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]

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A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

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A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

BMC Genomics. 2013 May 10;14(1):317

Authors: Dermauw W, Osborne EJ, Clark RM, Grbi M, Tirry L, Van Leeuwen T

Abstract
BACKGROUND: The ABC (ATP-binding cassette) gene superfamily is widespread across all living species. The majority of ABC genes encode ABC transporters, which are membrane-spanning proteins capable of transferring substrates across biological membranes by hydrolyzing ATP. Although ABC transporters have often been associated with resistance to drugs and toxic compounds, within the Arthropoda ABC gene families have only been characterized in detail in several insects and a crustacean. In this study, we report a genome-wide survey and expression analysis of the ABC gene superfamily in the spider mite, Tetranychus urticae, a chelicerate ~ 450 million years diverged from other Arthropod lineages. T. urticae is a major agricultural pest, and is among of the most polyphagous arthropod herbivores known. The species resists a staggering array of toxic plant secondary metabolites, and has developed resistance to all major classes of pesticides in use for its control. RESULTS: We identified 103 ABC genes in the T. urticae genome, the highest number discovered in a metazoan species to date. Within the T. urticae ABC gene set, all members of the eight currently described subfamilies (A to H) were detected. A phylogenetic analysis revealed that the high number of ABC genes in T. urticae is due primarily to lineage-specific expansions of ABC genes within the ABCC, ABCG and ABCH subfamilies. In particular, the ABCC subfamily harbors the highest number of T. urticae ABC genes (39). In a comparative genomic analysis, we found clear orthologous relationships between a subset of T. urticae ABC proteins and ABC proteins in both vertebrates and invertebrates known to be involved in fundamental cellular processes. These included members of the ABCB-half transporters, and the ABCD, ABCE and ABCF families. Furthermore, one-to-one orthologues could be distinguished between T. urticae proteins and human ABCC10, ABCG5 and ABCG8, the Drosophila melanogaster sulfonylurea receptor and ecdysone-regulated transporter E23. Finally, expression profiling revealed that ABC genes in the ABCC, ABCG ABCH subfamilies were differentially expressed in multi-pesticide resistant mite strains and in mites transferred to challenging (toxic) host plants. CONCLUSIONS: In this study we present the first comprehensive analysis of ABC genes in a polyphagous arthropod herbivore. We demonstrate that the broad plant host range and high levels of pesticide resistance in T. urticae are associated with lineage-specific expansions of ABC genes, many of which respond transcriptionally to xenobiotic exposure. This ABC catalogue will serve as a basis for future biochemical and toxicological studies. Obtaining functional evidence that these ABC subfamilies contribute to xenobiotic tolerance should be the priority of future research.

PMID: 23663308 [PubMed - as supplied by publisher]

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ATF4 and IRE1? inhibit DNA repair protein DNA-dependent protein kinase 1 induced by heat shock.

Related Articles

ATF4 and IRE1? inhibit DNA repair protein DNA-dependent protein kinase 1 induced by heat shock.

Mol Cell Biochem. 2012 Dec;371(1-2):225-32

Authors: Zhu H, Guo FJ, Zhao W, Zhou J, Liu Y, Song F, Wang Y

Abstract
With the increase of environment temperature, more and more attentions are payed to the effects of heat stress. Cells under heat shock either are adapted to the condition or are damaged and dead. In this paper, we found that heat shock induced endoplasmic reticulum (ER) stress. ATF4, PERK, and IRE1? were induced by heat shock of 45 �C in the transcriptional level. Under the stress of 45 �C, PERK was phosphorylated and XBP1s was detected. The result indicated that heat shock could induce the ER stress. We found that heat shock of 45 �C induced the dysregulation of HSP70 and DNA-PKcs, and downregulated the expression of PARP1 and XRCC1. Further results showed that after the knockdown of ATF4 or IRE1?, the expression of DNA-PKcs and XRCC1 were increased. It was indicated that ATF4 and IRE1? could inhibit the expression of DNA-PKcs and XRCC1 under the heat stress. Our results suggested that heat shock could activate ER stress. IRE1? and ATF4, as the important ER stress molecules, could inhibit the expression of DNA repair proteins DNA-PKcs, XRCC1, and HSP70 under heat shock. Downregulation of DNA repair proteins could aggravate the cell damage that may cause cell apoptosis. This may explain that heat shock could increase the lethality of chemotherapeutic drugs on tumor cells.

PMID: 23001845 [PubMed - indexed for MEDLINE]

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ATF4 and IRE1? inhibit DNA repair protein DNA-dependent protein kinase 1 induced by heat shock.

Related Articles

ATF4 and IRE1? inhibit DNA repair protein DNA-dependent protein kinase 1 induced by heat shock.

