5-alpha-reductase: 2013-01-06

2013年1月12日星期六

Post Stroke Use of Selective Serotonin Reuptake Inhibitors and Clinical Outcome Among Patients With Ischemic Stroke: A Nationwide Propensity Score-matched Follow-up Study.

Post Stroke Use of Selective Serotonin Reuptake Inhibitors and Clinical Outcome Among Patients With Ischemic Stroke: A Nationwide Propensity Score-matched Follow-up Study.

Stroke. 2013 Jan 10;

Authors: Mortensen JK, Larsson H, Johnsen SP, Andersen G

Abstract
BACKGROUND AND PURPOSE: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed after stroke. We aimed to investigate whether potential antiplatelet or vasospastic effects have important clinical implications. METHODS: Using data from Danish medical registries, we did a nationwide follow-up study among ischemic stroke patients between 2003 and 2009. We identified 5833 SSRI users, and propensity score matched these patients with nonusers in a 1:1 ratio, followed by Cox regression analysis to compute hazard ratios (HRs) of acute myocardial infarction, recurrent stroke, major bleeding, and death. RESULTS: Median follow-up time (from 30 days after discharge to death/end of follow-up) was 1159 days. In total, 2.9% had myocardial infarction, 8.1% recurrent ischemic stroke, 20.2% major bleeding, 1.4% intracranial bleeding, and 34.4% died during follow-up. SSRI users had a lower risk of the combined outcome of myocardial infarction or recurrent ischemic stroke (adjusted HR, 0.77; confidence interval [CI], 0.62-0.96). However, the SSRI users also experienced a higher risk of overall major bleeding (adjusted HR, 1.33; CI, 1.14-1.55) and a nonsignificantly higher risk of intracranial bleedings (adjusted HR, 1.14; CI, 0.62-2.12). Mortality increased in SSRI users (adjusted HR, 1.13; CI, 1.00-1.28) and death caused by bleeding increased (adjusted HR, 1.89; CI, 0.97-3.66) as compared with death by other causes (adjusted HR, 1.11; CI; 0.98-1.26). CONCLUSIONS: SSRI use after ischemic stroke was associated with a lower risk of new cardiovascular events and also with an increased bleeding risk. There was an increased mortality among SSRI users, which may be related to the increased bleeding risk.

PMID: 23306326 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

Reduced group IVA phospholipase A2 expression is associated with unfavorable outcome for patients with gastric cancer.

Reduced group IVA phospholipase A2 expression is associated with unfavorable outcome for patients with gastric cancer.

Med Oncol. 2013 Mar;30(1):454

Authors: Zhang X, Wu Q, Gan L, Yu GZ, Wang R, Wang ZS, Wang JJ, Wang X

Abstract
Arachidonic acid metabolic pathway has been implicated in the inflammation-associated tumorigenesis of gastrointestinal cancers. As the rate-limiting enzyme of arachidonic acid production, group IVA phospholipase A2 (PLA2G4A) is hypothesized to play a fundamental role in gastric tumorigenesis as well as cyclooxygenase-2 (COX-2). However, little is known about the expression and role of PLA2G4A in gastric cancer, and the association of PLA2G4A with COX-2 remains to be elucidated. In this study, the mRNA expression of PLA2G4A and COX-2 in 60 pairs of fresh gastric tumors and corresponding adjacent non-cancerous mucosa was detected by using real-time quantitative PCR and the immunostaining of the both proteins in paired samples from 866 gastric cancer patients were assessed by using immunohistochemistry method. The clinicopathological and the prognostic relevance of PLA2G4A and COX-2 expression were determined. The results revealed a significantly reduced expression of PLA2G4A in gastric tumors compared to in non-cancerous tissues, as opposite to the increased expression of COX-2. PLA2G4A was significantly associated with tumor size (P�=�0.003), tumor grade (P�<�0.001), intestinal type (P�=�0.003), T classification (P�<�0.001), N classification (P�<�0.001), and thereby TNM stage (P�<�0.001). PLA2G4A and COX-2 expression were both identified as independent prognostic factors in multivariate Cox model analysis (P�=�0.024 for PLA2G4A and P�<�0.001 for COX-2). Moreover, the reduced PLA2G4A and increased COX-2 expression was both associated with unfavorable survival for patients with gastric cancer. PLA2G4A might serve as a promising target for future therapeutic approaches to gastric cancer combined with COX-2 inhibitors.

