5-alpha-reductase: 2013-02-03

2013年2月9日星期六

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

BJU Int. 2012 Dec;110(11):1747-53

Authors: Iacovelli R, Lanoy E, Albiges L, Escudier B

Abstract
UNLABELLED: Study Type--Prognosis (cohort series) Level of Evidence 2b. What's known on the subject? and What does the study add? In the literature, few studies have evaluated the role of tumour burden (TB) in metastatic real cell carcinoma (mRCC), even though it has been considered as important in localized tumours. In metastatic patients the role of TB is uncertain because it was analyzed in chemotherapy treated patients or using a partial evaluation of TB. This study, first reports the independent prognostic and predictive role of TB in mRCC patients treated with targeted agents in prospective clinical trials. TB is able to predict prognosis independently to localization of metastases and prognostic class defined by MSKCC criteria, moreover it is strictly related to patient's performance status.
OBJECTIVE: ? To investigate the possible prognostic role of baseline tumour burden (TB) in terms of progression-free survival (PFS) and overall survival (OS), in patients with metastatic renal cell carcinoma (mRCC).
PATIENTS AND METHODS: ? A homogenous group of patients with mRCC enrolled in second-line trials post-cytokine treatment were selected for the present analysis. ? The Response Evaluation Criteria in Solid Tumors (the sum of the longest unidimensional diameter of each target lesion) were used to assess TB. ? The PFS and OS rates were estimated using the Kaplan-Meier method and compared across the groups using the log-rank test. ? The association between TB and PFS or OS was evaluated using a Cox proportional hazards model. Multivariable analyses were adjusted for other prognostic variables: the Memorial Sloan Kettering Cancer Centre (MSKCC) risk class and treatment.
RESULTS: ? A total of 124 patients were included in the final analysis. Of these, 66% received sorafenib or sunitinib and 34% received placebo. The median follow-up was 80.1 month. ? TB was directly related to PFS and OS and these associations remained significant after adjusting for modified MSKCC risk class and treatment,. ? Each 1-cm increase in TB increased the risk of progression by 4.5% (hazard ratio [HR]: 1.05; 95% confidence interval [CI] 1.02-1.07; P < 0.001) and the risk of death by 5% (HR: 1.05; 95% CI 1.03-1.08; P < 0.001).
CONCLUSIONS: ? TB is easy to calculate from standard computed tomography and significantly relates to OS in patients with mRCC. ? We report for the first time the independent prognostic role of baseline TB in multivariate analysis. ?? We believe that this information could be translated into clinical practice.

PMID: 23106948 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

Protein kinase A antagonist inhibits ?-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

Protein kinase A antagonist inhibits ?-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

Mol Cancer. 2011;10:149

Authors: Brudvik KW, Paulsen JE, Aandahl EM, Roald B, Task�n K

Abstract
BACKGROUND: The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of ?-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E(2) (PGE(2)) - PI-3 kinase pathways. Recent reports show that PGE(2)-induced phosphorylation of ?-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE(2) on ?-catenin homeostasis.
FINDINGS: Treatment of Apc(Min/+) mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of ?-catenin, ?-catenin nuclear translocation and expression of the ?-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE(2)-induced ?-catenin phosphorylation and c-Myc upregulation.
CONCLUSION: Based on our findings we suggest that PGE(2) act through PKA to promote ?-catenin nuclear translocation and tumor development in Apc(Min/+) mice in vivo, indicating that the direct regulatory effect of PKA on ?-catenin nuclear translocation is operative in intestinal cancer.

PMID: 22168384 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Protein kinase A antagonist inhibits ?-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

Protein kinase A antagonist inhibits ?-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

Mol Cancer. 2011;10:149

Authors: Brudvik KW, Paulsen JE, Aandahl EM, Roald B, Task�n K

PMID: 22168384 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Everolimus Limits Aortic Aneurysm in the Apolipoprotein E-Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes.

Everolimus Limits Aortic Aneurysm in the Apolipoprotein E-Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes.

Arterioscler Thromb Vasc Biol. 2013 Feb 7;

Authors: Moran CS, Jose RJ, Moxon JV, Roomberg A, Norman PE, Rush C, K�rner H, Golledge J

Abstract
OBJECTIVE: We aimed to determine the effect of mechanistic target of rapamycin inhibitor everolimus on abdominal aortic aneurysm within the angiotensin II (A2)-infused apolipoprotein E-deficient mouse model.Approach and Results-Abdominal aortic aneurysm was induced via subcutaneous infusion of A2. Flow cytometry demonstrated increased circulating and aortic C-C chemokine receptor 2 (CCR2) monocytes during A2 infusion. The number of CCR2 monocytes present within the aorta was positively correlated with suprarenal aortic diameter. Simultaneous infusion of everolimus via a second subcutaneous osmotic micropump inhibited A2-induced aortic dilatation. Using flow cytometry and Western blot analysis, decreased aortic dilatation was associated with reduced development of CCR2 bone marrow monocytes, fewer numbers of circulating CCR2 monocytes, and lower aortic CCR2 concentration. In vitro, everolimus inhibited A2-stimulated production of IFN? and IFN?-induced CCR2 expression in apolipoprotein E-deficient mouse bone marrow monocytes. Further, everolimus diminished IFN?/LPS-stimulated M1 polarization in apolipoprotein E-deficient mouse bone marrow monocyte-differentiated macrophages. CONCLUSIONS: Systemic administration of everolimus limits aortic aneurysm in the A2-infused apolipoprotein E-deficient mouse model via suppressed development of bone marrow CCR2 monocytes and reduced egress of these cells into the circulation.

PMID: 23393391 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

Evaluation of Below-the-Knee Drug-Eluting Stents With Frequency-Domain Optical Coherence Tomography:.

Evaluation of Below-the-Knee Drug-Eluting Stents With Frequency-Domain Optical Coherence Tomography:.

