have focused on mechanisms in redox homeostasis. The insights into these mechanisms may inform the development of therapeutics that manipulate redox homeostasis to eliminate ECM-detached cancer cells. Here, we review how ECM-detached cancer cells balance redox metabolism for survival. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Pathways of DNA unlinking: A story of stepwise simplification.

Science.gov (United States)

Stolz, Robert; Yoshida, Masaaki; Brasher, Reuben; Flanner, Michelle; Ishihara, Kai; Sherratt, David J; Shimokawa, Koya; Vazquez, Mariel

2017-09-29

In Escherichia coli DNA replication yields interlinked chromosomes. Controlling topological changes associated with replication and returning the newly replicated chromosomes to an unlinked monomeric state is essential to cell survival. In the absence of the topoisomerase topoIV, the site-specific recombination complex XerCD- dif-FtsK can remove replication links by local reconnection. We previously showed mathematically that there is a unique minimal pathway of unlinking replication links by reconnection while stepwise reducing the topological complexity. However, the possibility that reconnection preserves or increases topological complexity is biologically plausible. In this case, are there other unlinking pathways? Which is the most probable? We consider these questions in an analytical and numerical study of minimal unlinking pathways. We use a Markov Chain Monte Carlo algorithm with Multiple Markov Chain sampling to model local reconnection on 491 different substrate topologies, 166 knots and 325 links, and distinguish between pathways connecting a total of 881 different topologies. We conclude that the minimal pathway of unlinking replication links that was found under more stringent assumptions is the most probable. We also present exact results on unlinking a 6-crossing replication link. These results point to a general process of topology simplification by local reconnection, with applications going beyond DNA.

ERLIN2 promotes breast cancer cell survival by modulating endoplasmic reticulum stress pathways

International Nuclear Information System (INIS)

Wang, Guohui; Yang, Zeng-Quan; Liu, Gang; Wang, Xiaogang; Sethi, Seema; Ali-Fehmi, Rouba; Abrams, Judith; Zheng, Ze; Zhang, Kezhong; Ethier, Stephen

2012-01-01

Amplification of the 8p11-12 region has been found in approximately 15% of human breast cancer and is associated with poor prognosis. Previous genomic analysis has led us to identify the endoplasmic reticulum (ER) lipid raft-associated 2 (ERLIN2) gene as one of the candidate oncogenes within the 8p11-12 amplicon in human breast cancer, particularly in the luminal subtype. ERLIN2, an ER membrane protein, has recently been identified as a novel mediator of ER-associated degradation. Yet, the biological roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast carcinogenesis remain unclear. We established the MCF10A-ERLIN2 cell line, which stably over expresses ERLIN2 in human nontransformed mammary epithelial cells (MCF10A) using the pLenti6/V5-ERLIN2 construct. ERLIN2 over expressing cells and their respective parental cell lines were assayed for in vitro transforming phenotypes. Next, we knocked down the ERLIN2 as well as the ER stress sensor IRE1α activity in the breast cancer cell lines to characterize the biological roles and molecular basis of the ERLIN2 in carcinogenesis. Finally, immunohistochemical staining was performed to detect ERLIN2 expression in normal and cancerous human breast tissues We found that amplification of the ERLIN2 gene and over expression of the ERLIN2 protein occurs in both luminal and Her2 subtypes of breast cancer. Gain- and loss-of-function approaches demonstrated that ERLIN2 is a novel oncogenic factor associated with the ER stress response pathway. The IRE1α/XBP1 axis in the ER stress pathway modulated expression of ERLIN2 protein levels in breast cancer cells. We also showed that over expression of ERLIN2 facilitated the adaptation of breast epithelial cells to ER stress by supporting cell growth and protecting the cells from ER stress-induced cell death. ERLIN2 may confer a selective growth advantage for breast cancer cells by facilitating a cytoprotective response to various cellular stresses

ERLIN2 promotes breast cancer cell survival by modulating endoplasmic reticulum stress pathways

Directory of Open Access Journals (Sweden)

Wang Guohui

2012-06-01

Full Text Available Abstract Background Amplification of the 8p11-12 region has been found in approximately 15% of human breast cancer and is associated with poor prognosis. Previous genomic analysis has led us to identify the endoplasmic reticulum (ER lipid raft-associated 2 (ERLIN2 gene as one of the candidate oncogenes within the 8p11-12 amplicon in human breast cancer, particularly in the luminal subtype. ERLIN2, an ER membrane protein, has recently been identified as a novel mediator of ER-associated degradation. Yet, the biological roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast carcinogenesis remain unclear. Methods We established the MCF10A-ERLIN2 cell line, which stably over expresses ERLIN2 in human nontransformed mammary epithelial cells (MCF10A using the pLenti6/V5-ERLIN2 construct. ERLIN2 over expressing cells and their respective parental cell lines were assayed for in vitro transforming phenotypes. Next, we knocked down the ERLIN2 as well as the ER stress sensor IRE1α activity in the breast cancer cell lines to characterize the biological roles and molecular basis of the ERLIN2 in carcinogenesis. Finally, immunohistochemical staining was performed to detect ERLIN2 expression in normal and cancerous human breast tissues Results We found that amplification of the ERLIN2 gene and over expression of the ERLIN2 protein occurs in both luminal and Her2 subtypes of breast cancer. Gain- and loss-of-function approaches demonstrated that ERLIN2 is a novel oncogenic factor associated with the ER stress response pathway. The IRE1α/XBP1 axis in the ER stress pathway modulated expression of ERLIN2 protein levels in breast cancer cells. We also showed that over expression of ERLIN2 facilitated the adaptation of breast epithelial cells to ER stress by supporting cell growth and protecting the cells from ER stress-induced cell death. Conclusions ERLIN2 may confer a selective growth advantage for breast cancer cells by

Hierarchically organized layout for visualization of biochemical pathways.

Science.gov (United States)

Tsay, Jyh-Jong; Wu, Bo-Liang; Jeng, Yu-Sen

2010-01-01

Many complex pathways are described as hierarchical structures in which a pathway is recursively partitioned into several sub-pathways, and organized hierarchically as a tree. The hierarchical structure provides a natural way to visualize the global structure of a complex pathway. However, none of the previous research on pathway visualization explores the hierarchical structures provided by many complex pathways. In this paper, we aim to develop algorithms that can take advantages of hierarchical structures, and give layouts that explore the global structures as well as local structures of pathways. We present a new hierarchically organized layout algorithm to produce layouts for hierarchically organized pathways. Our algorithm first decomposes a complex pathway into sub-pathway groups along the hierarchical organization, and then partition each sub-pathway group into basic components. It then applies conventional layout algorithms, such as hierarchical layout and force-directed layout, to compute the layout of each basic component. Finally, component layouts are joined to form a final layout of the pathway. Our main contribution is the development of algorithms for decomposing pathways and joining layouts. Experiment shows that our algorithm is able to give comprehensible visualization for pathways with hierarchies, cycles as well as complex structures. It clearly renders the global component structures as well as the local structure in each component. In addition, it runs very fast, and gives better visualization for many examples from previous related research. 2009 Elsevier B.V. All rights reserved.

Regulation of apoptotic pathways by Stylophora pistillata (Anthozoa, Pocilloporidae to survive thermal stress and bleaching.

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Hagit Kvitt

Full Text Available Elevated seawater temperatures are associated with coral bleaching events and related mortality. Nevertheless, some coral species are able to survive bleaching and recover. The apoptotic responses associated to this ability were studied over 3 years in the coral Stylophora pistillata from the Gulf of Eilat subjected to long term thermal stress. These include caspase activity and the expression profiles of the S. pistillata caspase and Bcl-2 genes (StyCasp and StyBcl-2-like cloned in this study. In corals exposed to thermal stress (32 or 34°C, caspase activity and the expression levels of the StyBcl-2-like gene increased over time (6-48 h and declined to basal levels within 72 h of thermal stress. Distinct transcript levels were obtained for the StyCasp gene, with stimulated expression from 6 to 48 h of 34°C thermal stress, coinciding with the onset of bleaching. Increased cell death was detected in situ only between 6 to 48 h of stress and was limited to the gastroderm. The bleached corals survived up to one month at 32°C, and recovered back symbionts when placed at 24°C. These results point to a two-stage response in corals that withstand thermal stress: (i the onset of apoptosis, accompanied by rapid activation of anti-oxidant/anti-apoptotic mediators that block the progression of apoptosis to other cells and (ii acclimatization of the coral to the chronic thermal stress alongside the completion of symbiosis breakdown. Accordingly, the coral's ability to rapidly curb apoptosis appears to be the most important trait affecting the coral's thermotolerance and survival.

Research advances in Hedgehog signaling pathway in hepatocellular carcinoma

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LIU Jia

2015-02-01

Full Text Available Hedgehog (Hh signaling pathway is present in many animals and plays an important role in regulating embryonic development and differentiation. Aberrant activation of Hh signaling contributes to the pathogenesis of many malignancies. Recent studies have shown that dysregulated Hh signaling pathway participates in the tumorigenesis, tumor invasion, and metastasis of hepatocellular carcinoma (HCC. Investigation of the relationship between Hh signaling pathway and HCC will help elucidate the molecular mechanism of pathogenesis of HCC and provide a new insight into the development of novel anticancer therapy and therapeutic target.

AKTivation of the PI3K/AKT/mTOR signaling pathway by KSHV

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Aadra P Bhatt

2013-01-01

Full Text Available As an obligate intracellular parasite, the Kaposi sarcoma-associated herpesvirus (KSHV relies on host cell machinery to meet its needs for survival, viral replication, production, and dissemination of progeny virions. KSHV is a ɣ-herpesvirus that is associated with three different malignancies: Kaposi sarcoma (KS, and two B cell lymphoproliferative disorders, primary effusion lymphoma (PEL and multicentric Castleman disease (MCD. KSHV viral proteins modulate cellular phosphatidylinositol-3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR signaling pathway, which is a ubiquitous pathway that also controls B lymphocyte proliferation and development. We review the mechanisms by which KSHV manipulates the PI3K/AKT/mTOR pathway, with a specific focus on B cells.

Imprecise system reliability and component importance based on survival signature

International Nuclear Information System (INIS)

Feng, Geng; Patelli, Edoardo; Beer, Michael; Coolen, Frank P.A.

2016-01-01

The concept of the survival signature has recently attracted increasing attention for performing reliability analysis on systems with multiple types of components. It opens a new pathway for a structured approach with high computational efficiency based on a complete probabilistic description of the system. In practical applications, however, some of the parameters of the system might not be defined completely due to limited data, which implies the need to take imprecisions of component specifications into account. This paper presents a methodology to include explicitly the imprecision, which leads to upper and lower bounds of the survival function of the system. In addition, the approach introduces novel and efficient component importance measures. By implementing relative importance index of each component without or with imprecision, the most critical component in the system can be identified depending on the service time of the system. Simulation method based on survival signature is introduced to deal with imprecision within components, which is precise and efficient. Numerical example is presented to show the applicability of the approach for systems. - Highlights: • Survival signature is a novel way for system reliability and component importance • High computational efficiency based on a complete description of system. • Include explicitly the imprecision, which leads to bounds of the survival function. • A novel relative importance index is proposed as importance measure. • Allows to identify critical components depending on the service time of the system.

Virtual Institute of Microbial Stress and Survival: Deduction of Stress Response Pathways in Metal and Radionuclide Reducing Microorganisms

Energy Technology Data Exchange (ETDEWEB)

None

2004-04-17

The projects application goals are to: (1) To understand bacterial stress-response to the unique stressors in metal/radionuclide contamination sites; (2) To turn this understanding into a quantitative, data-driven model for exploring policies for natural and biostimulatory bioremediation; (3) To implement proposed policies in the field and compare results to model predictions; and (4) Close the experimental/computation cycle by using discrepancies between models and predictions to drive new measurements and construction of new models. The projects science goals are to: (1) Compare physiological and molecular response of three target microorganisms to environmental perturbation; (2) Deduce the underlying regulatory pathways that control these responses through analysis of phenotype, functional genomic, and molecular interaction data; (3) Use differences in the cellular responses among the target organisms to understand niche specific adaptations of the stress and metal reduction pathways; (4) From this analysis derive an understanding of the mechanisms of pathway evolution in the environment; and (5) Ultimately, derive dynamical models for the control of these pathways to predict how natural stimulation can optimize growth and metal reduction efficiency at field sites.

MiR-23a-5p modulates mycobacterial survival and autophagy during mycobacterium tuberculosis infection through TLR2/MyD88/NF-κB pathway by targeting TLR2.

Science.gov (United States)

Gu, Xing; Gao, Yan; Mu, De-Guang; Fu, En-Qing

2017-05-15

Autophagy plays a pivotal role in activating the antimicrobial host defense against Mycobacterium tuberculosis (M.tb.). The emerging roles of microRNAs (miRNAs) in regulating immune responses have attracted increasing attention in recent years. Appreciating the potential of host-directed therapies designed to control autophagy during mycobacterial infection, we focused on the influence of miR-23a-5p on the activation of macrophage autophagy during M.tb. infection in bone marrow-derived macrophages (BMDMs) and murine RAW264.7 cells. Here, we demonstrated that M.tb.-infection of macrophages lead to markedly enhanced expression of miR-23a-5p in a time- and dose-dependent manner. Furthermore, forced expression of miR-23a-5p accelerated the survival rate of intracellular mycobacteria, while transfection with miR-23a-5p inhibitors attenuated mycobacterial survival. More importantly, overexpression of miR-23a-5p dramatically prevented M.tb.-induced activation of autophagy in macrophages, whereas inhibitors of miR-23a-5p remarkably accelerated M.tb.-induced autophagy. Mechanistically, miR-23a-5p is able to modulate TLR2/MyD88/NF-κB signaling activity by targeting TLR2 in RAW264.7 cells in response to M.tb.-infection. Collectively, these findings demonstrated that miR-23a-5p modulated the innate host defense by promoting mycobacteria survival and inhibiting the activation of autophagy against M.tb. through TLR2/MyD88/NF-κB pathway by targeting TLR2, which may provide a promising therapeutic target for tuberculosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Cyclic di-GMP is essential for the survival of the lyme disease spirochete in ticks.

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Ming He

2011-06-01

Full Text Available Cyclic dimeric GMP (c-di-GMP is a bacterial second messenger that modulates many biological processes. Although its role in bacterial pathogenesis during mammalian infection has been documented, the role of c-di-GMP in a pathogen's life cycle within a vector host is less understood. The enzootic cycle of the Lyme disease pathogen Borrelia burgdorferi involves both a mammalian host and an Ixodes tick vector. The B. burgdorferi genome encodes a single copy of the diguanylate cyclase gene (rrp1, which is responsible for c-di-GMP synthesis. To determine the role of c-di-GMP in the life cycle of B. burgdorferi, an Rrp1-deficient B. burgdorferi strain was generated. The rrp1 mutant remains infectious in the mammalian host but cannot survive in the tick vector. Microarray analyses revealed that expression of a four-gene operon involved in glycerol transport and metabolism, bb0240-bb0243, was significantly downregulated by abrogation of Rrp1. In vitro, the rrp1 mutant is impaired in growth in the media containing glycerol as the carbon source (BSK-glycerol. To determine the contribution of the glycerol metabolic pathway to the rrp1 mutant phenotype, a glp mutant, in which the entire bb0240-bb0243 operon is not expressed, was generated. Similar to the rrp1 mutant, the glp mutant has a growth defect in BSK-glycerol medium. In vivo, the glp mutant is also infectious in mice but has reduced survival in ticks. Constitutive expression of the bb0240-bb0243 operon in the rrp1 mutant fully rescues the growth defect in BSK-glycerol medium and partially restores survival of the rrp1 mutant in ticks. Thus, c-di-GMP appears to govern a catabolic switch in B. burgdorferi and plays a vital role in the tick part of the spirochetal enzootic cycle. This work provides the first evidence that c-di-GMP is essential for a pathogen's survival in its vector host.

Long-term survival and causes of death after stroke

DEFF Research Database (Denmark)

Brønnum-Hansen, Henrik; Davidsen, M; Thorvaldsen, P

2001-01-01

As part of the Danish contribution to the World Health Organization (WHO) MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Project, a register of patients with stroke was established in 1982. The purpose of the present study was to analyze long-term survival and causes of death...