PMID: 23307260 [PubMed - in process]

c-met inhibitors zm-447439 rad001

Interleukin-11 protects against renal ischemia and reperfusion injury.

Interleukin-11 protects against renal ischemia and reperfusion injury.

Am J Physiol Renal Physiol. 2012 Oct 15;303(8):F1216-24

Authors: Lee HT, Park SW, Kim M, Ham A, Anderson LJ, Brown KM, D'Agati VD, Cox GN

Abstract
Renal ischemia reperfusion (IR) injury causes renal tubular necrosis, apoptosis, and inflammation leading to acute and chronic kidney dysfunction. IL-11 is a multifunctional hematopoietic cytokine clinically approved to treat chemotherapy-induced thrombocytopenia. Recent studies suggest that IL-11 also has potent antiapoptotic and antinecrotic properties. In this study, we tested the hypothesis that exogenous IL-11 protects against renal IR injury and determined the mechanisms involved in renal protection. Pretreatment with human recombinant IL-11 (HR IL-11) or with long-acting site-specific polyethylene glycol (PEG)-conjugated human IL-11 analog (PEGylated IL-11) produced partial but significant protection against renal IR injury in mice. In addition, HR IL-11 or PEGylated IL-11 given 30-60 min after IR also provided renal protection in mice. Significant reductions in renal tubular necrosis and neutrophil infiltration as well as tubular apoptosis were observed in mice treated with HR IL-11 or PEGylated IL-11. Furthermore, HR IL-11 or PEGylated IL-11 decreased both necrosis and apoptosis in human proximal tubule (HK-2) cells in culture. Mechanistically, IL-11 increased nuclear translocation of hypoxia-inducible factor-1? (HIF-1?) and induced sphingosine kinase-1 (SK1) expression and activity in HK-2 cells. Moreover, selective HIF-1? inhibitors blocked IL-11-mediated induction of SK1 in HK-2 cells. Finally, HR IL-11 or PEGylated IL-11 failed to protect against renal IR injury in SK1-deficient mice. Together, our data show powerful renal protective effects of exogenous IL-11 against IR injury by reducing necrosis, inflammation, and apoptosis through induction of SK1 via HIF-1?.

PMID: 22859402 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.

Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.

Brain Behav Immun. 2013 Jan 7;

Authors: Ruud J, Nilsson A, Ruud LE, Wang W, Nilsberth C, Iresj� BM, Lundholm K, Engblom D, Blomqvist A

Abstract
It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE(2) levels in plasma - a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE(2)-levels in the cerebrospinal fluid. Neutralization of plasma PGE(2) with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1), affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP(4) receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE(2) and neuronal EP(4) signaling.

PMID: 23305935 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

MET Is Required for the Maximal Action of 20-Hydroxyecdysone during Bombyx Metamorphosis.

MET Is Required for the Maximal Action of 20-Hydroxyecdysone during Bombyx Metamorphosis.

PLoS One. 2012;7(12):e53256

Authors: Guo E, He Q, Liu S, Tian L, Sheng Z, Peng Q, Guan J, Shi M, Li K, Gilbert LI, Wang J, Cao Y, Li S

Abstract
Little is known about how the putative juvenile hormone (JH) receptor, the bHLH-PAS transcription factor MET, is involved in 20-hydroxyecdysone (20E; the molting hormone) action. Here we report that two MET proteins found in the silkworm, Bombyx mori, participate in 20E signal transduction. Met is 20E responsive and its expression peaks during molting and pupation, when the 20E titer is high. As found with results from RNAi knockdown of EcR-USP (the ecdysone receptor genes), RNAi knockdown of Met at the early wandering stage disrupts the 20E-triggered transcriptional cascade, preventing tissue remodeling (including autophagy, apoptosis and destruction of larval tissues and generation of adult structures) and causing lethality during the larval-pupal transition. MET physically interacts with EcR-USP. Moreover, MET, EcR-USP and the 20E-response element (EcRE) form a protein-DNA complex, implying that MET might modulate 20E-induced gene transcription by interacting with EcR-USP. In conclusion, the 20E induction of MET is required for the maximal action of 20E during Bombyx metamorphosis.

PMID: 23300902 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

2013年1月11日星期五

The cyclooxygenase-2 inhibitor parecoxib inhibits surgery-induced proinflammatory cytokine expression in the hippocampus in aged rats.