J Endovasc Ther. 2013 Feb;20(1):80-93

Authors: Paraskevopoulos I, Spiliopoulos S, Davlouros P, Karnabatidis D, Katsanos K, Alexopoulos D, Siablis D

Abstract
Purpose : To report the use of intravascular frequency-domain optical coherence tomography (FD-OCT) to detect and characterize in-stent neointimal tissue following infrapopliteal drug-eluting stent (DES) placement in patients suffering from critical limb ischemia. Methods : This prospective study included 12 patients (7 men; mean age 72.8�7.2 years) who had previously received 21 infrapopliteal sirolimus- or everolimus-eluting stents. The patients returned for regular angiographic follow-up or presented with clinical relapse of symptoms over a mean follow-up of 13.5�7.3 months (range 6-33), at which time FD-OCT imaging was performed. Study endpoints were technical imaging success, defined as successful FD-OCT acquisition and visualization of the arterial lumen and complete vessel wall, and the detection and characterization of in-stent neointimal hyperplasia according to widely accepted OCT criteria. Results : OCT imaging was successfully completed in 19 of the 21 stents. Binary in-stent restenosis (ISR>50%) was detected in 10/19 stents. Percent restenosis was higher after longer follow-up (60.6%�19.8% ?1 year vs. 35.3%�20.6% <1 year, p=0.03) and in symptomatic vs. asymptomatic patients (61.5%�20.4% vs. 37.2%�19.3%, p=0.04). Neoatherosclerosis findings included lipid-laden neointima (16/19), neointimal neovascularization (13/19), neointimal calcifications (6/19), and thrombus (5/19); no cases of thin-cap fibroatheroma were identified. Neointimal calcifications were more frequent after ?12 months of follow-up compared to <12 months (46.6% vs. 0%, p=0.02). Conclusion : FD-OCT of the infrapopliteal arteries following DES placement is safe and feasible and may demonstrate features of developing neointimal neoatherosclerosis. The latter might play a key role as a mechanism of below-the-knee ISR and warrants further investigation.

PMID: 23391087 [PubMed - in process]

ecdysone chir-258 dovitinib

2013年2月8日星期五

Cyclin D1 overexpression perturbs DNA replication and induces replication-associated DNA double-strand breaks in acquired radioresistant cells.

Cyclin D1 overexpression perturbs DNA replication and induces replication-associated DNA double-strand breaks in acquired radioresistant cells.

Cell Cycle. 2013 Feb 6;12(5)

Authors: Shimura T, Ochiai Y, Noma N, Oikawa T, Sano Y, Fukumoto M

Abstract
Fractionated radiotherapy (RT) is widely used in cancer treatment, because it preserves normal tissues. However, repopulation of radioresistant tumors during fractionated RT limits the efficacy of RT. We recently demonstrated that a moderate level of long-term fractionated radiation confers acquired radioresistance to tumor cells, which is caused by DNA-PK/AKT/GSK3?-mediated cyclin D1 overexpression. The resulting cyclin D1 overexpression leads to forced progression of the cell cycle to S-phase, concomitant with induction of DNA double-strand breaks (DSBs). In this study, we investigated the molecular mechanisms underlying cyclin D1 overexpression-induced DSBs during DNA replication in acquired radioresistant cells. DNA fiber data demonstrated that replication forks progressed slowly in acquired radioresistant cells compared with corresponding parental cells in HepG2 and HeLa cell lines. Slowly progressing replication forks were also observed in HepG2 and HeLa cells that overexpressed a nondegradable cyclin D1 mutant. We also found that knockdown of Mus81endonuclease, which is responsible for resolving aberrant replication forks, suppressed DSB formation in acquired radioresistant cells. Consequently, Mus81 created DSBs to remove aberrant replication forks in response to replication perturbation triggered by cyclin D1 overexpression. After treating cells with a specific inhibitor for DNA-PK or ATM, apoptosis rates increased in acquired radioresistant cells but not in parental cells by inhibiting the DNA damage response to cyclin D1-mediated DSBs. This suggested that these inhibitors might eradicate acquired radioresistant cells and improve fractionated RT outcomes.

PMID: 23388457 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models.

Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models.

Breast Cancer Res. 2013 Jan 23;15(1):R8

Authors: Issa A, Gill JW, Heideman MR, Sahin O, Wiemann S, Dey JH, Hynes NE

Abstract
ABSTRACT: INTRODUCTION: Targeting receptor tyrosine kinases (RTKs) with kinase inhibitors is a clinically validated anti-cancer approach, however, the effectiveness of individual inhibitors is often short-lived and resistance emerges. Experimental approaches have revealed numerous feed-back loops in tumor cells and that blocking one signaling pathway, be it the receptor or downstream targets, is often not sufficient to cause tumor regression. Alterations in fibroblast growth factor receptor (FGFR) activity have been implicated in breast cancer. Using breast cancer models with autocrine activation of fibroblast growth factor receptors (FGFR), we have examined the impact of targeting FGFRs in vivo with a selective kinase inhibitor in combination with an inhibitor of PI3K/mTOR or with a pan-ErbB inhibitor. METHODS: The 4T1 or 67NR mammary cancer cells are models for basal-like breast cancer and display constitutive FGFR activity. Upon their injection into fat pads of female Balb/c mice both tumor cell lines form tumors; 4T1 tumors, but not 67NR tumors metastasize to lungs. Tumor growth was measured in mice treated with an FGFR inhibitor (dovitinib/TKI258), a PI3K/ mTOR inhibitor (NVP-BEZ235) or with a pan-ErbB inhibitor (AEE788). Inhibitors were administered individually or in combination and lung metastases were quantified in the 4T1 model. To uncover mechanisms underlying inhibitor activity, tumor lysates were examined by western analyses for signaling activity of FGFR/FRS2, ErbB2, the Erk and the PI3K/Akt/mTOR pathways. Tumor sections were examined for proliferation, apoptosis and vessel density using antibodies for P-Histone H3, cleaved Caspase-3 and CD31, respectively. A transcriptome analysis was carried out on tumors treated with dovitinib for different times to identify pathways upregulated by FGFR inhibition. Anti-phosphotyrosine receptor antibody arrays (P-Tyr RTK) were used to screen in an unbiased manner for active receptors in 4T1 tumors. RESULTS: Treatment of 4T1 and 67NR tumor-bearing mice with the combination of dovitinib + NVP-BEZ235 causes tumor stasis. Western analysis of tumor lysates shows strong down-regulation of the FRS2/Erk and PI3K/Akt/mTOR signaling pathways. Examination of tumor sections revealed that the combination treatment results in a significant decrease in proliferation and high numbers of apoptotic cells, in comparison to tumors treated with individual inhibitors. Using P-Tyr RTK arrays, we identified high levels of P-EGFR and P-ErbB2 in 4T1 tumors. Testing AEE788 in the 4T1 and 67NR models revealed that only the combination of dovitinib + AEE788 resulted in blockade of the PI3K/Akt/mTOR pathway, prolonged tumor stasis and in the 4T1 model, a highly significant decrease in lung metastasis. Analyses of the tumor sections revealed that the combination of dovitinib + AEE788 caused a significant decrease in proliferation and high levels of apoptosis. The results show that in vivo these breast cancer models become dependent upon co-activation of FGFR and ErbB receptors for PI3K pathway activity. CONCLUSIONS: The work presented here shows that in the 4T1 and 67NR breast cancer models the combination of dovitinib + NVP-BEZ235 or dovitinib + AEE788 leads to a strong inhibition of tumor growth and, for the 4T1 model, a block in metastatic spread. Only these combinations strongly down-regulate the FGFR/FRS2/Erk and the PI3K/Akt/mTOR signaling pathways and cause high levels of apoptosis. Interestingly, the decrease in mitosis and increase in apoptosis was consistently stronger in the dovitinib + AEE788 treatment-group suggesting that targeting ErbB receptors has broader downstream effects compared to targeting only PI3K/mTOR. In experiments aimed at testing the durability of treatment-response, this combination was also more effective. Considering that sub-classes of human breast tumors co-express ErbB receptors and FGFRs, these results might have implications for targeted therapy.