Targeted inhibition of the phosphoinositide 3-kinase impairs cell proliferation, survival, and invasion in colon cancer

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Yang F

2017-09-01

Full Text Available Fei Yang,1,* Jun-Yi Gao,2,* Hua Chen,1 Zhen-Hua Du,1 Xue-Qun Zhang,3 Wei Gao4 1Department of Pathology, Jinan Central Hospital Affiliated to Shandong University, Jinan, 2Department of Clinical Medicine, Weifang Medical College, Weifang, 3Graduate School, Taishan Medical University, Xintai, 4Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, People’s Republic of China *These authors contributed equally to this work Background: Colon cancer is the third most common cancer in the world, and its metastasis and drug resistance are challenging for its effective treatment. The PI3K/Akt/mTOR pathway plays a crucial role in the pathogenesis of colon cancer. The aim of this study was to investigate the targeting of PI3K in colon cancer cells HT-29 and HCT-116 in vitro. Methods: In HT-29 and HCT-116 cells, BEZ235, a dual inhibitor of PI3K/mTOR, and shRNAtarget to PI3KCA were used to inhibit PI3K/Akt/mTOR pathway. The inhibition efficiency of PI3K/Akt/mTOR pathway was detected by RT-PCR and Western blot. Cell proliferation, migration, invasion, and apoptosis were evaluated by Cell Counting Kit-8, Transwell, and flow cytometry assays. The expression of apoptosis-related proteins (cleavage caspase 3, Bcl-2, Bax, and Bim were also detected. Results: We found that in HT-29 and HCT-116 cells, the treatment of BEZ235 (1 µM and PI3KCA knockdown inhibited the activation of PI3K/Akt/mTOR pathway and significantly suppressed cell proliferation, migration, and invasion of HT-29 and HCT-116 cells. In addition, we confirmed that knockdown of BEZ235 and PI3KCA induced cell apoptosis through the upregulated levels of cleavage caspase 3 and Bax and downregulated expression of Bcl-2 and Bim. Conclusion: Our results indicated that targeted inhibition of the PI3K/Akt/mTOR pathway impaired cell proliferation, survival, and invasion in human colon cancer. Keywords: human colon cancer, PI3K/Akt/mTOR pathway, BEZ235, PI3KCA knockdown

SEMA6D Expression and Patient Survival in Breast Invasive Carcinoma

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Dongquan Chen

2015-01-01

Full Text Available Breast cancer (BC is the second most common cancer diagnosed in American women and is also the second leading cause of cancer death in women. Research has focused heavily on BC metastasis. Multiple signaling pathways have been implicated in regulating BC metastasis. Our knowledge of regulation of BC metastasis is, however, far from complete. Identification of new factors during metastasis is an essential step towards future therapy. Our labs have focused on Semaphorin 6D (SEMA6D, which was implicated in immune responses, heart development, and neurogenesis. It will be interesting to know SEMA6D-related genomic expression profile and its implications in clinical outcome. In this study, we examined the public datasets of breast invasive carcinoma from The Cancer Genome Atlas (TCGA. We analyzed the expression of SEMA6D along with its related genes, their functions, pathways, and potential as copredictors for BC patients’ survival. We found 6-gene expression profile that can be used as such predictors. Our study provides evidences for the first time that breast invasive carcinoma may contain a subtype based on SEMA6D expression. The expression of SEMA6D gene may play an important role in promoting patient survival, especially among triple negative breast cancer patients.

MicroRNAs That Contribute to Coordinating the Immune Response in Drosophila melanogaster.

Science.gov (United States)

Atilano, Magda L; Glittenberg, Marcus; Monteiro, Annabel; Copley, Richard R; Ligoxygakis, Petros

2017-09-01

Small noncoding RNAs called microRNAs (miRNAs) have emerged as post-transcriptional regulators of gene expression related to host defenses. Here, we have used Drosophila melanogaster to explore the contribution of individual or clusters of miRNAs in countering systemic Candida albicans infection. From a total of 72 tested, we identify 6 miRNA allelic mutant backgrounds that modulate the survival response to infection and the ability to control pathogen number. These mutants also exhibit dysregulation of the Toll pathway target transcripts Drosomycin ( Drs ) and Immune-Induced Molecule 1 ( IM1 ). These are characteristics of defects in Toll signaling, and consistent with this, we demonstrate dependency for one of the miRNA mutants on the NF-κΒ homolog Dif. We also quantify changes in the miRNA expression profile over time in response to three pathogen types, and identify 13 mature miRNA forms affected by pathogens that stimulate Toll signaling. To complement this, we provide a genome-wide map of potential NF-κB sites in proximity to miRNA genes. Finally, we demonstrate that systemic C. albicans infection contributes to a reduction in the total amount of branch-chained amino acids, which is miRNA-regulated. Overall, our data reveal a new layer of miRNA complexity regulating the fly response to systemic fungal infection. Copyright © 2017 Atilano et al.

Roles of StearoylCoA Desaturase-1 in the Regulation of Cancer Cell Growth, Survival and Tumorigenesis

International Nuclear Information System (INIS)

Igal, R. Ariel

2011-01-01

The development and maintenance of defining features of cancer, such as unremitting cell proliferation, evasion of programmed cell death, and the capacity for colonizing local tissues and distant organs, demand a massive production of structural, signaling and energy-storing lipid biomolecules of appropriate fatty acid composition. Due to constitutive activation of fatty acid biosynthesis, cancer cell lipids are enriched with saturated (SFA) and, in particular, monounsaturated fatty acids (MUFA), which are generated by StearoylCoA desaturase-1, the main enzyme that transforms SFA into MUFA. An increasing number of experimental and epidemiological studies suggest that high levels of SCD1 activity is a major factor in establishing the biochemical and metabolic perturbations that favors the oncogenic process. This review examines evidence that suggests the critical implication of SCD1 in the modulation of multiple biological mechanisms, specifically lipid biosynthesis and proliferation and survival signaling pathways that contribute to the development and progression of cancer

Roles of StearoylCoA Desaturase-1 in the Regulation of Cancer Cell Growth, Survival and Tumorigenesis

Energy Technology Data Exchange (ETDEWEB)

Igal, R. Ariel [Department of Nutritional Sciences and Rutgers Center for Lipid Research, Rutgers, the State University of New Jersey, 96 Lipman Drive, New Brunswick, NJ 08901 (United States)

2011-05-20

The development and maintenance of defining features of cancer, such as unremitting cell proliferation, evasion of programmed cell death, and the capacity for colonizing local tissues and distant organs, demand a massive production of structural, signaling and energy-storing lipid biomolecules of appropriate fatty acid composition. Due to constitutive activation of fatty acid biosynthesis, cancer cell lipids are enriched with saturated (SFA) and, in particular, monounsaturated fatty acids (MUFA), which are generated by StearoylCoA desaturase-1, the main enzyme that transforms SFA into MUFA. An increasing number of experimental and epidemiological studies suggest that high levels of SCD1 activity is a major factor in establishing the biochemical and metabolic perturbations that favors the oncogenic process. This review examines evidence that suggests the critical implication of SCD1 in the modulation of multiple biological mechanisms, specifically lipid biosynthesis and proliferation and survival signaling pathways that contribute to the development and progression of cancer.

Independent contribution of individual white matter pathways to language function in pediatric epilepsy patients

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Michael J. Paldino, M.D.

2014-01-01

Conclusions: Scalar metrics derived from the left uncinate, inferior fronto-occipital, and arcuate fasciculi were independently associated with language function. These results support the importance of these pathways in human language function in patients with MCDs.

How Does Thymine DNA Survive Ultrafast Dimerization Damage?

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Hongjuan Wang

2016-12-01

Full Text Available The photodimerization reaction between the two adjacent thymine bases within a single strand has been the subject of numerous studies due to its potential to induce DNA mutagenesis and possible tumorigenesis in human skin cells. It is well established that the cycloaddition photoreaction takes place on a picosecond time scale along barrierless or low barrier singlet/triplet pathways. However, the observed dimerization quantum yield in different thymine multimer is considerable lower than might be expected. A reasonable explanation is required to understand why thymine in DNA is able to survive ultrafast dimerization damage. In this work, accurate quantum calculations based on the combined CASPT2//CASSCF/AMBER method were conducted to map the excited state relaxation pathways of the thymine monomer in aqueous solution and of the thymine oligomer in DNA. A monomer-like decay pathway, induced by the twisting of the methyl group, is found to provide a bypass channel to ensure the photostability of thymine in single-stranded oligomers. This fast relaxation path is regulated by the conical intersection between the bright SCT(1ππ* state with the intra-base charge transfer character and the ground state to remove the excess excitation energy, thereby achieving the ground-state recovery with high efficiency.

Born to be Alive: A Role for the BCL-2 Family in Melanoma Tumor Cell Survival, Apoptosis, and Treatment

Energy Technology Data Exchange (ETDEWEB)

Anvekar, Rina A.; Asciolla, James J.; Missert, Derek J.; Chipuk, Jerry E., E-mail: jerry.chipuk@mssm.edu [Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY (United States); Department of Dermatology, Mount Sinai School of Medicine, New York, NY (United States); The Tisch Cancer Institute, Mount Sinai Medical Center, New York, NY (United States)

2011-10-13

The global incidence of melanoma has dramatically increased during the recent decades, yet the advancement of primary and adjuvant therapies has not kept a similar pace. The development of melanoma is often centered on cellular signaling that hyper-activates survival pathways, while inducing a concomitant blockade to cell death. Aberrations in cell death signaling not only promote tumor survival and enhanced metastatic potential, but also create resistance to anti-tumor strategies. Chemotherapeutic agents target melanoma tumor cells by inducing a form of cell death called apoptosis, which is governed by the BCL-2 family of proteins. The BCL-2 family is comprised of anti-apoptotic proteins (e.g., BCL-2, BCL-xL, and MCL-1) and pro-apoptotic proteins (e.g., BAK, BAX, and BIM), and their coordinated regulation and function are essential for optimal responses to chemotherapeutics. Here we will discuss what is currently known about the mechanisms of BCL-2 family function with a focus on the signaling pathways that maintain melanoma tumor cell survival. Importantly, we will critically evaluate the literature regarding how chemotherapeutic strategies directly impact on BCL-2 family function and offer several suggestions for future regimens to target melanoma and enhance patient survival.

Modeling of DNA damage-cluster, cell-cycle and repair pathway dependent radiosensitivity after low- and high-LET irradiation; Modellierung der DNA-Schadenscluster-, Zellzyklus- und Reparaturweg-abhaengigen Strahlenempfindlichkeit nach niedrig- und hoch-LET-Bestrahlung

Energy Technology Data Exchange (ETDEWEB)

Guenther, Paul

2017-07-17

This work focuses on modeling of the effects of ionizing radiation on cells, primarily on, the influence of the DNA repair pathway availability and the radiation quality on the cell-survival probability. The availability of DNA repair pathways depends on the replication state and defects of the DNA repair pathways. The radiation quality manifests itself in the microscopic ionization pattern. The Giant LOop Binary LEsion (GLOBLE) model and the Local Effect Model (LEM) describe the cell-survival after photon and ion irradiation, respectively. Both models assume that cell survival can be modeled based on the spatial distribution of Double-Strand Breaks (DSB) of the DNA (damage pattern), within a higher order chromatin structure. Single DSB are referred to as isolated DSB (iDSB) and two or more DSB in close proximity (within 540 nm) are called complex DSB (cDSB). In order to predict the cell-survival, the GLOBLE-Model considers different iDSB repair-pathways and their availability. One central assumption of the LEM is that the same damage patterns imply same effects, regardless of the radiation quality. In order to predict the damage pattern the microscopic local dose distribution of ions, described by the amorphous track structure, is evaluated. The cell survival after ion irradiation is predicted from a comparison with corresponding damage patterns after photon irradiation. The cell-survival curves after high dose photon irradiation cannot be predicted from the Linear Quadratic (LQ) Model due to their transition towards a linear dose dependence. This work uses the GLOBLE-Model to introduce a novel mechanistic approach, which allows the threshold dose to be predicted for the transition from a linear quadratic dose dependence, of survival curves at low doses, to a linear dose dependence at high doses. Furthermore, a method is presented, which allows LEM to predict the survival of synchronous cells after ion irradiation based on the cell survival after photon

Brain-wide pathway for waste clearance captured by contrast-enhanced MRI

OpenAIRE

Iliff, Jeffrey J.; Lee, Hedok; Yu, Mei; Feng, Tian; Logan, Jean; Nedergaard, Maiken; Benveniste, Helene

2013-01-01

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes t...

Nucleotide excision repair pathway assessment in DNA exposed to low-intensity red and infrared lasers

International Nuclear Information System (INIS)

Fonseca, A.S.; Campos, V.M.A.; Magalhaes, L.A.G.; Paoli, F.

2015-01-01

Low-intensity lasers are used for prevention and management of oral mucositis induced by anticancer therapy, but the effectiveness of treatment depends on the genetic characteristics of affected cells. This study evaluated the survival and induction of filamentation of Escherichia coli cells deficient in the nucleotide excision repair pathway, and the action of T 4 endonuclease V on plasmid DNA exposed to low-intensity red and near-infrared laser light. Cultures of wild-type (strain AB1157) E. coli and strain AB1886 (deficient in uvrA protein) were exposed to red (660 nm) and infrared (808 nm) lasers at various fluences, powers and emission modes to study bacterial survival and filamentation. Also, plasmid DNA was exposed to laser light to study DNA lesions produced in vitro by T 4 endonuclease V. Low-intensity lasers: i) had no effect on survival of wild-type E. coli but decreased the survival of uvrA protein-deficient cells, ii) induced bacterial filamentation, iii) did not alter the electrophoretic profile of plasmids in agarose gels, and iv) did not alter the electrophoretic profile of plasmids incubated with T 4 endonuclease V. These results increase our understanding of the effects of laser light on cells with various genetic characteristics, such as xeroderma pigmentosum cells deficient in nucleotide excision pathway activity in patients with mucositis treated by low-intensity lasers. (author)

Nucleotide excision repair pathway assessment in DNA exposed to low-intensity red and infrared lasers

Energy Technology Data Exchange (ETDEWEB)

Fonseca, A.S.; Campos, V.M.A.; Magalhaes, L.A.G., E-mail: adnfonseca@ig.com.br [Instituto de Biologia Roberto Alcantara Gomes, Rio de Janeiro, RJ (Brazil). Departamento de Biofisica e Biometria. Lab. de Ciencias Radiologicas; Paoli, F. [Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, MG (Brazil). Instituto de Ciencias Biologicas. Departamento de Morfologia

2015-10-15

Low-intensity lasers are used for prevention and management of oral mucositis induced by anticancer therapy, but the effectiveness of treatment depends on the genetic characteristics of affected cells. This study evaluated the survival and induction of filamentation of Escherichia coli cells deficient in the nucleotide excision repair pathway, and the action of T{sub 4} endonuclease V on plasmid DNA exposed to low-intensity red and near-infrared laser light. Cultures of wild-type (strain AB1157) E. coli and strain AB1886 (deficient in uvrA protein) were exposed to red (660 nm) and infrared (808 nm) lasers at various fluences, powers and emission modes to study bacterial survival and filamentation. Also, plasmid DNA was exposed to laser light to study DNA lesions produced in vitro by T{sub 4} endonuclease V. Low-intensity lasers: i) had no effect on survival of wild-type E. coli but decreased the survival of uvrA protein-deficient cells, ii) induced bacterial filamentation, iii) did not alter the electrophoretic profile of plasmids in agarose gels, and iv) did not alter the electrophoretic profile of plasmids incubated with T{sub 4} endonuclease V. These results increase our understanding of the effects of laser light on cells with various genetic characteristics, such as xeroderma pigmentosum cells deficient in nucleotide excision pathway activity in patients with mucositis treated by low-intensity lasers. (author)

Nur77 inhibits oxLDL induced apoptosis of macrophages via the p38 MAPK signaling pathway

International Nuclear Information System (INIS)

Shao, Qin; Han, Fei; Peng, Shi; He, Ben

2016-01-01

The interaction between macrophages and oxLDL plays a crucial role in the initiation and progression of atherosclerosis. As a key initiator in a number of plaque promoting processes, oxLDL induces variable effects such as cell apoptosis or proliferation. Orphan nuclear receptor Nur77 is potently induced in macrophages by diverse stimuli, suggesting that it is of importance in vascular inflammation resulting in atherosclerosis, but whether Nur77 induction is detrimental or protective is unclear. In our study, we explore the role of Nur77 in the regulation of oxLDL-induced macrophage apoptosis and the signaling pathways that are involved. We found that oxLDL induced Nur77 expression in a dose and time dependent fashion, and cell viability was decreased in parallel. To determine whether Nur77 induction contributes to the loss of cell viability or is a protective mechanism, the effect of Nur77 overexpression was examined. Importantly, Nur77 overexpression inhibited the oxLDL-induced decrease of cell viability, inhibited the production of apoptotic bodies and restored DNA synthesis following oxLDL exposure. Furthermore, we found that Nur77 induction is mediated through the p38 MAPK signaling pathway. After pretreatment with SB203580, cell viability was decreased, the expression of CyclinA2 and PCNA was attenuated and the percentage of cell apoptosis was enhanced. Likewise, Nur77 overexpression increased the expression of the cell cycle genes PCNA and p21, and attenuated the increase in caspase-3. On the other hand, knockdown of Nur77 expression by specific siRNA resulted in the increased expression of caspase 3. The results demonstrate that Nur77 is induced by oxLDL via the p38 MAPK signaling pathway, which is involved in the regulation of cell survival. Nur77 enhanced cell survival via suppressing apoptosis, without affecting cell proliferation of activated macrophages, which may be beneficial in patients with atherosclerosis. - Highlights: • oxLDL could induce Nur77

