Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2–q29 in squamous cell carcinoma of the lung

<p>Abstract</p> <p>Background</p> <p>The underlying genetic alterations for squamous cell carcinoma (SCC) and adenocarcinoma (AC) carcinogenesis are largely unknown.</p> <p>Methods</p> <p>High-resolution array- CGH was performed to identify the differences in the patterns of genomic imbalances between SCC and AC of non-small cell lung cancer (NSCLC).</p> <p>Results</p> <p>On a genome-wide profile, SCCs showed higher frequency of gains than ACs (<it>p </it>= 0.067). More specifically, statistically significant differences were observed across the histologic subtypes for gains at 2q14.2, 3q26.2–q29, 12p13.2–p13.33, and 19p13.3, as well as losses at 3p26.2–p26.3, 16p13.11, and 17p11.2 in SCC, and gains at 7q22.1 and losses at 15q22.2–q25.2 occurred in AC (<it>P </it>< 0.05). The most striking difference between SCC and AC was gains at the 3q26.2–q29, occurring in 86% (19/22) of SCCs, but in only 21% (3/14) of ACs. Many significant genes at the 3q26.2–q29 regions previously linked to a specific histology, such as EVI1,<it>MDS1, PIK3CA </it>and <it>TP73L</it>, were observed in SCC (<it>P </it>< 0.05). In addition, we identified the following possible target genes (> 30% of patients) at 3q26.2–q29: <it>LOC389174 </it>(3q26.2),<it>KCNMB3 </it>(3q26.32),<it>EPHB3 </it>(3q27.1), <it>MASP1 </it>and <it>SST </it>(3q27.3), <it>LPP </it>and <it>FGF12 </it>(3q28), and <it>OPA1</it>,<it>KIAA022</it>,<it>LOC220729</it>, <it>LOC440996</it>,<it>LOC440997</it>, and <it>LOC440998 </it>(3q29), all of which were significantly targeted in SCC (<it>P </it>< 0.05). Among these same genes, high-level amplifications were detected for the gene, <it>EPHB3</it>, at 3q27.1, and <it>MASP1 </it>and <it>SST</it>, at 3q27.3 (18, 18, and 14%, respectively). Quantitative real time PCR demonstrated array CGH detected potential candidate genes that were over expressed in SCCs.</p> <p>Conclusion</p> <p>Using whole-genome array CGH, we have successfully identified significant differences and unique information of chromosomal signatures prevalent between the SCC and AC subtypes of NSCLC. The newly identified candidate target genes may prove to be highly attractive candidate molecular markers for the classification of NSCLC histologic subtypes, and could potentially contribute to the pathogenesis of the squamous cell carcinoma of the lung.</p

Primary versus secondary source of data in observational studies and heterogeneity in meta-analyses of drug effects: a survey of major medical journals

The data from individual observational studies included in meta-analyses of drug effects are collected either from ad hoc methods (i.e. "primary data") or databases that were established for non-research purposes (i.e. "secondary data"). The use of secondary sources may be prone to measurement bias and confounding due to over-the-counter and out-of-pocket drug consumption, or non-adherence to treatment. In fact, it has been noted that failing to consider the origin of the data as a potential cause of heterogeneity may change the conclusions of a meta-analysis. We aimed to assess to what extent the origin of data is explored as a source of heterogeneity in meta-analyses of observational studies.publishe

Two euAGAMOUS genes control C-function in Medicago truncatula