The cyclooxygenase-2 inhibitor parecoxib inhibits surgery-induced proinflammatory cytokine expression in the hippocampus in aged rats.

J Surg Res. 2012 Nov;178(1):e1-8

Authors: Peng M, Wang YL, Wang FF, Chen C, Wang CY

Abstract
BACKGROUND: Neuroinflammatory response triggered by surgery has been increasingly reported to be associated with postoperative cognitive dysfunction. Proinflammatory cytokines, such as interleukin 1? (IL-1?) and tumor necrosis factor ? (TNF-?), play a pivotal role in mediating surgery-induced neuroinflammation. The role of cyclooxygenase-2 (COX-2), a critical regulator in inflammatory response, in surgery-induced neuroinflammation is still unknown. The aim of the study was to investigate the changes of COX-2 expression and prostaglandin E2 (PGE2) production in the hippocampus in aged rats following partial hepatectomy. The effects of selective COX-2 inhibitor (parecoxib) on hippocampal proinflammatory cytokine expression were also evaluated.
METHODS: Aged rats were randomly divided into three groups: control (n = 10), surgery (n = 30), and parecoxib (n = 30). Control animals received sterile saline to control for the effects of injection stress. Rats in the surgery group received partial hepatectomy under isoflurane anesthesia and sterile saline injection. Rats in the parecoxib group received surgery and anesthesia similar to surgery group rats, and parecoxib treatment. On postanesthetic days 1, 3, and 7, animals were euthanized to assess levels of hippocampal COX-2 expression, PGE2 production, and cytokines IL-1? and TNF-? expression. The effects of parecoxib on proinflammatory cytokine expression were also assessed.
RESULTS: Partial hepatectomy significantly increased COX-2 expression, PGE2 production, and proinflammatory cytokine expression in the hippocampus in aged rats on postoperative days 1 and 3. Parecoxib inhibited hippocampal IL-1? and TNF-? expression through downregulation of the COX-2/PGE2 pathway.
CONCLUSION: COX-2 may play a critical role in surgery-induced neuroinflammation. The COX-2 inhibitor may be a promising candidate for treatment of neuroinflammation caused by surgical trauma.

PMID: 22959208 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Incidence, medical and socio-behavioural predictors of psychiatric events in an 11-year follow-up of HIV-infected patients on antiretroviral therapy.

Incidence, medical and socio-behavioural predictors of psychiatric events in an 11-year follow-up of HIV-infected patients on antiretroviral therapy.

Antivir Ther. 2012;17(6):1079-83

Authors: Protopopescu C, Raffi F, Brunet-Fran�ois C, Salmon D, Verdon R, Reboud P, Carrieri MP, Leport C, Spire B, Michel L, APROCO-COPILOTE (ANRS CO8) Study Group

Abstract
BACKGROUND: Psychiatric disorders are relatively common among HIV-infected patients. However, there are few studies about their potential risk factors. This analysis aimed to measure the incidence of severe psychiatric events (PE) among patients receiving combination antiretroviral therapy (cART) of the French APROCO-COPILOTE (ANRS CO8) cohort, and to identify the medical and socio-behavioural correlates of their first episode of depression, suicide or suicide attempt (D/S/SA).
METHODS: APROCO-COPILOTE is a cohort of patients started on a protease inhibitor regimen between 1997 and 1999, with prospective medical standardized records and self-administered questionnaires collecting socio-demographic and socio-behavioural data. This analysis included all 11-year follow-up visits for 1,095 patients having completed baseline self-administered questionnaires. A proportional hazard Cox model was used to identify the correlates of a first D/S/SA event.
RESULTS: The overall prevalence of severe PE remained low: 50 patients experienced 67 events (incidence rate [95% CI] =1.04 [0.82, 1.32] per 100 person-years). Depression (n=16), suicides (n=5) and suicide attempts (n=14) were the most frequently diagnosed PE (0.54 [0.39, 0.76] per 100 person-years) among 25 patients. Multivariate results showed that unemployment, unstable housing, detectable viral load and smoking more than 20 cigarettes/day were independently associated with D/S/SA.
CONCLUSIONS: Although the incidence of severe PE remained relatively low among the patients of APROCO-COPILOTE cohort, this study's results underline a clinically important problem in HIV-infected patients receiving cART. Furthermore, our findings not only emphasize the importance of comprehensive care, especially for socially vulnerable patients, but may also help future studies designed to assess the effectiveness of interventions in reducing the risk of PE during cART.

