Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Related Articles

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

Novel dual cyclooxygenase and lipoxygenase inhibitors targeting hyaluronan-CD44v6 pathway and inducing cytotoxicity in colon cancer cells.

Novel dual cyclooxygenase and lipoxygenase inhibitors targeting hyaluronan-CD44v6 pathway and inducing cytotoxicity in colon cancer cells.

Bioorg Med Chem. 2013 Feb 27;

Authors: Misra S, Ghatak S, Patil N, Dandawate P, Ambike V, Adsule S, Unni D, Venkateswara Swamy K, Padhye S

Abstract
Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzyme have been found to play a role in promoting growth in colon cancer cell lines. The di-tert-butyl phenol class of compounds has been found to inhibit both COX-2 and 5-LOX enzymes with proven effectiveness in arresting tumor growth. In the present study, the structural analogs of 2,6 di-tert-butyl-p-benzoquinone (BQ) appended with hydrazide side chain were found to inhibit COX-2 and 5-LOX enzymes at micromolar concentrations. Molecular docking of the compounds into COX-2 and 5-LOX protein cavities indicated strong binding interactions supporting the observed cytototoxicities. The signaling interaction between endogenous hyaluronan and CD44 has been shown to regulate COX-2 activities through ErbB2 receptor tyrosine kinase (RTK) activation. In the present studies it has been observed for the first time, that three of our COX/5-LOX dual inhibitors inhibit proliferation upon hydrazide substitution and prevent the activity of pro-angiogenic factors in HCA-7, HT-29, Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressed in colon cancer cells, through inhibition of the hyaluronan/CD44v6 cell survival pathway. Since there is a substantial enhancement in the antiproliferative activities of these compounds upon hydrazide substitution, the present work opens up new opportunities for evolving novel active compounds of BQ series for inhibiting colon cancer.

PMID: 23517721 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Curcuminoids in neurodegenerative diseases.

Related Articles

Curcuminoids in neurodegenerative diseases.

Recent Pat CNS Drug Discov. 2012 Dec;7(3):184-204

Authors: Kim DS, Kim JY, Han Y

Abstract
Neurodegeneration is a term used to describe progressive deterioration of structure and/or function of neurons that affects different parts of the central nervous system and leads to eventual death. Neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Down's syndrome (DS), multiple sclerosis (MS), glaucoma, age-related macular degeneration (AMD), and diabetic encephalopathy (DE). Although the initial events that trigger these disorders may be different from each other, they share similar biochemical reactions that lead to neurodegeneration. Curcuminoids, polyphenol compounds from turmeric (Curcuma longa), possess diverse biological properties that modulate debilitating biochemical processes involved in AD that include attenuation of mitochondrial dysfunction-induced oxidative stress and inflammatory responses to inflammatory cytokines, COX-2, and iNOS. Curcuminoids also bind to ?-amyloid (A?) plaques to inhibit amyloid accumulation and aggregation in the brain, in addition to inhibiting the toxic A? oligomer formation and oligomer-dependent A? toxicity. These properties can be further elaborated to DS, glaucoma and AMD. Curcuminoids also prevent ?-synuclein aggregation in PD; attenuate ROS-induced COX-2 expression in ALS; ameliorate the symptoms of MS, DE and traumatic brain injury, in addition to neurodamages caused by heavy metal poisoning. These results demonstrate curcuminoids may be potentially effective therapeutic means to treat neurodegenerative diseases. A bulk of patents discloses methods to improve bioavailability of curcuminoids for therapeutic development. This review provides a comprehensive description on the current progress on curcuminoids against neurodegenerative diseases.

PMID: 22742420 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Image-based high-throughput screening for inhibitors of angiogenesis.

Related Articles

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Mol Cancer Ther. 2013 Feb 26;

Authors: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Graus Porta D, Anderson L, Shi MM, Yovine A, Slamon DJ

Abstract
The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer (EC) has generated an opportunity for a novel target-based therapy. Here we explore the therapeutic potential of two FGFR inhibitors, the multi-kinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of EC. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle and apoptosis using a panel of 20 molecularly characterized human EC cell lines. Anchorage independent growth was studied using soft agar assays. In vivo studies were conducted using EC xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared to their FGFR2 wild-type counterparts (p=0.073 and p=0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell cycle arrest and significantly increased apoptosis in FGFR2 mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2 mutant EC cells but the activity of dovitinib was less restricted to FGFR2 mutant lines when compared to NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2 mutated EC xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type EC xenograft models including complete tumor regressions in a long term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2 mutated EC. Dovitinib may have antitumor activity in EC beyond FGFR2 mutated cases and may permit greater flexibility in patient selection.

PMID: 23443805 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

Image-based high-throughput screening for inhibitors of angiogenesis.