[EN] C-function MADS-box transcription factors belong to the AGAMOUS (AG) lineage and specify both stamen and carpel identity and floral meristem determinacy. In core eudicots, the AG lineage is further divided into two branches, the euAG and PLE lineages. Functional analyses across flowering plants strongly support the idea that duplicated AG lineage genes have different degrees of subfunctionalization of the C-function. The legume Medicago truncatula contains three C-lineage genes in its genome: two euAG genes (MtAGa and MtAGb) and one PLENA-like gene (MtSHP). This species is therefore a good experimental system to study the effects of gene duplication within the AG subfamily. We have studied the respective functions of each euAG genes in M. truncatula employing expression analyses and reverse genetic approaches. Our results show that the M. truncatula euAG- and PLENA-like genes are an example of subfunctionalization as a result of a change in expression pattern. MtAGa and MtAGb are the only genes showing a full C-function activity, concomitant with their ancestral expression profile, early in the floral meristem, and in the third and fourth floral whorls during floral development. In contrast, MtSHP expression appears late during floral development suggesting it does not contribute significantly to the C-function. Furthermore, the redundant MtAGa and MtAGb paralogs have been retained which provides the overall dosage required to specify the C-function in M. truncatula.This work was funded by grants BIO2009-08134 and BIO2012-39849-C02-01 from the Spanish Ministry of Economy and Competitiveness and the Ramon y Cajal Program (RYC-2007-00627 to CGM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Serwatowska, J.; Roque Mesa, EM.; Gómez Mena, MC.; Constantin, GD.; Wen, J.; Mysore, KS.; Lund, OS.... (2014). Two euAGAMOUS genes control C-function in Medicago truncatula. PLoS ONE. 9(8):103770-1-103770-12. https://doi.org/10.1371/journal.pone.0103770S103770-1103770-1298Prunet, N., & Jack, T. P. (2013). Flower Development in Arabidopsis: There Is More to It Than Learning Your ABCs. Flower Development, 3-33. doi:10.1007/978-1-4614-9408-9_1Causier, B., Schwarz-Sommer, Z., & Davies, B. (2010). Floral organ identity: 20 years of ABCs. Seminars in Cell & Developmental Biology, 21(1), 73-79. doi:10.1016/j.semcdb.2009.10.005Irish, V. F. (2010). The flowering of Arabidopsis flower development. The Plant Journal, 61(6), 1014-1028. doi:10.1111/j.1365-313x.2009.04065.xHeijmans, K., Morel, P., & Vandenbussche, M. (2012). MADS-box Genes and Floral Development: the Dark Side. Journal of Experimental Botany, 63(15), 5397-5404. doi:10.1093/jxb/ers233Bowman, J. L., Smyth, D. R., & Meyerowitz, E. M. (1989). Genes directing flower development in Arabidopsis. The Plant Cell, 1(1), 37-52. doi:10.1105/tpc.1.1.37Yanofsky, M. F., Ma, H., Bowman, J. L., Drews, G. N., Feldmann, K. A., & Meyerowitz, E. M. (1990). The protein encoded by the Arabidopsis homeotic gene agamous resembles transcription factors. Nature, 346(6279), 35-39. doi:10.1038/346035a0Bradley, D., Carpenter, R., Sommer, H., Hartley, N., & Coen, E. (1993). Complementary floral homeotic phenotypes result from opposite orientations of a transposon at the plena locus of antirrhinum. Cell, 72(1), 85-95. doi:10.1016/0092-8674(93)90052-rPinyopich, A., Ditta, G. S., Savidge, B., Liljegren, S. J., Baumann, E., Wisman, E., & Yanofsky, M. F. (2003). Assessing the redundancy of MADS-box genes during carpel and ovule development. Nature, 424(6944), 85-88. doi:10.1038/nature01741Liljegren, S. J., Ditta, G. S., Eshed, Y., Savidge, B., Bowman, J. L., & Yanofsky, M. F. (2000). SHATTERPROOF MADS-box genes control seed