PMID: 22544079 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk.

Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk.

Int J Med Sci. 2012;9(6):498-505

Authors: Zhi Y, Yu J, Liu Y, Wei Q, Yuan F, Zhou X, Song B, Chen Z, Yang J

Abstract
DNA repair is a primary defense mechanism against damage caused by exogenous and endogenous sources. We examined the associations between bladder cancer and 7 polymorphisms from 5 genes involved in the maintenance of genetic stability (MMR: MLH1-93G>A; BER: XRCC1--77T>C and Arg399Gln; NER:XPC Lys939Gln and PAT +/-; DSBR:ATM G5557A and XRCC7 G6721T) in 302 incident bladder cancer cases and 311 hospital controls. Genotyping was done using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The homozygous variant of XRCC7 G6721T (Odds Ratio [OR]: 2.36; 95% Confidence Interval [CI]: 1.13-4.92) was associated with increased bladder cancer risk. In an analysis of combined genotypes, the combination of XRCC1Arg399Gln (Gln allele) with XRCC1-77 T/T led to an increase in risk (OR: 1.61; 95% CI: 1.10-2.36). Moreover, when the XPCLys939Gln (Gln allele) (nucleotide excision repair [NER]) was present together with XRCC7 (T allele) (double strand break repair [DSBR]), the bladder cancer risk dramatically increased (OR: 4.42; 95% CI: 1.23-15.87). Our results suggest that there are multigenic variations in the DNA repair pathway involved in bladder cancer susceptibility, despite the existence of ethnic group differences.

PMID: 22927776 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Incidence, medical and socio-behavioural predictors of psychiatric events in an 11-year follow-up of HIV-infected patients on antiretroviral therapy.

Incidence, medical and socio-behavioural predictors of psychiatric events in an 11-year follow-up of HIV-infected patients on antiretroviral therapy.

Antivir Ther. 2012;17(6):1079-83

Authors: Protopopescu C, Raffi F, Brunet-Fran�ois C, Salmon D, Verdon R, Reboud P, Carrieri MP, Leport C, Spire B, Michel L, APROCO-COPILOTE (ANRS CO8) Study Group

PMID: 22544079 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

2013年1月10日星期四

A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.

A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.

Am J Respir Crit Care Med. 2012 Oct 1;186(7):666-76

Authors: Tu L, De Man FS, Girerd B, Huertas A, Chaumais MC, Lecerf F, Fran�ois C, Perros F, Dorfm�ller P, Fadel E, Montani D, Eddahibi S, Humbert M, Guignabert C

Abstract
RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival.
OBJECTIVES: We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).
MEASUREMENTS AND MAIN RESULTS: In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension.
CONCLUSIONS: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.

PMID: 22798315 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

PIK3CA Genotype and a PIK3CA Mutation-Related Gene Signature and Response to Everolimus and Letrozole in Estrogen Receptor Positive Breast Cancer.

PIK3CA Genotype and a PIK3CA Mutation-Related Gene Signature and Response to Everolimus and Letrozole in Estrogen Receptor Positive Breast Cancer.

PLoS One. 2013;8(1):e53292

Authors: Loi S, Michiels S, Baselga J, Bartlett JM, Singhal SK, Sabine VS, Sims AH, Sahmoud T, Dixon JM, Piccart MJ, Sotiriou C

Abstract
The phosphatidylinositol 3' kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer support mTOR activation is a major means of estrogen-independent tumor growth. Hence the means to identify a responsive breast cancer population that would most benefit from these compounds in the adjuvant or earlier stage setting is of high interest. Here we study PIK3CA genotype as well as a previously reported PI3K/mTOR-pathway gene signature (PIK3CA-GS) and their ability to estimate the level of PI3K pathway activation in two clinical trials of newly diagnosed ER-positive breast cancer patients- a total of 81 patients- one of which was randomized between letrozole and placebo vs letrozole and everolimus. The main objectives were to correlate the baseline PIK3CA genotype and GS with the relative change from baseline to day 15 in Ki67 (which has been shown to be prognostic in breast cancer) and phosphorylated S6 (S240) immunohistochemistry (a substrate of mTOR). In the randomized dataset, the PIK3CA-GS could identify those patients with the largest relative decreases in Ki67 to letrozole/everolimus (R?=?-0.43, p?=?0.008) compared with letrozole/placebo (R?=?0.07, p?=?0.58; interaction test p?=?0.02). In a second dataset of pre-surgical everolimus alone, the PIK3CA-GS was not significantly correlated with relative change in Ki67 (R?=?-0.11, p?=?0.37) but with relative change in phosphorlyated S6 (S240) (R?=?-0.46, p?=?0.028). PIK3CA genotype was not significantly associated with any endpoint in either datasets. Our results suggest that the PIK3CA-GS has potential to identify those ER-positive BCs who may benefit from the addition of everolimus to letrozole. Further evaluation of the PIK3CA-GS as a predictive biomarker is warranted as it may facilitate better selection of responsive patient populations for mTOR inhibition in combination with letrozole.