PMID: 23343422 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

Targeting the HGF/c-MET Pathway in Hepatocellular Carcinoma.

Targeting the HGF/c-MET Pathway in Hepatocellular Carcinoma.

Clin Cancer Res. 2013 Feb 6;

Authors: Goyal L, Muzumdar MD, Zhu AX

Abstract
Hepatocellular carcinoma (HCC) is a significant cause of cancer-related morbidity and mortality worldwide. Despite improvements in local therapies including surgical resection, liver transplantation, and transarterial embolization, the prognosis remains poor for the majority of patients who develop recurrence or present with advanced disease. Systemic therapy with the tyrosine kinase inhibitor sorafenib represents a milestone in advanced HCC, but provides a limited survival benefit. Ongoing efforts to study hepatocarcinogenesis have identified an important role of c-MET signaling in the promotion of tumor growth, angiogenesis, and metastasis. In this review, we summarize the preclinical data from human tissue, cell lines, and animal models that implicate c-MET in the pathogenesis of HCC. We also evaluate potential biomarkers that may estimate prognosis or predict response to c-MET inhibitors for more rational clinical trial design. Finally, we discuss the latest clinical trials of c-MET inhibitors in advanced HCC.

PMID: 23388504 [PubMed - as supplied by publisher]

dovitinib dna-pk

The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II.

The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II.

Biochem Pharmacol. 2012 Dec 15;84(12):1617-26

Authors: Hasinoff BB, Wu X, Nitiss JL, Kanagasabai R, Yalowich JC

Abstract
Dovitinib (TKI258/CHIR258) is a multi-kinase inhibitor in phase III development for the treatment of several cancers. Dovitinib is a benzimidazole-quinolinone compound that structurally resembles the bisbenzimidazole minor groove binding dye Hoechst 33258. Dovitinib bound to DNA as shown by its ability to increase the DNA melting temperature and by increases in its fluorescence spectrum that occurred upon the addition of DNA. Molecular modeling studies of the docking of dovitinib into an X-ray structure of a Hoechst 33258-DNA complex showed that dovitinib could reasonably be accommodated in the DNA minor groove. Because DNA binders are often topoisomerase I (EC 5.99.1.2) and topoisomerase II (EC 5.99.1.3) inhibitors, the ability of dovitinib to inhibit these DNA processing enzymes was also investigated. Dovitinib inhibited the catalytic decatenation activity of topoisomerase II?. It also inhibited the DNA-independent ATPase activity of yeast topoisomerase II which suggested that it interacted with the ATP binding site. Using isolated human topoisomerase II?, dovitinib stabilized the enzyme-cleavage complex and acted as a topoisomerase II? poison. Dovitinib was also found to be a cellular topoisomerase II poison in human leukemia K562 cells and induced double-strand DNA breaks in K562 cells as evidenced by increased phosphorylation of H2AX. Finally, dovitinib inhibited the topoisomerase I-catalyzed relaxation of plasmid DNA and acted as a cellular topoisomerase I poison. In conclusion, the cell growth inhibitory activity and the anticancer activity of dovitinib may result not only from its ability to inhibit multiple kinases, but also, in part, from its ability to target topoisomerase I and topoisomerase II.

PMID: 23041231 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

2013年2月7日星期四

Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond.

Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond.

Front Pharmacol. 2013;4:5

Authors: Davidson D, Amrein L, Panasci L, Aloyz R

Abstract
Many current chemotherapies function by damaging genomic DNA in rapidly dividing cells ultimately leading to cell death. This therapeutic approach differentially targets cancer cells that generally display rapid cell division compared to normal tissue cells. However, although these treatments are initially effective in arresting tumor growth and reducing tumor burden, resistance and disease progression eventually occur. A major mechanism underlying this resistance is increased levels of cellular DNA repair. Most cells have complex mechanisms in place to repair DNA damage that occurs due to environmental exposures or normal metabolic processes. These systems, initially overwhelmed when faced with chemotherapy induced DNA damage, become more efficient under constant selective pressure and as a result chemotherapies become less effective. Thus, inhibiting DNA repair pathways using target specific small molecule inhibitors may overcome cellular resistance to DNA damaging chemotherapies. Non-homologous end joining a major mechanism for the repair of double-strand breaks (DSB) in DNA is regulated in part by the serine/threonine kinase, DNA dependent protein kinase (DNA-PK). The DNA-PK holoenzyme acts as a scaffold protein tethering broken DNA ends and recruiting other repair molecules. It also has enzymatic activity that may be involved in DNA damage signaling. Because of its' central role in repair of DSBs, DNA-PK has been the focus of a number of small molecule studies. In these studies specific DNA-PK inhibitors have shown efficacy in synergizing chemotherapies in vitro. However, compounds currently known to specifically inhibit DNA-PK are limited by poor pharmacokinetics: these compounds have poor solubility and have high metabolic lability in vivo leading to short serum half-lives. Future improvement in DNA-PK inhibition will likely be achieved by designing new molecules based on the recently reported crystallographic structure of DNA-PK. Computer based drug design will not only assist in identifying novel functional moieties to replace the metabolically labile morpholino group but will also facilitate the design of molecules to target the DNA-PKcs/Ku80 interface or one of the autophosphorylation sites.