dispersal in Arabidopsis. Nature, 404(6779), 766-770. doi:10.1038/35008089Davies, B., Motte, P., Keck, E., Saedler, H., Sommer, H., & Schwarz-Sommer, Z. (1999). PLENA and FARINELLI: redundancy and regulatory interactions between two Antirrhinum MADS-box factors controlling flower development. The EMBO Journal, 18(14), 4023-4034. doi:10.1093/emboj/18.14.4023Kramer, E. M., Jaramillo, M. A., & Di Stilio, V. S. (2004). Patterns of Gene Duplication and Functional Evolution During the Diversification of the AGAMOUS Subfamily of MADS Box Genes in Angiosperms. Genetics, 166(2), 1011-1023. doi:10.1534/genetics.166.2.1011Becker, A. (2003). The major clades of MADS-box genes and their role in the development and evolution of flowering plants. Molecular Phylogenetics and Evolution, 29(3), 464-489. doi:10.1016/s1055-7903(03)00207-0Irish, V. F. (2003). The evolution of floral homeotic gene function. BioEssays, 25(7), 637-646. doi:10.1002/bies.10292Zahn, L. M., Leebens-Mack, J. H., Arrington, J. M., Hu, Y., Landherr, L. L., dePamphilis, C. W., … Ma, H. (2006). Conservation and divergence in the AGAMOUS subfamily of MADS-box genes: evidence of independent sub- and neofunctionalization events. Evolution Development, 8(1), 30-45. doi:10.1111/j.1525-142x.2006.05073.xFerrandiz, C. (2000). Negative Regulation of the SHATTERPROOF Genes by FRUITFULL During Arabidopsis Fruit Development. Science, 289(5478), 436-438. doi:10.1126/science.289.5478.436Ma, H., Yanofsky, M. F., & Meyerowitz, E. M. (1991). AGL1-AGL6, an Arabidopsis gene family with similarity to floral homeotic and transcription factor genes. Genes & Development, 5(3), 484-495. doi:10.1101/gad.5.3.484Savidge, B., Rounsley, S. D., & Yanofsky, M. F. (1995). Temporal relationship between the transcription of two Arabidopsis MADS box genes and the floral organ identity genes. The Plant Cell, 7(6), 721-733. doi:10.1105/tpc.7.6.721Colombo, M., Brambilla, V., Marcheselli, R., Caporali, E., Kater, M. M., & Colombo, L. (2010). A new role for the SHATTERPROOF genes during Arabidopsis gynoecium development. Developmental Biology, 337(2), 294-302. doi:10.1016/j.ydbio.2009.10.043Fourquin, C., & Ferrándiz, C. (2012). Functional analyses of AGAMOUS family members in Nicotiana benthamiana clarify the evolution of early and late roles of C-function genes in eudicots. The Plant Journal, 71(6), 990-1001. doi:10.1111/j.1365-313x.2012.05046.xKapoor, M., Tsuda, S., Tanaka, Y., Mayama, T., Okuyama, Y., Tsuchimoto, S., & Takatsuji, H. (2002). Role of petuniapMADS3in determination of floral organ and meristem identity, as revealed by its loss of function. The Plant Journal, 32(1), 115-127. doi:10.1046/j.1365-313x.2002.01402.xPan, I. L., McQuinn, R., Giovannoni, J. J., & Irish, V. F. (2010). Functional diversification of AGAMOUS lineage genes in regulating tomato flower and fruit development. Journal of Experimental Botany, 61(6), 1795-1806. doi:10.1093/jxb/erq046Pnueli, L., Hareven, D., Rounsley, S. D., Yanofsky, M. F., & Lifschitz, E. (1994). Isolation of the tomato AGAMOUS gene TAG1 and analysis of its homeotic role in transgenic plants. The Plant Cell, 6(2), 163-173. doi:10.1105/tpc.6.2.163Dreni, L., & Kater, M. M. (2013). MADSreloaded: evolution of theAGAMOUSsubfamily genes. New Phytologist, 201(3), 717-732. doi:10.1111/nph.12555Brunner, A. M. (2000). Plant Molecular Biology, 44(5), 619-634. doi:10.1023/a:1026550205851Perl-Treves, R., Kahana, A., Rosenman, N., Xiang, Y., & Silberstein, L. (1998). Expression of Multiple AGAMOUS-Like Genes in Male and Female Flowers