Mol Cell Biochem. 2012 Dec;371(1-2):225-32

Authors: Zhu H, Guo FJ, Zhao W, Zhou J, Liu Y, Song F, Wang Y

Abstract
With the increase of environment temperature, more and more attentions are payed to the effects of heat stress. Cells under heat shock either are adapted to the condition or are damaged and dead. In this paper, we found that heat shock induced endoplasmic reticulum (ER) stress. ATF4, PERK, and IRE1? were induced by heat shock of 45 �C in the transcriptional level. Under the stress of 45 �C, PERK was phosphorylated and XBP1s was detected. The result indicated that heat shock could induce the ER stress. We found that heat shock of 45 �C induced the dysregulation of HSP70 and DNA-PKcs, and downregulated the expression of PARP1 and XRCC1. Further results showed that after the knockdown of ATF4 or IRE1?, the expression of DNA-PKcs and XRCC1 were increased. It was indicated that ATF4 and IRE1? could inhibit the expression of DNA-PKcs and XRCC1 under the heat stress. Our results suggested that heat shock could activate ER stress. IRE1? and ATF4, as the important ER stress molecules, could inhibit the expression of DNA repair proteins DNA-PKcs, XRCC1, and HSP70 under heat shock. Downregulation of DNA repair proteins could aggravate the cell damage that may cause cell apoptosis. This may explain that heat shock could increase the lethality of chemotherapeutic drugs on tumor cells.

PMID: 23001845 [PubMed - indexed for MEDLINE]

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ATF4 and IRE1? inhibit DNA repair protein DNA-dependent protein kinase 1 induced by heat shock.

Related Articles

ATF4 and IRE1? inhibit DNA repair protein DNA-dependent protein kinase 1 induced by heat shock.

Mol Cell Biochem. 2012 Dec;371(1-2):225-32

Authors: Zhu H, Guo FJ, Zhao W, Zhou J, Liu Y, Song F, Wang Y

Abstract
With the increase of environment temperature, more and more attentions are payed to the effects of heat stress. Cells under heat shock either are adapted to the condition or are damaged and dead. In this paper, we found that heat shock induced endoplasmic reticulum (ER) stress. ATF4, PERK, and IRE1? were induced by heat shock of 45 �C in the transcriptional level. Under the stress of 45 �C, PERK was phosphorylated and XBP1s was detected. The result indicated that heat shock could induce the ER stress. We found that heat shock of 45 �C induced the dysregulation of HSP70 and DNA-PKcs, and downregulated the expression of PARP1 and XRCC1. Further results showed that after the knockdown of ATF4 or IRE1?, the expression of DNA-PKcs and XRCC1 were increased. It was indicated that ATF4 and IRE1? could inhibit the expression of DNA-PKcs and XRCC1 under the heat stress. Our results suggested that heat shock could activate ER stress. IRE1? and ATF4, as the important ER stress molecules, could inhibit the expression of DNA repair proteins DNA-PKcs, XRCC1, and HSP70 under heat shock. Downregulation of DNA repair proteins could aggravate the cell damage that may cause cell apoptosis. This may explain that heat shock could increase the lethality of chemotherapeutic drugs on tumor cells.

PMID: 23001845 [PubMed - indexed for MEDLINE]

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Diseases associated with defective responses to DNA damage.

Related Articles

Diseases associated with defective responses to DNA damage.

Cold Spring Harb Perspect Biol. 2012 Dec;4(12)

Authors: O'Driscoll M

Abstract
Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.

PMID: 23209155 [PubMed - indexed for MEDLINE]

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A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

Related Articles

A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

BMC Genomics. 2013 May 10;14(1):317

Authors: Dermauw W, Osborne EJ, Clark RM, Grbi M, Tirry L, Van Leeuwen T

Abstract
BACKGROUND: The ABC (ATP-binding cassette) gene superfamily is widespread across all living species. The majority of ABC genes encode ABC transporters, which are membrane-spanning proteins capable of transferring substrates across biological membranes by hydrolyzing ATP. Although ABC transporters have often been associated with resistance to drugs and toxic compounds, within the Arthropoda ABC gene families have only been characterized in detail in several insects and a crustacean. In this study, we report a genome-wide survey and expression analysis of the ABC gene superfamily in the spider mite, Tetranychus urticae, a chelicerate ~ 450 million years diverged from other Arthropod lineages. T. urticae is a major agricultural pest, and is among of the most polyphagous arthropod herbivores known. The species resists a staggering array of toxic plant secondary metabolites, and has developed resistance to all major classes of pesticides in use for its control. RESULTS: We identified 103 ABC genes in the T. urticae genome, the highest number discovered in a metazoan species to date. Within the T. urticae ABC gene set, all members of the eight currently described subfamilies (A to H) were detected. A phylogenetic analysis revealed that the high number of ABC genes in T. urticae is due primarily to lineage-specific expansions of ABC genes within the ABCC, ABCG and ABCH subfamilies. In particular, the ABCC subfamily harbors the highest number of T. urticae ABC genes (39). In a comparative genomic analysis, we found clear orthologous relationships between a subset of T. urticae ABC proteins and ABC proteins in both vertebrates and invertebrates known to be involved in fundamental cellular processes. These included members of the ABCB-half transporters, and the ABCD, ABCE and ABCF families. Furthermore, one-to-one orthologues could be distinguished between T. urticae proteins and human ABCC10, ABCG5 and ABCG8, the Drosophila melanogaster sulfonylurea receptor and ecdysone-regulated transporter E23. Finally, expression profiling revealed that ABC genes in the ABCC, ABCG ABCH subfamilies were differentially expressed in multi-pesticide resistant mite strains and in mites transferred to challenging (toxic) host plants. CONCLUSIONS: In this study we present the first comprehensive analysis of ABC genes in a polyphagous arthropod herbivore. We demonstrate that the broad plant host range and high levels of pesticide resistance in T. urticae are associated with lineage-specific expansions of ABC genes, many of which respond transcriptionally to xenobiotic exposure. This ABC catalogue will serve as a basis for future biochemical and toxicological studies. Obtaining functional evidence that these ABC subfamilies contribute to xenobiotic tolerance should be the priority of future research.