Nur77 inhibits oxLDL induced apoptosis of macrophages via the p38 MAPK signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Shao, Qin; Han, Fei; Peng, Shi; He, Ben, E-mail: heben@medmail.com.cn

2016-03-18

The interaction between macrophages and oxLDL plays a crucial role in the initiation and progression of atherosclerosis. As a key initiator in a number of plaque promoting processes, oxLDL induces variable effects such as cell apoptosis or proliferation. Orphan nuclear receptor Nur77 is potently induced in macrophages by diverse stimuli, suggesting that it is of importance in vascular inflammation resulting in atherosclerosis, but whether Nur77 induction is detrimental or protective is unclear. In our study, we explore the role of Nur77 in the regulation of oxLDL-induced macrophage apoptosis and the signaling pathways that are involved. We found that oxLDL induced Nur77 expression in a dose and time dependent fashion, and cell viability was decreased in parallel. To determine whether Nur77 induction contributes to the loss of cell viability or is a protective mechanism, the effect of Nur77 overexpression was examined. Importantly, Nur77 overexpression inhibited the oxLDL-induced decrease of cell viability, inhibited the production of apoptotic bodies and restored DNA synthesis following oxLDL exposure. Furthermore, we found that Nur77 induction is mediated through the p38 MAPK signaling pathway. After pretreatment with SB203580, cell viability was decreased, the expression of CyclinA2 and PCNA was attenuated and the percentage of cell apoptosis was enhanced. Likewise, Nur77 overexpression increased the expression of the cell cycle genes PCNA and p21, and attenuated the increase in caspase-3. On the other hand, knockdown of Nur77 expression by specific siRNA resulted in the increased expression of caspase 3. The results demonstrate that Nur77 is induced by oxLDL via the p38 MAPK signaling pathway, which is involved in the regulation of cell survival. Nur77 enhanced cell survival via suppressing apoptosis, without affecting cell proliferation of activated macrophages, which may be beneficial in patients with atherosclerosis. - Highlights: • oxLDL could induce Nur77

Paravascular pathways contribute to vasculitis and neuroinflammation after subarachnoid hemorrhage independently of glymphatic control.

Science.gov (United States)

Luo, C; Yao, X; Li, J; He, B; Liu, Q; Ren, H; Liang, F; Li, M; Lin, H; Peng, J; Yuan, T F; Pei, Z; Su, H

2016-03-31

Subarachnoid hemorrhage (SAH) is a devastating disease with high mortality. The mechanisms underlying its pathological complications have not been fully identified. Here, we investigate the potential involvement of the glymphatic system in the neuropathology of SAH. We demonstrate that blood components rapidly enter the paravascular space following SAH and penetrate into the perivascular parenchyma throughout the brain, causing disastrous events such as cerebral vasospasm, delayed cerebral ischemia, microcirculation dysfunction and widespread perivascular neuroinflammation. Clearance of the paravascular pathway with tissue-type plasminogen activator ameliorates the behavioral deficits and alleviates histological injury of SAH. Interestingly, AQP4(-/-) mice showed no improvements in neurological deficits and neuroinflammation at day 7 after SAH compared with WT control mice. In conclusion, our study proves that the paravascular pathway dynamically mediates the pathological complications following acute SAH independently of glymphatic control.

Formulating accident occurrence as a survival process.

Science.gov (United States)

Chang, H L; Jovanis, P P

1990-10-01

A conceptual framework for accident occurrence is developed based on the principle of the driver as an information processor. The framework underlies the development of a modeling approach that is consistent with the definition of exposure to risk as a repeated trial. Survival theory is proposed as a statistical technique that is consistent with the conceptual structure and allows the exploration of a wide range of factors that contribute to highway operating risk. This survival model of accident occurrence is developed at a disaggregate level, allowing safety researchers to broaden the scope of studies which may be limited by the use of traditional aggregate approaches. An application of the approach to motor carrier safety is discussed as are potential applications to a variety of transportation industries. Lastly, a typology of highway safety research methodologies is developed to compare the properties of four safety methodologies: laboratory experiments, on-the-road studies, multidisciplinary accident investigations, and correlational studies. The survival theory formulation has a mathematical structure that is compatible with each safety methodology, so it may facilitate the integration of findings across methodologies.

The self-renewal signaling pathways utilized by gastric cancer stem cells.

Science.gov (United States)

Fu, Ying; Li, Hui; Hao, Xishan

2017-04-01

Gastric cancer is a leading cause of cancer-related mortality worldwide. Cancer stem cells are the source of tumor recurrence and metastasis. Self-renewal is a marker of cancer stem cells and also the basis of long-lasting survival and tumor progression. Although the mechanism of gastric cancer stem cell self-renewal is not clear, there are several signaling pathways and environmental factors known to be involved. This mini review describes recent developments in the self-renewal signaling pathway of gastric cancer stem cell research. Advancements made in this field of research will likely support the development of novel therapeutic strategies for gastric cancer.

The Relationships between Mothers' Work Pathways and Physical and Mental Health

Science.gov (United States)

Frech, Adrianne; Damaske, Sarah

2012-01-01

We contribute to research on the relationships between gender, work, and health by using longitudinal, theoretically driven models of mothers' diverse work pathways and adjusting for unequal selection into these pathways. Using the National Longitudinal Study of Youth-1979 (N = 2,540), we find full-time, continuous employment following a first…

Pathway Distiller - multisource biological pathway consolidation.

Science.gov (United States)

Doderer, Mark S; Anguiano, Zachry; Suresh, Uthra; Dashnamoorthy, Ravi; Bishop, Alexander J R; Chen, Yidong

2012-01-01

One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets. After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment. We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/PathwayDistiller), is established to allow

To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

International Nuclear Information System (INIS)

Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda; Jia, William; Rennie, Paul S.

2011-01-01

Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge

To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

Energy Technology Data Exchange (ETDEWEB)

Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Jia, William [Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Rennie, Paul S., E-mail: prennie@interchange.ubc.ca [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada)

2011-03-24

Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge.

To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

Directory of Open Access Journals (Sweden)

Paul S. Rennie

2011-03-01

Full Text Available Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i the PI3K/Akt pathway, (ii receptor tyrosine kinases, (iii the p38 MAPK pathway, and (iv the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge.

Gluconeogenesis: An ancient biochemical pathway with a new twist

OpenAIRE

Miyamoto, Tetsuya; Amrein, Hubert

2017-01-01

Synthesis of sugars from simple carbon sources is critical for survival of animals under limited nutrient availability. Thus, sugar-synthesizing enzymes should be present across the entire metazoan spectrum. Here, we explore the evolution of glucose and trehalose synthesis using a phylogenetic analysis of enzymes specific for the two pathways. Our analysis reveals that the production of trehalose is the more ancestral biochemical process, found in single cell organisms and primitive metazoans...

Partitioning of excess mortality in population-based cancer patient survival studies using flexible parametric survival models

Directory of Open Access Journals (Sweden)

Eloranta Sandra

2012-06-01

Full Text Available Abstract Background Relative survival is commonly used for studying survival of cancer patients as it captures both the direct and indirect contribution of a cancer diagnosis on mortality by comparing the observed survival of the patients to the expected survival in a comparable cancer-free population. However, existing methods do not allow estimation of the impact of isolated conditions (e.g., excess cardiovascular mortality on the total excess mortality. For this purpose we extend flexible parametric survival models for relative survival, which use restricted cubic splines for the baseline cumulative excess hazard and for any time-dependent effects. Methods In the extended model we partition the excess mortality associated with a diagnosis of cancer through estimating a separate baseline excess hazard function for the outcomes under investigation. This is done by incorporating mutually exclusive background mortality rates, stratified by the underlying causes of death reported in the Swedish population, and by introducing cause of death as a time-dependent effect in the extended model. This approach thereby enables modeling of temporal trends in e.g., excess cardiovascular mortality and remaining cancer excess mortality simultaneously. Furthermore, we illustrate how the results from the proposed model can be used to derive crude probabilities of death due to the component parts, i.e., probabilities estimated in the presence of competing causes of death. Results The method is illustrated with examples where the total excess mortality experienced by patients diagnosed with breast cancer is partitioned into excess cardiovascular mortality and remaining cancer excess mortality. Conclusions The proposed method can be used to simultaneously study disease patterns and temporal trends for various causes of cancer-consequent deaths. Such information should be of interest for patients and clinicians as one way of improving prognosis after cancer is

Naturally occurring genetic variability in expression of Gsta4 is associated with differential survival of axotomized rat motoneurons

DEFF Research Database (Denmark)

Mikael, Ström; Al Nimer, Faiez; Lindblom, Rickard

2012-01-01

A large number of molecular pathways have been implicated in the degeneration of axotomized motoneurons. We previously have demonstrated substantial differences in the survival rate of axotomized motoneurons across different rat strains. Identification of genetic differences underlying such natur...

Riboflavin Provisioning Underlies Wolbachia’s Fitness Contribution to Its Insect Host

Science.gov (United States)

Moriyama, Minoru; Nikoh, Naruo; Hosokawa, Takahiro

2015-01-01

ABSTRACT Endosymbiotic bacteria of the genus Wolbachia represent the most successful symbiotic bacteria in the terrestrial ecosystem. The success of Wolbachia has been ascribed to its remarkable phenotypic effects on host reproduction, such as cytoplasmic incompatibility, whereby maternally inherited bacteria can spread in their host populations at the expense of their host’s fitness. Meanwhile, recent theoretical as well as empirical studies have unveiled that weak and/or conditional positive fitness effects may significantly facilitate invasion and spread of Wolbachia infections in host populations. Here, we report a previously unrecognized nutritional aspect, the provision of riboflavin (vitamin B2), that potentially underpins the Wolbachia-mediated fitness benefit to insect hosts. A comparative genomic survey for synthetic capability of B vitamins revealed that only the synthesis pathway for riboflavin is highly conserved among diverse insect-associated Wolbachia strains, while the synthesis pathways for other B vitamins were either incomplete or absent. Molecular phylogenetic and genomic analyses of riboflavin synthesis genes from diverse Wolbachia strains revealed that, in general, their phylogenetic relationships are concordant with Wolbachia’s genomic phylogeny, suggesting that the riboflavin synthesis genes have been stably maintained in the course of Wolbachia evolution. In rearing experiments with bedbugs (Cimex lectularius) on blood meals in which B vitamin contents were manipulated, we demonstrated that Wolbachia’s riboflavin provisioning significantly contributes to growth, survival, and reproduction of the insect host. These results provide a physiological basis upon which Wolbachia-mediated positive fitness consequences are manifested and shed new light on the ecological and evolutionary relevance of Wolbachia infections. PMID:26556278

The Cardiopulmonary Effects of Ambient Air Pollution and Mechanistic Pathways: A Comparative Hierarchical Pathway Analysis

Science.gov (United States)

Thomas, Duncan C.; Zhang, Junfeng; Kipen, Howard M.; Rich, David Q.; Zhu, Tong; Huang, Wei; Hu, Min; Wang, Guangfa; Wang, Yuedan; Zhu, Ping; Lu, Shou-En; Ohman-Strickland, Pamela; Diehl, Scott R.; Eckel, Sandrah P.

2014-01-01

Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2–3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system. PMID:25502951

The cardiopulmonary effects of ambient air pollution and mechanistic pathways: a comparative hierarchical pathway analysis.

Directory of Open Access Journals (Sweden)

Ananya Roy

Full Text Available Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001 and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005. These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours and the hemostasis pathway responds gradually over a 2-3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system.

Prolonged hypoxia increases survival even in Zebrafish (Danio rerio showing cardiac arrhythmia.

Directory of Open Access Journals (Sweden)

Renate Kopp

Full Text Available Tolerance towards hypoxia is highly pronounced in zebrafish. In this study even beneficial effects of hypoxia, specifically enhanced survival of zebrafish larvae, could be demonstrated. This effect was actually more pronounced in breakdance mutants, which phenotypically show cardiac arrhythmia. Breakdance mutants (bre are characterized by chronically reduced cardiac output. Despite an about 50% heart rate reduction, they become adults, but survival rate significantly drops to 40%. Normoxic bre animals demonstrate increased hypoxia inducible factor 1 a (Hif-1α expression, which indicates an activated hypoxic signaling pathway. Consequently, cardiovascular acclimation, like cardiac hypertrophy and increased erythrocyte concentration, occurs. Thus, it was hypothesized, that under hypoxic conditions survival might be even more reduced. When bre mutants were exposed to hypoxic conditions, they surprisingly showed higher survival rates than under normoxic conditions and even reached wildtype values. In hypoxic wildtype zebrafish, survival yet exceeded normoxic control values. To specify physiological acclimation, cardiovascular and metabolic parameters were measured before hypoxia started (3 dpf, when the first differences in survival rate occurred (7 dpf and when survival rate plateaued (15 dpf. Hypoxic animals expectedly demonstrated Hif-1α accumulation and consequently enhanced convective oxygen carrying capacity. Moreover, bre animals showed a significantly enhanced heart rate under hypoxic conditions, which reached normoxic wildtype values. This improvement in convective oxygen transport ensured a sufficient oxygen and nutrient supply and was also reflected in the significantly higher mitochondrial activity. The highly optimized energy metabolism observed in hypoxic zebrafish larvae might be decisive for periods of higher energy demand due to organ development, growth and increased activity. However, hypoxia increased survival only during a

Response of the JAK-STAT signaling pathway to oxygen deprivation in the red eared slider turtle, Trachemys scripta elegans.

Science.gov (United States)

Bansal, Saumya; Biggar, Kyle K; Krivoruchko, Anastasia; Storey, Kenneth B

2016-11-15

The red-eared slider turtle, Trachemys scripta elegans, is a model organism commonly used to study the environmental stress of anoxia. It exhibits multiple biochemical adaptations to ensure its survival during the winter months where quantities of oxygen are largely depleted. We proposed that JAK-STAT signaling would display stress responsive regulation to mediate the survival of the red-eared slider turtle, Trachemys scripta elegans, during anoxic stress. Importantly, the JAK-STAT signaling pathway is involved in transmitting extracellular signals to the nucleus resulting in the expression of select genes that aid cell survival and growth. Immunoblotting was used to compare the relative phosphorylation levels of JAK proteins, STAT proteins, and two of its inhibitors, SOCS and PIAS, in response to anoxia. A clear activation of the JAK-STAT pathway was observed in the liver tissue while no significant changes were found in the skeletal muscle. To further support our findings we also found an increase in mRNA transcripts of downstream targets of STATs, namely bcl-xL and bcl-2, using PCR analysis in the liver tissues. These findings suggest an important role for the JAK-STAT pathway in exhibiting natural anoxia tolerance by the red-eared slider turtle. Copyright © 2016 Elsevier B.V. All rights reserved.

Gene expression meta-analysis identifies chromosomal regions involved in ovarian cancer survival

DEFF Research Database (Denmark)

Thomassen, Mads; Jochumsen, Kirsten M; Mogensen, Ole

2009-01-01

the relation of gene expression and chromosomal position to identify chromosomal regions of importance for early recurrence of ovarian cancer. By use of *Gene Set Enrichment Analysis*, we have ranked chromosomal regions according to their association to survival. Over-representation analysis including 1...... using death (P = 0.015) and recurrence (P = 0.002) as outcome. The combined mutation score is strongly associated to upregulation of several growth factor pathways....