of Cucumber (Cucumis sativus L.). Plant and Cell Physiology, 39(7), 701-710. doi:10.1093/oxfordjournals.pcp.a029424Yu, D., Kotilainen, M., Pöllänen, E., Mehto, M., Elomaa, P., Helariutta, Y., … Teeri, T. H. (1999). Organ identity genes and modified patterns of flower development in Gerbera hybrida (Asteraceae). The Plant Journal, 17(1), 51-62. doi:10.1046/j.1365-313x.1999.00351.xDong, Z., Zhao, Z., Liu, C., Luo, J., Yang, J., Huang, W., … Luo, D. (2005). Floral Patterning in Lotus japonicus. Plant Physiology, 137(4), 1272-1282. doi:10.1104/pp.104.054288Hofer, J. M., & Noel Ellis, T. (2014). Developmental specialisations in the legume family. Current Opinion in Plant Biology, 17, 153-158. doi:10.1016/j.pbi.2013.11.014Fourquin, C., del Cerro, C., Victoria, F. C., Vialette-Guiraud, A., de Oliveira, A. C., & Ferrándiz, C. (2013). A Change in SHATTERPROOF Protein Lies at the Origin of a Fruit Morphological Novelty and a New Strategy for Seed Dispersal in Medicago Genus. Plant Physiology, 162(2), 907-917. doi:10.1104/pp.113.217570Hewitt EJ (1966) Sand and Water Culture Methods Used in the Study of Plant Nutrition. Farnham Royal, UK: Commonwealth Agricultural Bureau.Cheng, X., Wang, M., Lee, H.-K., Tadege, M., Ratet, P., Udvardi, M., … Wen, J. (2013). An efficient reverse genetics platform in the model legumeMedicago truncatula. New Phytologist, 201(3), 1065-1076. doi:10.1111/nph.12575D’ Erfurth, I., Cosson, V., Eschstruth, A., Lucas, H., Kondorosi, A., & Ratet, P. (2003). Efficient transposition of theTnt1tobacco retrotransposon in the model legumeMedicago truncatula. The Plant Journal, 34(1), 95-106. doi:10.1046/j.1365-313x.2003.01701.xTadege, M., Ratet, P., & Mysore, K. S. (2005). Insertional mutagenesis: a Swiss Army knife for functional genomics of Medicago truncatula. Trends in Plant Science, 10(5), 229-235. doi:10.1016/j.tplants.2005.03.009Tadege, M., Wen, J., He, J., Tu, H., Kwak, Y., Eschstruth, A., … Mysore, K. S. (2008). Large-scale insertional mutagenesis using the Tnt1 retrotransposon in the model legume Medicago truncatula. The Plant Journal, 54(2), 335-347. doi:10.1111/j.1365-313x.2008.03418.xCheng, X., Wen, J., Tadege, M., Ratet, P., & Mysore, K. S. (2010). Reverse Genetics in Medicago truncatula Using Tnt1 Insertion Mutants. Plant Reverse Genetics, 179-190. doi:10.1007/978-1-60761-682-5_13Benlloch, R., d’ Erfurth, I., Ferrandiz, C., Cosson, V., Beltrán, J. P., Cañas, L. A., … Ratet, P. (2006). Isolation of mtpim Proves Tnt1 a Useful Reverse Genetics Tool in Medicago truncatula and Uncovers New Aspects of AP1-Like Functions in Legumes. Plant Physiology, 142(3), 972-983. doi:10.1104/pp.106.083543Larkin, M. A., Blackshields, G., Brown, N. P., Chenna, R., McGettigan, P. A., McWilliam, H., … Higgins, D. G. (2007). Clustal W and Clustal X version 2.0. Bioinformatics, 23(21), 2947-2948. doi:10.1093/bioinformatics/btm404Altschul, S. (1997). Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Research, 25(17), 3389-3402. doi:10.1093/nar/25.17.3389Tamura, K., Dudley, J., Nei, M., & Kumar, S. (2007). MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) Software Version 4.0. Molecular Biology and Evolution, 24(8), 1596-1599. doi:10.1093/molbev/msm092Dellaporta, S. L., Wood, J., & Hicks, J. B. (1983). A plant DNA minipreparation: Version II. Plant Molecular Biology Reporter, 1(4), 19-21. doi:10.1007/bf02712670Schmittgen, T. D., & Livak, K. J. (2008). Analyzing real-time PCR data by the comparative CT method. Nature Protocols, 3(6), 