PMID: 23663308 [PubMed - as supplied by publisher]

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Association between polymorphisms in DNA repair genes (XRCC1 and XRCC7) and risk of preeclampsia.

Related Articles

Association between polymorphisms in DNA repair genes (XRCC1 and XRCC7) and risk of preeclampsia.

Arch Gynecol Obstet. 2012 Dec;286(6):1459-62

Authors: Saadat I, Beyzaei Z, Aghaei F, Kamrani S, Saadat M

Abstract
PURPOSE: Although the exact genes involved in preeclampsia (PE) are still not fully discovered, an important role for oxidative stress in its pathogenesis is accepted. XRCC1 (MIM: 194360) and XRCC7 (MIM: 600899) play a crucial role in the DNA repair pathways. Functional polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) and XRCC7 (G6721T) may be risk factors for PE. In the present study, the association between the genetic polymorphisms of XRCC1 and XRCC7 and risk of PE is investigated.
METHODS: The present case-control study was performed on 151 preeclapmtic patients, and a total of 344 normal pregnant women, as a control group. Control women had no history of pregnancies with PE.
RESULTS: Neither polymorphism of Arg194Trp XRCC1 nor polymorphism of G6721T XRCC7 associated with the risk of PE. The Gln/Gln genotype of Arg399Gln XRCC1 polymorphism increased the risk of PE (OR=2.39, 95 % CI: 1.38-4.14, P=0.002). Statistical analysis revealed that the haplotype "194Arg-399Gln" showed higher frequency among PE patients compared to the controls (OR=1.65, 95% CI: 1.23-2.19, P=0.001).
CONCLUSIONS: The present results suggest that the 399Gln allele of the XRCC1 is significant risk factor for PE development.

PMID: 22825692 [PubMed - indexed for MEDLINE]

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Association between polymorphisms in DNA repair genes (XRCC1 and XRCC7) and risk of preeclampsia.

Related Articles

Association between polymorphisms in DNA repair genes (XRCC1 and XRCC7) and risk of preeclampsia.

Arch Gynecol Obstet. 2012 Dec;286(6):1459-62

Authors: Saadat I, Beyzaei Z, Aghaei F, Kamrani S, Saadat M

Abstract
PURPOSE: Although the exact genes involved in preeclampsia (PE) are still not fully discovered, an important role for oxidative stress in its pathogenesis is accepted. XRCC1 (MIM: 194360) and XRCC7 (MIM: 600899) play a crucial role in the DNA repair pathways. Functional polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) and XRCC7 (G6721T) may be risk factors for PE. In the present study, the association between the genetic polymorphisms of XRCC1 and XRCC7 and risk of PE is investigated.
METHODS: The present case-control study was performed on 151 preeclapmtic patients, and a total of 344 normal pregnant women, as a control group. Control women had no history of pregnancies with PE.
RESULTS: Neither polymorphism of Arg194Trp XRCC1 nor polymorphism of G6721T XRCC7 associated with the risk of PE. The Gln/Gln genotype of Arg399Gln XRCC1 polymorphism increased the risk of PE (OR=2.39, 95 % CI: 1.38-4.14, P=0.002). Statistical analysis revealed that the haplotype "194Arg-399Gln" showed higher frequency among PE patients compared to the controls (OR=1.65, 95% CI: 1.23-2.19, P=0.001).
CONCLUSIONS: The present results suggest that the 399Gln allele of the XRCC1 is significant risk factor for PE development.

PMID: 22825692 [PubMed - indexed for MEDLINE]

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Association between polymorphisms in DNA repair genes (XRCC1 and XRCC7) and risk of preeclampsia.

Related Articles

Association between polymorphisms in DNA repair genes (XRCC1 and XRCC7) and risk of preeclampsia.

Arch Gynecol Obstet. 2012 Dec;286(6):1459-62

Authors: Saadat I, Beyzaei Z, Aghaei F, Kamrani S, Saadat M

Abstract
PURPOSE: Although the exact genes involved in preeclampsia (PE) are still not fully discovered, an important role for oxidative stress in its pathogenesis is accepted. XRCC1 (MIM: 194360) and XRCC7 (MIM: 600899) play a crucial role in the DNA repair pathways. Functional polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) and XRCC7 (G6721T) may be risk factors for PE. In the present study, the association between the genetic polymorphisms of XRCC1 and XRCC7 and risk of PE is investigated.
METHODS: The present case-control study was performed on 151 preeclapmtic patients, and a total of 344 normal pregnant women, as a control group. Control women had no history of pregnancies with PE.
RESULTS: Neither polymorphism of Arg194Trp XRCC1 nor polymorphism of G6721T XRCC7 associated with the risk of PE. The Gln/Gln genotype of Arg399Gln XRCC1 polymorphism increased the risk of PE (OR=2.39, 95 % CI: 1.38-4.14, P=0.002). Statistical analysis revealed that the haplotype "194Arg-399Gln" showed higher frequency among PE patients compared to the controls (OR=1.65, 95% CI: 1.23-2.19, P=0.001).
CONCLUSIONS: The present results suggest that the 399Gln allele of the XRCC1 is significant risk factor for PE development.