Related Articles

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Design, synthesis and in vivo anti-inflammatory activities of 2,4-diaryl-5-4H-imidazolone derivatives.

Related Articles

Design, synthesis and in vivo anti-inflammatory activities of 2,4-diaryl-5-4H-imidazolone derivatives.

Molecules. 2012;17(10):12262-75

Authors: El-Araby M, Omar A, Hassanein HH, El-Helby AG, Abdel-Rahman AA

Abstract
A series of 2,4-diaryl-5(4H)-imidazolones were prepared and evaluated for their anti-inflammatory activities. Some selected 2,4-diaryl-5(4H)-imidazolones exhibited excellent anti-inflammatory activity in the carrageenan-induced rat paw edema model. Structure Activity Relationships within the series were studied. The substitution at the N-sulfonamide moiety by a small hydrophilic acetyl group resulted in compounds with superior in vivo anti-inflammatory properties. As expected from their COX-2 selectivity, most of the active compounds lacked gastrointestinal toxicity in vivo in rats after a 3-day treatment of 25 mg/kg/day.

PMID: 23079497 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Outcomes of Malaysian patients with advanced lung adenocarcinoma and unknown epidermal growth factor receptor mutation status treated with gefitinib.

Related Articles

Outcomes of Malaysian patients with advanced lung adenocarcinoma and unknown epidermal growth factor receptor mutation status treated with gefitinib.

Asia Pac J Clin Oncol. 2012 Sep;8(3):267-74

Authors: Liam CK, Ruthranesan M, Lee CH, Pang YK, Chua KT, Lim BK

Abstract
AIMS: To evaluate the response and progression-free survival (PFS) of Malaysian patients with advanced lung adenocarcinoma and unknown epidermal growth factor receptor (EGFR) mutation status treated with gefitinib.
METHODS: A retrospective analysis of consecutive patients with EGFR mutation unknown stage III or IV lung adenocarcinoma with EGFR mutation unknown treated with gefitinib until disease progression.
RESULTS: Of 71 patients, none had complete response while 26 (36.6%) had partial response and 26 (36.6%) had stable disease. Multivariate analysis showed the independent predictor of response to gefitinib was Eastern Cooperative Oncology Group (ECOG) performance status 1 (odds ratio [OR] 5.39, 95% confidence interval [CI 1.64-17.74]P = 0.006). The median PFS was 6.5 months and was significantly longer in female than male patients (39.0 vs 21.2 weeks; P < 0.001), never smokers vs smokers (32.3 vs 8.3 weeks, P = 0.001), and stage III versus stage IV disease (44 vs 24 weeks, P = 0.021). In a multivariate Cox proportional hazards model with age group, gender, ethnicity, smoking history, disease stage, ECOG performance status and prior cytotoxic chemotherapy as covariates, the independent predictors of longer median PFS were female gender (HR 95% CI 0.38 [0.22-0.66]; P < 0.001) and stage III disease (HR 95% CI 0.54 [0.30-0.98], P = 0.042).
CONCLUSION: In our patients with EGFR mutation unknown advanced lung adenocarcinoma treated with gefitinib, the response rate was 36.6% and the median PFS was significantly longer in female patients, never smokers and patients with stage III disease.

PMID: 22897510 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Related Articles

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Image-based high-throughput screening for inhibitors of angiogenesis.

Related Articles

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Mol Cancer Ther. 2013 Feb 26;

Authors: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Graus Porta D, Anderson L, Shi MM, Yovine A, Slamon DJ

Abstract
The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer (EC) has generated an opportunity for a novel target-based therapy. Here we explore the therapeutic potential of two FGFR inhibitors, the multi-kinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of EC. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle and apoptosis using a panel of 20 molecularly characterized human EC cell lines. Anchorage independent growth was studied using soft agar assays. In vivo studies were conducted using EC xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared to their FGFR2 wild-type counterparts (p=0.073 and p=0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell cycle arrest and significantly increased apoptosis in FGFR2 mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2 mutant EC cells but the activity of dovitinib was less restricted to FGFR2 mutant lines when compared to NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2 mutated EC xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type EC xenograft models including complete tumor regressions in a long term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2 mutated EC. Dovitinib may have antitumor activity in EC beyond FGFR2 mutated cases and may permit greater flexibility in patient selection.

PMID: 23443805 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

Image-based high-throughput screening for inhibitors of angiogenesis.