PMID: 23386830 [PubMed - in process]

zm-447439 rad001 ecdysone

Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond.

Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond.

Front Pharmacol. 2013;4:5

Authors: Davidson D, Amrein L, Panasci L, Aloyz R

PMID: 23386830 [PubMed - in process]

chir-258 dovitinib dna-pk

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

PLoS One. 2013;8(2):e55131

Authors: Hentze JL, Moeller ME, J�rgensen AF, Bengtsson MS, Bordoy AM, Warren JT, Gilbert LI, Andersen O, Rewitz KF

Abstract
Insect steroid hormones (ecdysteroids) are important for female reproduction in many insect species and are required for the initiation and coordination of vital developmental processes. Ecdysteroids are also important for adult male physiology and behavior, but their exact function and site of synthesis remains unclear, although previous studies suggest that the reproductive system may be their source. We have examined expression profiles of the ecdysteroidogenic Halloween genes, during development and in adults of the flour beetle Tribolium castaneum. Genes required for the biosynthesis of ecdysone (E), the precursor of the molting hormone 20-hydroxyecdysone (20E), are expressed in the tubular accessory glands (TAGs) of adult males. In contrast, expression of the gene encoding the enzyme mediating 20E synthesis was detected in the ovaries of females. Further, Spookiest (Spot), an enzyme presumably required for endowing tissues with competence to produce ecdysteroids, is male specific and predominantly expressed in the TAGs. We also show that prothoracicotropic hormone (PTTH), a regulator of E synthesis during larval development, regulates ecdysteroid levels in the adult stage in Drosophila melanogaster and the gene for its receptor Torso seems to be expressed specifically in the accessory glands of males. The composite results suggest strongly that the accessory glands of adult male insects are the main source of E, but not 20E. The finding of a possible male-specific source of E raises the possibility that E and 20E have sex-specific roles analogous to the vertebrate sex steroids, where males produce primarily testosterone, the precursor of estradiol. Furthermore this study provides the first evidence that PTTH regulates ecdysteroid synthesis in the adult stage and could explain the original finding that some adult insects are a rich source of PTTH.

PMID: 23383307 [PubMed - in process]

ecdysone chir-258 dovitinib

[Associated everolimus with tacrolimus during the first year after heart transplantation: Initial experience.]

[Associated everolimus with tacrolimus during the first year after heart transplantation: Initial experience.]

Med Clin (Barc). 2013 Feb 2;

Authors: Cardona M, Castel MA, Farrero M, P�rez-Villa F

PMID: 23384432 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

Timing of stroke in patients undergoing total hip replacement and matched controls: a nationwide cohort study.

Timing of stroke in patients undergoing total hip replacement and matched controls: a nationwide cohort study.

Stroke. 2012 Dec;43(12):3225-9

Authors: Lalmohamed A, Vestergaard P, Cooper C, de Boer A, Leufkens HG, van Staa TP, de Vries F

Abstract
BACKGROUND AND PURPOSE: Stroke is a potentially fatal complication of total hip replacements (THR). However, timing of stroke in THR patients compared with matched controls and influence of drug use remain unknown. The objective of this study was to determine timing of stroke in patients with THR compared with matched control subjects.
METHODS: A nationwide cohort study was conducted within the Danish registers (1998-2007). Included patients were those with a primary THR in the study period (n=66,583) and were matched by age, sex, and region to three referent subjects without THR or total knee replacements. Time-dependent Cox models were used to derive hazard ratios and were adjusted for disease history and drug use.
RESULTS: A 4.7-fold increased risk of ischemic stroke (adjusted hazard ratio, 4.69; 95% CI, 3.12-7.06), and a 4.4-fold increased risk of hemorrhagic stroke (adjusted hazard ratio, 4.40; 95% CI, 2.01-9.62) were found within 2 weeks following THR, compared with matched controls. The risk remained elevated during the first 6 postoperative weeks for ischemic stroke, and the first 12 weeks for hemorrhagic stroke. Outpatient antiplatelet drug use lowered the 6-week hazard ratios for ischemic stroke by 70%, although not affecting risk of hemorrhagic stroke.
CONCLUSIONS: This study shows, that THR patients have a 4.7-fold increased risk of ischemic stroke, and a 4.4-fold increased risk of hemorrhagic stroke during the first 2 weeks postsurgery. Risk assessment of stroke in individual patients undergoing THR (ie, evaluate other risk factors for stroke) should be considered during the first 6 to 12 weeks.

PMID: 23132782 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

2013年2月6日星期三

mTOR Inhibitors Alone and in Combination with JAK2 Inhibitors Effectively Inhibit Cells of Myeloproliferative Neoplasms.

mTOR Inhibitors Alone and in Combination with JAK2 Inhibitors Effectively Inhibit Cells of Myeloproliferative Neoplasms.

PLoS One. 2013;8(1):e54826

Authors: Bogani C, Bartalucci N, Martinelli S, Tozzi L, Guglielmelli P, Bosi A, Vannucchi AM, Associazione Italiana per la Ricerca sul Cancro AGIMM Gruppo Italiano Malattie Mieloproliferative

Abstract
BACKGROUND: Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN), usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells.
FINDINGS: Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001) and an ATP-competitive (PP242) mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib). mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with polycythemia vera.
CONCLUSIONS/SIGNIFICANCE: These findings support mTOR inhibitors as novel potential drugs for the treatment of MPN and advocate for clinical trials exploiting the combination of mTOR and JAK2 inhibitor.