PMID: 22825692 [PubMed - indexed for MEDLINE]

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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]

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Diseases associated with defective responses to DNA damage.

Related Articles

Diseases associated with defective responses to DNA damage.

Cold Spring Harb Perspect Biol. 2012 Dec;4(12)

Authors: O'Driscoll M

Abstract
Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.

PMID: 23209155 [PubMed - indexed for MEDLINE]

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Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma.

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Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma.

J Clin Oncol. 2013 Jan 10;31(2):181-6

Authors: Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, Rini BI, Srinivas S, Stein MN, Adams LM, Ottesen LH, Laubscher KH, Sherman L, McDermott DF, Haas NB, Flaherty KT, Ross R, Eisenberg P, Meltzer PS, Merino MJ, Bottaro DP, Linehan WM, Srinivasan R

Abstract
PURPOSE: Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC.
PATIENTS AND METHODS: Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR).
RESULTS: Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.
CONCLUSION: Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.

PMID: 23213094 [PubMed - indexed for MEDLINE]

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Structural modeling and simulation studies of human cyclooxygenase (COX) isozymes with selected terpenes: Implications in drug designing and development.

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Structural modeling and simulation studies of human cyclooxygenase (COX) isozymes with selected terpenes: Implications in drug designing and development.

Comput Biol Med. 2013 Jul 1;43(6):744-50

Authors: Singh S, Pandey VP, Naaz H, Singh P, Dwivedi UN

Abstract
In view of recently implicated role of COX-1 in human health and diseases, including cancer, development of safe and selective drugs, as COX-1 inhibitor is desirable. Human COX-1 and COX-2 isozymes have been modeled using in silico tools and relative efficacies of terpenoids as their inhibitors have been investigated by docking. The docking analyses of 10 selected terpenoids along with drugs revealed that all of the terpenoids were more potent inhibitors of COX-1 rather than COX-2 with the oleanolic acid as the most potent inhibitor of COX in general (binding energy [-18.68Kcal/mol and -18.25Kcal/mol] and estimated Ki [5.57�10(-8)�M and 11.4�10(-8)�M] for COX-1 and COX-2, respectively) and ?-carotene as most selective inhibitor of COX-1. Furthermore, ibuprofen and aspirin were found to be preferential inhibitor of COX-1 and COX-2, respectively.

PMID: 23668350 [PubMed - in process]

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Targeting FGFR With Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer.

Targeting FGFR With Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer.

Clin Cancer Res. 2013 May 8;

Authors: Andre F, Bachelot T, Campone M, Dalenc F, Perez-Garcia J, Hurvitz SA, Turner NC, Rugo H, Smith JW, Deudon S, Shi MM, Zhang Y, Kay A, Graus Porta D, Yovine A, Baselga J

Abstract
PURPOSE: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers. EXPERIMENTAL DESIGN: Preclinical activity of dovitinib was evaluated in breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included four groups of patients with human epidermal growth factor receptor 2-negative metastatic breast cancer based on FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative polymerase chain reaction (qPCR). RESULTS: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified but not in FGFR-normal breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease > 6 months was observed in five (25%) and one (3%) patients with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer. CONCLUSIONS: Dovitinib demonstrated antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.

PMID: 23658459 [PubMed - as supplied by publisher]

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Association between polymorphisms in DNA repair genes (XRCC1 and XRCC7) and risk of preeclampsia.

Related Articles

Association between polymorphisms in DNA repair genes (XRCC1 and XRCC7) and risk of preeclampsia.

Arch Gynecol Obstet. 2012 Dec;286(6):1459-62

Authors: Saadat I, Beyzaei Z, Aghaei F, Kamrani S, Saadat M

Abstract
PURPOSE: Although the exact genes involved in preeclampsia (PE) are still not fully discovered, an important role for oxidative stress in its pathogenesis is accepted. XRCC1 (MIM: 194360) and XRCC7 (MIM: 600899) play a crucial role in the DNA repair pathways. Functional polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) and XRCC7 (G6721T) may be risk factors for PE. In the present study, the association between the genetic polymorphisms of XRCC1 and XRCC7 and risk of PE is investigated.
METHODS: The present case-control study was performed on 151 preeclapmtic patients, and a total of 344 normal pregnant women, as a control group. Control women had no history of pregnancies with PE.
RESULTS: Neither polymorphism of Arg194Trp XRCC1 nor polymorphism of G6721T XRCC7 associated with the risk of PE. The Gln/Gln genotype of Arg399Gln XRCC1 polymorphism increased the risk of PE (OR=2.39, 95 % CI: 1.38-4.14, P=0.002). Statistical analysis revealed that the haplotype "194Arg-399Gln" showed higher frequency among PE patients compared to the controls (OR=1.65, 95% CI: 1.23-2.19, P=0.001).
CONCLUSIONS: The present results suggest that the 399Gln allele of the XRCC1 is significant risk factor for PE development.

PMID: 22825692 [PubMed - indexed for MEDLINE]

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Diseases associated with defective responses to DNA damage.

Related Articles

Diseases associated with defective responses to DNA damage.

Cold Spring Harb Perspect Biol. 2012 Dec;4(12)

Authors: O'Driscoll M

Abstract
Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.