Related Articles

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Mol Cancer Ther. 2013 Feb 26;

Authors: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Graus Porta D, Anderson L, Shi MM, Yovine A, Slamon DJ

Abstract
The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer (EC) has generated an opportunity for a novel target-based therapy. Here we explore the therapeutic potential of two FGFR inhibitors, the multi-kinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of EC. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle and apoptosis using a panel of 20 molecularly characterized human EC cell lines. Anchorage independent growth was studied using soft agar assays. In vivo studies were conducted using EC xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared to their FGFR2 wild-type counterparts (p=0.073 and p=0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell cycle arrest and significantly increased apoptosis in FGFR2 mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2 mutant EC cells but the activity of dovitinib was less restricted to FGFR2 mutant lines when compared to NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2 mutated EC xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type EC xenograft models including complete tumor regressions in a long term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2 mutated EC. Dovitinib may have antitumor activity in EC beyond FGFR2 mutated cases and may permit greater flexibility in patient selection.

PMID: 23443805 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001

Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma.

Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma.

Int J Hepatol. 2013;2013:103830

Authors: Zhou Q, Wong CH, Lau CP, Hui CW, Lui VW, Chan SL, Yeo W

Abstract
Mammalian target of rapamycin (mTOR) and the microtubules are shown to be potential targets for treating hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we evaluated the antitumor activity by cotargeting of the mTOR (using allosteric mTOR inhibitor everolimus) and the microtubules (using novel microtubule-stabilizing agent patupilone) in HCC models. In vitro studies showed that either targeting mTOR signaling with everolimus or targeting microtubules with patupilone was able to suppress HCC cell growth in a dose-dependent manner. Cotargeting of the mTOR (by everolimus) and the microtubules (by patupilone, at low nM) resulted in enhanced growth inhibition in HCC cells (achieving maximal growth inhibition of 60-87%), demonstrating potent antitumor activity of this combination. In vivo studies showed that everolimus treatment alone for two weeks was able to inhibit the growth of Hep3B xenografts. Strikingly, the everolimus/patupilone combination induced a more significant antitumor activity. Mechanistic study demonstrated that this enhanced antitumor effect was accompanied by marked cell apoptosis induction and antiangiogenic activity, which were more significant than single-agent treatments. Our findings demonstrated that the everolimus/patupilone combination, which had potent antitumor activity, was a potential therapeutic strategy for HCC.

PMID: 23509629 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

Evaluation of anti-inflammatory activity of selected legumes from Pakistan: in vitro inhibition of cyclooxygenase-2.

Related Articles

Evaluation of anti-inflammatory activity of selected legumes from Pakistan: in vitro inhibition of cyclooxygenase-2.

Pak J Pharm Sci. 2013 Jan;26(1):185-7

Authors: Zia-Ul-Haq M, Landa P, Kutil Z, Qayum M, Ahmad S

Abstract
Crude methanolic extracts of selected legumes namely, black gram (Vigna mungo L.), green gram (Vigna radiata (L.) R. Wilczek ), soybean (Glycine max (L.) Merr.) and lentil (Lens culinaris Medik.) were investigated for anti-inflammatory effects, using COX-2 producing PGE(2) inhibitory assay. Percentage inhibition observed was 73.93, 79.84, 92.17 and 74.47 for black gram, green gram, soybean and lentil respectively at 20?g/ml extract concentration. The 100?g/ml concentration showed increase in the percent inhibition except for soybean. This is the first report on COX-2 inhibitory potential of food legumes.

PMID: 23261746 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Mol Cancer Ther. 2013 Feb 26;

Authors: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Graus Porta D, Anderson L, Shi MM, Yovine A, Slamon DJ

Abstract
The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer (EC) has generated an opportunity for a novel target-based therapy. Here we explore the therapeutic potential of two FGFR inhibitors, the multi-kinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of EC. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle and apoptosis using a panel of 20 molecularly characterized human EC cell lines. Anchorage independent growth was studied using soft agar assays. In vivo studies were conducted using EC xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared to their FGFR2 wild-type counterparts (p=0.073 and p=0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell cycle arrest and significantly increased apoptosis in FGFR2 mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2 mutant EC cells but the activity of dovitinib was less restricted to FGFR2 mutant lines when compared to NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2 mutated EC xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type EC xenograft models including complete tumor regressions in a long term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2 mutated EC. Dovitinib may have antitumor activity in EC beyond FGFR2 mutated cases and may permit greater flexibility in patient selection.

PMID: 23443805 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Mol Cancer Ther. 2013 Feb 26;

Authors: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Graus Porta D, Anderson L, Shi MM, Yovine A, Slamon DJ

Abstract
The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer (EC) has generated an opportunity for a novel target-based therapy. Here we explore the therapeutic potential of two FGFR inhibitors, the multi-kinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of EC. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle and apoptosis using a panel of 20 molecularly characterized human EC cell lines. Anchorage independent growth was studied using soft agar assays. In vivo studies were conducted using EC xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared to their FGFR2 wild-type counterparts (p=0.073 and p=0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell cycle arrest and significantly increased apoptosis in FGFR2 mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2 mutant EC cells but the activity of dovitinib was less restricted to FGFR2 mutant lines when compared to NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2 mutated EC xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type EC xenograft models including complete tumor regressions in a long term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2 mutated EC. Dovitinib may have antitumor activity in EC beyond FGFR2 mutated cases and may permit greater flexibility in patient selection.