PMID: 23382981 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

Timing of stroke in patients undergoing total hip replacement and matched controls: a nationwide cohort study.

Timing of stroke in patients undergoing total hip replacement and matched controls: a nationwide cohort study.

Stroke. 2012 Dec;43(12):3225-9

Authors: Lalmohamed A, Vestergaard P, Cooper C, de Boer A, Leufkens HG, van Staa TP, de Vries F

PMID: 23132782 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

The Ataxia Telangiectasia mutated kinase controls Ig? allelic exclusion by inhibiting secondary V?-to-J? rearrangements.

The Ataxia Telangiectasia mutated kinase controls Ig? allelic exclusion by inhibiting secondary V?-to-J? rearrangements.

J Exp Med. 2013 Feb 4;

Authors: Steinel NC, Lee BS, Tubbs AT, Bednarski JJ, Schulte E, Yang-Iott KS, Schatz DG, Sleckman BP, Bassing CH

Abstract
Allelic exclusion is enforced through the ability of antigen receptor chains expressed from one allele to signal feedback inhibition of V-to-(D)J recombination on the other allele. To achieve allelic exclusion by such means, only one allele can initiate V-to-(D)J recombination within the time required to signal feedback inhibition. DNA double-strand breaks (DSBs) induced by the RAG endonuclease during V(D)J recombination activate the Ataxia Telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) kinases. We demonstrate that ATM enforces Ig? allelic exclusion, and that RAG DSBs induced during Ig? recombination in primary pre-B cells signal through ATM, but not DNA-PK, to suppress initiation of additional Ig? rearrangements. ATM promotes high-density histone H2AX phosphorylation to create binding sites for MDC1, which functions with H2AX to amplify a subset of ATM-dependent signals. However, neither H2AX nor MDC1 is required for ATM to enforce Ig? allelic exclusion and suppress Ig? rearrangements. Upon activation in response to RAG Ig? cleavage, ATM signals down-regulation of Gadd45? with concomitant repression of the Gadd45? targets Rag1 and Rag2. Our data indicate that ATM kinases activated by RAG DSBs during Ig? recombination transduce transient H2AX/MDC1-independent signals that suppress initiation of further Ig? rearrangements to control Ig? allelic exclusion.

PMID: 23382544 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Hepatitis B reactivation related to everolimus.

Hepatitis B reactivation related to everolimus.

World J Hepatol. 2013 Jan 27;5(1):43-5

Authors: Sezgin G�ksu S, Bilal S, Co?kun H?

Abstract
Reactivation of hepatitis B virus (HBV) during chemotherapy is a well known complication in patients with chronic hepatitis B and cancer. The clinical manifestations range from subclinical elevation of liver enzymes to severe, potentially fatal fulminant hepatitis. Reactivation can occur in a patient with previous inactive HBV infection; either an inactive carrier or a patient with resolved hepatitis. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved in renal cell carcinoma, neuroendocrine tumours and breast cancer. mTOR inhibitors are a new generation of drugs for targeted treatment; therefore, little about their side effects is known. Here, we report a patient with renal cell carcinoma who experienced a flare of hepatitis B infection during treatment with everolimus. Clinicians should be aware of HBV reactivation in patients who are undergoing treatment with everolimus, and screening for hepatitis B infection and prophylactic antiviral treatment should be considered.

PMID: 23383366 [PubMed - in process]

rad001 ecdysone chir-258

Pancreatic ?-Cell Dysfunction and Risk of New-Onset Diabetes After Kidney Transplantation.

Pancreatic ?-Cell Dysfunction and Risk of New-Onset Diabetes After Kidney Transplantation.

Diabetes Care. 2013 Feb 1;

Authors: Zelle DM, Corpeleijn E, Deinum J, Stolk RP, Gans RO, Navis G, Bakker SJ

Abstract
OBJECTIVEChronic exposure to calcineurin inhibitors and corticosteroids poses renal transplant recipients (RTR) at high risk for development of new-onset diabetes after transplantation (NODAT). Pancreatic ?-cell dysfunction may be crucial to the pathophysiology of NODAT and specific markers for ?-cell dysfunction may have additive value for predicting NODAT in this population. Therefore, we prospectively investigated whether proinsulin, as a marker of pancreatic ?-cell dysfunction, is associated with future development of NODAT and improves prediction of it.RESEARCH DESIGN AND METHODSAll RTR between 2001 and 2003 with a functioning graft for ?1 year were considered eligible for inclusion, except for subjects with diabetes at baseline who were excluded. We recorded incidence of NODAT until April 2012.RESULTSA total of 487 RTR (age 50 � 12 years, 55% men) participated at a median time of 6.0 (interquartile range [IQR], 2.6-11.5) years after transplantation. Median fasting proinsulin levels were 16.6 (IQR, 11.0-24.2) pmol/L. During median follow-up for 10.1 (IQR, 9.1-10.4) years, 42 (35%) RTR had development of NODAT in the highest quartile of the distribution of proinsulin versus 34 (9%) in the lowest three quartiles (P < 0.001). In Cox regression analyses, proinsulin (hazard ratio, 2.29; 95% confidence interval, 1.85-2.83; P < 0.001) was strongly associated with NODAT development. This was independent of age, sex, calcineurine inhibitors, prednisolone use, components of the metabolic syndrome, or homeostasis model assessment.CONCLUSIONSIn conclusion, fasting proinsulin is strongly associated with NODAT development in RTR. Our results highlight the role of ?-cell dysfunction in the pathophysiology of NODAT and indicate the potential value of proinsulin for identification of RTR at increased risk for NODAT.

PMID: 23378624 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

2013年2月5日星期二

?-Methylacyl-CoA racemase (AMACR): Metabolic enzyme, drug metabolizer and cancer marker P504S.

?-Methylacyl-CoA racemase (AMACR): Metabolic enzyme, drug metabolizer and cancer marker P504S.