PMID: 23209155 [PubMed - indexed for MEDLINE]

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A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

Related Articles

A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

BMC Genomics. 2013 May 10;14(1):317

Authors: Dermauw W, Osborne EJ, Clark RM, Grbi M, Tirry L, Van Leeuwen T

Abstract
BACKGROUND: The ABC (ATP-binding cassette) gene superfamily is widespread across all living species. The majority of ABC genes encode ABC transporters, which are membrane-spanning proteins capable of transferring substrates across biological membranes by hydrolyzing ATP. Although ABC transporters have often been associated with resistance to drugs and toxic compounds, within the Arthropoda ABC gene families have only been characterized in detail in several insects and a crustacean. In this study, we report a genome-wide survey and expression analysis of the ABC gene superfamily in the spider mite, Tetranychus urticae, a chelicerate ~ 450 million years diverged from other Arthropod lineages. T. urticae is a major agricultural pest, and is among of the most polyphagous arthropod herbivores known. The species resists a staggering array of toxic plant secondary metabolites, and has developed resistance to all major classes of pesticides in use for its control. RESULTS: We identified 103 ABC genes in the T. urticae genome, the highest number discovered in a metazoan species to date. Within the T. urticae ABC gene set, all members of the eight currently described subfamilies (A to H) were detected. A phylogenetic analysis revealed that the high number of ABC genes in T. urticae is due primarily to lineage-specific expansions of ABC genes within the ABCC, ABCG and ABCH subfamilies. In particular, the ABCC subfamily harbors the highest number of T. urticae ABC genes (39). In a comparative genomic analysis, we found clear orthologous relationships between a subset of T. urticae ABC proteins and ABC proteins in both vertebrates and invertebrates known to be involved in fundamental cellular processes. These included members of the ABCB-half transporters, and the ABCD, ABCE and ABCF families. Furthermore, one-to-one orthologues could be distinguished between T. urticae proteins and human ABCC10, ABCG5 and ABCG8, the Drosophila melanogaster sulfonylurea receptor and ecdysone-regulated transporter E23. Finally, expression profiling revealed that ABC genes in the ABCC, ABCG ABCH subfamilies were differentially expressed in multi-pesticide resistant mite strains and in mites transferred to challenging (toxic) host plants. CONCLUSIONS: In this study we present the first comprehensive analysis of ABC genes in a polyphagous arthropod herbivore. We demonstrate that the broad plant host range and high levels of pesticide resistance in T. urticae are associated with lineage-specific expansions of ABC genes, many of which respond transcriptionally to xenobiotic exposure. This ABC catalogue will serve as a basis for future biochemical and toxicological studies. Obtaining functional evidence that these ABC subfamilies contribute to xenobiotic tolerance should be the priority of future research.

PMID: 23663308 [PubMed - as supplied by publisher]

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A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

Related Articles

A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

BMC Genomics. 2013 May 10;14(1):317

Authors: Dermauw W, Osborne EJ, Clark RM, Grbi M, Tirry L, Van Leeuwen T

Abstract
BACKGROUND: The ABC (ATP-binding cassette) gene superfamily is widespread across all living species. The majority of ABC genes encode ABC transporters, which are membrane-spanning proteins capable of transferring substrates across biological membranes by hydrolyzing ATP. Although ABC transporters have often been associated with resistance to drugs and toxic compounds, within the Arthropoda ABC gene families have only been characterized in detail in several insects and a crustacean. In this study, we report a genome-wide survey and expression analysis of the ABC gene superfamily in the spider mite, Tetranychus urticae, a chelicerate ~ 450 million years diverged from other Arthropod lineages. T. urticae is a major agricultural pest, and is among of the most polyphagous arthropod herbivores known. The species resists a staggering array of toxic plant secondary metabolites, and has developed resistance to all major classes of pesticides in use for its control. RESULTS: We identified 103 ABC genes in the T. urticae genome, the highest number discovered in a metazoan species to date. Within the T. urticae ABC gene set, all members of the eight currently described subfamilies (A to H) were detected. A phylogenetic analysis revealed that the high number of ABC genes in T. urticae is due primarily to lineage-specific expansions of ABC genes within the ABCC, ABCG and ABCH subfamilies. In particular, the ABCC subfamily harbors the highest number of T. urticae ABC genes (39). In a comparative genomic analysis, we found clear orthologous relationships between a subset of T. urticae ABC proteins and ABC proteins in both vertebrates and invertebrates known to be involved in fundamental cellular processes. These included members of the ABCB-half transporters, and the ABCD, ABCE and ABCF families. Furthermore, one-to-one orthologues could be distinguished between T. urticae proteins and human ABCC10, ABCG5 and ABCG8, the Drosophila melanogaster sulfonylurea receptor and ecdysone-regulated transporter E23. Finally, expression profiling revealed that ABC genes in the ABCC, ABCG ABCH subfamilies were differentially expressed in multi-pesticide resistant mite strains and in mites transferred to challenging (toxic) host plants. CONCLUSIONS: In this study we present the first comprehensive analysis of ABC genes in a polyphagous arthropod herbivore. We demonstrate that the broad plant host range and high levels of pesticide resistance in T. urticae are associated with lineage-specific expansions of ABC genes, many of which respond transcriptionally to xenobiotic exposure. This ABC catalogue will serve as a basis for future biochemical and toxicological studies. Obtaining functional evidence that these ABC subfamilies contribute to xenobiotic tolerance should be the priority of future research.