PMID: 23443805 [PubMed - as supplied by publisher]

zm-447439 rad001 ecdysone

Ribonucleotide reductase small subunit M2 serves as a prognostic biomarker and predicts poor survival of colorectal cancers.

Related Articles

Ribonucleotide reductase small subunit M2 serves as a prognostic biomarker and predicts poor survival of colorectal cancers.

Clin Sci (Lond). 2013 May;124(9):567-78

Authors: Liu X, Zhang H, Lai L, Wang X, Loera S, Xue L, He H, Zhang K, Hu S, Huang Y, Nelson RA, Zhou B, Zhou L, Chu P, Zhang S, Zheng S, Yen Y

Abstract
The overexpression of RRM2 [RR (ribonucleotide reductase) small subunit M2] dramatically enhances the ability of the cancer cell to proliferate and to invade. To investigate further the relevance of RRM2 and CRCs (colorectal cancers), we correlated the expression of RRM2 with the clinical outcome of CRCs. A retrospective outcome study was conducted on CRCs collected from the COH [(City of Hope) National Medical Center, 217 cases] and ZJU (Zhejiang University, 220 cases). IHC (immunohistochemistry) was employed to determine the protein expression level of RRM2, and quantitative real-time PCR was employed to validate. Multivariate logistic analysis indicated that the adjusted ORs (odds ratios) of RRM2-high for distant metastases were 2.06 [95% CI (confidence interval), 1.01-4.30] and 5.89 (95% CI, 1.51-39.13) in the COH and ZJU sets respectively. The Kaplan-Meier analysis displayed that high expression of RRM2 had a negative impact on the OS (overall survival) and PFS (progress-free survival) of CRC in both sets significantly. The multivariate Cox analysis further demonstrated that HRs (hazard ratios) of RRM2-high for OS were 1.88 (95% CI, 1.03-3.36) and 2.06 (95% CI, 1.10-4.00) in the COH and ZJU sets respectively. Stratification analysis demonstrated that the HR of RRM2 dramatically increased to 12.22 (95% CI, 1.62-258.31) in the MMR (mismatch repair) gene-deficient subgroup in the COH set. Meanwhile, a real-time study demonstrated that down-regulation of RRM2 by siRNA (small interfering RNA) could significantly and specifically reduce the cell growth and adhesion ability in HT-29 and HCT-8 cells. Therefore RRM2 is an independent prognostic factor and predicts poor survival of CRCs. It is also a potential predictor for identifying good responders to chemotherapy for CRCs.

PMID: 23113760 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Evaluation of anti-inflammatory activity of selected legumes from Pakistan: in vitro inhibition of cyclooxygenase-2.

Related Articles

Evaluation of anti-inflammatory activity of selected legumes from Pakistan: in vitro inhibition of cyclooxygenase-2.

Pak J Pharm Sci. 2013 Jan;26(1):185-7

Authors: Zia-Ul-Haq M, Landa P, Kutil Z, Qayum M, Ahmad S

Abstract
Crude methanolic extracts of selected legumes namely, black gram (Vigna mungo L.), green gram (Vigna radiata (L.) R. Wilczek ), soybean (Glycine max (L.) Merr.) and lentil (Lens culinaris Medik.) were investigated for anti-inflammatory effects, using COX-2 producing PGE(2) inhibitory assay. Percentage inhibition observed was 73.93, 79.84, 92.17 and 74.47 for black gram, green gram, soybean and lentil respectively at 20?g/ml extract concentration. The 100?g/ml concentration showed increase in the percent inhibition except for soybean. This is the first report on COX-2 inhibitory potential of food legumes.

PMID: 23261746 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

The effect of statins on acute and long-term outcome after ischemic stroke in the elderly.

Related Articles

The effect of statins on acute and long-term outcome after ischemic stroke in the elderly.