Prog Lipid Res. 2013 Jan 29;

Authors: Lloyd MD, Yevglevskis M, Lee GL, Wood PJ, Threadgill MD, Woodman TJ

Abstract
?-Methylacyl-CoA racemase (AMACR; P504S) catalyzes a key chiral inversion step in the metabolism of branched-chain fatty acids, ibuprofen and related drugs. Protein levels are increased in all prostate and some other cancer cells and it is used as a marker (P504S). The enzyme requires no cofactors and catalyzes its reaction by a stepwise 1,1-proton transfer via an enolate intermediate. The biological role of AMACR in cancer is complex, linking lipid metabolism with nuclear receptor (e.g. FXR and PPAR) activity and expression of enzymes such as cyclooxygenase-2 (COX-2). The roles of the various splice variants and the effects of single-nucleotide polymorphisms (SNPs) in cancers are discussed. A number of rationally designed AMACR inhibitors have been reported in the literature as potential cancer treatments. The opportunities and challenges for development of acyl-CoA esters as inhibitors are discussed from a medicinal chemical viewpoint. Other challenges for drug development include the problems in assaying enzymatic activity and the prediction of structure-activity relationships (SAR). Inhibitors of AMACR have potential to provide a novel treatment for castrate-resistant prostate cancers but this potential can only be realized once the biology is well understood. Recent work on the role of AMACR in parasitic diseases is also reviewed.

PMID: 23376124 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

Abluminal biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent (COMPARE II): a randomised, controlled, non-inferiority trial.

Abluminal biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent (COMPARE II): a randomised, controlled, non-inferiority trial.

Lancet. 2013 Jan 29;

Authors: Smits PC, Hofma S, Togni M, V�zquez N, Vald�s M, Voudris V, Slagboom T, Goy JJ, Vuillomenet A, Serra A, Nouche RT, den Heijer P, van der Ent M

Abstract
BACKGROUND: Drug-eluting stents with durable biocompatible or biodegradable polymers have been developed to address the risk of thrombosis associated with first-generation drug-eluting stents. We aimed to compare the safety and efficacy of a biodegradable polymer-coated biolimus-eluting stent with a thin-strut everolimus-eluting stent coated with a durable biocompatible polymer. METHODS: This open-label, prospective, randomised, controlled, non-inferiority trial was undertaken at 12 sites across Europe. We used limited exclusion criteria (age >18 years, life expectancy >5 years, reference vessel diameter 2�0-4�0 mm) to enrol patients eligible for percutaneous coronary intervention. Patients were randomly allocated (2:1) by computer-generated random numbers to receive either a biodegradable polymer biolimus-eluting stent (Nobori, Terumo, Tokyo, Japan) or a durable fluoropolymer-based everolimus-eluting stent (Xience V or Prime, Abbott Vascular, Santa Clara, CA, USA, or Promus, Boston Scientific, Natick, MA, USA). The primary endpoint was a composite of safety (cardiac death and non-fatal myocardial infarction) and efficacy (clinically indicated target vessel revascularisation) at 12 months, analysed by intention to treat. Patients received dual antiplatelet therapy for 12 months after discharge. The trial is registered with ClinicalTrials.gov, number NCT01233453. FINDINGS: From Jan 12, 2009, to Feb 7, 2011, we enrolled 2707 patients (4025 lesions), 1795 of whom were assigned to receive the biolimus-eluting stent (2638 lesions) and 912 to an everolimus-eluting stent (1387 lesions). 2688 (99�3%) patients completed 12 months' follow-up. Significantly more patients in the biolimus-eluting stent group received a non-assigned stent than did those in the everolimus-eluting stent group (105 [5�9%] vs 19 [2�1%]; p<0�0001). The primary endpoint occurred in 93 (5�2%) patients in the biolimus-eluting stent group and 44 (4�8%) patients in the everolimus-eluting stent group at 12 months (relative risk 1�07 [95% CI 0�75-1�52]; p(non-inferiority)<0�0001). Analysis per protocol did not change the outcome of this trial (p(non-inferiority)<0�0001). INTERPRETATION: Biodegradable polymer biolimus-eluting stents are as safe and efficacious as the current standard of a thin-strut everolimus-eluting stent with a durable biocompatible polymer. We need to follow-up patients for longer to show whether the biolimus-eluting stent reduces the risk of stent thrombosis after 1 year when compared with the everolimus-eluting stent. FUNDING: Terumo Europe (Leuven, Belgium) and the Research Foundation of the Cardiology Department, Maasstad Hospital (Rotterdam, Netherlands).

PMID: 23374650 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

?-Methylacyl-CoA racemase (AMACR): Metabolic enzyme, drug metabolizer and cancer marker P504S.

?-Methylacyl-CoA racemase (AMACR): Metabolic enzyme, drug metabolizer and cancer marker P504S.

Prog Lipid Res. 2013 Jan 29;

Authors: Lloyd MD, Yevglevskis M, Lee GL, Wood PJ, Threadgill MD, Woodman TJ

PMID: 23376124 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

Sodium Arsenite Induces Cyclooxygenase-2 Expression in Human Uroepithelial Cells through MAPK Pathway Activation and Reactive Oxygen Species Induction.

Sodium Arsenite Induces Cyclooxygenase-2 Expression in Human Uroepithelial Cells through MAPK Pathway Activation and Reactive Oxygen Species Induction.