Regulation of the PI3K pathway through a p85a monomer-homodimer equilibrium

KAUST Repository

Aljedani, Safia Salim Eid

2017-01-08

The phosphatidylinositol-3-kinase a (PI3Ka) is heterodimeric enzyme that is composed of p85a regulatory subunit and a p110a catalytic subunit. PI3Ka plays a key role in cell survival, growth and differentation. Owing to its role as a key regulator, the PI3Ka pathway is the most frequently mutated pathway in human cancers, and is targeted by many viruses to insure their survival and successful reproduction. Previous studies have shown that the equilibrium of p85 monomers and dimers regulates the PI3K pathway, suggesting that interrupting this equilibrium could lead to disease development. Moreover, studies suggest that the p85a monomers and dimers have opposing effects on PI3Ka signaling as only the p85a dimers bind to the PTEN phosphatase, whereas p85a monomers bind to the catalytic p110 subunit. However, the mechanism for dimerisation is controversial, and it is unknown why PTEN or p110a bind only dimer or monomer. Therefore, we combine molecular biology, biophsical, computational and structural methods to investigate the suprosingly complex p85 dimerisation mechanism and its control by ligands. Results may inspire novel theraputic approaches.

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

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Zhongqi Ge

2018-04-01

Full Text Available Summary: Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies. : Ge et al. analyze a cohort of 9,125 TCGA samples across 33 cancer types to provide a comprehensive characterization of the ubiquitin pathway. They detect somatic driver candidates in the ubiquitin pathway and identify a cluster of patients with poor survival, highlighting the importance of this pathway in cancer development. Keywords: ubiquitin pathway, pan-cancer analysis, The Cancer Genome Atlas, tumor subtype, cancer prognosis, therapeutic targets, biomarker, FBXW7

A Key Enzyme of the NAD+ Salvage Pathway in Thermus thermophilus: Characterization of Nicotinamidase and the Impact of Its Gene Deletion at High Temperatures.

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Taniguchi, Hironori; Sungwallek, Sathidaphorn; Chotchuang, Phatcharin; Okano, Kenji; Honda, Kohsuke

2017-09-01

NAD (NAD + ) is a cofactor related to many cellular processes. This cofactor is known to be unstable, especially at high temperatures, where it chemically decomposes to nicotinamide and ADP-ribose. Bacteria, yeast, and higher organisms possess the salvage pathway for reconstructing NAD + from these decomposition products; however, the importance of the salvage pathway for survival is not well elucidated, except for in pathogens lacking the NAD + de novo synthesis pathway. Herein, we report the importance of the NAD + salvage pathway in the thermophilic bacterium Thermus thermophilus HB8 at high temperatures. We identified the gene encoding nicotinamidase (TTHA0328), which catalyzes the first reaction of the NAD + salvage pathway. This recombinant enzyme has a high catalytic activity against nicotinamide ( K m of 17 μM, k cat of 50 s -1 , k cat / K m of 3.0 × 10 3 s -1 · mM -1 ). Deletion of this gene abolished nicotinamide deamination activity in crude extracts of T. thermophilus and disrupted the NAD + salvage pathway in T. thermophilus Disruption of the salvage pathway led to the severe growth retardation at a higher temperature (80°C), owing to the drastic decrease in the intracellular concentrations of NAD + and NADH. IMPORTANCE NAD + and other nicotinamide cofactors are essential for cell metabolism. These molecules are unstable and decompose, even under the physiological conditions in most organisms. Thermophiles can survive at high temperatures where NAD + decomposition is, in general, more rapid. This study emphasizes that NAD + instability and its homeostasis can be one of the important factors for thermophile survival in extreme temperatures. Copyright © 2017 American Society for Microbiology.

Metabolomic NMR fingerprinting to identify and predict survival of patients with metastatic colorectal cancer

DEFF Research Database (Denmark)

Bertini, Ivano; Cacciatore, Stefano; Jensen, Benny V

2012-01-01

Earlier detection of patients with metastatic colorectal cancer (mCRC) might improve their treatment and survival outcomes. In this study, we used proton nuclear magnetic resonance ((1)H-NMR) to profile the serum metabolome in patients with mCRC and determine whether a disease signature may exist...... survival (HR, 3.4; 95% confidence interval, 2.06-5.50; P = 1.33 × 10(-6)). A number of metabolites concurred with the (1)H-NMR fingerprint of mCRC, offering insights into mCRC metabolic pathways. Our findings establish that (1)H-NMR profiling of patient serum can provide a strong metabolomic signature of m...

Small molecule screening identifies targetable zebrafish pigmentation pathways

DEFF Research Database (Denmark)

Colanesi, Sarah; Taylor, Kerrie L; Temperley, Nicholas D

2012-01-01

Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish and investig......Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish...... and investigate the effects of a few of these compounds in further detail. We identified and confirmed 57 compounds that altered pigment cell patterning, number, survival, or differentiation. Additional tissue targets and toxicity of small molecules are also discussed. Given that the majority of cell types...

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.

LENUS (Irish Health Repository)

Wander, Seth A

2011-04-01

Mammalian target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation, and survival via mTOR complex 1 (mTORC1) and mTORC2. The mTOR pathway is often aberrantly activated in cancers. While hypoxia, nutrient deprivation, and DNA damage restrain mTORC1 activity, multiple genetic events constitutively activate mTOR in cancers. Here we provide a brief overview of the signaling pathways up- and downstream of mTORC1 and -2, and discuss the insights into therapeutic anticancer targets - both those that have been tried in the clinic with limited success and those currently under clinical development - that knowledge of these pathways gives us.

Transcriptomic studies reveal a key metabolic pathway contributing to a well-maintained photosynthetic system under drought stress in foxtail millet (Setaria italica L.

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Weiping Shi

2018-05-01

Full Text Available Drought stress is one of the most important abiotic factors limiting crop productivity. A better understanding of the effects of drought on millet (Setaria italica L. production, a model crop for studying drought tolerance, and the underlying molecular mechanisms responsible for drought stress responses is vital to improvement of agricultural production. In this study, we exposed the drought resistant F1 hybrid, M79, and its parental lines E1 and H1 to drought stress. Subsequent physiological analysis demonstrated that M79 showed higher photosynthetic energy conversion efficiency and drought tolerance than its parents. A transcriptomic study using leaves collected six days after drought treatment, when the soil water content was about ∼20%, identified 3066, 1895, and 2148 differentially expressed genes (DEGs in M79, E1 and H1 compared to the respective untreated controls, respectively. Further analysis revealed 17 Gene Ontology (GO enrichments and 14 Kyoto Encyclopedia of Genes and Genomes (KEGG pathways in M79, including photosystem II (PSII oxygen-evolving complex, peroxidase (POD activity, plant hormone signal transduction, and chlorophyll biosynthesis. Co-regulation analysis suggested that these DEGs in M79 contributed to the formation of a regulatory network involving multiple biological processes and pathways including photosynthesis, signal transduction, transcriptional regulation, redox regulation, hormonal signaling, and osmotic regulation. RNA-seq analysis also showed that some photosynthesis-related DEGs were highly expressed in M79 compared to its parental lines under drought stress. These results indicate that various molecular pathways, including photosynthesis, respond to drought stress in M79, and provide abundant molecular information for further analysis of the underlying mechanism responding to this stress.

Transcriptomic studies reveal a key metabolic pathway contributing to a well-maintained photosynthetic system under drought stress in foxtail millet (Setaria italica L.).

Science.gov (United States)

Shi, Weiping; Cheng, Jingye; Wen, Xiaojie; Wang, Jixiang; Shi, Guanyan; Yao, Jiayan; Hou, Liyuan; Sun, Qian; Xiang, Peng; Yuan, Xiangyang; Dong, Shuqi; Guo, Pingyi; Guo, Jie

2018-01-01

Drought stress is one of the most important abiotic factors limiting crop productivity. A better understanding of the effects of drought on millet ( Setaria italica L.) production, a model crop for studying drought tolerance, and the underlying molecular mechanisms responsible for drought stress responses is vital to improvement of agricultural production. In this study, we exposed the drought resistant F 1 hybrid, M79, and its parental lines E1 and H1 to drought stress. Subsequent physiological analysis demonstrated that M79 showed higher photosynthetic energy conversion efficiency and drought tolerance than its parents. A transcriptomic study using leaves collected six days after drought treatment, when the soil water content was about ∼20%, identified 3066, 1895, and 2148 differentially expressed genes (DEGs) in M79, E1 and H1 compared to the respective untreated controls, respectively. Further analysis revealed 17 Gene Ontology (GO) enrichments and 14 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in M79, including photosystem II (PSII) oxygen-evolving complex, peroxidase (POD) activity, plant hormone signal transduction, and chlorophyll biosynthesis. Co-regulation analysis suggested that these DEGs in M79 contributed to the formation of a regulatory network involving multiple biological processes and pathways including photosynthesis, signal transduction, transcriptional regulation, redox regulation, hormonal signaling, and osmotic regulation. RNA-seq analysis also showed that some photosynthesis-related DEGs were highly expressed in M79 compared to its parental lines under drought stress. These results indicate that various molecular pathways, including photosynthesis, respond to drought stress in M79, and provide abundant molecular information for further analysis of the underlying mechanism responding to this stress.

Desert hedgehog promotes ischemia-induced angiogenesis by ensuring peripheral nerve survival.

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Renault, Marie-Ange; Chapouly, Candice; Yao, Qinyu; Larrieu-Lahargue, Frédéric; Vandierdonck, Soizic; Reynaud, Annabel; Petit, Myriam; Jaspard-Vinassa, Béatrice; Belloc, Isabelle; Traiffort, Elisabeth; Ruat, Martial; Duplàa, Cécile; Couffinhal, Thierry; Desgranges, Claude; Gadeau, Alain-Pierre

2013-03-01

Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves. The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia. We induced hindlimb ischemia in wild-type and Dhh(-/-) mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh(-/-). By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that denervation of the leg, immediately after the onset of ischemia, severely impairs ischemia-induced angiogenesis and decreases expression of vascular endothelial growth factor A, angiopoietin 1, and neurotrophin 3 in the ischemic muscle. This study demonstrates the crucial roles of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis.

What affects local community hospitals' survival in turbulent times?

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Chiang, Hung-Che; Wang, Shiow-Ing

2015-06-01

Hospital closures became a prevalent phenomenon in Taiwan after the implementation of a national health insurance program. A wide range of causes contributes to the viability of hospitals, but little is known about the situation under universal coverage health systems. The purpose of present study is to recognize the factors that may contribute to hospital survival under the universal coverage health system. This is a retrospective case-control study. Local community hospitals that contracted with the Bureau of National Health Insurance in 1998 and remained open during the period 1998-2011 are the designated cases. Controls are local community hospitals that closed during the same period. Using longitudinal representative health claim data, 209 local community hospitals that closed during 1998-2011 were compared with 165 that remained open. Variables related to institutional characteristics, degree of competition, characteristics of patients and financial performance were analyzed by logistic regression models. Hospitals' survival was positively related to specialty hospital, the number of respiratory care beds, the physician to population ratio, the number of clinics in the same region, a highly competitive market and the occupancy rate of elderly patients in the hospital. Teaching hospitals, investor-owned hospitals, the provision of obstetrics services or home care, and the number of medical centers or other local community hospitals may jeopardize the chance of survival. Factors-enhanced local hospitals to survive under the universal coverage health system have been identified. Hospital managers could manipulate these findings and adapt strategies for subsistence. © The Author 2015. Published by Oxford University Press in association with the International Society for Quality in Health Care; all rights reserved.

Ecdysone receptor agonism leading to lethal molting disruption in arthropods: Review and adverse outcome pathway development

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Molting is a key biological process in growth, development, reproduction and survival in arthropods. Complex neuroendocrine pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting compounds (EDCs). For example, s...

Plasmodium strain determines dendritic cell function essential for survival from malaria.

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Michelle N Wykes

2007-07-01

Full Text Available The severity of malaria can range from asymptomatic to lethal infections involving severe anaemia and cerebral disease. However, the molecular and cellular factors responsible for these differences in disease severity are poorly understood. Identifying the factors that mediate virulence will contribute to developing antiparasitic immune responses. Since immunity is initiated by dendritic cells (DCs, we compared their phenotype and function following infection with either a nonlethal or lethal strain of the rodent parasite, Plasmodium yoelii, to identify their contribution to disease severity. DCs from nonlethal infections were fully functional and capable of secreting cytokines and stimulating T cells. In contrast, DCs from lethal infections were not functional. We then transferred DCs from mice with nonlethal infections to mice given lethal infections and showed that these DCs mediated control of parasitemia and survival. IL-12 was necessary for survival. To our knowledge, our studies have shown for the first time that during a malaria infection, DC function is essential for survival. More importantly, the functions of these DCs are determined by the strain of parasite. Our studies may explain, in part, why natural malaria infections may have different outcomes.

Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

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Daniel L. Suzman

2015-09-01

Full Text Available Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

Induced DNA repair pathway in mammalian cells

International Nuclear Information System (INIS)

Overberg, R.

1985-01-01

The survival of cultured rat kangaroo cells (PtK-2) and human xeroderma pigmentosum cells incubated with 5 μM cycloheximide subsequent to ultraviolet irradiation is lower than that of cells incubated without cycloheximide. The drop in survival is considerably larger than that produced by incubation of unirradiated cells with cycloheximide. The phenomenon was also observed when PtK-2 cells were incubated with emetine, another protein synthesis inhibitor, or with 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole, a RNA synthesis inhibitor. PtK cells which received a preliminary UV treatment followed by an incubation period without cycloheximide and then a second irradiation and 24 hour incubation with cycloheximide, survived the effects of the second irradiation better than cells which were incubated in the presence of cycloheximide after the first and second UV irradiation. The application of cycloheximide for 24 hours after UV irradiation of PtK cells resulted in one-half as many 6-thioguanine resistant cells as compared to the number of 6-thioguanine resistant cells found when cycloheximide was not used. These experiments indicate that a UV-inducible cycloheximide-sensitive DNA repair pathway is present in PtK and xeroderma pigmentosum cells, which is error-prone in PtK cells

Survival analysis

International Nuclear Information System (INIS)

Badwe, R.A.

1999-01-01

The primary endpoint in the majority of the studies has been either disease recurrence or death. This kind of analysis requires a special method since all patients in the study experience the endpoint. The standard method for estimating such survival distribution is Kaplan Meier method. The survival function is defined as the proportion of individuals who survive beyond certain time. Multi-variate comparison for survival has been carried out with Cox's proportional hazard model

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

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Rawat, Siddhartha

2014-01-01

ABSTRACT Chronic infection with hepatitis B virus (HBV) is a risk factor for developing liver diseases such as hepatocellular carcinoma (HCC). HBx is a multifunctional protein encoded by the HBV genome; HBx stimulates HBV replication and is thought to play an important role in the development of HBV-associated HCC. HBx can activate the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in some cell lines; however, whether HBx regulates PI3K/AKT signaling in normal hepatocytes has not been evaluated. In studies described here, we assessed HBx activation of PI3K/AKT signaling in an ex vivo model of cultured primary hepatocytes and determined how this HBx activity affects HBV replication. We report that HBx activates AKT in primary hepatocytes and that the activation of AKT decreases HBV replication and HBV mRNA and core protein levels. We show that the transcription factor hepatocyte nuclear factor 4α (HNF4α) is a target of HBx-regulated AKT, and we link HNF4α to HBx-regulated AKT modulation of HBV transcription and replication. Although we and others have shown that HBx stimulates and is likely required for HBV replication, we now report that HBx also activates signals that can diminish the overall level of HBV replication. While this may seem counterintuitive, we show that an important effect of HBx activation of AKT is inhibition of apoptosis. Consequently, our studies suggest that HBx balances HBV replication and cell survival by stimulating signaling pathways that enhance hepatocyte survival at the expense of higher levels of HBV replication. IMPORTANCE Chronic hepatitis B virus (HBV) infection is a common cause of the development of liver cancer. Regulation of cell signaling pathways by the HBV HBx protein is thought to influence the development of HBV-associated liver cancer. HBx stimulates, and may be essential for, HBV replication. We show that HBx activates AKT in hepatocytes to reduce HBV replication. While this seems contradictory to an

Complex interplay between intrinsic and extrinsic drivers of long-term survival trends in southern elephant seals

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McMahon Clive R

2007-03-01

Full Text Available Abstract Background Determining the relative contribution of intrinsic and extrinsic factors to fluctuations in population size, trends and demographic composition is analytically complex. It is often only possible to examine the combined effects of these factors through measurements made over long periods, spanning an array of population densities or levels of food availability. Using age-structured mark-recapture models and datasets spanning five decades (1950–1999, and two periods of differing relative population density, we estimated age-specific probabilities of survival and examined the combined effects of population density and environmental conditions on juvenile survival of southern elephant seals at Macquarie Island. Results First-year survival decreased with density during the period of highest population size, and survival increased during years when the Southern Oscillation Index (SOI anomaly (deviation from a 50-year mean during the mother's previous foraging trip to sea was positive (i.e., El Niño. However, when environmental stochasticity and density were considered together, the effect of density on first-year survival effectively disappeared. Ignoring density effects also leads to models placing too much emphasis on the environmental conditions prevailing during the naïve pup's first year at sea. Conclusion Our analyses revealed that both the state of the environment and population density combine to modify juvenile survival, but that the degree to which these processes contributed to the variation observed was interactive and complex. This underlines the importance of evaluating the relative contribution of both the intrinsic and extrinsic factors that regulate animal populations because false conclusions regarding the importance of population regulation may be reached if they are examined in isolation.