Am J Geriatr Pharmacother. 2012 Oct;10(5):313-22

Authors: Hjalmarsson C, Bokemark L, Manhem K, Mehlig K, Andersson B

Abstract
BACKGROUND: Although treatment with statins has produced beneficial effects when used as secondary prevention, its primary protective role is still somewhat controversial. Moreover, few studies have evaluated the effect of statins in older patients with stroke.
OBJECTIVE: The aim was to investigate whether treatment with statins decreases stroke severity and/or improves survival and outcome after stroke in an older population.
METHODS: We investigated the association between previous statin use and stroke severity (National Institutes of Health Stroke Scale [NIHSS]), as well as the effect of poststroke statin treatment on 12-month functional outcome (modified Rankin Scale [mRS] score) in 799 patients (mean age, 78 years), with acute ischemic stroke. The effect of statin treatment on survival was examined using the Cox proportional hazard model, after adjusting for relevant covariates.
RESULTS: Statins did not decrease stroke severity and did not improve 30-day survival. However, both the 12-month survival (hazard ratio = 0.33; 95% CI, 0.20-to 0.54; P < 0.001) and the 12-month functional outcome (odds ratio = 2.09; 95% CI, 1.25-3.52; P = 0.005) were significantly better in the group treated with statins.
CONCLUSIONS: Significantly better survival and functional outcome were noted with poststroke statins at the end of the 12-month follow-up period. Statins seem to provide beneficial effects for the long-term functional outcome and survival in the elderly.

PMID: 23063287 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Evaluation of XIENCE V Everolimus-Eluting and Taxus Express(2) Paclitaxel-Eluting Coronary Stents in Patients With Jailed Side Branches From the SPIRIT IV Trial at 2 Years.

Related Articles

Evaluation of XIENCE V Everolimus-Eluting and Taxus Express(2) Paclitaxel-Eluting Coronary Stents in Patients With Jailed Side Branches From the SPIRIT IV Trial at 2 Years.

Am J Cardiol. 2013 Mar 14;

Authors: Forrest JK, Lansky AJ, Meller SM, Hou L, Sood P, Applegate RJ, Wang JC, Skelding KA, Shah A, Kereiakes DJ, Sudhir K, Cristea E, Yaqub M, Stone GW

Abstract
The aim of this study was to determine whether patients from the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With de Novo Native Coronary Artery Lesions (SPIRIT) IV trial who underwent percutaneous coronary intervention, who had target lesions with jailed side branches, had improved clinical outcomes when treated with the XIENCE V versus Taxus Express(2) drug-eluting stent. In the SPIRIT III randomized trial, patients with target lesions with jailed side branches after XIENCE V compared with Taxus Express(2) implantation had lower 2-year rates of major adverse cardiac events. The SPIRIT IV trial represents a larger more diverse patient population compared with SPIRIT III. In the large-scale, prospective, multicenter, randomized SPIRIT IV trial, 3,687 patients who underwent coronary stenting with up to 3 de novo native coronary artery lesions were randomized 2:1 to receive XIENCE V versus Taxus Express(2) stents. Two-year clinical outcomes of patients with or without jailed side branches after stenting were compared. A jailed side branch was defined as any side branch >1.0 mm in diameter within the target segment being stented, excluding bifurcations deemed to require treatment. Of the 3,687 patients in SPIRIT IV, a total of 1,426 had side branches that were jailed during angioplasty of the target lesion. Patients with jailed side branches after XIENCE V compared with Taxus Express(2) implantation had significantly lower 2-year rates of target lesion failure (6.5% vs 11.9%, p�= 0.001), major adverse cardiac events (6.6% vs 12.2%, p�= 0.0008), ischemia-driven target vessel revascularization (4.1% vs 7.9%, p�= 0.004), and stent thrombosis (0.6% vs 2.8%, p�= 0.001). In conclusion, patients with jailed side branches after stenting with XIENCE V compared to Taxus Express(2) devices had superior clinical outcomes at 2 years in the large-scale randomized SPIRIT IV trial.

PMID: 23499270 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

DNA nanotechnology: a future perspective.

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DNA nanotechnology: a future perspective.

Nanoscale Res Lett. 2013;8(1):119

Authors: Zahid M, Kim B, Hussain R, Amin R, Park SH

Abstract
In addition to its genetic function, DNA is one of the most distinct and smart self-assembling nanomaterials. DNA nanotechnology exploits the predictable self-assembly of DNA oligonucleotides to design and assemble innovative and highly discrete nanostructures. Highly ordered DNA motifs are capable of providing an ultra-fine framework for the next generation of nanofabrications. The majority of these applications are based upon the complementarity of DNA base pairing: adenine with thymine, and guanine with cytosine. DNA provides an intelligent route for the creation of nanoarchitectures with programmable and predictable patterns. DNA strands twist along one helix for a number of bases before switching to the other helix by passing through a crossover junction. The association of two crossovers keeps the helices parallel and holds them tightly together, allowing the assembly of bigger structures. Because of the DNA molecule's unique and novel characteristics, it can easily be applied in a vast variety of multidisciplinary research areas like biomedicine, computer science, nano/optoelectronics, and bionanotechnology.

PMID: 23497147 [PubMed - in process]

chir-258 dovitinib dna-pk

Image-based high-throughput screening for inhibitors of angiogenesis.

Related Articles

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

Design, Synthesis, and Structure-Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents.