Toxicol In Vitro. 2013 Jan 30;

Authors: Wang H, Xi S, Xu Y, Wang F, Zheng Y, Li B, Li X, Zheng Q, Sun G

Abstract
Arsenic can induce reactive oxygen species (ROS) leading to oxidative stress and carcinogenesis. Bladder is one of the major target organs of arsenic, and cyclooxygenase-2 (COX-2) may play an important role in arsenic-induced bladder cancer. However, the mechanism by which arsenic induces COX-2 in bladder cells remains unclear. This study aimed at investigating arsenic-mediated intracellular redox status and signaling cascades leading to COX-2 induction in human uroepithelial cells (SV-HUC-1). SV-HUC-1 cells were exposed to sodium arsenite and COX-2 expression, mitogen-activated protein kinase (MAPK) phosphorylation, glutathione (GSH) levels, ROS induction and Nrf2 expression were quantified. Our results demonstrate that arsenite (1-10 ?M) elevates COX-2 expression, GSH levels, ROS and Nrf2 expression. Arsenite treatment for 24 h stimulates phosphorylation of ERK and p38, but not JNK in SV-HUC-1 cells. Induction of Cox-2 mRNA levels by arsenite was attenuated by inhibitors of ERK, p38 and JNK. Arsenite-induced ROS generation and COX-2 expression were significantly attenuated by treatment with melatonin (a ROS scavenger), but enhanced by DL-buthionine-(S, R)-sulfoximine (BSO, an inhibitor of gamma-glutamylcysteine synthetase (?-GCS) resulting in lower GSH and increased ROS levels). These data indicate that arsenite promotes an induction of ROS, which results in an induction of COX-2 expression through activation of the MAPK pathway.

PMID: 23376440 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

2013年2月4日星期一

Developmental checkpoints and feedback circuits time insect maturation.

Developmental checkpoints and feedback circuits time insect maturation.

Curr Top Dev Biol. 2013;103:1-33

Authors: Rewitz KF, Yamanaka N, O'Connor MB

Abstract
The transition from juvenile to adult is a fundamental process that allows animals to allocate resource toward reproduction after completing a certain amount of growth. In insects, growth to a species-specific target size induces pulses of the steroid hormone ecdysone that triggers metamorphosis and reproductive maturation. The past few years have seen significant progress in understanding the interplay of mechanisms that coordinate timing of ecdysone production and release. These studies show that the neuroendocrine system monitors complex size-related and nutritional signals, as well as external cues, to time production and release of ecdysone. Based on results discussed here, we suggest that developmental progression to adulthood is controlled by checkpoints that regulate the genetic timing program enabling it to adapt to different environmental conditions. These checkpoints utilize a number of signaling pathways to modulate ecdysone production in the prothoracic gland. Release of ecdysone activates an autonomous cascade of both feedforward and feedback signals that determine the duration of the ecdysone pulse at each developmental transitions. Conservation of the genetic mechanisms that coordinate the juvenile-adult transition suggests that insights from the fruit fly Drosophila will provide a framework for future investigation of developmental timing in metazoans.

PMID: 23347514 [PubMed - in process]

chir-258 dovitinib dna-pk

Everolimus-Eluting Stents Versus Sirolimus- or Paclitaxel-Eluting Stents: Two-Year Results from the Guthrie Health Off-Label Stent (GHOST) Registry.

Everolimus-Eluting Stents Versus Sirolimus- or Paclitaxel-Eluting Stents: Two-Year Results from the Guthrie Health Off-Label Stent (GHOST) Registry.

J Interv Cardiol. 2013 Jan 31;

Authors: Harjai KJ, Kondareddy S, Pinkosky B, Harjai N, Orshaw P, Boura J

Abstract
OBJECTIVES: We sought to compare the safety and effectiveness of everolimus-eluting stents (EES) versus first generation drug-eluting stents (FG-DES; sirolimus-eluting stent [SES] or paclitaxel-eluting stent [PES]). METHODS: In 2,126 patients undergoing percutaneous coronary intervention (PCI), we compared the 2-year incidence of stent thrombosis (ST) and target vessel revascularization (TVR) between the EES versus FG-DES groups. Secondary end-points included all-cause death, myocardial infarction (MI), death or MI, and major adverse cardiovascular events (MACE, including death, MI, ST, or TVR). Further, we evaluated these end-points in 2 propensity-matched subgroups: EES versus SES; EES versus PES. RESULTS: Complete 2-year follow-up was available in 1,911 (90%) patients. Compared to FG-DES, implantation of EES was associated with trends towards lower ST (0.9% vs. 2.8%, P?=?0.068) and TVR (3.8% vs. 7.2%, P?=?0.052), which persisted after adjustment for baseline differences (for ST, adjusted hazard ratio, HR 0.32; 95% confidence interval, 95% CI 0.10-1.02, P?=?0.053; for TVR, HR 0.40; 95% CI 0.22-0.75, P?=?0.004). Compared to SES, EES implantation was associated with lower TVR and a trend towards lower ST. Compared to PES, EES implantation was associated with less ST and TVR and trends towards lower death/MI and MACE. In the EES group, no ST was seen after the first 3 months. CONCLUSIONS: The use of EES compared to FG-DES appears to be associated with reductions in ST and TVR at 2-year follow-up. Improved outcomes with EES are observed in comparison with SES as well as PES.

PMID: 23363439 [PubMed - as supplied by publisher]

zm-447439 rad001 ecdysone

What goes up must come down: transcription factors have their say in making ecdysone pulses.

What goes up must come down: transcription factors have their say in making ecdysone pulses.

Curr Top Dev Biol. 2013;103:35-71

Authors: Ou Q, King-Jones K

Abstract
Insect metamorphosis is one of the most fascinating biological processes in the animal kingdom. The dramatic transition from an immature juvenile to a reproductive adult is under the control of the steroid hormone ecdysone, also known as the insect molting hormone. During Drosophila development, periodic pulses of ecdysone are released from the prothoracic glands, upon which the hormone is rapidly converted in peripheral tissues to its biologically active form, 20-hydroxyecdysone. Each hormone pulse has a unique profile and causes different developmental events, but we only have a rudimentary understanding of how the timing, amplitude, and duration of a given pulse are controlled. A key component involved in the timing of ecdysone pulses is PTTH, a brain-derived neuropeptide. PTTH stimulates ecdysone production through a Ras/Raf/ERK signaling cascade; however, comparatively little is known about the downstream targets of this pathway. In recent years, it has become apparent that transcriptional regulation plays a critical role in regulating the synthesis of ecdysone, but only one transcription factor has a well-defined link to PTTH. Interestingly, many of the ecdysteroidogenic transcription factors were originally characterized as primary response genes in the ecdysone signaling cascade that elicits the biological responses to the hormone in target tissues. To review these developments, we will first provide an overview of the transcription factors that act in the Drosophila ecdysone regulatory hierarchy. We will then discuss the roles of these transcriptional regulators in controlling ecdysone synthesis. In the last section, we will briefly outline transcription factors that likely have roles in regulating ecdysone synthesis but have not been formally identified as downstream effectors of ecdysone.