1101-1108. doi:10.1038/nprot.2008.73Constantin, G. D., Krath, B. N., MacFarlane, S. A., Nicolaisen, M., Elisabeth Johansen, I., & Lund, O. S. (2004). Virus-induced gene silencing as a tool for functional genomics in a legume species. The Plant Journal, 40(4), 622-631. doi:10.1111/j.1365-313x.2004.02233.xWesley, S. V., Helliwell, C. A., Smith, N. A., Wang, M., Rouse, D. T., Liu, Q., … Waterhouse, P. M. (2001). Construct design for efficient, effective and high-throughput gene silencing in plants. The Plant Journal, 27(6), 581-590. doi:10.1046/j.1365-313x.2001.01105.xGuerineau F, Mullineaux P (1993) Plant transformation and expression vectors. In: Croy R, editor. Plant Molecular Biology. Oxford, UK: Bios Scientific Publishers, Academic Press. pp. 121–147.Clough, S. J., & Bent, A. F. (1998). Floral dip: a simplified method forAgrobacterium-mediated transformation ofArabidopsis thaliana. The Plant Journal, 16(6), 735-743. doi:10.1046/j.1365-313x.1998.00343.xBenlloch, R., Roque, E., Ferrándiz, C., Cosson, V., Caballero, T., Penmetsa, R. V., … Madueño, F. (2009). Analysis of B function in legumes: PISTILLATA proteins do not require the PI motif for floral organ development inMedicago truncatula. The Plant Journal, 60(1), 102-111. doi:10.1111/j.1365-313x.2009.03939.xRoque, E., Serwatowska, J., Cruz Rochina, M., Wen, J., Mysore, K. S., Yenush, L., … Cañas, L. A. (2012). Functional specialization of duplicated AP3-like genes inMedicago truncatula. The Plant Journal, 73(4), 663-675. doi:10.1111/tpj.12068Flanagan, C. A., Hu, Y., & Ma, H. (1996). Specific expression of the AGL1 MADS-box gene suggests regulatory functions in Arabidopsis gynoecium and ovule development. The Plant Journal, 10(2), 343-353. doi:10.1046/j.1365-313x.1996.10020343.xSieburth, L. E., & Meyerowitz, E. M. (1997). Molecular dissection of the AGAMOUS control region shows that cis elements for spatial regulation are located intragenically. The Plant Cell, 9(3), 355-365. doi:10.1105/tpc.9.3.355Busch, M. A. (1999). Activation of a Floral Homeotic Gene in Arabidopsis. Science, 285(5427), 585-587. doi:10.1126/science.285.5427.585Moyroud, E., Minguet, E. G., Ott, F., Yant, L., Posé, D., Monniaux, M., … Parcy, F. (2011). Prediction of Regulatory Interactions from Genome Sequences Using a Biophysical Model for the Arabidopsis LEAFY Transcription Factor. The Plant Cell, 23(4), 1293-1306. doi:10.1105/tpc.111.083329Grønlund, M., Constantin, G., Piednoir, E., Kovacev, J., Johansen, I. E., & Lund, O. S. (2008). Virus-induced gene silencing in Medicago truncatula and Lathyrus odorata. Virus Research, 135(2), 345-349. doi:10.1016/j.virusres.2008.04.005Mandel, M. A., Bowman, J. L., Kempin, S. A., Ma, H., Meyerowitz, E. M., & Yanofsky, M. F. (1992). Manipulation of flower structure in transgenic tobacco. Cell, 71(1), 133-143. doi:10.1016/0092-8674(92)90272-eMizukami, Y., & Ma, H. (1992). Ectopic expression of the floral homeotic gene AGAMOUS in transgenic Arabidopsis plants alters floral organ identity. Cell, 71(1), 119-131. doi:10.1016/0092-8674(92)90271-dCannon, S. B., Sterck, L., Rombauts, S., Sato, S., Cheung, F., Gouzy, J., … Young, N. D. (2006). Legume genome evolution viewed through the Medicago truncatula and Lotus japonicus genomes. Proceedings of the National Academy of Sciences, 103(40), 14959-14964. doi:10.1073/pnas.0603228103Young, N. D., & Bharti, A. K. (2012). Genome-Enabled Insights into Legume Biology. Annual Review of Plant Biology, 63(1), 283-305. doi:10.1146/annurev-arplant-042110-103754Jager, M. (2003). MADS-Box Genes in Ginkgo biloba and the Evolution