HIV-1 Disease Progression Is Associated with Bile-Salt Stimulated Lipase (BSSL) Gene Polymorphism

Background: DC-SIGN expressed by dendritic cells captures HIV-1 resulting in trans-infection of CD4+ T-lymphocytes. However, BSSL (bile-salt stimulated lipase) binding to DC-SIGN interferes with HIV-1 capture. DC-SIGN binding properties of BSSL associate with the polymorphic repeated motif of BSSL exon 11. Furthermore, BSSL binds to HIV-1 co-receptor CXCR4. We hypothesized that BSSL modulates HIV-1 disease progression and emergence of CXCR4 using HIV-1 (X4) variants. Results: The relation between BSSL genotype and HIV-1 disease progression and emergence of X4 variants was studied using Kaplan Meier and multivariate Cox proportional hazard analysis in a cohort of HIV-1 infected men having sex with men (n = 334, with n = 130 seroconverters). We analyzed the association of BSSL genotype with set-point viral load and CD4 cell count, both pre-infection and post-infection at viral set-point. The number of repeats in BSSL exon 11 were highly variable ranging from 10 to 18 in seropositive individuals and from 5-17 in HRSN with 16 repeats being dominant (>80% carry at least one allele with 16 repeats). We defined 16 to 18 repeats as high (H) and less than 16 repeats as low (L) repeat numbers. Homozygosity for the high (H) repeat number BSSL genotype (HH) correlated with high CD4 cell numbers prior to infection (p = 0.007). In HIV-1 patients, delayed disease progression was linked to the HH BSSL genotype (RH = 0.462 CI = 0.282-0.757, p = 0.002) as was delayed emergence of X4 variants (RH = 0.525, 95% CI = 0.290-0.953, p = 0.034). The LH BSSL genotype, previously found to be associated with enhanced DC-SIGN binding of human milk, was identified to correlate with accelerated disease progression in our cohort of HIV-1 infected MSM (RH = 0.517, 95% CI = 0.328-0.818, p = 0.005). Conclusion: We identify BSSL as a marker for HIV-1 disease progression and emergence of X4 variants. Additionally, we identified a relation between BSSL genotype and CD4 cell counts prior to infectio

Thermospermine catabolism increases Arabidopsis thaliana resistance to Pseudomonas viridiflava