Related Articles

Design, Synthesis, and Structure-Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents.

Bioconjug Chem. 2013 Mar 15;

Authors: Uddin J, Crews BA, Ghebreselasie K, Marnett LJ

Abstract
Cycloxygenase-2 (COX-2) is an attractive target for molecular imaging because it is an inducible enzyme that is expressed in response to inflammatory and proliferative stimuli. Recently, we reported that conjugation of indomethacin with carboxy-X-rhodamine dyes results in the formation of effective, targeted, optical imaging agents able to detect COX-2 in inflammatory tissues and pre-malignant and malignant tumors (Uddin et al. Cancer Res. 2010, 70, 3618-3627). The present paper summarizes the details of the structure-activity relationship (SAR) studies performed for lead optimization of these dyes. A wide range of fluorescent conjugates were designed and synthesized, and each of them was tested for their ability to selectively inhibit COX-2 as the purified protein and in human cancer cells. The SAR study revealed that indomethacin conjugates are the best COX-2-targeted agents compared to the other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors (COXIBs). An n-butyldiamide linker is optimal for tethering bulky fluorescent functionalities onto the NSAID or COXIB cores. The activity of conjugates also depends on the size, shape, and electronic properties of the organic fluorophores. These reagents are taken up by COX-2-expressing cells in culture, and the uptake is blocked by pretreatment with a COX inhibitor. In in vivo settings, these reagents become highly enriched in COX-2-expressing tumors compared to surrounding normal tissue, and they accumulate selectively in COX-2-expressing tumors as compared with COX-2-negative tumors implanted in the same mice. Thus, COX-2-targeted fluorescent inhibitors are useful for preclinical and clinical detection of lesions containing elevated levels of COX-2.

PMID: 23488616 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001

The Effects of Cyclooxygenase Inhibitors on the Brain Inflammatory Response Following Traumatic Brain Injury in Rats.

Related Articles

The Effects of Cyclooxygenase Inhibitors on the Brain Inflammatory Response Following Traumatic Brain Injury in Rats.

Iran J Basic Med Sci. 2012 9;15(5):1102-1105

Authors: Keshavarzi Z, Khaksari M, Razmi Z, Soltani Hekmat A, Naderi V, Rostami S

Abstract
OBJECTIVES: Cytokines such as IL-1? are involved in inflammatory responses. This study evaluated the role of two different kinds of drugs (ibuprofen and celecoxib) on brain IL-10 and IL-1? after traumatic brain injury (TBI) in male rats.
MATERIALS AND METHODS: Rats were assigned into 6 groups: intact, sham, TBI, and treated rats with vehicle, celecoxib or iboprophen. Cytokine concentrations were quantified by ELISA kits.
RESULTS: Groups showed no significant difference in brain IL-10 either after TBI induction or after treatment with ibuprofen or celecoxib. Serum IL-10 in vehicle or ibuprofen treated animals was lower than in sham groups (P< 0.01). Brain IL-1? decreased after treatment by ibuprofen or celecoxib (P< 0.001). There was no statistical difference in serum IL-1? in TBI and intact. Serum IL-1? significantly decreased in rats that received celecoxib compared to TBI group (P< 0.01).
CONCLUSION: Based on our study IL-1? can decrease through both cyclooxygenase 1 (COX-1) and COX-2 pathway but serum IL-1? can decrease only by COX-2 pathway.

PMID: 23492757 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Second line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients.

Related Articles

Second line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients.

Eur J Cancer. 2013 Mar 8;

Authors: Levy A, Menard J, Albiges L, Loriot Y, Di Palma M, Fizazi K, Escudier B

Abstract
BACKGROUND: Sequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. The goal of this study was to evaluate these questions in a large series of pts treated in our institution. PATIENTS AND METHODS: Data from all mRCC patients treated at the IGR from 2005 to 2009 with first line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mammalian target of rapamycin - mTOR)) were analysed. Only patients with subsequent follow-up have been included in this analysis. Patients were defined as 'non-eligible' for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response) or (iii) if they refused a second line treatment. RESULTS: 251 patients, median age 60years, median follow-up 20.2months were treated with targeted therapy with a median overall survival (OS) of 25.8months. Median OS with SU (127), SO (60) or B (61) were 26.3, 16.4 and 32.5months respectively. Only three patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n=61/103), 52% (n=30/58) and 79% (n=38/48) for Su, So and B, respectively. Memorial Sloan-Kettering Cancer Centre (MSKCC) classification (P=0.02) and first line agent (P=0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of performance status score (PS)=0 compared to SO (53%) and SU (48%) (P=0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8months for a tyrosine kinase inhibitor (TKI) (n=98; 75%) and 16.6months for an mTOR (n=32; 42%) (P=0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively. CONCLUSION: The median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for second line treatment.