of the AGAMOUS Family. Molecular Biology and Evolution, 20(5), 842-854. doi:10.1093/molbev/msg089Johansen, B., Pedersen, L. B., Skipper, M., & Frederiksen, S. (2002). MADS-box gene evolution—structure and transcription patterns. Molecular Phylogenetics and Evolution, 23(3), 458-480. doi:10.1016/s1055-7903(02)00032-5Rutledge, R., Regan, S., Nicolas, O., Fobert, P., Côté, C., Bosnich, W., … Stewart, D. (1998). Characterization of an AGAMOUS homologue from the conifer black spruce ( Picea mariana ) that produces floral homeotic conversions when expressed in Arabidopsis. The Plant Journal, 15(5), 625-634. doi:10.1046/j.1365-313x.1998.00250.xParcy, F., Nilsson, O., Busch, M. A., Lee, I., & Weigel, D. (1998). A genetic framework for floral patterning. Nature, 395(6702), 561-566. doi:10.1038/26903Causier, B., Bradley, D., Cook, H., & Davies, B. (2009). Conserved intragenic elements were critical for the evolution of the floral C-function. The Plant Journal, 58(1), 41-52. doi:10.1111/j.1365-313x.2008.03759.xAiroldi, C. A., & Davies, B. (2012). Gene Duplication and the Evolution of Plant MADS-box Transcription Factors. Journal of Genetics and Genomics, 39(4), 157-165. doi:10.1016/j.jgg.2012.02.008Giménez, E., Pineda, B., Capel, J., Antón, M. T., Atarés, A., Pérez-Martín, F., … Lozano, R. (2010). Functional Analysis of the Arlequin Mutant Corroborates the Essential Role of the ARLEQUIN/TAGL1 Gene during Reproductive Development of Tomato. PLoS ONE, 5(12), e14427. doi:10.1371/journal.pone.0014427Kater, M. M., Colombo, L., Franken, J., Busscher, M., Masiero, S., Van Lookeren Campagne, M. M., & Angenent, G. C. (1998). Multiple AGAMOUS Homologs from Cucumber and Petunia Differ in Their Ability to Induce Reproductive Organ Fate. The Plant Cell, 10(2), 171-182. doi:10.1105/tpc.10.2.171Tsuchimoto, S., van der Krol, A. R., & Chua, N. H. (1993). Ectopic expression of pMADS3 in transgenic petunia phenocopies the petunia blind mutant. The Plant Cell, 5(8), 843-853. doi:10.1105/tpc.5.8.843Airoldi, C. A., Bergonzi, S., & Davies, B. (2010). Single amino acid change alters the ability to specify male or female organ identity. Proceedings of the National Academy of Sciences, 107(44), 18898-18902. doi:10.1073/pnas.1009050107Causier, B., Castillo, R., Zhou, J., Ingram, R., Xue, Y., Schwarz-Sommer, Z., & Davies, B. (2005). Evolution in Action: Following Function in Duplicated Floral Homeotic Genes. Current Biology, 15(16), 1508-1512. doi:10.1016/j.cub.2005.07.063Birchler, J. A., & Veitia, R. A. (2007). The Gene Balance Hypothesis: From Classical Genetics to Modern Genomics. The Plant Cell, 19(2), 395-402. doi:10.1105/tpc.106.049338Birchler, J. A., & Veitia, R. A. (2009). The gene balance hypothesis: implications for gene regulation, quantitative traits and evolution. New Phytologist, 186(1), 54-62. doi:10.1111/j.1469-8137.2009.03087.xEdger, P. P., & Pires, J. C. (2009). Gene and genome duplications: the impact of dosage-sensitivity on the fate of nuclear genes. Chromosome Research, 17(5), 699-717. doi:10.1007/s10577-009-9055-9Freeling, M. (2006). Gene-balanced duplications, like tetraploidy, provide predictable drive to increase morphological complexity. Genome Research, 16(7), 805-814. doi:10.1101/gr.368140

Class III β-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel

Critics have suggested that neoadjuvant chemotherapy (NACT) followed by interval debulking may select for resistant clones or cancer stem cells when compared to primary cytoreduction. β-tubulins are chemotherapeutic targets of taxanes and epothilones. Class III β-tubulin overexpression has been linked to chemoresistance and hypoxia. Herein, we describe changes in class III β-tubulin in patients with advanced ovarian carcinoma in response to NACT, in relationship to clinical outcome, and between patients who underwent NACT versus primary debulking; we characterize in vitro chemosensitivity to paclitaxel/patupilone of cell lines established from this patient population, and class III β-tubulin expression following repeated exposure to paclitaxel. Using immunohistochemistry, we observed among 22 paired specimens obtained before/after NACT decreased expression of class III β-tubulin following therapy within stroma (p=0.07), but not tumor (p=0.63). Poor median overall survival was predicted by high levels of class III β-tubulin in both tumor (HR 3.66 [1.11,12.05], p=0.03) and stroma (HR 4.53 [1.28,16.1], p=0.02). Class III β-tubulin expression by quantitative-real-time-polymerase-chain-reaction was higher among patients who received NACT (n=12) compared to primary cytoreduction (n=14) (mean±SD fold-change: 491.2±115.9 vs 224.1±55.66, p=0.037). In vitro subculture with paclitaxel resulted in class III β-tubulin upregulation, however, cell lines that overexpressed class III β-tubulin remained sensitive to patupilone. Overexpression of class III β-tubulin in patients dispositioned to NACT may thus identify an intrinsically aggressive phenotype, and predict poor overall survival and paclitaxel resistance. Decreases in stromal expression may represent normalization of the tumor microenvironment following therapy. Epothilones warrant study for patients who have received neoadjuvant carboplatin and paclitaxel

Treinamento físico de natação promove remodelamento cardíaco e melhora a perfusão sanguínea no músculo cardíaco de SHR via mecanismo dependente de adenosina

INTRODUÇÃO: Exercícios físicos são utilizados como terapia não farmacológica para o tratamento da hipertensão arterial, e o treinamento físico (TF) por natação é reconhecido por produzir remodelamento cardíaco em animais experimentais. Entretanto, a ação vasodilatadora da adenosina (ado) resultante do exercício físico como prevenção e tratamento da hipertensão é pouco explorada. OBJETIVO: Avaliar o remodelamento cardíaco e o papel da adenosina na distribuição do fluxo sanguíneo para o miocárdio após treinamento físico em SHR. Método: 28 SHR machos babies e adultos foram submetidos ao TF aeróbio de natação, durante 10 semanas (5x/sem -1h/dia). Foram utilizados protocolos de microesferas coloridas para avaliar fluxo sanguíneo, técnicas de morfologia para avaliar hipertrofia cardíaca e análises bioquímicas para verificar atividade de enzimas envolvidas na formação de adenosina. RESULTADOS: TF por natação atenuou a evolução da HA em SHR babies (S: 145 ± 2; T: 140 ± 2mmHg), promoveu bradicardia de repouso em SHR adultos (S: 340 ± 4; T: 321 ± 6bpm) e desenvolveu HC nos dois grupos (TB: 12%; TA: 10%). Na condição basal, o TF aumentou o FS coronário em SHR babies (S: 4.745 ± 2.145; T: 6.970 ± 2.374mi/coração) e maior resposta vasodilatadora à infusão de adenosina foi observada (S: 18.946 ± 6.685; T: 25.045 ± 7.031mi/coração). Neste grupo, o TF promoveu maior atividade da enzima 5'-nucleotidase, levando à maior formação de adenosina (S: 0,45 ± 0,09; T: 1,01 ± 0,05). CONCLUSÃO: O TF de natação, além de desenvolver HC e apresentar maior hidrólise de AMP, promoveu aumento no FS coronário, sendo mostrado que desempenha um importante papel na regulação da hipertensã