Radioinduced intestinal fibrosis: from molecular mechanisms to therapy applications. Contribution of the TGF--β1, of the CTGF and of the transduction pathway of the Rho/ROCK signal

International Nuclear Information System (INIS)

Haydont, V.

2006-12-01

Delayed radiation enteritis is an intestinal fibrosis induced by accidental or therapeutic radiation for pelvic and abdominal cancer treatments. Studies of molecular mechanisms involved in the development and maintenance of fibrosis have showed the respective contribution of CTGF, low TGF-β1 concentrations and Rho/ROCK pathway. Thus, based on the relationship between CTGF, TGF-β1 and Rho pathway, 2 therapeutics strategies have been develop. First, a pravastatin curative gift leads to a fibro-lysis involving an inhibition of Rho and in cascade a reduction of CTGF expression and extracellular matrix deposition. The data suggest that reversal of established radiation fibrosis in the gut is possible. Second, a pravastatin prophylactic gift prevents the installation of a chronic fibrosis but does not protect the tumor. On the base of these results, the radiation therapy department of the Institut Gustave Roussy will soon initiate 2 clinical trials. (author)

COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer

International Nuclear Information System (INIS)

Glynn, Sharon A; Ambs, Stefan; Prueitt, Robyn L; Ridnour, Lisa A; Boersma, Brenda J; Dorsey, Tiffany M; Wink, David A; Goodman, Julie E; Yfantis, Harris G; Lee, Dong H

2010-01-01

Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype

Shengui Sansheng San extraction is an angiogenic switch via regulations of AKT/mTOR, ERK1/2 and Notch1 signal pathways after ischemic stroke.

Science.gov (United States)

Liu, Bowen; Luo, Cheng; Zheng, Zhaoguang; Xia, Zhenyan; Zhang, Qian; Ke, Chienchih; Liu, Renshyan; Zhao, Yonghua

2018-05-15

angiogenic switch. Due to suppressed VEGFR2/Notch1 cascades and activated AKT/mTOR and ERK1/2 signals in BMECs, a feedback loop of angiogenic homeostasis is established. Furthermore, the comprehensive mediations of SDF-1α/CXCR4 axis, AKT/mTOR/HIF-α, ERK1/2 and Notch1 pathways in penumbra contribute to the improvements of neurological function, survival rate and infarct volume post-stroke. Copyright © 2018 Elsevier GmbH. All rights reserved.

Stress responses during ageing: molecular pathways regulating protein homeostasis.

Science.gov (United States)

Kyriakakis, Emmanouil; Princz, Andrea; Tavernarakis, Nektarios

2015-01-01

The ageing process is characterized by deterioration of physiological function accompanied by frailty and ageing-associated diseases. The most broadly and well-studied pathways influencing ageing are the insulin/insulin-like growth factor 1 signaling pathway and the dietary restriction pathway. Recent studies in diverse organisms have also delineated emerging pathways, which collectively or independently contribute to ageing. Among them the proteostatic-stress-response networks, inextricably affect normal ageing by maintaining or restoring protein homeostasis to preserve proper cellular and organismal function. In this chapter, we survey the involvement of heat stress and endoplasmic reticulum stress responses in the regulation of longevity, placing emphasis on the cross talk between different response mechanisms and their systemic effects. We further discuss novel insights relevant to the molecular pathways mediating these stress responses that may facilitate the development of innovative interventions targeting age-related pathologies such as diabetes, cancer, cardiovascular and neurodegenerative diseases.

Designing a Care Pathway Model - A Case Study of the Outpatient Total Hip Arthroplasty Care Pathway.

Science.gov (United States)

Oosterholt, Robin I; Simonse, Lianne Wl; Boess, Stella U; Vehmeijer, Stephan Bw

2017-03-09

Although the clinical attributes of total hip arthroplasty (THA) care pathways have been thoroughly researched, a detailed understanding of the equally important organisational attributes is still lacking. The aim of this article is to contribute with a model of the outpatient THA care pathway that depicts how the care team should be organised to enable patient discharge on the day of surgery. The outpatient THA care pathway enables patients to be discharged on the day of surgery, shortening the length of stay and intensifying the provision and organisation of care. We utilise visual care modelling to construct a visual design of the organisation of the care pathway. An embedded case study was conducted of the outpatient THA care pathway at a teaching hospital in the Netherlands. The data were collected using a visual care modelling toolkit in 16 semi-structured interviews. Problems and inefficiencies in the care pathway were identified and addressed in the iterative design process. The results are two visual models of the most critical phases of the outpatient THA care pathway: diagnosis & preparation (1) and mobilisation & discharge (4). The results show the care team composition, critical value exchanges, and sequence that enable patient discharge on the day of surgery. The design addressed existing problems and is an optimisation of the case hospital's pathway. The network of actors consists of the patient (1), radiologist (1), anaesthetist (1), nurse specialist (1), pharmacist (1), orthopaedic surgeon (1,4), physiotherapist (1,4), nurse (4), doctor (4) and patient application (1,4). The critical value exchanges include patient preparation (mental and practical), patient education, aligned care team, efficient sequence of value exchanges, early patient mobilisation, flexible availability of the physiotherapist, functional discharge criteria, joint decision making and availability of the care team.

Evasion Mechanisms Used by Pathogens to Escape the Lectin Complement Pathway

DEFF Research Database (Denmark)

Rosbjerg, Anne; Genster, Ninette; Pilely, Katrine

2017-01-01

the level of activity. The result is a pro-inflammatory response meant to combat foreign microbes. Microbial elimination is, however, not a straight forward procedure; pathogens have adapted to their environment by evolving a collection of evasion mechanisms that circumvent the human complement system....... Complement evasion strategies features different ways of exploiting human complement proteins and moreover features different pathogen-derived proteins that interfere with the normal processes. Accumulated, these mechanisms target all three complement activation pathways as well as the final common part...... of the cascade. This review will cover the currently known lectin pathway evasion mechanisms and give examples of pathogens that operate these to increase their chance of invasion, survival and dissemination....

Low-dose radiation induces drosophila innate immunity through toll pathway activation

International Nuclear Information System (INIS)

Seong, Ki Moon; Kim, Cha Soon; Lee, Byung-Sub; Nam, Seon Young; Yang, Kwang Hee; Kim, Ji-Young; Jin, Young-Woo; Park, Joong-Jean; Min, Kyung-Jin

2012-01-01

Numerous studies report that exposing certain organisms to low-dose radiation induces beneficial effects on lifespan, tumorigenesis, and immunity. By analyzing survival after bacterial infection and antimicrobial peptide gene expression in irradiated flies, we demonstrate that low-dose irradiation of Drosophila enhances innate immunity. Low-dose irradiation of flies significantly increased resistance against gram-positive and gram-negative bacterial infections, as well as expression of several antimicrobial peptide genes. Additionally, low-dose irradiation also resulted in a specific increase in expression of key proteins of the Toll signaling pathway and phosphorylated forms of p38 and N-terminal kinase (JNK). These results indicate that innate immunity is activated after low-dose irradiation through Toll signaling pathway in Drosophila. (author)

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Science.gov (United States)

Klapacz, Joanna; Pottenger, Lynn H.; Engelward, Bevin P.; Heinen, Christopher D.; Johnson, George E.; Clewell, Rebecca A.; Carmichael, Paul L.; Adeleye, Yeyejide; Andersen, Melvin E.

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. PMID:27036068

Rewriting the Metabolic Blueprint: Advances in Pathway Diversification in Microorganisms

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Gazi Sakir Hossain

2018-02-01

Full Text Available Living organisms have evolved over millions of years to fine tune their metabolism to create efficient pathways for producing metabolites necessary for their survival. Advancement in the field of synthetic biology has enabled the exploitation of these metabolic pathways for the production of desired compounds by creating microbial cell factories through metabolic engineering, thus providing sustainable routes to obtain value-added chemicals. Following the past success in metabolic engineering, there is increasing interest in diversifying natural metabolic pathways to construct non-natural biosynthesis routes, thereby creating possibilities for producing novel valuable compounds that are non-natural or without elucidated biosynthesis pathways. Thus, the range of chemicals that can be produced by biological systems can be expanded to meet the demands of industries for compounds such as plastic precursors and new antibiotics, most of which can only be obtained through chemical synthesis currently. Herein, we review and discuss novel strategies that have been developed to rewrite natural metabolic blueprints in a bid to broaden the chemical repertoire achievable in microorganisms. This review aims to provide insights on recent approaches taken to open new avenues for achieving biochemical production that are beyond currently available inventions.

Rewriting the Metabolic Blueprint: Advances in Pathway Diversification in Microorganisms.

Science.gov (United States)

Hossain, Gazi Sakir; Nadarajan, Saravanan Prabhu; Zhang, Lei; Ng, Tee-Kheang; Foo, Jee Loon; Ling, Hua; Choi, Won Jae; Chang, Matthew Wook

2018-01-01

Living organisms have evolved over millions of years to fine tune their metabolism to create efficient pathways for producing metabolites necessary for their survival. Advancement in the field of synthetic biology has enabled the exploitation of these metabolic pathways for the production of desired compounds by creating microbial cell factories through metabolic engineering, thus providing sustainable routes to obtain value-added chemicals. Following the past success in metabolic engineering, there is increasing interest in diversifying natural metabolic pathways to construct non-natural biosynthesis routes, thereby creating possibilities for producing novel valuable compounds that are non-natural or without elucidated biosynthesis pathways. Thus, the range of chemicals that can be produced by biological systems can be expanded to meet the demands of industries for compounds such as plastic precursors and new antibiotics, most of which can only be obtained through chemical synthesis currently. Herein, we review and discuss novel strategies that have been developed to rewrite natural metabolic blueprints in a bid to broaden the chemical repertoire achievable in microorganisms. This review aims to provide insights on recent approaches taken to open new avenues for achieving biochemical production that are beyond currently available inventions.

20(S-ginsenoside Rg3 promotes senescence and apoptosis in gallbladder cancer cells via the p53 pathway

Directory of Open Access Journals (Sweden)

Zhang F

2015-08-01

Full Text Available Fei Zhang,* Maolan Li,* Xiangsong Wu,* Yunping Hu, Yang Cao, Xu’an Wang, Shanshan Xiang, Huaifeng Li, Lin Jiang, Zhujun Tan, Wei Lu, Hao Weng, Yijun Shu, Wei Gong, Xuefeng Wang, Yong Zhang, Weibin Shi, Ping Dong,# Jun Gu,# Yingbin Liu#Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work #These authors jointly directed this work Abstract: Gallbladder cancer (GBC, the most frequent malignancy of the biliary tract, is associated with high mortality and extremely poor prognosis. 20(S-ginsenoside Rg3 (20(S-Rg3 is a steroidal saponin with high pharmacological activity. However, the anticancer effect of 20(S-Rg3 in human GBC has not yet been determined. In this study, we primarily found that 20(S-Rg3 exposure suppressed the survival of both NOZ and GBC-SD cell lines in a concentration-dependent manner. Moreover, induction of cellular senescence and G0/G1 arrest by 20(S-Rg3 were accompanied by a large accumulation of p53 and p21 as a result of murine double minute 2 (MDM2 inhibition. 20(S-Rg3 also caused a remarkable increase in apoptosis via the activation of the mitochondrial-mediated intrinsic caspase pathway. Furthermore, intraperitoneal injection of 20(S-Rg3 (20 or 40 mg/kg for 3 weeks markedly inhibited the growth of xenografts in nude mice. Our results demonstrated that 20(S-Rg3 potently inhibited growth and survival of GBC cells both in vitro and in vivo. 20(S-Rg3 attenuated GBC growth probably via activation of the p53 pathway, and subsequent induction of cellular senescence and mitochondrial-dependent apoptosis. Therefore, 20(S-Rg3 may be a potential chemotherapeutic agent for GBC therapy.Keywords: gallbladder cancer, 20(S-ginsenoside Rg3, senescence, apoptosis, p53 pathway

Prediction of novel target genes and pathways involved in bevacizumab-resistant colorectal cancer

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Makondi, Precious Takondwa; Lee, Chia-Hwa; Huang, Chien-Yu; Chu, Chi-Ming; Chang, Yu-Jia

2018-01-01

Bevacizumab combined with cytotoxic chemotherapy is the backbone of metastatic colorectal cancer (mCRC) therapy; however, its treatment efficacy is hampered by therapeutic resistance. Therefore, understanding the mechanisms underlying bevacizumab resistance is crucial to increasing the therapeutic efficacy of bevacizumab. The Gene Expression Omnibus (GEO) database (dataset, GSE86525) was used to identify the key genes and pathways involved in bevacizumab-resistant mCRC. The GEO2R web tool was used to identify differentially expressed genes (DEGs). Functional and pathway enrichment analyses of the DEGs were performed using the Database for Annotation, Visualization, and Integrated Discovery(DAVID). Protein–protein interaction (PPI) networks were established using the Search Tool for the Retrieval of Interacting Genes/Proteins database(STRING) and visualized using Cytoscape software. A total of 124 DEGs were obtained, 57 of which upregulated and 67 were downregulated. PPI network analysis showed that seven upregulated genes and nine downregulated genes exhibited high PPI degrees. In the functional enrichment, the DEGs were mainly enriched in negative regulation of phosphate metabolic process and positive regulation of cell cycle process gene ontologies (GOs); the enriched pathways were the phosphoinositide 3-kinase-serine/threonine kinase signaling pathway, bladder cancer, and microRNAs in cancer. Cyclin-dependent kinase inhibitor 1A(CDKN1A), toll-like receptor 4 (TLR4), CD19 molecule (CD19), breast cancer 1, early onset (BRCA1), platelet-derived growth factor subunit A (PDGFA), and matrix metallopeptidase 1 (MMP1) were the DEGs involved in the pathways and the PPIs. The clinical validation of the DEGs in mCRC (TNM clinical stages 3 and 4) revealed that high PDGFA expression levels were associated with poor overall survival, whereas high BRCA1 and MMP1 expression levels were associated with favorable progress free survival(PFS). The identified genes and pathways

Prediction of novel target genes and pathways involved in bevacizumab-resistant colorectal cancer.

Directory of Open Access Journals (Sweden)

Precious Takondwa Makondi

Full Text Available Bevacizumab combined with cytotoxic chemotherapy is the backbone of metastatic colorectal cancer (mCRC therapy; however, its treatment efficacy is hampered by therapeutic resistance. Therefore, understanding the mechanisms underlying bevacizumab resistance is crucial to increasing the therapeutic efficacy of bevacizumab. The Gene Expression Omnibus (GEO database (dataset, GSE86525 was used to identify the key genes and pathways involved in bevacizumab-resistant mCRC. The GEO2R web tool was used to identify differentially expressed genes (DEGs. Functional and pathway enrichment analyses of the DEGs were performed using the Database for Annotation, Visualization, and Integrated Discovery(DAVID. Protein-protein interaction (PPI networks were established using the Search Tool for the Retrieval of Interacting Genes/Proteins database(STRING and visualized using Cytoscape software. A total of 124 DEGs were obtained, 57 of which upregulated and 67 were downregulated. PPI network analysis showed that seven upregulated genes and nine downregulated genes exhibited high PPI degrees. In the functional enrichment, the DEGs were mainly enriched in negative regulation of phosphate metabolic process and positive regulation of cell cycle process gene ontologies (GOs; the enriched pathways were the phosphoinositide 3-kinase-serine/threonine kinase signaling pathway, bladder cancer, and microRNAs in cancer. Cyclin-dependent kinase inhibitor 1A(CDKN1A, toll-like receptor 4 (TLR4, CD19 molecule (CD19, breast cancer 1, early onset (BRCA1, platelet-derived growth factor subunit A (PDGFA, and matrix metallopeptidase 1 (MMP1 were the DEGs involved in the pathways and the PPIs. The clinical validation of the DEGs in mCRC (TNM clinical stages 3 and 4 revealed that high PDGFA expression levels were associated with poor overall survival, whereas high BRCA1 and MMP1 expression levels were associated with favorable progress free survival(PFS. The identified genes and pathways

Neural crest contributions to the lamprey head

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McCauley, David W.; Bronner-Fraser, Marianne

2003-01-01

The neural crest is a vertebrate-specific cell population that contributes to the facial skeleton and other derivatives. We have performed focal DiI injection into the cranial neural tube of the developing lamprey in order to follow the migratory pathways of discrete groups of cells from origin to destination and to compare neural crest migratory pathways in a basal vertebrate to those of gnathostomes. The results show that the general pathways of cranial neural crest migration are conserved throughout the vertebrates, with cells migrating in streams analogous to the mandibular and hyoid streams. Caudal branchial neural crest cells migrate ventrally as a sheet of cells from the hindbrain and super-pharyngeal region of the neural tube and form a cylinder surrounding a core of mesoderm in each pharyngeal arch, similar to that seen in zebrafish and axolotl. In addition to these similarities, we also uncovered important differences. Migration into the presumptive caudal branchial arches of the lamprey involves both rostral and caudal movements of neural crest cells that have not been described in gnathostomes, suggesting that barriers that constrain rostrocaudal movement of cranial neural crest cells may have arisen after the agnathan/gnathostome split. Accordingly, neural crest cells from a single axial level contributed to multiple arches and there was extensive mixing between populations. There was no apparent filling of neural crest derivatives in a ventral-to-dorsal order, as has been observed in higher vertebrates, nor did we find evidence of a neural crest contribution to cranial sensory ganglia. These results suggest that migratory constraints and additional neural crest derivatives arose later in gnathostome evolution.