PMID: 23301057 [PubMed - in process]

rad001 ecdysone chir-258

The ganglioside G(D2) induces the constitutive activation of c-Met in MDA-MB-231 breast cancer cells expressing the G(D3) synthase.

The ganglioside G(D2) induces the constitutive activation of c-Met in MDA-MB-231 breast cancer cells expressing the G(D3) synthase.

Glycobiology. 2012 Jun;22(6):806-16

Authors: Cazet A, Bobowski M, Rombouts Y, Lefebvre J, Steenackers A, Popa I, Gu�rardel Y, Le Bourhis X, Tulasne D, Delannoy P

Abstract
We have recently established and characterized cellular clones deriving from MDA-MB-231 breast cancer cells that express the human G(D3) synthase (GD3S), the enzyme that controls the biosynthesis of b- and c-series gangliosides. The GD3S positive clones show a proliferative phenotype in the absence of serum or growth factors and an increased tumor growth in severe immunodeficient mice. This phenotype results from the constitutive activation of the receptor tyrosine kinase c-Met in spite of the absence of ligand and subsequent activation of mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/Akt pathways. Here, we show by mass spectrometry analysis of total glycosphingolipids that G(D3) and G(D2) are the main gangliosides expressed by the GD3S positive clones. Moreover, G(D2) colocalized with c-Met at the plasma membrane and small interfering RNA silencing of the G(M2)/G(D2) synthase efficiently reduced the expression of G(D2) as well as c-Met phosphorylation and reversed the proliferative phenotype. Competition assays using anti-G(D2) monoclonal antibodies also inhibit proliferation and c-Met phosphorylation of GD3S positive clones in serum-free conditions. Altogether, these results demonstrate the involvement of the disialoganglioside G(D2) in MDA-MB-231 cell proliferation via the constitutive activation of c-Met. The accumulation of G(D2) in c-Met expressing cells could therefore reinforce the tumorigenicity and aggressiveness of breast cancer tumors.

PMID: 22301273 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Cell Cycle. 2012 Jul 1;11(13):2567-77

Authors: Marxer M, Foucar CE, Man WY, Chen Y, Ma HT, Poon RY

Abstract
Aurora kinases are overexpressed in many cancers and are targets for anticancer drugs. The yeast homolog of Aurora B kinase, IPL1, was found to be a ploidy-specific lethality gene. Given that polyploidization is a common feature of many cancers, we hypothesized polyploidization also sensitizes mammalian cells to inhibition of Aurora kinases. Using two models of apparent diploid vs. tetraploid cell lines (one based on the hepatocellular carcinoma cell line Hep3B and another on untransformed mouse fibroblasts), we found that tetraploid cells were more sensitive to Aurora B inhibition than their diploid counterparts. Apoptosis could be induced in tetraploid cells by two different Aurora B inhibitors. Furthermore, tetraploid cells were sensitive to Aurora B inhibition but were not affected by Aurora A inhibition. Interestingly, the underlying mechanism was due to mitotic slippage and the subsequent excessive genome reduplication. In support of this, abolition of cytokinesis with dihydrocytochalasin B resulted in similar effects on tetraploid cells as Aurora B inhibition. These results indicate that inhibition of Aurora B or cytokinesis can promote apoptosis effectively in polyploid cancer cells.

PMID: 22722494 [PubMed - in process]

zm-447439 rad001 ecdysone

Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB.

Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB.

PLoS One. 2012;7(12):e52951

Authors: Abrahams KA, Cox JA, Spivey VL, Loman NJ, Pallen MJ, Constantinidou C, Fern�ndez R, Alemparte C, Remui��n MJ, Barros D, Ballell L, Besra GS

Abstract
Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1-4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 �M against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5� MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism (937)ACC>(937)GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 �M for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization.