PMID: 23663308 [PubMed - as supplied by publisher]

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Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Comp Biochem Physiol A Mol Integr Physiol. 2013 May 4;

Authors: Kim J, Hepat R, Lee D, Kim Y

Abstract
Parasitization by an endoparasitoid wasp, Cotesia plutellae, inhibits a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella. This study tested an inhibitory effect of C. plutellae bracovirus (CpBV) on the metamorphosis of P. xylostella. Parasitized P. xylostella exhibited significantly reduced prothoracic gland (PTG) development at the last instar compared to nonparasitized larvae. Expression of the ecdysone receptor was markedly suppressed during the last instar larvae parasitized by C. plutellae. By contrast, expression of the insulin receptor significantly increased in the parasitized larvae. Microinjection of CpBV significantly inhibited the larva-to-pupa metamorphosis of nonparasitized larvae in a dose-dependent manner. Injection of CpBV also inhibited the expression of the ecdysone receptor and increased the expression of the insulin receptor. Individual CpBV segments were transiently expressed in its encoded genes in nonparasitized larvae and screened to determine antimetamorphic viral gene(s). Out of 21 CpBV segments, two viral segments (CpBV-S22 and CpBV-S27) were proved to inhibit larva-to-pupa metamorphosis by transient expression assay. RNA interference of each gene encoded in the viral segments was applied to determine antimetamorphic gene(s). Protein tyrosine phosphatase, early expressed gene, and four hypothetical genes were selected to be associated with the antimetamorphic activity of CpBV. These results suggest that antimetamorphosis of P. xylostella parasitized by C. plutellae is induced by inhibiting PTG development and subsequent ecdysteroid signaling with viral factors of CpBV.

PMID: 23651929 [PubMed - as supplied by publisher]

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Sotrastaurin in Calcineurin Inhibitor-Free Regimen Using Everolimus in De Novo Kidney Transplant Recipients.

Sotrastaurin in Calcineurin Inhibitor-Free Regimen Using Everolimus in De Novo Kidney Transplant Recipients.

Am J Transplant. 2013 May 9;

Authors: Tedesco-Silva H, Kho MM, Hartmann A, Vitko S, Russ G, Rostaing L, Budde K, Campistol JM, Eris J, Krishnan I, Gopalakrishnan U, Klupp J

Abstract
Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300?mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200?mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300?mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200?mg, 300?mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300?mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

PMID: 23659755 [PubMed - as supplied by publisher]

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Inhibition of MET receptor tyrosine kinase and its ligand hepatocyte growth factor.

Related Articles

Inhibition of MET receptor tyrosine kinase and its ligand hepatocyte growth factor.

J Thorac Oncol. 2012 Dec;7(16 Suppl 5):S372-4

Authors: Sadiq AA, Salgia R

PMID: 23160322 [PubMed - indexed for MEDLINE]

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Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Comp Biochem Physiol A Mol Integr Physiol. 2013 May 4;

Authors: Kim J, Hepat R, Lee D, Kim Y

Abstract
Parasitization by an endoparasitoid wasp, Cotesia plutellae, inhibits a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella. This study tested an inhibitory effect of C. plutellae bracovirus (CpBV) on the metamorphosis of P. xylostella. Parasitized P. xylostella exhibited significantly reduced prothoracic gland (PTG) development at the last instar compared to nonparasitized larvae. Expression of the ecdysone receptor was markedly suppressed during the last instar larvae parasitized by C. plutellae. By contrast, expression of the insulin receptor significantly increased in the parasitized larvae. Microinjection of CpBV significantly inhibited the larva-to-pupa metamorphosis of nonparasitized larvae in a dose-dependent manner. Injection of CpBV also inhibited the expression of the ecdysone receptor and increased the expression of the insulin receptor. Individual CpBV segments were transiently expressed in its encoded genes in nonparasitized larvae and screened to determine antimetamorphic viral gene(s). Out of 21 CpBV segments, two viral segments (CpBV-S22 and CpBV-S27) were proved to inhibit larva-to-pupa metamorphosis by transient expression assay. RNA interference of each gene encoded in the viral segments was applied to determine antimetamorphic gene(s). Protein tyrosine phosphatase, early expressed gene, and four hypothetical genes were selected to be associated with the antimetamorphic activity of CpBV. These results suggest that antimetamorphosis of P. xylostella parasitized by C. plutellae is induced by inhibiting PTG development and subsequent ecdysteroid signaling with viral factors of CpBV.

PMID: 23651929 [PubMed - as supplied by publisher]

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Targeting FGFR With Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer.

Targeting FGFR With Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer.

Clin Cancer Res. 2013 May 8;

Authors: Andre F, Bachelot T, Campone M, Dalenc F, Perez-Garcia J, Hurvitz SA, Turner NC, Rugo H, Smith JW, Deudon S, Shi MM, Zhang Y, Kay A, Graus Porta D, Yovine A, Baselga J

Abstract
PURPOSE: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers. EXPERIMENTAL DESIGN: Preclinical activity of dovitinib was evaluated in breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included four groups of patients with human epidermal growth factor receptor 2-negative metastatic breast cancer based on FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative polymerase chain reaction (qPCR). RESULTS: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified but not in FGFR-normal breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease > 6 months was observed in five (25%) and one (3%) patients with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer. CONCLUSIONS: Dovitinib demonstrated antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.