PMID: 23490648 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

A Human Pancreatic Beta Cell G1/S Molecule Cell Cycle Atlas.

Related Articles

A Human Pancreatic Beta Cell G1/S Molecule Cell Cycle Atlas.

Diabetes. 2013 Mar 14;

Authors: Fiaschi-Taesch NM, Kleinberger JW, Salim F, Troxell R, Wills R, Tanwir M, Casinelli G, Cox AE, Takane KK, Scott DK, Stewart AF

Abstract
Expansion of pancreatic beta cells is a key goal of diabetes research, yet induction of adult human beta cell replication has proven frustratingly difficult. In part, this reflects a lack of understanding of cell cycle control in the human beta cell. Here, we provide a comprehensive immunocytochemical "atlas" of G1/S control molecules in the human beta cell. This "atlas" reveals that the majority these molecules, previously known to be present in islets, are actually present in the beta cell. More importantly, and in contrast to anticipated results, the "human beta cell G1/S atlas" reveals that almost all of the critical G1/S cell cycle control molecules are located in the cytoplasm of the quiescent human beta cell. Indeed, the only nuclear G1/S molecules are the cell cycle inhibitors, pRb, p57, and variably, p21: none of the cyclins or cdks necessary to drive human beta cell proliferation are present in the nuclear compartment. This observation may provide an explanation for the refractoriness of human beta cells to proliferation. Thus, in addition to known obstacles to human beta cell proliferation, restriction of G1/S molecules to the cytoplasm of the human beta cell represents an unanticipated obstacle to therapeutic human beta cell expansion.

PMID: 23493570 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Second line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients.

Related Articles

Second line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients.

Eur J Cancer. 2013 Mar 8;

Authors: Levy A, Menard J, Albiges L, Loriot Y, Di Palma M, Fizazi K, Escudier B

Abstract
BACKGROUND: Sequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. The goal of this study was to evaluate these questions in a large series of pts treated in our institution. PATIENTS AND METHODS: Data from all mRCC patients treated at the IGR from 2005 to 2009 with first line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mammalian target of rapamycin - mTOR)) were analysed. Only patients with subsequent follow-up have been included in this analysis. Patients were defined as 'non-eligible' for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response) or (iii) if they refused a second line treatment. RESULTS: 251 patients, median age 60years, median follow-up 20.2months were treated with targeted therapy with a median overall survival (OS) of 25.8months. Median OS with SU (127), SO (60) or B (61) were 26.3, 16.4 and 32.5months respectively. Only three patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n=61/103), 52% (n=30/58) and 79% (n=38/48) for Su, So and B, respectively. Memorial Sloan-Kettering Cancer Centre (MSKCC) classification (P=0.02) and first line agent (P=0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of performance status score (PS)=0 compared to SO (53%) and SU (48%) (P=0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8months for a tyrosine kinase inhibitor (TKI) (n=98; 75%) and 16.6months for an mTOR (n=32; 42%) (P=0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively. CONCLUSION: The median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for second line treatment.

PMID: 23490648 [PubMed - as supplied by publisher]

zm-447439 rad001 ecdysone

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Related Articles

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Pancreatic well-differentiated neuroendocrine neoplasms (pWDNENs): what place for everolimus and sunitinib derived from ESMO clinical practice guidelines in the therapeutic algorithm?

Related Articles

Pancreatic well-differentiated neuroendocrine neoplasms (pWDNENs): what place for everolimus and sunitinib derived from ESMO clinical practice guidelines in the therapeutic algorithm?

Ann Oncol. 2013 Mar 13;

Authors: Pusceddu S, Buzzoni R, De Braud F

Abstract

PMID: 23493138 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001

A Human Pancreatic Beta Cell G1/S Molecule Cell Cycle Atlas.

Related Articles

A Human Pancreatic Beta Cell G1/S Molecule Cell Cycle Atlas.

Diabetes. 2013 Mar 14;

Authors: Fiaschi-Taesch NM, Kleinberger JW, Salim F, Troxell R, Wills R, Tanwir M, Casinelli G, Cox AE, Takane KK, Scott DK, Stewart AF

Abstract
Expansion of pancreatic beta cells is a key goal of diabetes research, yet induction of adult human beta cell replication has proven frustratingly difficult. In part, this reflects a lack of understanding of cell cycle control in the human beta cell. Here, we provide a comprehensive immunocytochemical "atlas" of G1/S control molecules in the human beta cell. This "atlas" reveals that the majority these molecules, previously known to be present in islets, are actually present in the beta cell. More importantly, and in contrast to anticipated results, the "human beta cell G1/S atlas" reveals that almost all of the critical G1/S cell cycle control molecules are located in the cytoplasm of the quiescent human beta cell. Indeed, the only nuclear G1/S molecules are the cell cycle inhibitors, pRb, p57, and variably, p21: none of the cyclins or cdks necessary to drive human beta cell proliferation are present in the nuclear compartment. This observation may provide an explanation for the refractoriness of human beta cells to proliferation. Thus, in addition to known obstacles to human beta cell proliferation, restriction of G1/S molecules to the cytoplasm of the human beta cell represents an unanticipated obstacle to therapeutic human beta cell expansion.