PMID: 23300833 [PubMed - in process]

ecdysone chir-258 dovitinib

2013年1月9日星期三

Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk.

Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk.

Int J Med Sci. 2012;9(6):498-505

Authors: Zhi Y, Yu J, Liu Y, Wei Q, Yuan F, Zhou X, Song B, Chen Z, Yang J

PMID: 22927776 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

Increased Risk of Pneumonia Among Patients With Inflammatory Bowel Disease.

Increased Risk of Pneumonia Among Patients With Inflammatory Bowel Disease.

Am J Gastroenterol. 2013 Jan 8;

Authors: Long MD, Martin C, Sandler RS, Kappelman MD

Abstract
OBJECTIVES:Patients with inflammatory bowel disease (IBD) may be at increased risk for infections. We aimed to determine the pneumonia risk in IBD and how specific medications affect this risk.METHODS:We performed a retrospective cohort and a nested case-control study using administrative data from IMS Health Inc., LifeLink Health Plan Claims Database. Limitations to this data set include lack of clinical details to validate exposures and outcomes. In the cohort, IBD patients were matched to four individuals without IBD. Pneumonia risk was evaluated by incidence rate ratio (IRR) and adjusted Cox proportional hazards models (hazard ratio (HR)). In the nested case-control, 4,856 IBD patients with pneumonia were matched to four IBD patients without pneumonia by incidence density sampling. We used conditional logistic regression to determine the associations between medications and pneumonia.RESULTS:The cohort included 50,932 patients with Crohn's disease (CD), 56,403 patients with ulcerative colitis (UC), and 1,269 with unspecified IBD; matched to 434,416 individuals without IBD. Median follow-up within the cohort was 24 months. The IBD cohort had an increased pneumonia risk when compared with non-IBD (IRR 1.82, 95% confidence interval (CI) 1.75-1.88). In adjusted Cox analysis, pneumonia risk remained increased for the IBD vs. non-IBD cohort (HR 1.54, 95% CI 1.49-1.60), with increased risk in both CD (HR 1.71, 95% CI 1.62-1.80) and UC (HR 1.41, 95% CI 1.34-1.48). In the nested case-control analysis, use of biologic medications (odds ratio (OR) 1.32, 95% CI 1.11-1.57), corticosteroids (OR 1.91, 95% CI 1.72-2.12), thiopurines (OR 1.13, 95% CI 1.00-1.27), proton-pump inhibitors (PPIs) (OR 1.15, 95% CI 1.04-1.26), or narcotics (2.28, 95% CI 2.09-2.48) was independently associated with pneumonia.CONCLUSIONS:Patients with IBD are at increased risk for pneumonia. Medications such as corticosteroids and narcotics are particularly associated with pneumonia in this population. An emphasis upon primary prevention of pneumonia through vaccination and reduction of risk factors is warranted.Am J Gastroenterol advance online publication, 8 January 2013; doi:10.1038/ajg.2012.406.

PMID: 23295276 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Angioedema in a Patient With Renal Cell Cancer Treated With Everolimus in Combination With an Angiotensin-Converting Enzyme Inhibitor.

Angioedema in a Patient With Renal Cell Cancer Treated With Everolimus in Combination With an Angiotensin-Converting Enzyme Inhibitor.

J Clin Oncol. 2013 Jan 7;

Authors: Rothermundt C, Gillessen S

PMID: 23295800 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

Angioedema in a Patient With Renal Cell Cancer Treated With Everolimus in Combination With an Angiotensin-Converting Enzyme Inhibitor.

Angioedema in a Patient With Renal Cell Cancer Treated With Everolimus in Combination With an Angiotensin-Converting Enzyme Inhibitor.

J Clin Oncol. 2013 Jan 7;

Authors: Rothermundt C, Gillessen S

PMID: 23295800 [PubMed - as supplied by publisher]

zm-447439 rad001 ecdysone

Effects of flavocoxid, a dual inhibitor of COX and 5-lipoxygenase enzymes, on benign prostatic hyperplasia.

Effects of flavocoxid, a dual inhibitor of COX and 5-lipoxygenase enzymes, on benign prostatic hyperplasia.