Interleukin-6 receptor pathways in coronary heart disease

DEFF Research Database (Denmark)

Sarwar, Nadeem; Butterworth, Adam S; Freitag, Daniel F

2012-01-01

Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied ...

Pathways to College for Former Foster Youth: Understanding Factors that Contribute to Educational Success

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Merdinger, Joan M.; Hines, Alice M.; Osterling, Kathy Lemon; Wyatt, Paige

2005-01-01

This article presents early descriptive findings from the Pathways to College study, a multimethod and multiphase study of emancipated foster youth. Results based on a sample of 216 emancipated foster youth attending a four-year university indicate that many of their experiences are characteristic of individuals manifesting resilience in the face…

Clinical evidence on the magnitude of change in growth pathway activity in relation to Tamoxifen resistance is required.

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Mansouri, Sepideh; Farahmand, Leila; Teymourzadeh, Azin; Majidzadeh-A, Keivan

2017-08-08

Despite prolonged disease-free survival and overall survival rates in estrogen receptor (ER)-positive patients undergoing adjuvant treatment, Tamoxifen therapy tends to fail due to eventual acquisition of resistance. Although numerous studies have emphasized the role of receptor tyrosine kinases (RTKs) in the development of Tamoxifen resistance, inadequate clinical evidence is available regarding the alteration of biomarker expression during acquired resistance, thus undermining the validity of the findings. Results of two meta-analyses investigating the effect of HER2 status on the prognosis of Tamoxifen-receiving patients have demonstrated that despite HER2-negative patients having longer disease-free survival; there is no difference in overhaul survival between the two groups. Furthermore, due to the intricate molecular interactions among estrogen receptors including ERα36, ERα66, and also RTKs, it is not surprising that RTK suppression does not restore Tamoxifen sensitivity. In considering such a complex network, we speculate that by the time HER2/EGFR is suppressed via targeted therapies, activation of ERα66 and ERα36 initiate molecular signaling pathways downstream of RTKs, thereby enhancing cell proliferation even in the presence of both Tamoxifen and RTK inhibitors. Although clinical findings regarding the molecular pathways downstream of RTKs have been thoroughly discussed in this review, further clinical studies are required in determining a consistency between preclinical and clinical findings. Discovering the best targets in preventing tumor progression requires thorough comprehension of estrogen-dependent and estrogen-independent pathways during Tamoxifen resistance development. Indeed, exploring additional clinically-proven targets would allow for better characterized treatments being available for breast cancer patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

MicroRNA-gene signaling pathways in pancreatic cancer

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Alexandra Drakaki

2013-10-01

Full Text Available Pancreatic cancer is the fourth most frequent cause of cancer-related deaths and is characterized by early metastasis and pronounced resistance to chemotherapy and radiation therapy. Despite extensive esearch efforts, there is not any substantial progress regarding the identification of novel drugs against pancreatic cancer. Although the introduction of the chemotherapeutic agent gemcitabine improved clinical response, the prognosis of these patients remained extremely poor with a 5-year survival rate of 3-5%. Thus, the identification of the novel molecular pathways involved in pancreatic oncogenesis and the development of new and potent therapeutic options are highly desirable. Here, we describe how microRNAs control signaling pathways that are frequently deregulated during pancreatic oncogenesis. In addition, we provide evidence that microRNAs could be potentially used as novel pancreatic cancer therapeutics through reversal of chemotherapy and radiotherapy resistance or regulation of essential molecular pathways. Further studies should integrate the deregulated genes and microRNAs into molecular networks in order to identify the central regulators of pancreatic oncogenesis. Targeting these central regulators could lead to the development of novel targeted therapeutic approaches for pancreatic cancer patients.

Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation

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Gurzov, E N; Barthson, J; Marhfour, I

2012-01-01

Destruction of insulin-producing pancreatic β-cells by local autoimmune inflammation is a hallmark of type 1 diabetes. Histochemical analysis of pancreases from non-obese diabetic mice indicated activation of the transcription factor JunB/AP-1 (activator protein-1) after autoimmune infiltration......-cells and human islet cells against pro-inflammatory mediators. These results were confirmed in genetically modified islets derived from Ubi-JunB transgenic mice. Our findings identify ATF3 as a novel downstream target of JunB in the survival mechanism of β-cells under inflammatory stress....

Is there a hierarchy of survival reflexes?

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Macphail, Kieran

2013-10-01

A hierarchy of survival reflexes for prioritising assessment and treatment in patients with pain of insidious onset is hypothesised. The hierarchy asserts that some systems are more vital than others and that the central nervous system (CNS) prioritises systems based on their significance to survival. The hypothesis suggests that dysfunction in more important systems will cause compensation in less important systems. This paper presents studies examining these effects for each system, arguing that each section of the hierarchy may have effects on other systems within the hierarchy. This concept is untested empirically, highly speculative and substantial research is required to validate the suggested hierarchical prioritisation by the CNS. Nonetheless, the hierarchy does provide a theoretical framework to use to exclude contributing systems in patients with pain of insidious onset. Copyright © 2013 Elsevier Ltd. All rights reserved.

Microparticles shed from multidrug resistant breast cancer cells provide a parallel survival pathway through immune evasion.

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Jaiswal, Ritu; Johnson, Michael S; Pokharel, Deep; Krishnan, S Rajeev; Bebawy, Mary

2017-02-06

introduce a new paradigm in cancer cell biology with significant implications in understanding breast cancer colonization at distant sites. Most importantly, this is also the first demonstration that MPs serve as conduits in a parallel pathway supporting the cellular survival of MDR cancer cells through immune evasion.

The Survival and Welfare Implications of Altruism when Preferences are Endogenous

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Poulsen, Anders

This paper is a contribution to the economic literature studying altruism. In a simple evolutionary model of endogenous preferences we show that individuals with altruistic preferences can survive. We also analyze the material welfare implications of altruism. Policies that promote altruism in th...

Human T-Cell Leukemia Virus Type 1 Tax-Deregulated Autophagy Pathway and c-FLIP Expression Contribute to Resistance against Death Receptor-Mediated Apoptosis

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Wang, Weimin; Zhou, Jiansuo; Shi, Juan; Zhang, Yaxi; Liu, Shilian

2014-01-01

ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) Tax protein is considered to play a central role in the process that leads to adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax-expressing cells show resistance to apoptosis induced by Fas ligand (FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). The regulation of Tax on the autophagy pathway in HeLa cells and peripheral T cells was recently reported, but the function and underlying molecular mechanism of the Tax-regulated autophagy are not yet well defined. Here, we report that HTLV-1 Tax deregulates the autophagy pathway, which plays a protective role during the death receptor (DR)-mediated apoptosis of human U251 astroglioma cells. The cellular FLICE-inhibitory protein (c-FLIP), which is upregulated by Tax, also contributes to the resistance against DR-mediated apoptosis. Both Tax-induced autophagy and Tax-induced c-FLIP expression require Tax-induced activation of IκB kinases (IKK). Furthermore, Tax-induced c-FLIP expression is regulated through the Tax-IKK-NF-κB signaling pathway, whereas Tax-triggered autophagy depends on the activation of IKK but not the activation of NF-κB. In addition, DR-mediated apoptosis is correlated with the degradation of Tax, which can be facilitated by the inhibitors of autophagy. IMPORTANCE Our study reveals that Tax-deregulated autophagy is a protective mechanism for DR-mediated apoptosis. The molecular mechanism of Tax-induced autophagy is also illuminated, which is different from Tax-increased c-FLIP. Tax can be degraded via manipulation of autophagy and TRAIL-induced apoptosis. These results outline a complex regulatory network between and among apoptosis, autophagy, and Tax and also present evidence that autophagy represents a new possible target for therapeutic intervention for the HTVL-1 related diseases. PMID:24352466

A model of survival following pre-hospital cardiac arrest based on the Victorian Ambulance Cardiac Arrest Register.

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Fridman, Masha; Barnes, Vanessa; Whyman, Andrew; Currell, Alex; Bernard, Stephen; Walker, Tony; Smith, Karen L

2007-11-01

This study describes the epidemiology of sudden cardiac arrest patients in Victoria, Australia, as captured via the Victorian Ambulance Cardiac Arrest Register (VACAR). We used the VACAR data to construct a new model of out-of-hospital cardiac arrest (OHCA), which was specified in accordance with observed trends. All cases of cardiac arrest in Victoria that were attended by Victorian ambulance services during the period of 2002-2005. Overall survival to hospital discharge was 3.8% among 18,827 cases of OHCA. Survival was 15.7% among 1726 bystander witnessed, adult cardiac arrests of presumed cardiac aetiology, presenting in ventricular fibrillation or ventricular tachycardia (VF/VT), where resuscitation was attempted. In multivariate logistic regression analysis, bystander CPR, cardiac arrest (CA) location, response time, age and sex were predictors of VF/VT, which, in turn, was a strong predictor of survival. The same factors that affected VF/VT made an additional contribution to survival. However, for bystander CPR, CA location and response time this additional contribution was limited to VF/VT patients only. There was no detectable association between survival and age younger than 60 years or response time over 15min. The new model accounts for relationships among predictors of survival. These relationships indicate that interventions such as reduced response times and bystander CPR act in multiple ways to improve survival.

Low mannose-binding lectin serum levels are associated with reduced kidney graft survival

DEFF Research Database (Denmark)

Bay, Jakob Thaning; Sørensen, Søren S; Hansen, Jesper M

2013-01-01

Activation of the complement system is initiated by the alternative, the classical, or the lectin pathway. As the complement system is involved in the pathophysiology of graft rejection after kidney transplantation, we investigated the possible role of mannose-binding lectin in kidney transplanta...... immunity in maintaining kidney graft survival, but these are probably overruled by HLA immunization.Kidney International advance online publication, 21 November 2012; doi:10.1038/ki.2012.373....

Network survivability performance

Science.gov (United States)

1993-11-01

This technical report has been developed to address the survivability of telecommunications networks including services. It responds to the need for a common understanding of, and assessment techniques for network survivability, availability, integrity, and reliability. It provides a basis for designing and operating telecommunications networks to user expectations for network survivability and a foundation for continuing industry activities in the subject area. This report focuses on the survivability of both public and private networks and covers a wide range of users. Two frameworks are established for quantifying and categorizing service outages, and for classifying network survivability techniques and measures. The performance of the network survivability techniques is considered; however, recommended objectives are not established for network survivability performance.

Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis

International Nuclear Information System (INIS)

Goc, Anna; Kochuparambil, Samith T; Al-Husein, Belal; Al-Azayzih, Ahmad; Mohammad, Shuaib; Somanath, Payaningal R

2012-01-01

Recent studies suggest the potential benefits of statins as anti-cancer agents. Mechanisms by which statins induce apoptosis in cancer cells are not clear. We previously showed that simvastatin inhibit prostate cancer cell functions and tumor growth. Molecular mechanisms by which simvastatin induce apoptosis in prostate cancer cells is not completely understood. Effect of simvastatin on PC3 cell apoptosis was compared with docetaxel using apoptosis, TUNEL and trypan blue viability assays. Protein expression of major candidates of the intrinsic pathway downstream of simvastatin-mediated Akt inactivation was analyzed. Gene arrays and western analysis of PC3 cells and tumor lysates were performed to identify the candidate genes mediating extrinsic apoptosis pathway by simvastatin. Data indicated that simvastatin inhibited intrinsic cell survival pathway in PC3 cells by enhancing phosphorylation of Bad, reducing the protein expression of Bcl-2, Bcl-xL and cleaved caspases 9/3. Over-expression of PC3 cells with Bcl-2 or DN-caspase 9 did not rescue the simvastatin-induced apoptosis. Simvastatin treatment resulted in increased mRNA and protein expression of molecules such as TNF, Fas-L, Traf1 and cleaved caspase 8, major mediators of intrinsic apoptosis pathway and reduced protein levels of pro-survival genes Lhx4 and Nme5. Our study provides the first report that simvastatin simultaneously modulates intrinsic and extrinsic pathways in the regulation of prostate cancer cell apoptosis in vitro and in vivo, and render reasonable optimism that statins could become an attractive anti-cancer agent

Pathway Analysis in Attention Deficit Hyperactivity Disorder: An Ensemble Approach

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Mooney, Michael A.; McWeeney, Shannon K.; Faraone, Stephen V.; Hinney, Anke; Hebebrand, Johannes; Nigg, Joel T.; Wilmot, Beth

2016-01-01

Despite a wealth of evidence for the role of genetics in attention deficit hyperactivity disorder (ADHD), specific and definitive genetic mechanisms have not been identified. Pathway analyses, a subset of gene-set analyses, extend the knowledge gained from genome-wide association studies (GWAS) by providing functional context for genetic associations. However, there are numerous methods for association testing of gene sets and no real consensus regarding the best approach. The present study applied six pathway analysis methods to identify pathways associated with ADHD in two GWAS datasets from the Psychiatric Genomics Consortium. Methods that utilize genotypes to model pathway-level effects identified more replicable pathway associations than methods using summary statistics. In addition, pathways implicated by more than one method were significantly more likely to replicate. A number of brain-relevant pathways, such as RhoA signaling, glycosaminoglycan biosynthesis, fibroblast growth factor receptor activity, and pathways containing potassium channel genes, were nominally significant by multiple methods in both datasets. These results support previous hypotheses about the role of regulation of neurotransmitter release, neurite outgrowth and axon guidance in contributing to the ADHD phenotype and suggest the value of cross-method convergence in evaluating pathway analysis results. PMID:27004716

The Wnt antagonist, Dickkopf-1, as a target for the treatment of neurodegenerative disorders

NARCIS (Netherlands)

Caraci, Filippo; Busceti, Carla; Biagioni, Francesca; Aronica, Eleonora; Mastroiacovo, Federica; Cappuccio, Irene; Battaglia, Giuseppe; Bruno, Valeria; Caricasole, Andrea; Copani, Agata; Nicoletti, Ferdinando

2008-01-01

The canonical Wnt pathway contributes to the regulation of neuronal survival and homeostasis in the CNS. Recent evidence suggests that an increased expression of Dickkopf-1 (Dkk-1), a secreted protein that negatively modulates the canonical Wnt pathway, is causally related to processes of

Beta-hydroxy-beta-methylbutyrate (HMB) stimulates myogenic cell proliferation, differentiation and survival via the MAPK/ERK and PI3K/Akt pathways.

Science.gov (United States)

Kornasio, Reut; Riederer, Ingo; Butler-Browne, Gillian; Mouly, Vincent; Uni, Zehava; Halevy, Orna

2009-05-01

Beta-hydroxy-beta-methylbutyrate (HMB), a leucine catabolite, has been shown to prevent exercise-induced protein degradation and muscle damage. We hypothesized that HMB would directly regulate muscle-cell proliferation and differentiation and would attenuate apoptosis, the latter presumably underlying satellite-cell depletion during muscle degradation or atrophy. Adding various concentrations of HMB to serum-starved myoblasts induced cell proliferation and MyoD expression as well as the phosphorylation of MAPK/ERK. HMB induced differentiation-specific markers, increased IGF-I mRNA levels and accelerated cell fusion. Its inhibition of serum-starvation- or staurosporine-induced apoptosis was reflected by less apoptotic cells, reduced BAX expression and increased levels of Bcl-2 and Bcl-X. Annexin V staining and flow cytometry analysis showed reduced staurosporine-induced apoptosis in human myoblasts in response to HMB. HMB enhanced the association of the p85 subunit of PI3K with tyrosine-phosphorylated proteins. HMB elevated Akt phosphorylation on Thr308 and Ser473 and this was inhibited by Wortmannin, suggesting that HMB acts via Class I PI3K. Blocking of the PI3K/Akt pathway with specific inhibitors revealed its requirement in mediating the promotive effects of HMB on muscle cell differentiation and fusion. These direct effects of HMB on myoblast differentiation and survival resembling those of IGF-I, at least in culture, suggest its positive influence in preventing muscle wasting.