PMID: 23658459 [PubMed - as supplied by publisher]

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Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore.

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Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore.

Toxicol Appl Pharmacol. 2013 Apr 15;268(2):149-56

Authors: Gharanei M, Hussain A, Janneh O, Maddock HL

Abstract
Chemotherapeutic agents such as doxorubicin are known to cause or exacerbate cardiovascular cell death when an underlying heart condition is present. However, the mechanism of doxorubicin-induced cardiotoxicity is unclear. Here we assess the cardiotoxic effects of doxorubicin in conditions of myocardial ischaemia reperfusion and the mechanistic basis of protection, in particular the role of the mitochondrial permeability transition pore (mPTP) in such protection. The effects of doxorubicin (1?M)�cyclosporine A (CsA, 0.2?M; inhibits mPTP) were investigated in isolated male Sprague-Dawley rats using Langendorff heart and papillary muscle contraction models subjected to simulated ischaemia and reperfusion injury. Isolated rat cardiac myocytes were used in an oxidative stress model to study the effects of drug treatment on mPTP by confocal microscopy. Western blot analysis evaluated the effects of drug treatment on p-Akt and p-Erk 1/2 levels. Langendorff and the isometric contraction models showed a detrimental effect of doxorubicin throughout reperfusion/reoxygenation as well as increased p-Akt and p-Erk levels. Interestingly, CsA not only reversed the detrimental effects of doxorubicin, but also reduced p-Akt and p-Erk levels. In the sustained oxidative stress assay to study mPTP opening, doxorubicin decreased the time taken to depolarization and hypercontracture, but these effects were delayed in the presence of CsA. Collectively, our data suggest for the first that doxorubicin exacerbates myocardial injury in an ischaemia reperfusion model. If the inhibition of mPTP ameliorates the cardiotoxic effects of doxorubicin, then more selective inhibitors of mPTP should be further investigated for their utility in patients receiving doxorubicin.

PMID: 23262186 [PubMed - indexed for MEDLINE]

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Targeting FGFR With Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer.

Targeting FGFR With Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer.

Clin Cancer Res. 2013 May 8;

Authors: Andre F, Bachelot T, Campone M, Dalenc F, Perez-Garcia J, Hurvitz SA, Turner NC, Rugo H, Smith JW, Deudon S, Shi MM, Zhang Y, Kay A, Graus Porta D, Yovine A, Baselga J

Abstract
PURPOSE: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers. EXPERIMENTAL DESIGN: Preclinical activity of dovitinib was evaluated in breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included four groups of patients with human epidermal growth factor receptor 2-negative metastatic breast cancer based on FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative polymerase chain reaction (qPCR). RESULTS: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified but not in FGFR-normal breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease > 6 months was observed in five (25%) and one (3%) patients with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer. CONCLUSIONS: Dovitinib demonstrated antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.

PMID: 23658459 [PubMed - as supplied by publisher]

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Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

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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]

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Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Ann Indian Acad Neurol. 2013 Jan;16(1):47-52

Authors: Rabadi MH, Rabadi FM, Hallford G, Aston CE

Abstract
OBJECTIVE: Musculoskeletal pain commonly occurs in the elderly, many of whom are also prone to suffer from strokes. We studied whether short-term use (? 4 weeks) of cyclooxygenase-2 (COX-2) inhibitors for musculoskeletal pain in stroke patients helped them to participate in their therapies and was safe and efficacious.
MATERIALS AND METHODS: Three hundred and three patients admitted consecutively with first ischemic stroke were studied. Two cohorts were defined, based on whether patients with acute stroke had sufficient musculoskeletal pain that warranted oral COX-2 inhibitors (COX-2 group) or not (case-matched controls). Primary efficacy measures were change in Fugl-Meyer (F-M) pain score and change in total functional independence measure (TFIM) scores on discharge from hospital. Safety was judged by the incidence of vascular episodes during the study period.
RESULTS: From the original 303 patients, 64 patients in the COX-2 group were matched with 64 patients in the non-COX-2 group. The groups were matched for age (�5 years), gender, and admission TFIM score (� 5 points). Baseline characteristics between the 2 groups were similar. The primary and secondary outcome measures were similar between the 2 groups, except for ambulation endurance, which favored the non-COX-2 group (P < 0.03). Greater change in the pain score (less pain) was found in the COX-2 group; this effect was strongest in patients who were independent prior to their stroke (on post hoc analysis). There were too few adverse events in either group of any significance.
CONCLUSIONS: The short-term use of COX-2 inhibitors reduced musculoskeletal pain in acute stroke patients, improved functional motor outcome, and were found to be safe.