This work investigated the roles of the tetraamine thermospermine (TSpm) by analysing its contribution to Arabidopsis basal defence against the biotrophic bacterium Pseudomonas viridiflava. The participation of polyamine oxidases (PAOs) in TSpm homeostasis and TSpm-mediated defence was also investigated. Exogenous supply of TSpm, as well as ectopic expression of the TSpm biosynthetic gene ACL5, increased Arabidopsis Col-0 resistance to P. viridiflava, while null acl5 mutants were less resistant than Col-0 plants. The above-mentioned increase in resistance was blocked by the PAO inhibitor SL-11061, thus demonstrating the participation of TSpm oxidation. Analysis of PAO genes expression in transgenic 35S::ACL5 and Col-0 plants supplied with TSpm suggests that PAO 1, 3, and 5 are the main PAOs involved in TSpm catabolism. In summary, TSpm exhibited the potential to perform defensive functions previously reported for its structural isomer Spm, and the relevance of these findings is discussed in the context of ACL5 expression and TSpm concentration in planta. Moreover, this work demonstrates that manipulation of TSpm metabolism modifies plant resistance to pathogens.The gift of SL-11061 by Dr Frydman (SLIL Biomedical Corporation, Madison, WI) is greatly appreciated. This work was supported by Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Argentina (PIP 5740, PIP 0395), Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina (PICT 1119, ANPCYT), Universidad Nacional de General San Martin, Argentina (SJ10/30), Ministerio de Economia y Competitividad, Spain (BIO2011-23828), and Fundacion Carolina (postdoctoral fellowship to MM). MM, FLP, and OAR are members of the Research Career of CONICET.Marina, M.; Vera Sirera, FJ.; Rambla Nebot, JL.; Gonzalez, ME.; Blazquez Rodriguez, MA.; Carbonell Gisbert, J.; Pieckenstain, FL.... (2013). Thermospermine catabolism increases Arabidopsis thaliana resistance to Pseudomonas viridiflava. Journal of Experimental Botany. 64(5):1393-1402. https://doi.org/10.1093/jxb/ert012S13931402645Alonso, J. M. (2003). Genome-Wide Insertional Mutagenesis of Arabidopsis thaliana. Science, 301(5633), 653-657. doi:10.1126/science.1086391Alippi, A. M., Dal Bo, E., Ronco, L. B., Lopez, M. V., Lopez, A. C., & Aguilar, O. M. (2003). Pseudomonas populations causing pith necrosis of tomato and pepper in Argentina are highly diverse. Plant Pathology, 52(3), 287-302. doi:10.1046/j.1365-3059.2003.00850.xAngelini, R., Bragaloni, M., Federico, R., Infantino, A., & Porta-Pugua, A. (1993). Involvement of Polyamines, Diamine Oxidase and Peroxidase in Resistance of Chickpea to Ascochyta rabiei. Journal of Plant Physiology, 142(6), 704-709. doi:10.1016/s0176-1617(11)80906-5Clough, 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.xCona, A., Rea, G., Angelini, R., Federico, R., & Tavladoraki, P. (2006). Functions of amine oxidases in plant development and defence. Trends in Plant Science, 11(2), 80-88. doi:10.1016/j.tplants.2005.12.009Fincato, P., Moschou, P. N., Spedaletti, V., Tavazza, R., Angelini, R., Federico, R., … Tavladoraki, P. (2010). Functional diversity inside the Arabidopsis polyamine oxidase gene family. Journal of Experimental Botany, 62(3), 1155-1168. doi:10.1093/jxb/erq341Gonzalez, M. E., Marco, F., Minguet, E. G., Carrasco-Sorli, P., Blázquez, M. A., Carbonell, J., … Pieckenstain, F. L. (2011). Perturbation of spermine synthase Gene Expression and Transcript Profiling Provide New Insights on the Role of the Tetraamine Spermine in Arabidopsis Defense against Pseudomonas viridiflava. Plant Physiology, 156(4), 2266-2277. doi:10.1104/pp.110.171413Hanzawa, Y., Imai, A., Michael, A. J., Komeda, Y., & Takahashi, T. (2002). Characterization of the spermidine synthase-related gene family inArabidopsis thaliana. FEBS Letters, 527(1-3), 176-180. doi:10.1016/s0014-5793(02)03217-9Hanzawa, Y. (2000). ACAULIS5, an Arabidopsis gene required for stem elongation, encodes a spermine synthase. The EMBO Journal, 19(16), 4248-4256. doi:10.1093/emboj/19.16.4248Igarashi, K., & Kashiwagi, K. (2000). Polyamines: Mysterious Modulators of Cellular Functions. Biochemical and Biophysical Research Communications, 271(3), 559-564. doi:10.1006/bbrc.2000.2601Imai, A., Akiyama, T., Kato, T., Sato, S., Tabata, S., Yamamoto, K. T., & Takahashi, T. (2003). Spermine is not essential for survival of Arabidopsis. FEBS Letters, 556(1-3), 148-152. doi:10.1016/s0014-5793(03)01395-4Imai, A. (2006). The dwarf phenotype of the Arabidopsis acl5 mutant is suppressed by a mutation in an upstream ORF of a bHLH gene. Development, 133(18), 3575-3585. doi:10.1242/dev.02535Jakob, K., Goss, E. M., Araki, H., Van, T., Kreitman, M., & Bergelson, J. (2002). Pseudomonas viridiflavaandP. syringae—Natural Pathogens ofArabidopsis thaliana. Molecular Plant-Microbe Interactions, 15(12), 1195-1203. doi:10.1094/mpmi.2002.15.12.1195Kakehi, J. -i., Kuwashiro, Y., Niitsu, M., & Takahashi, T. (2008). Thermospermine is Required for Stem Elongation in Arabidopsis thaliana. Plant and Cell Physiology, 49(9), 1342-1349. doi:10.1093/pcp/pcn109Kamada-Nobusada, T., Hayashi, M., Fukazawa, M., Sakakibara, H., & Nishimura, M. (2008). A Putative Peroxisomal Polyamine Oxidase, AtPAO4, is Involved in Polyamine Catabolism in Arabidopsis thaliana. Plant and Cell Physiology, 49(9), 