Br J Pharmacol. 2012 Sep;167(1):95-108

Authors: Altavilla D, Minutoli L, Polito F, Irrera N, Arena S, Magno C, Rinaldi M, Burnett BP, Squadrito F, Bitto A

Abstract
BACKGROUND AND PURPOSE: Inflammation plays a key role in the development of benign prostatic hyperplasia (BPH). Eicosanoids derived from the COX and 5-lipoxygenase (5-LOX) pathways are elevated in the enlarging prostate. Flavocoxid is a novel flavonoid-based 'dual inhibitor' of the COX and 5-LOX enzymes. This study evaluated the effects of flavocoxid in experimental BPH.
EXPERIMENTAL APPROACH: Rats were treated daily with testosterone propionate (3?mg�kg(-1) ?s.c.) or its vehicle for 14 days to induce BPH. Animals receiving testosterone were randomized to receive vehicle (1?mL�kg(-1) , i.p.) or flavocoxid (20?mg�kg(-1) , i.p.) for 14 days. Histological changes, eicosanoid content and mRNA and protein levels for apoptosis-related proteins and growth factors were assayed in prostate tissue. The effects of flavocoxid were also tested on human prostate carcinoma PC3 cells.
KEY RESULTS: Flavocoxid reduced prostate weight and hyperplasia, blunted inducible expression of COX-2 and 5-LOX as well as the increased production of PGE(2) and leukotriene B(4) (LTB(4) ), enhanced pro-apoptotic Bax and caspase-9 and decreased the anti-apoptotic Bcl-2 mRNA. Flavocoxid also reduced EGF and VEGF expression. In PC3 cells, flavocoxid stimulated apoptosis and inhibited growth factor expression. Flavocoxid-mediated induction of apoptosis was inhibited by the pan-caspase inhibitor, Z-VAD-FMK, in PC3 cells, suggesting an essential role of caspases in flavocoxid-mediated apoptosis during prostatic growth.
CONCLUSION AND IMPLICATIONS: Our results show that a 'dual inhibitor' of the COX and 5-LOX enzymes, such as flavocoxid, might represent a rational approach to reduce BPH through modulation of eicosanoid production and a caspase-induced apoptotic mechanism.

PMID: 22471974 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

2013年1月8日星期二

Initial experience in the clinical use of everolimus-eluting bioresorbable vascular scaffold (BVS) in a single institution.

Initial experience in the clinical use of everolimus-eluting bioresorbable vascular scaffold (BVS) in a single institution.

Int J Cardiol. 2013 Jan 2;

Authors: Liang M, Kajiya T, Lee CH, Chan M, Teo SG, Chan KH, Tan HC, Low AF

PMID: 23290080 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.

A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.

Am J Respir Crit Care Med. 2012 Oct 1;186(7):666-76

Authors: Tu L, De Man FS, Girerd B, Huertas A, Chaumais MC, Lecerf F, Fran�ois C, Perros F, Dorfm�ller P, Fadel E, Montani D, Eddahibi S, Humbert M, Guignabert C

PMID: 22798315 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Cell Cycle. 2012 Jul 1;11(13):2567-77

Authors: Marxer M, Foucar CE, Man WY, Chen Y, Ma HT, Poon RY

PMID: 22722494 [PubMed - in process]

zm-447439 rad001 ecdysone

Modulation of DNA repair by pharmacological inhibitors of the PIKK protein kinase family.

Modulation of DNA repair by pharmacological inhibitors of the PIKK protein kinase family.

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5352-9

Authors: Finlay MR, Griffin RJ

Abstract
Modulation of DNA repair pathways in oncology has been an area of intense interest in the last decade, not least as a consequence of the promising clinical activity of poly(ADP-ribose) polymerase (PARP) inhibitors. In this review article, we highlight inhibitors of the phosphatidylinositol 3-kinase related kinase (PIKK) family as of potential interest in the treatment of cancer, both in combination with DNA-damaging therapies and as stand-alone agents.

PMID: 22835870 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Phenol oxidase is a necessary enzyme for the silkworm molting which is regulated by molting hormone.

Phenol oxidase is a necessary enzyme for the silkworm molting which is regulated by molting hormone.