Solar irradiance limits the long-term survival of Listeria monocytogenes in seawater.

Science.gov (United States)

NicAogáin, K; Magill, D; O'Donoghue, B; Conneely, A; Bennett, C; O'Byrne, C P

2018-03-01

Seafood has often been implicated in outbreaks of food-borne illness caused by Listeria monocytogenes but the source of contamination is usually not known. In this study we investigated the possibility that this pathogen could survive in seawater for an extended time period. Freshly collected seawater samples were inoculated with 1 × 10 8  CFU per ml of L. monocytogenes EGD-e and survival was monitored by plate counting for up to 25 days. When incubated in the dark, either at ambient temperatures (4-14°C) or at 16°C, >10 4  CFU per ml survivors were present after 25 days. However, when the seawater cell suspensions were exposed to ambient light (solar irradiation) and temperatures, L. monocytogenes lost viability rapidly and no survivors could be detected after the 80 h time point. Both UV-A and visible light in the blue region of the spectrum (470 nm) were found to contribute to this effect. The stress inducible sigma factor σ B was found to play a role in survival of L. monocytogenes in seawater. Together these data demonstrate that solar irradiation is a critical determinant of L. monocytogenes survival in marine environments. The data further suggest the possibility of controlling this food-borne pathogen in food-processing environments using visible light. Listeria monocytogenes is a food-borne bacterial pathogen capable of causing the life-threatening infection, listeriosis. In seafood the route of contamination from the environment is often not well understood as this pathogen is not generally thought to survive well in seawater. Here we provide evidence that L. monocytogenes is capable of surviving for long periods of time in seawater when light is excluded. Sunlight is demonstrated to have a significant effect on the survival of this pathogen in seawater, and both visible (470 nm) and UV-A light are shown to contribute to this effect. © 2017 The Society for Applied Microbiology.

Little Smoky Woodland Caribou Calf Survival Enhancement Project

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Kirkby G. Smith

2011-09-01

Full Text Available The Little Smoky woodland caribou (Rangifer tarandus herd is a boreal ecotype located in west central Alberta, Canada. This herd has declined steadily over the past decade and is currently thought to number approximately 80 animals. Factors contributing to the herds' decline appear related to elevated predator-caused mortality rates resulting from industrial caused landscape change. At current rates of decline, the herd is at risk of extirpation. A calf survival enhancement project was initiated in the first half of 2006 as a means of enhancing recruitment while other longer-term approaches were implemented. A total of 10 pregnant females were captured in early March and held in captivity until all calves were at least 3 weeks old. Before release, calves were radiocollared with expandable drop-off collars. Following release, survival of mother and offspring were tracked at intervals until the fall rut. Survival of penned calves was compared to "wild-born" calves at heel of non captive radiocollared females. This approach is compared to other techniques designed to increase recruitment in caribou.

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.

Science.gov (United States)

Klapacz, Joanna; Pottenger, Lynn H; Engelward, Bevin P; Heinen, Christopher D; Johnson, George E; Clewell, Rebecca A; Carmichael, Paul L; Adeleye, Yeyejide; Andersen, Melvin E

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. Copyright © 2015 Elsevier B.V. All rights reserved.

Survival analysis of heart failure patients: A case study.

Science.gov (United States)

Ahmad, Tanvir; Munir, Assia; Bhatti, Sajjad Haider; Aftab, Muhammad; Raza, Muhammad Ali

2017-01-01

This study was focused on survival analysis of heart failure patients who were admitted to Institute of Cardiology and Allied hospital Faisalabad-Pakistan during April-December (2015). All the patients were aged 40 years or above, having left ventricular systolic dysfunction, belonging to NYHA class III and IV. Cox regression was used to model mortality considering age, ejection fraction, serum creatinine, serum sodium, anemia, platelets, creatinine phosphokinase, blood pressure, gender, diabetes and smoking status as potentially contributing for mortality. Kaplan Meier plot was used to study the general pattern of survival which showed high intensity of mortality in the initial days and then a gradual increase up to the end of study. Martingale residuals were used to assess functional form of variables. Results were validated computing calibration slope and discrimination ability of model via bootstrapping. For graphical prediction of survival probability, a nomogram was constructed. Age, renal dysfunction, blood pressure, ejection fraction and anemia were found as significant risk factors for mortality among heart failure patients.

The Surface-Exposed Protein SntA Contributes to Complement Evasion in Zoonotic Streptococcus suis.

Science.gov (United States)

Deng, Simin; Xu, Tong; Fang, Qiong; Yu, Lei; Zhu, Jiaqi; Chen, Long; Liu, Jiahui; Zhou, Rui

2018-01-01

Streptococcus suis is an emerging zoonotic pathogen causing streptococcal toxic shock like syndrome (STSLS), meningitis, septicemia, and even sudden death in human and pigs. Serious septicemia indicates this bacterium can evade the host complement surveillance. In our previous study, a functionally unknown protein SntA of S. suis has been identified as a heme-binding protein, and contributes to virulence in pigs. SntA can interact with the host antioxidant protein AOP2 and consequently inhibit its antioxidant activity. In the present study, SntA is identified as a cell wall anchored protein that functions as an important player in S. suis complement evasion. The C3 deposition and membrane attack complex (MAC) formation on the surface of sntA -deleted mutant strain Δ sntA are demonstrated to be significantly higher than the parental strain SC-19 and the complementary strain CΔ sntA . The abilities of anti-phagocytosis, survival in blood, and in vivo colonization of Δ sntA are obviously reduced. SntA can interact with C1q and inhibit hemolytic activity via the classical pathway. Complement activation assays reveal that SntA can also directly activate classical and lectin pathways, resulting in complement consumption. These two complement evasion strategies may be crucial for the pathogenesis of this zoonotic pathogen. Concerning that SntA is a bifunctional 2',3'-cyclic nucleotide 2'-phosphodiesterase/3'-nucleotidase in many species of Gram-positive bacteria, these complement evasion strategies may have common biological significance.

Kynurenine Pathway Metabolites in Humans: Disease and Healthy States

Directory of Open Access Journals (Sweden)

Yiquan Chen

2009-01-01

Full Text Available Tryptophan is an essential amino acid that can be metabolised through different pathways, a major route being the kynurenine pathway. The first enzyme of the pathway, indoleamine-2,3-dioxygenase, is strongly stimulated by inflammatory molecules, particularly interferon gamma. Thus, the kynurenine pathway is often systematically up-regulated when the immune response is activated. The biological significance is that 1 the depletion of tryptophan and generation of kynurenines play a key modulatory role in the immune response; and 2 some of the kynurenines, such as quinolinic acid, 3-hydroxykynurenine and kynurenic acid, are neuroactive. The kynurenine pathway has been demonstrated to be involved in many diseases and disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, AIDS dementia complex, malaria, cancer, depression and schizophrenia, where imbalances in tryptophan and kynurenines have been found. This review compiles most of these studies and provides an overview of how the kynurenine pathway might be contributing to disease development, and the concentrations of tryptophan and kynurenines in the serum, cerebrospinal fluid and brain tissues in control and patient subjects.

The JAK/STAT pathway in obesity and diabetes.

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Gurzov, Esteban N; Stanley, William J; Pappas, Evan G; Thomas, Helen E; Gough, Daniel J

2016-08-01

Diabetes mellitus are complex, multi-organ metabolic pathologies characterized by hyperglycemia. Emerging evidence shows that the highly conserved and potent JAK/STAT signaling pathway is required for normal homeostasis, and, when dysregulated, contributes to the development of obesity and diabetes. In this review, we analyze the role of JAK/STAT activation in the brain, liver, muscle, fat and pancreas, and how this affects the course of the disease. We also consider the therapeutic implications of targeting the JAK/STAT pathway in treatment of obesity and diabetes. © 2016 Federation of European Biochemical Societies.

High MRPS23 expression contributes to hepatocellular carcinoma proliferation and indicates poor survival outcomes.

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Pu, Meng; Wang, Jianlin; Huang, Qike; Zhao, Ge; Xia, Congcong; Shang, Runze; Zhang, Zhuochao; Bian, Zhenyuan; Yang, Xishegn; Tao, Kaishan

2017-07-01

Hepatocellular carcinoma is one of the most prevalent neoplasms and the leading cause of cancer-related mortality worldwide. Mitochondrial ribosomal protein S23 is encoded by a nuclear gene and participates in mitochondrial protein translation. Mitochondrial ribosomal protein S23 overexpression has been found in many types of cancer. In this study, we explored mitochondrial ribosomal protein S23 expression in primary hepatocellular carcinoma tissues compared with matched adjacent non-tumoral liver tissues using mitochondrial ribosomal protein S23 messenger RNA and protein levels collected from public databases and clinical samples. Immunohistochemistry was performed to analyze the relationship between mitochondrial ribosomal protein S23 and various clinicopathological features. The results indicated that mitochondrial ribosomal protein S23 was significantly overexpressed in hepatocellular carcinoma. High mitochondrial ribosomal protein S23 expression was correlated with the tumor size and tumor-metastasis-node stage. Moreover, patients with high mitochondrial ribosomal protein S23 expression levels presented poorer survival rates. Mitochondrial ribosomal protein S23 was an independent prognostic factor for survival, especially at the early stage of hepatocellular carcinoma. In addition, the downregulation of mitochondrial ribosomal protein S23 decreased the proliferation of hepatocellular carcinoma in vitro and in vivo. In conclusion, we verified for the first time that mitochondrial ribosomal protein S23 expression was upregulated in hepatocellular carcinoma. High mitochondrial ribosomal protein S23 levels can predict poor clinical outcomes in hepatocellular carcinoma, and this protein plays a key role in tumor proliferation. Therefore, mitochondrial ribosomal protein S23 may be a potential therapeutic target for hepatocellular carcinoma.

Dual biosynthetic pathways to phytosterol via cycloartenol and lanosterol in Arabidopsis.

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Ohyama, Kiyoshi; Suzuki, Masashi; Kikuchi, Jun; Saito, Kazuki; Muranaka, Toshiya

2009-01-20

The differences between the biosynthesis of sterols in higher plants and yeast/mammals are believed to originate at the cyclization step of oxidosqualene, which is cyclized to cycloartenol in higher plants and lanosterol in yeast/mammals. Recently, lanosterol synthase genes were identified from dicotyledonous plant species including Arabidopsis, suggesting that higher plants possess dual biosynthetic pathways to phytosterols via lanosterol, and through cycloartenol. To identify the biosynthetic pathway to phytosterol via lanosterol, and to reveal the contributions to phytosterol biosynthesis via each cycloartenol and lanosterol, we performed feeding experiments by using [6-(13)C(2)H(3)]mevalonate with Arabidopsis seedlings. Applying (13)C-{(1)H}{(2)H} nuclear magnetic resonance (NMR) techniques, the elucidation of deuterium on C-19 behavior of phytosterol provided evidence that small amounts of phytosterol were biosynthesized via lanosterol. The levels of phytosterol increased on overexpression of LAS1, and phytosterols derived from lanosterol were not observed in a LAS1-knockout plant. This is direct evidence to indicate that the biosynthetic pathway for phytosterol via lanosterol exists in plant cells. We designate the biosynthetic pathway to phytosterols via lanosterol "the lanosterol pathway." LAS1 expression is reported to be induced by the application of jasmonate and is thought to have evolved from an ancestral cycloartenol synthase to a triterpenoid synthase, such as beta-amyrin synthase and lupeol synthase. Considering this background, the lanosterol pathway may contribute to the biosynthesis of not only phytosterols, but also steroids as secondary metabolites.

The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma

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Erculj Nina

2014-09-01

Full Text Available Background. We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL. Patients and methods. In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms.

Post-Communist Welfare Pathways

DEFF Research Database (Denmark)

Cerami, Alfio; Vanhuysse, Pieter

. The authors' impressive analysis of causal factors, including political elites' strategic use of social policy, makes the book an original and important contribution to the comparative welfare state literature.'- Professor Linda J. Cook, Brown University“ 'This edited volume is extraordinarily good...... factors such as micro-causal mechanisms, ideas, discourses, path departures, power politics, and elite strategies. This book includes contributions from leading international Experts such as Claus Offe, Robert Kaufman, Stefan Haggard, Tomasz Inglot, and Mitchell Orenstein, to examine welfare in specific...... countries and across social policy domains. By providing a broad overview based on a theoretical foundation and drawing on recent empirical evidence, Post-Communist Welfare Pathways offers a comprehensive, state-of-the-art account of the progress that has been made since 1989, and the main challenges...

The participation of the Fanconi anemia pathway in the replication of UV-damage DNA

International Nuclear Information System (INIS)

Federico, M.B.; Vallerga, M.B.; Mansilla, S.F.; Speroni, J.; Habif, M.; D'Alessio, C.; Gottifredi, V.

2011-01-01

When cells are challenged with genotoxic agents, replicating cells must use damaged DNA as templates. In this way, active replication forks do not collapse and cell viability is protected. After UV irradiation a specialized DNA polymerase pol eta uses UV damaged DNA as template. Intriguingly, Pol eta lost in human cells does not steeply increase UV sensitivity. This suggests that compensatory mechanisms promote cell survival when pol eta is absent. We have found an increase and sustained FANCD2 ubiquitination and focal formation after UV irradiation when pol eta is lost. FANCD2 is a key marker of the activation of the FANCONI ANEMIA (FA) pathway. While there is limited information regarding a role of the FA pathway after UV irradiation, it is well established that FANCD2 ubiquitination is linked to the recruitment of homologous recombination (HR) specific markers to other lesions. We therefore thought that cell viability in the absence of pol eta might result from the activation of FANDC2-dependent HR at collapsed replication forks. We are currently analyzing markers of damage such as γH2AX phosphorylation, markers of HR such as Rad51, markers of double strand breaks accumulation such as 53BP1 and setting up viability assays. This information might allow us to predict if FANCD2 can trigger HR after UV and if this contributes to cell viability when pol eta is absent. (authors)

L-carnitine contributes to enhancement of neurogenesis from mesenchymal stem cells through Wnt/β-catenin and PKA pathway.

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Fathi, Ezzatollah; Farahzadi, Raheleh; Charoudeh, Hojjatollah Nozad

2017-03-01

The identification of factors capable of enhancing neurogenesis has great potential for cellular therapies in neurodegenerative diseases. Multiple studies have shown the neuroprotective effects of L-carnitine (LC). This study determined whether neuronal differentiation of rat adipose tissue-derived mesenchymal stem cells (ADSCs) can be activated by LC. In this study, protein kinase A (PKA) and Wnt/β-catenin pathways were detected to show if this activation was due to these pathways. The expression of LC-induced neurogenesis markers in ADSCs was characterized using real-time PCR. ELISA was conducted to assess the expression of cyclic adenosine monophosphate (cAMP) and PKA. The expression of β-catenin, reduced dickkopf1 (DKK1), low-density lipoprotein receptor-related protein 5 (LRP5), Wnt1, and Wnt3a genes as Wnt/β-catenin signaling members were used to detect the Wnt/β-catenin pathway. It was observed that LC could promote neurogenesis in ADSCs as well as expression of some neurogenic markers. Moreover, LC causes to increase the cAMP levels and PKA activity. Treatment of ADSCs with H-89 (dihydrochloride hydrate) as PKA inhibitor significantly inhibited the promotion of neurogenic markers, indicating that the PKA signaling pathway could be involved in neurogenesis induction. Analyses of real-time PCR data showed that the mRNA expressions of β-catenin, DKK1, LRP5c-myc, Wnt1, and Wnt3a were increased in the presence of LC. Therefore, the present study showed that LC promotes ADSCs neurogenesis and the LC-induced neurogenic markers could be due to both the PKA and Wnt/β-catenin signaling pathway. Impact statement Neural tissue has long been believed as incapable of regeneration and the identification of cell types and factors capable of neuronal differentiation has generated intense interest. Mesenchymal stem cells (MSCs) are considered as potential targets for stem cell-based therapy. L-carnitin (LC) as an antioxidant may have neuroprotective effects in

The Drosophila T-box transcription factor Midline functions within the Notch–Delta signaling pathway to specify sensory organ precursor cell fates and regulates cell survival within the eye imaginal disc

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Das, Sudeshna; Chen, Q. Brent; Saucier, Joseph D.; Drescher, Brandon; Zong, Yan; Morgan, Sarah; Forstall, John; Meriwether, Andrew; Toranzo, Randy; Leal, Sandra M.