1272-1282. doi:10.1093/pcp/pcn114Knott, J. M., Römer, P., & Sumper, M. (2007). Putative spermine synthases fromThalassiosira pseudonanaandArabidopsis thalianasynthesize thermospermine rather than spermine. FEBS Letters, 581(16), 3081-3086. doi:10.1016/j.febslet.2007.05.074Maiale, S. J., Marina, M., Sánchez, D. H., Pieckenstain, F. L., & Ruiz, O. A. (2008). In vitro and in vivo inhibition of plant polyamine oxidase activity by polyamine analogues. Phytochemistry, 69(14), 2552-2558. doi:10.1016/j.phytochem.2008.07.003Marina, M., Maiale, S. J., Rossi, F. R., Romero, M. F., Rivas, E. I., Gárriz, A., … Pieckenstain, F. L. (2008). Apoplastic Polyamine Oxidation Plays Different Roles in Local Responses of Tobacco to Infection by the Necrotrophic Fungus Sclerotinia sclerotiorum and the Biotrophic Bacterium Pseudomonas viridiflava. Plant Physiology, 147(4), 2164-2178. doi:10.1104/pp.108.122614Marini, F., Betti, L., Scaramagli, S., Biondi, S., & Torrigiani, P. (2001). Polyamine metabolism is upregulated in response to tobacco mosaic virus in hypersensitive, but not in susceptible, tobacco. New Phytologist, 149(2), 301-309. doi:10.1046/j.1469-8137.2001.00017.xMinguet, E. G., Vera-Sirera, F., Marina, A., Carbonell, J., & Blazquez, M. A. (2008). Evolutionary Diversification in Polyamine Biosynthesis. Molecular Biology and Evolution, 25(10), 2119-2128. doi:10.1093/molbev/msn161Mitsuya, Y., Takahashi, Y., Berberich, T., Miyazaki, A., Matsumura, H., Takahashi, H., … Kusano, T. (2009). Spermine signaling plays a significant role in the defense response of Arabidopsis thaliana to cucumber mosaic virus. Journal of Plant Physiology, 166(6), 626-643. doi:10.1016/j.jplph.2008.08.006Mitsuya, Y., Takahashi, Y., Uehara, Y., Berberich, T., Miyazaki, A., Takahashi, H., & Kusano, T. (2007). Identification of a novel Cys2/His2-type zinc-finger protein as a component of a spermine-signaling pathway in tobacco. Journal of Plant Physiology, 164(6), 785-793. doi:10.1016/j.jplph.2006.05.011Møller, S. G., & McPherson, M. J. (1998). Developmental expression and biochemical analysis of the Arabidopsis atao1 gene encoding an H 2 O 2 ‐generating diamine oxidase. The Plant Journal, 13(6), 781-791. doi:10.1046/j.1365-313x.1998.00080.xMoschou, P. N., Sarris, P. F., Skandalis, N., Andriopoulou, A. H., Paschalidis, K. A., Panopoulos, N. J., & Roubelakis-Angelakis, K. A. (2009). Engineered Polyamine Catabolism Preinduces Tolerance of Tobacco to Bacteria and Oomycetes. Plant Physiology, 149(4), 1970-1981. doi:10.1104/pp.108.134932Muniz, L., Minguet, E. G., Singh, S. K., Pesquet, E., Vera-Sirera, F., Moreau-Courtois, C. L., … Tuominen, H. (2008). ACAULIS5 controls Arabidopsis xylem specification through the prevention of premature cell death. Development, 135(15), 2573-2582. doi:10.1242/dev.019349Murashige, T., & Skoog, F. (1962). A Revised Medium for Rapid Growth and Bio Assays with Tobacco Tissue Cultures. Physiologia Plantarum, 15(3), 473-497. doi:10.1111/j.1399-3054.1962.tb08052.xOber, D., Gibas, L., Witte, L., & Hartmann, T. (2003). Evidence for general occurrence of homospermidine in plants and its supposed origin as by-product of deoxyhypusine synthase. Phytochemistry, 62(3), 339-344. doi:10.1016/s0031-9422(02)00553-8Oshima, T. (2007). Unique polyamines produced by an extreme thermophile, Thermus thermophilus. Amino Acids, 33(2), 367-372. doi:10.1007/s00726-007-0526-zPanicot, M., Minguet, E. G., Ferrando, A., Alcázar, R., Blázquez, M. A., Carbonell, J., … Tiburcio, A. F. (2002). A Polyamine Metabolon Involving Aminopropyl Transferase Complexes in Arabidopsis. The Plant Cell, 14(10), 2539-2551. doi:10.1105/tpc.004077Pfaffl, M. W. (2002). Relative expression software tool (REST(C)) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Research, 30(9), 36e-36. doi:10.1093/nar/30.9.e36Rambla, J. L., Vera-Sirera, F., Blázquez, M. A., Carbonell, J., & Granell, A. (2010). Quantitation of biogenic tetraamines in Arabidopsis thaliana. Analytical Biochemistry, 397(2), 208-211. doi:10.1016/j.ab.2009.10.013Rea, G., Metoui, O., Infantino, A., Federico, R., & Angelini, R. (2002). Copper Amine Oxidase Expression in Defense Responses to Wounding and Ascochyta rabiei Invasion. Plant Physiology, 128(3), 865-875. doi:10.1104/pp.010646Sagor, G. H. M., Takahashi, H., Niitsu, M., Takahashi, Y., Berberich, T., & Kusano, T. (2012). Exogenous thermospermine has an activity to induce a subset of the defense genes and restrict cucumber mosaic virus multiplication in Arabidopsis thaliana. Plant Cell Reports, 31(7), 1227-1232. doi:10.1007/s00299-012-1243-yShah, N., Thomas, T., Shirahata, A., Sigal, L. H., & Thomas, T. J. (1999). Activation of Nuclear Factor κB by Polyamines in Breast Cancer Cells†. 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PO-34 - Optimal doses of tinzaparin to reduce both cancer-associated thrombosis and tumor growth in a mouse model of ectopic pancreatic syngeneic tumor

International audienc

Involvement of tissue factor expressed by cancer cells on tumor growth and thrombosis associated with cancer

International audienc

On the use of anti-platelet drugs to diminish both tumor growth and thrombosis

International audienc

Do platelet transfusions work?

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17–21, 2021. The conference, now held annually, highlighted cutting-edge advances in basic