Mol Biol Rep. 2012 Dec 29;

Authors: Wang MX, Lu Y, Cai ZZ, Liang S, Niu YS, Miao YG

Abstract
Insect molting is an important developmental process of metamorphosis, which is initiated by molting hormone. The molting process includes the activation of dermal cells, epidermal cells separation, molting fluid secretion, the formation of new epidermis and old epidermis excoriation etc. Polyphenol oxidases (PPOs), dopa decarboxylase and acetyltransferase are necessary enzymes for this process. Traditionally, the phenol oxidase was considered as an enzyme for epidermal layer's tanning and melanization. This work suggested that polyphenol oxidases are one set of the key enzymes in molting, which closely related with the role of ecdysone in regulation of molting processes. The data showed that the expression peak of phenol oxidase in silkworm is higher during molting stage, and decreases after molting. The significant increase in the ecdysone levels of haemolymph was observed in the artificially fed silkworm larvae with ecdysone hormone. Consistently, the phenol oxidase expression was significantly elevated compared to the control. PPO1 RNAi induced phenol oxidase expression obviously declined in the silkworm larvae, and caused the pupae incomplete pupation. Overall, the results described that the phenol oxidase expression is regulated by the molting hormone, and is a necessary enzyme for the silkworm molting.

PMID: 23275200 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

2013年1月7日星期一

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Cell Cycle. 2012 Jul 1;11(13):2567-77

Authors: Marxer M, Foucar CE, Man WY, Chen Y, Ma HT, Poon RY

PMID: 22722494 [PubMed - in process]

dovitinib dna-pk coxinhibitors

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8

Authors: Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD

Abstract
We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.

PMID: 22892116 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8

Authors: Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD

PMID: 22892116 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

An intact kidney slice model to investigate vasa recta properties and function in situ.

An intact kidney slice model to investigate vasa recta properties and function in situ.

Nephron Physiol. 2012;120(3):p17-31

Authors: Crawford C, Kennedy-Lydon T, Sprott C, Desai T, Sawbridge L, Munday J, Unwin RJ, Wildman SS, Peppiatt-Wildman CM

Abstract
BACKGROUND: Medullary blood flow is via vasa recta capillaries, which possess contractile pericytes. In vitro studies using isolated descending vasa recta show that pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in 'live' kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter.
RESULTS: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10-30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E(2)) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release).
CONCLUSIONS: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow.

PMID: 22833057 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

'Click' synthesis of a triazole-based inhibitor of Met functions in cancer cells.

'Click' synthesis of a triazole-based inhibitor of Met functions in cancer cells.

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4693-6

Authors: Colombo F, Tintori C, Furlan A, Borrelli S, Christodoulou MS, Dono R, Maina F, Botta M, Amat M, Bosch J, Passarella D

Abstract
The use of Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition permitted the synthesis of a new compound that is able to inhibit the HGF-induced scattering of MDCK (epithelial cells) and in vitro tumorigenesis of H1437 (non-small-cell lung cancer) and GTL-16 (human gastric carcinoma). In agreement with biochemical and biological results, docking studies within the ATP binding site of Met suggested for the new synthesized compound a binding mode similar to that of the active compound Triflorcas previously reported.

PMID: 22738633 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

2013年1月6日星期日

A new clue to explain resistance to mTOR inhibitors.

A new clue to explain resistance to mTOR inhibitors.

Cell Cycle. 2012 Mar 1;11(5):844

Authors: Huang S

PMID: 22336918 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8

Authors: Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD

PMID: 22892116 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439

Cardiovascular adverse effects of anti-inflammatory drugs.

Cardiovascular adverse effects of anti-inflammatory drugs.

Antiinflamm Antiallergy Agents Med Chem. 2012 Dec 31;

Authors: Roubille C, Martel-Pelletier J, Davy JM, Haraoui B, Pelletier JP

Abstract
Anti-inflammatory drugs consist of non-steroidal anti-inflammatory drugs (NSAIDs) including non-selective nsNSAIDs, aspirin, and cyclooxygenase-2 (COX-2)-selective inhibitors also referred to as coxibs, and glucocorticoids (GCs). They are worldwide prescribed drugs for many musculoskeletal conditions, such as osteoarthritis and inflammatory rheumatic diseases. Anti-inflammatory drugs can exert deleterious effects on the cardiovascular system, excluding aspirin. NSAIDs, especially coxibs, have been demonstrated to increase cardiovascular risk and have generated many concerns leading to the reassessment of their benefit/risk ratio. GCs may also induce cardiovascular events, but evidence seems to be less clear. Before prescribing these drugs, an assessment of cardiovascular risk may be judicious.In this review, anti-inflammatory drugs, coxibs, nsNSAIDs and GCs, and the risk of cardiovascular events will be discussed.

PMID: 23286294 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

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