PMID: 23493570 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001

Design, Synthesis, and Structure-Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents.

Related Articles

Design, Synthesis, and Structure-Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents.

Bioconjug Chem. 2013 Mar 15;

Authors: Uddin J, Crews BA, Ghebreselasie K, Marnett LJ

Abstract
Cycloxygenase-2 (COX-2) is an attractive target for molecular imaging because it is an inducible enzyme that is expressed in response to inflammatory and proliferative stimuli. Recently, we reported that conjugation of indomethacin with carboxy-X-rhodamine dyes results in the formation of effective, targeted, optical imaging agents able to detect COX-2 in inflammatory tissues and pre-malignant and malignant tumors (Uddin et al. Cancer Res. 2010, 70, 3618-3627). The present paper summarizes the details of the structure-activity relationship (SAR) studies performed for lead optimization of these dyes. A wide range of fluorescent conjugates were designed and synthesized, and each of them was tested for their ability to selectively inhibit COX-2 as the purified protein and in human cancer cells. The SAR study revealed that indomethacin conjugates are the best COX-2-targeted agents compared to the other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors (COXIBs). An n-butyldiamide linker is optimal for tethering bulky fluorescent functionalities onto the NSAID or COXIB cores. The activity of conjugates also depends on the size, shape, and electronic properties of the organic fluorophores. These reagents are taken up by COX-2-expressing cells in culture, and the uptake is blocked by pretreatment with a COX inhibitor. In in vivo settings, these reagents become highly enriched in COX-2-expressing tumors compared to surrounding normal tissue, and they accumulate selectively in COX-2-expressing tumors as compared with COX-2-negative tumors implanted in the same mice. Thus, COX-2-targeted fluorescent inhibitors are useful for preclinical and clinical detection of lesions containing elevated levels of COX-2.

PMID: 23488616 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

Pancreatic well-differentiated neuroendocrine neoplasms (pWDNENs): what place for everolimus and sunitinib derived from ESMO clinical practice guidelines in the therapeutic algorithm?

Related Articles

Pancreatic well-differentiated neuroendocrine neoplasms (pWDNENs): what place for everolimus and sunitinib derived from ESMO clinical practice guidelines in the therapeutic algorithm?

Ann Oncol. 2013 Mar 13;

Authors: Pusceddu S, Buzzoni R, De Braud F

Abstract

PMID: 23493138 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

Design, Synthesis, and Structure-Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents.

Related Articles

Design, Synthesis, and Structure-Activity Relationship Studies of Fluorescent Inhibitors of Cycloxygenase-2 as Targeted Optical Imaging Agents.

Bioconjug Chem. 2013 Mar 15;

Authors: Uddin J, Crews BA, Ghebreselasie K, Marnett LJ

Abstract
Cycloxygenase-2 (COX-2) is an attractive target for molecular imaging because it is an inducible enzyme that is expressed in response to inflammatory and proliferative stimuli. Recently, we reported that conjugation of indomethacin with carboxy-X-rhodamine dyes results in the formation of effective, targeted, optical imaging agents able to detect COX-2 in inflammatory tissues and pre-malignant and malignant tumors (Uddin et al. Cancer Res. 2010, 70, 3618-3627). The present paper summarizes the details of the structure-activity relationship (SAR) studies performed for lead optimization of these dyes. A wide range of fluorescent conjugates were designed and synthesized, and each of them was tested for their ability to selectively inhibit COX-2 as the purified protein and in human cancer cells. The SAR study revealed that indomethacin conjugates are the best COX-2-targeted agents compared to the other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors (COXIBs). An n-butyldiamide linker is optimal for tethering bulky fluorescent functionalities onto the NSAID or COXIB cores. The activity of conjugates also depends on the size, shape, and electronic properties of the organic fluorophores. These reagents are taken up by COX-2-expressing cells in culture, and the uptake is blocked by pretreatment with a COX inhibitor. In in vivo settings, these reagents become highly enriched in COX-2-expressing tumors compared to surrounding normal tissue, and they accumulate selectively in COX-2-expressing tumors as compared with COX-2-negative tumors implanted in the same mice. Thus, COX-2-targeted fluorescent inhibitors are useful for preclinical and clinical detection of lesions containing elevated levels of COX-2.

PMID: 23488616 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001