2014-01-01

We report that the T-box transcription factor Midline (Mid), an evolutionary conserved homolog of the vertebrate Tbx20 protein, functions within the Notch–Delta signaling pathway essential for specifying the fates of sensory organ precursor cells. This complements an established history of research showing that Mid regulates the cell-fate specification of diverse cell types within the developing heart, epidermis and central nervous system. Tbx20 has been detected in diverse neuronal and epithelial cells of embryonic eye tissues in both mice and humans. However, the mechanisms by which either Mid or Tbx20 function to regulate cell-fate specification or other critical aspects of eye development including cell survival have not yet been elucidated. We have also gathered preliminary evidence suggesting that Mid may play an indirect, but vital role in selecting SOP cells within the third-instar larval eye disc by regulating the expression of the proneural gene atonal. During subsequent pupal stages, Mid specifies SOP cell fates as a member of the Notch–Delta signaling hierarchy and is essential for maintaining cell viability within by inhibiting apoptotic pathways. We present several new hypotheses that seek to understand the role of Mid in regulating developmental processes downstream of the Notch receptor that are critical for specifying unique cell fates, patterning the adult eye and maintaining cellular homeostasis during eye disc morphogenesis. PMID:23962751

Analysis of DNA double-strand break repair pathways in mice

International Nuclear Information System (INIS)

Brugmans, Linda; Kanaar, Roland; Essers, Jeroen

2007-01-01

During the last years significant new insights have been gained into the mechanism and biological relevance of DNA double-strand break (DSB) repair in relation to genome stability. DSBs are a highly toxic DNA lesion, because they can lead to chromosome fragmentation, loss and translocations, eventually resulting in cancer. DSBs can be induced by cellular processes such as V(D)J recombination or DNA replication. They can also be introduced by exogenous agents DNA damaging agents such as ionizing radiation or mitomycin C. During evolution several pathways have evolved for the repair of these DSBs. The most important DSB repair mechanisms in mammalian cells are nonhomologous end-joining and homologous recombination. By using an undamaged repair template, homologous recombination ensures accurate DSB repair, whereas the untemplated nonhomologous end-joining pathway does not. Although both pathways are active in mammals, the relative contribution of the two repair pathways to genome stability differs in the different cell types. Given the potential differences in repair fidelity, it is of interest to determine the relative contribution of homologous recombination and nonhomologous end-joining to DSB repair. In this review, we focus on the biological relevance of DSB repair in mammalian cells and the potential overlap between nonhomologous end-joining and homologous recombination in different tissues

Branched-chain amino acid supplementation reduces oxidative stress and prolongs survival in rats with advanced liver cirrhosis.

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Motoh Iwasa

Full Text Available Long-term supplementation with branched-chain amino acids (BCAA is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05. The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver.

The Wnt/β-catenin signaling pathway tips the balance between apoptosis and reprograming of cell fusion hybrids.

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Lluis, Frederic; Pedone, Elisa; Pepe, Stefano; Cosma, Maria Pia

2010-11-01

Cell-cell fusion contributes to cell differentiation and developmental processes. We have previously showed that activation of Wnt/β-catenin enhances somatic cell reprograming after polyethylene glycol (PEG)-mediated fusion. Here, we show that neural stem cells and ESCs can fuse spontaneously in cocultures, although with very low efficiency (about 2%), as the hybrids undergo apoptosis. In contrast, when Wnt/β-catenin signaling is activated in ESCs and leads to accumulation of low amounts of β-catenin in the nucleus, activated ESCs can reprogram somatic cells with very high efficiency after spontaneous fusion. Furthermore, we also show that different levels of β-catenin accumulation in the ESC nuclei can modulate cell proliferation, although in our experimental setting, cell proliferation does not modulate the reprograming efficiency per se. Overall, the present study provides evidence that spontaneous fusion occurs, while the survival of the reprogramed clones is strictly dependent on induction of a Wnt-mediated reprograming pathway. Copyright © 2010 AlphaMed Press.

Designing a Care Pathway Model – A Case Study of the Outpatient Total Hip Arthroplasty Care Pathway

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Robin I. Oosterholt

2017-03-01

Full Text Available Introduction: Although the clinical attributes of total hip arthroplasty (THA care pathways have been thoroughly researched, a detailed understanding of the equally important organisational attributes is still lacking. The aim of this article is to contribute with a model of the outpatient THA care pathway that depicts how the care team should be organised to enable patient discharge on the day of surgery. Theory: The outpatient THA care pathway enables patients to be discharged on the day of surgery, short- ening the length of stay and intensifying the provision and organisation of care. We utilise visual care modelling to construct a visual design of the organisation of the care pathway. Methods: An embedded case study was conducted of the outpatient THA care pathway at a teaching hospital in the Netherlands. The data were collected using a visual care modelling toolkit in 16 semi- structured interviews. Problems and inefficiencies in the care pathway were identified and addressed in the iterative design process. Results: The results are two visual models of the most critical phases of the outpatient THA care pathway: diagnosis & preparation (1 and mobilisation & discharge (4. The results show the care team composition, critical value exchanges, and sequence that enable patient discharge on the day of surgery. Conclusion: The design addressed existing problems and is an optimisation of the case hospital’s pathway. The network of actors consists of the patient (1, radiologist (1, anaesthetist (1, nurse specialist (1, pharmacist (1, orthopaedic surgeon (1,4, physiotherapist (1,4, nurse (4, doctor (4 and patient applica- tion (1,4. The critical value exchanges include patient preparation (mental and practical, patient education, aligned care team, efficient sequence of value exchanges, early patient mobilisation, flexible availability of the physiotherapist, functional discharge criteria, joint decision making and availability of the care team.

Three Antagonistic Cyclic di-GMP-Catabolizing Enzymes Promote Differential Dot/Icm Effector Delivery and Intracellular Survival at the Early Steps of Legionella pneumophila Infection

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Allombert, Julie; Lazzaroni, Jean-Claude; Baïlo, Nathalie; Gilbert, Christophe; Charpentier, Xavier; Doublet, Patricia

2014-01-01

Legionella pneumophila is an intracellular pathogen which replicates within protozoan cells and can accidently infect alveolar macrophages, causing an acute pneumonia in humans. The second messenger cyclic di-GMP (c-di-GMP) has been shown to play key roles in the regulation of various bacterial processes, including virulence. While investigating the function of the 22 potential c-di-GMP-metabolizing enzymes of the L. pneumophila Lens strain, we found three that directly contribute to its ability to infect both protozoan and mammalian cells. These three enzymes display diguanylate cyclase (Lpl0780), phosphodiesterase (Lpl1118), and bifunctional diguanylate cyclase/phosphodiesterase (Lpl0922) activities, which are all required for the survival and intracellular replication of L. pneumophila. Mutants with deletions of the corresponding genes are efficiently taken up by phagocytic cells but are partially defective for the escape of the Legionella-containing vacuole (LCV) from the host degradative endocytic pathway and result in lower survival. In addition, Lpl1118 is required for efficient endoplasmic reticulum recruitment to the LCV. Trafficking and biogenesis of the LCV are dependent upon the orchestrated actions of several type 4 secretion system Dot/Icm effectors proteins, which exhibit differentially altered translocation in the three mutants. While translocation of some effectors remained unchanged, others appeared over- and undertranslocated. A general translocation offset of the large repertoire of Dot/Icm effectors may be responsible for the observed defects in the trafficking and biogenesis of the LCV. Our results suggest that L. pneumophila uses cyclic di-GMP signaling to fine-tune effector delivery and ensure effective evasion of the host degradative pathways and establishment of a replicative vacuole. PMID:24379287

Local-scale drivers of tree survival in a temperate forest.

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Wang, Xugao; Comita, Liza S; Hao, Zhanqing; Davies, Stuart J; Ye, Ji; Lin, Fei; Yuan, Zuoqiang

2012-01-01

Tree survival plays a central role in forest ecosystems. Although many factors such as tree size, abiotic and biotic neighborhoods have been proposed as being important in explaining patterns of tree survival, their contributions are still subject to debate. We used generalized linear mixed models to examine the relative importance of tree size, local abiotic conditions and the density and identity of neighbors on tree survival in an old-growth temperate forest in northeastern China at three levels (community, guild and species). Tree size and both abiotic and biotic neighborhood variables influenced tree survival under current forest conditions, but their relative importance varied dramatically within and among the community, guild and species levels. Of the variables tested, tree size was typically the most important predictor of tree survival, followed by biotic and then abiotic variables. The effect of tree size on survival varied from strongly positive for small trees (1-20 cm dbh) and medium trees (20-40 cm dbh), to slightly negative for large trees (>40 cm dbh). Among the biotic factors, we found strong evidence for negative density and frequency dependence in this temperate forest, as indicated by negative effects of both total basal area of neighbors and the frequency of conspecific neighbors. Among the abiotic factors tested, soil nutrients tended to be more important in affecting tree survival than topographic variables. Abiotic factors generally influenced survival for species with relatively high abundance, for individuals in smaller size classes and for shade-tolerant species. Our study demonstrates that the relative importance of variables driving patterns of tree survival differs greatly among size classes, species guilds and abundance classes in temperate forest, which can further understanding of forest dynamics and offer important insights into forest management.

Heritable temperament pathways to early callous–unemotional behaviour

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Waller, Rebecca; Trentacosta, Christopher J.; Shaw, Daniel S.; Neiderhiser, Jenae M.; Ganiban, Jody M.; Reiss, David; Leve, Leslie D.; Hyde, Luke W.

2016-01-01

Background Early callous–unemotional behaviours identify children at risk for antisocial behaviour. Recent work suggests that the high heritability of callous–unemotional behaviours is qualified by interactions with positive parenting. Aims To examine whether heritable temperament dimensions of fearlessness and low affiliative behaviour are associated with early callous–unemotional behaviours and whether parenting moderates these associations. Method Using an adoption sample (n = 561), we examined pathways from biological mother self-reported fearlessness and affiliative behaviour to child callous–unemotional behaviours via observed child fearlessness and affiliative behaviour, and whether adoptive parent observed positive parenting moderated pathways. Results Biological mother fearlessness predicted child callous–unemotional behaviours via earlier child fearlessness. Biological mother low affiliative behaviour predicted child callous–unemotional behaviours, although not via child affiliative behaviours. Adoptive mother positive parenting moderated the fearlessness to callous–unemotional behaviour pathway. Conclusions Heritable fearlessness and low interpersonal affiliation traits contribute to the development of callous–unemotional behaviours. Positive parenting can buffer these risky pathways. PMID:27765772

Viability of Hydrogen Pathways that Enhance Energy Security: A Comparison of China and Denmark

DEFF Research Database (Denmark)

Ren, Jingzheng; Andreasen, Kristian Peter; Sovacool, Benjamin

2014-01-01

When designed and built properly, hydrogen energy systems can enhance energy security through technological diversification and minimizing dependence on foreign imports of energy fuels. However, hydrogen can be produced from different feedstocks according to separate pathways, and these different...... pathways create particular consequences on a nation's overall energy security. The objective of this study is to investigate the superiorities and inferiorities of hydrogen pathways from the perspective of China and Denmark, and to determine which pathways best contribute to national energy security...

Activation of the Saccharomyces cerevisiae filamentation/invasion pathway by osmotic stress in high-osmolarity glycogen pathway mutants

Science.gov (United States)

Davenport, K. D.; Williams, K. E.; Ullmann, B. D.; Gustin, M. C.; McIntire, L. V. (Principal Investigator)

1999-01-01

Mitogen-activated protein kinase (MAPK) cascades are frequently used signal transduction mechanisms in eukaryotes. Of the five MAPK cascades in Saccharomyces cerevisiae, the high-osmolarity glycerol response (HOG) pathway functions to sense and respond to hypertonic stress. We utilized a partial loss-of-function mutant in the HOG pathway, pbs2-3, in a high-copy suppressor screen to identify proteins that modulate growth on high-osmolarity media. Three high-copy suppressors of pbs2-3 osmosensitivity were identified: MSG5, CAK1, and TRX1. Msg5p is a dual-specificity phosphatase that was previously demonstrated to dephosphorylate MAPKs in yeast. Deletions of the putative MAPK targets of Msg5p revealed that kss1delta could suppress the osmosensitivity of pbs2-3. Kss1p is phosphorylated in response to hyperosmotic shock in a pbs2-3 strain, but not in a wild-type strain nor in a pbs2-3 strain overexpressing MSG5. Both TEC1 and FRE::lacZ expressions are activated in strains lacking a functional HOG pathway during osmotic stress in a filamentation/invasion-pathway-dependent manner. Additionally, the cellular projections formed by a pbs2-3 mutant on high osmolarity are absent in strains lacking KSS1 or STE7. These data suggest that the loss of filamentation/invasion pathway repression contributes to the HOG mutant phenotype.

CD147-CD98hc complex contributes to poor prognosis of non-small cell lung cancer patients through promoting cell proliferation via the PI3K/Akt signaling pathway.

Science.gov (United States)

Fei, Fei; Li, Xiaofei; Xu, Li; Li, Deyang; Zhang, Zhipei; Guo, Xu; Yang, Hushan; Chen, Zhinan; Xing, Jinliang

2014-12-01

It has been reported that CD147 and CD98 heavy chain (CD98hc) form a complex on the cell plasma membrane of several cancers; however, whether this complex exists in non-small cell lung cancer (NSCLC) cells and affects the prognosis of patients remains to be elucidated. The expression of CD147 and CD98hc was assessed in tissue samples from 241 NSCLC patients and NSCLC cell lines. The correlation between CD147 and CD98hc expression and their association with the prognosis of NSCLC patients were analyzed. We also evaluated the impact of CD147 and CD98hc on the growth of NSCLC cells as well as Akt phosphorylation. Both CD147 and CD98hc were significantly upregulated in NSCLC cells, and their expression levels were significantly correlated (p CD147 and CD98hc could form a complex on NSCLC cells. Compared with NSCLC patients with CD147-/CD98hc-, those with CD147+/CD98hc+ exhibited a significantly poor overall survival (OS) with a hazard ratio (HR) of 1.92 (p = 0.010), and a significantly increased risk of recurrence with a HR of 1.97 (p = 0.004). Also, we demonstrated that the proliferation of lung cancer cell lines was significantly affected by knockdown and force-expression of the CD147-CD98hc complex. Western blot analysis indicated that the phosphorylation of Akt in NSCLC cells was significantly affected by knockdown and overexpression of either or both CD147 and CD98hc. Our findings indicate that the CD147-CD98hc complex significantly contributes to poor prognosis of NSCLC patients through promoting cell proliferation via the PI3K/Akt pathway.

Distribution and Joint Fish-Tag Survival of Juvenile Chinook Salmon Migrating through the Sacramento-San Joaquin River Delta, California, 2008

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Holbrook, Christopher M.; Perry, Russell W.; Adams, Noah S.

2009-01-01

Acoustic telemetry was used to obtain the movement histories of 915 juvenile fall-run Chinook salmon (Oncorhynchus tshawytscha) through the lower San Joaquin River and Sacramento-San Joaquin Delta, California, in 2008. Data were analyzed within a release-recapture framework to estimate survival, route distribution, and detection probabilities among three migration pathways through the Delta. The pathways included the primary route through the San Joaquin River and two less direct routes (Old River and Turner Cut). Strong inferences about survival were limited by premature tag failure, but estimates of fish distribution among migration routes should be unaffected by tag failure. Based on tag failure tests (N = 66 tags), we estimated that only 55-78 percent of the tags used in this study were still functioning when the last fish was detected exiting the study area 15 days after release. Due to premature tag failure, our 'survival' estimates represent the joint probability that both the tag and fish survived, not just survival of fish. Low estimates of fish-tag survival could have been caused by fish mortality or fish travel times that exceeded the life of the tag, but we were unable to differentiate between the two. Fish-tag survival through the Delta (from Durham Ferry to Chipps Island by all routes) ranged from 0.05 +or- 0.01 (SE) to 0.06 +or- 0.01 between the two weekly release groups. Among the three migration routes, fish that remained in the San Joaquin River exhibited the highest joint fish-tag survival (0.09 +or- 0.02) in both weeks, but only 22-33 percent of tagged fish used this route, depending on the week of release. Only 4-10 percent (depending on week) of tagged fish traveled through Turner Cut, but no tagged fish that used this route were detected exiting the Delta. Most fish (63-68 percent, depending on week of release) migrated through Old River, but fish-tag survival through this route (0.05 +or- 0.01) was only about one-half that of fish that