PMID: 23347515 [PubMed - in process]

rad001 ecdysone chir-258

The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II.

The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II.

Biochem Pharmacol. 2012 Dec 15;84(12):1617-26

Authors: Hasinoff BB, Wu X, Nitiss JL, Kanagasabai R, Yalowich JC

PMID: 23041231 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

Pharmacotherapy of Zollinger-Ellison syndrome.

Pharmacotherapy of Zollinger-Ellison syndrome.

Expert Opin Pharmacother. 2013 Jan 30;

Authors: Ito T, Igarashi H, Uehara H, Jensen RT

Abstract
Introduction: The role of pharmacotherapy in the management of patients with Zollinger-Ellison syndrome (ZES) is often equated with the medical management of acid hypersecretion. However, pharmacotherapy is also increasingly involved in the other management areas of these patients. Areas covered: This paper reviews the role of pharmacotherapy in all aspects of the management of patients with ZES. Newer aspects are emphasized. This includes the difficulty of diagnosing ZES in patients taking proton pump inhibitors. Also covered is the role of pharmacotherapy in controlling acid hypersecretion and other hormonal hypersecretory states these patients may develop, including hyperparathyroidism in patients with multiple endocrine neoplasia type 1 and ZES; tumor localization; and the treatment of advanced metastatic disease. The last includes chemotherapy, liver-directed therapies, biotherapy (somatostatin/interferon), peptide radio-receptor therapy and molecular-targeted therapies including the use of mTor inhibitors (everolimus) and tyrosine kinase inhibitors (sunitinib). Expert opinion: Pharmacotherapy is now involved in all aspects of the management of patients with ZES, with the result that ZES has progressed from being considered an entirely surgical disease initially to the present where medical treatment plays a major role in almost all aspects of the management of these patients.

PMID: 23363383 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001

2013年2月3日星期日

Rationale and design of MARQUEE: a phase III, randomized, double-blind study of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer.

Rationale and design of MARQUEE: a phase III, randomized, double-blind study of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer.

Clin Lung Cancer. 2012 Sep;13(5):391-5

Authors: Scagliotti GV, Novello S, Schiller JH, Hirsh V, Sequist LV, Soria JC, von Pawel J, Schwartz B, Von Roemeling R, Sandler AB

Abstract
We present the rationale and design for MARQUEE, a phase III, randomized, double-blind, placebo-controlled study of ARQ 197 plus erlotinib versus placebo plus erlotinib in previously treated subjects with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer (NSCLC). The design of MARQUEE is based on preclinical data, the current understanding of the role of cellular N-methyl-N'-nitroso-guanidine human osteosarcoma (MNNG HOS) transforming gene (MET) in NSCLC, and clinical data from a randomized phase II study. The available evidence suggests that dual inhibition of MET and the epidermal growth factor receptor (EGFR) may overcome resistance to EGFR inhibitors. In the phase II study, the combination of tivantinib plus erlotinib significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus erlotinib in the subset of patients with nonsquamous histology, a population enriched for MET overexpression. The primary endpoint in MARQUEE is OS. Secondary and exploratory objectives include determination of PFS, OS in molecular subgroups (defined by EGFR and KRAS mutation status, amplification or overexpression of MET, and serum hepatocyte growth factor), and safety. All patients will be tested for biomarkers, and the results will provide a wealth of information on the role of tivantinib in treating nonsquamous NSCLC.

PMID: 22440336 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

What goes up must come down: transcription factors have their say in making ecdysone pulses.

What goes up must come down: transcription factors have their say in making ecdysone pulses.

Curr Top Dev Biol. 2013;103:35-71

Authors: Ou Q, King-Jones K

PMID: 23347515 [PubMed - in process]

dovitinib dna-pk coxinhibitors

Homologous chromosomes move and rapidly initiate contact at the sites of double-strand breaks in genes in G 0-phase human cells.

Homologous chromosomes move and rapidly initiate contact at the sites of double-strand breaks in genes in G 0-phase human cells.

Cell Cycle. 2013 Jan 31;12(4)

Authors: Gandhi M, Evdokimova VN, Cuenco KT, Bakkenist CJ, Nikiforov YE

Abstract
We recently reported that homologous chromosomes make contact at the sites of double-strand breaks (DSBs) induced by ionizing radiation (IR) and the restriction endonuclease I-PpoI in G 0/G 1-phase somatic human cells. The contact involves short segments of homologous chromosomes and is centered on a DSB that occurs in a gene; contact does not occur at a DSB in intergenic DNA. Contact between homologous chromosomes is abrogated by inhibition of transcription and requires the kinase activity of ATM, but not DNA-PK. Here, we report additional insights into the mechanism underlying this novel phenomenon. We identify four patterns of homologous chromosome contact, and show that contact between homologous arms, but not centrosomes, is induced by IR. Significantly, we demonstrate that contact is induced by IR in non-proliferating, G 0-phase human cells derived from tissue explants. Finally, we show that contact between homologous chromosomes is detectable as early as 5 min after IR. These results point to the existence of a mechanism that rapidly localizes homologous chromosome arms at sites of DSBs in genes in G 0-phase human cells.

PMID: 23370393 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

Pharmacotherapy of Zollinger-Ellison syndrome.

Pharmacotherapy of Zollinger-Ellison syndrome.

Expert Opin Pharmacother. 2013 Jan 30;

Authors: Ito T, Igarashi H, Uehara H, Jensen RT

PMID: 23363383 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

Homologous chromosomes move and rapidly initiate contact at the sites of double-strand breaks in genes in G 0-phase human cells.

Homologous chromosomes move and rapidly initiate contact at the sites of double-strand breaks in genes in G 0-phase human cells.

Cell Cycle. 2013 Jan 31;12(4)

Authors: Gandhi M, Evdokimova VN, Cuenco KT, Bakkenist CJ, Nikiforov YE

PMID: 23370393 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001

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