PMID: 23661962 [PubMed - in process]

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Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Ann Indian Acad Neurol. 2013 Jan;16(1):47-52

Authors: Rabadi MH, Rabadi FM, Hallford G, Aston CE

Abstract
OBJECTIVE: Musculoskeletal pain commonly occurs in the elderly, many of whom are also prone to suffer from strokes. We studied whether short-term use (? 4 weeks) of cyclooxygenase-2 (COX-2) inhibitors for musculoskeletal pain in stroke patients helped them to participate in their therapies and was safe and efficacious.
MATERIALS AND METHODS: Three hundred and three patients admitted consecutively with first ischemic stroke were studied. Two cohorts were defined, based on whether patients with acute stroke had sufficient musculoskeletal pain that warranted oral COX-2 inhibitors (COX-2 group) or not (case-matched controls). Primary efficacy measures were change in Fugl-Meyer (F-M) pain score and change in total functional independence measure (TFIM) scores on discharge from hospital. Safety was judged by the incidence of vascular episodes during the study period.
RESULTS: From the original 303 patients, 64 patients in the COX-2 group were matched with 64 patients in the non-COX-2 group. The groups were matched for age (�5 years), gender, and admission TFIM score (� 5 points). Baseline characteristics between the 2 groups were similar. The primary and secondary outcome measures were similar between the 2 groups, except for ambulation endurance, which favored the non-COX-2 group (P < 0.03). Greater change in the pain score (less pain) was found in the COX-2 group; this effect was strongest in patients who were independent prior to their stroke (on post hoc analysis). There were too few adverse events in either group of any significance.
CONCLUSIONS: The short-term use of COX-2 inhibitors reduced musculoskeletal pain in acute stroke patients, improved functional motor outcome, and were found to be safe.

PMID: 23661962 [PubMed - in process]

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Sotrastaurin in Calcineurin Inhibitor-Free Regimen Using Everolimus in De Novo Kidney Transplant Recipients.

Sotrastaurin in Calcineurin Inhibitor-Free Regimen Using Everolimus in De Novo Kidney Transplant Recipients.

Am J Transplant. 2013 May 9;

Authors: Tedesco-Silva H, Kho MM, Hartmann A, Vitko S, Russ G, Rostaing L, Budde K, Campistol JM, Eris J, Krishnan I, Gopalakrishnan U, Klupp J

Abstract
Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300?mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200?mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300?mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200?mg, 300?mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300?mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

PMID: 23659755 [PubMed - as supplied by publisher]

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Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Comp Biochem Physiol A Mol Integr Physiol. 2013 May 4;

Authors: Kim J, Hepat R, Lee D, Kim Y

Abstract
Parasitization by an endoparasitoid wasp, Cotesia plutellae, inhibits a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella. This study tested an inhibitory effect of C. plutellae bracovirus (CpBV) on the metamorphosis of P. xylostella. Parasitized P. xylostella exhibited significantly reduced prothoracic gland (PTG) development at the last instar compared to nonparasitized larvae. Expression of the ecdysone receptor was markedly suppressed during the last instar larvae parasitized by C. plutellae. By contrast, expression of the insulin receptor significantly increased in the parasitized larvae. Microinjection of CpBV significantly inhibited the larva-to-pupa metamorphosis of nonparasitized larvae in a dose-dependent manner. Injection of CpBV also inhibited the expression of the ecdysone receptor and increased the expression of the insulin receptor. Individual CpBV segments were transiently expressed in its encoded genes in nonparasitized larvae and screened to determine antimetamorphic viral gene(s). Out of 21 CpBV segments, two viral segments (CpBV-S22 and CpBV-S27) were proved to inhibit larva-to-pupa metamorphosis by transient expression assay. RNA interference of each gene encoded in the viral segments was applied to determine antimetamorphic gene(s). Protein tyrosine phosphatase, early expressed gene, and four hypothetical genes were selected to be associated with the antimetamorphic activity of CpBV. These results suggest that antimetamorphosis of P. xylostella parasitized by C. plutellae is induced by inhibiting PTG development and subsequent ecdysteroid signaling with viral factors of CpBV.

PMID: 23651929 [PubMed - as supplied by publisher]

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Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Ann Indian Acad Neurol. 2013 Jan;16(1):47-52

Authors: Rabadi MH, Rabadi FM, Hallford G, Aston CE

Abstract
OBJECTIVE: Musculoskeletal pain commonly occurs in the elderly, many of whom are also prone to suffer from strokes. We studied whether short-term use (? 4 weeks) of cyclooxygenase-2 (COX-2) inhibitors for musculoskeletal pain in stroke patients helped them to participate in their therapies and was safe and efficacious.
MATERIALS AND METHODS: Three hundred and three patients admitted consecutively with first ischemic stroke were studied. Two cohorts were defined, based on whether patients with acute stroke had sufficient musculoskeletal pain that warranted oral COX-2 inhibitors (COX-2 group) or not (case-matched controls). Primary efficacy measures were change in Fugl-Meyer (F-M) pain score and change in total functional independence measure (TFIM) scores on discharge from hospital. Safety was judged by the incidence of vascular episodes during the study period.
RESULTS: From the original 303 patients, 64 patients in the COX-2 group were matched with 64 patients in the non-COX-2 group. The groups were matched for age (�5 years), gender, and admission TFIM score (� 5 points). Baseline characteristics between the 2 groups were similar. The primary and secondary outcome measures were similar between the 2 groups, except for ambulation endurance, which favored the non-COX-2 group (P < 0.03). Greater change in the pain score (less pain) was found in the COX-2 group; this effect was strongest in patients who were independent prior to their stroke (on post hoc analysis). There were too few adverse events in either group of any significance.
CONCLUSIONS: The short-term use of COX-2 inhibitors reduced musculoskeletal pain in acute stroke patients, improved functional motor outcome, and were found to be safe.

PMID: 23661962 [PubMed - in process]

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Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

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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]

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