Lateral resistance of plybamboo wall-panels

This paper deals with the experimental and theoretical behavior of plybamboo (kind of plywood made out of bamboo) wall-panels subjected to lateral load. The wall-panels are part of a house design method proposed in the author's PhD thesis for prefabricated social housing in developing countries. Sixteen fullscaled wallpanels with or without window and door openings were tested and their theoretical capacities estimated. Design wind and seismic loads were determined according to the International Building Code 2000. The results showed that all the specimens present ductile behavior adequate for expected wind and seismic loads. The theoretical models for calculating lateral capacities of timber framed walls gave lower values than the experimental ones. The wall-panels sheathed with plybamboo and traditional plywood showed similar behavior and hence, plybamboo could be used as an alternative sheathing material in timber frame construction. Key Words: Shear-Walls, Plybamboo, Timber Framed Walls, Structural Panels, Bamboo Structure

Supplementation of lamb diets with vitamin E and rosemary extracts on meat quality parameters

BACKGROUND Supranutritional supplementation of lamb diets with alpha-tocopherol is an effective method to reduce lipid oxidation and colour deterioration in meat products. However, alternative antioxidant sources have been proposed to replace the supranutritional vitamin E applications. RESULTS Indoor concentrate-fed Rasa Aragonesa male lambs (n = 480) were supplemented with increasing levels of all-rac-alpha-tocopheryl acetate (0.25, 0.5, 1.0 g kg(-1) compound feed), rosemary extract (0.20, 0.40, or 0.80 g kg(-1) compound feed), or rosemary extract embedded in a fat matrix (0.20, 0.40, or 0.80 g kg(-1) compound feed) for 14 days before slaughter. The longissimus thoracis et lumborum muscle from three lambs per pen (18 lambs per treatment) were modified-atmosphere packaged (70% O-2 + 30% CO2) and maintained under retail conditions for 14 days. Supranutritional supplementation with antioxidants had no effect (P > 0.05) on average daily weight gain, feed intake, and feed efficiency. Rosemary extract supplementation (with or without fat embedment) had no effect on lipid oxidation, myoglobin forms, or colour stability parameters, regardless of the dose. All vitamin E supplementation levels significantly affected lipid oxidation, colour stability (L*, C*, and h), myoglobin forms, and meat discoloration parameters compared with non-supplemented lambs. CONCLUSIONS This study demonstrates that, unlike vitamin E, neither dose nor protection of the rosemary extract had an effect on lipid oxidation or meat colour stability of lambs during the 14 days of storage under retail conditions

Comment bien produire en même temps des champignons et du bois dans les forêts de pin sylvestre ? Le cas pratique de la Catalogne

La production de champignons représente une des principales richesses de nos forêts. La combinaison de la production fongique et de la production de bois est un des défis les plus importants auxquels sont confrontés les gestionnaires et les propriétaires. Ceux-ci établissent des itinéraires sylvicoles qui maximisent les bénéfices que l’on peut tirer des bois, sans compromettre leur durabilité. Cet article apporte des données sur la production de champignons, et un itinéraire sylvicole multifonctionnel est proposé qui vise à maximiser les productions conjointes de bois et de champignons au sein des peuplements réguliers de Pinus sylvestris. Les résultats définis par le Centre de la Propietat Forestal de Catalunya, avec l’assistance du Centre Tecnològic Forestal de Catalunya, se basent sur le suivi des productions fongiques de parcelles permanentes au cours des quinze dernières années. Le modèle final proposé pour la production combinée de champignons et de bois avec structure régulière prévoit une période de rotation de la coupe de 120 ans (environ 50 cm de diamètre), un régime de deux éclaircies mixtes et une densité finale de 100 pieds/ha avec régénération par éclaircies successives en deux phases

Initiation of ovarian stimulation independent of the menstrual cycle (random-start) in an oocyte donation programme a large, single-center experience

Research Question Do live birth rates differ between recipients matched with donors using conventional ovarian stimulation versus those using random-start protocols? Design Retrospective analysis of 891 ovarian stimulations in egg donors (January-December 2018) and clinical outcomes in matched recipients (n=935). Donors commenced ovarian stimulation on day 1/3 of the menstrual cycle (n=223) or in the mid/late-follicular (n=388) or luteal phase (n=280) under a conventional antagonist protocol. Live birth rate of matched recipients was the main outcome. Results Duration of stimulation and total gonadotropins dose were comparable between conventional versus random-start groups. The number of collected eggs were also similar: 17.6±8.8 vs 17.2±8.5, p=0.6, respectively. Sub-group analysis showed an increased stimulation length (10.2±1.8 vs 9.8±1.7 vs 10.4±1.7, p<0.001) and gonadotropin consumption (2041.5±645.3 vs 2003.2±647.3 vs 2158.2±685.7 IU, p=0.01) in the luteal phase group vs the mid/late follicular and conventional groups; respectively. In matched recipients receiving fresh oocytes and undergoing fresh embryo transfer, the biochemical pregnancy (63.8% and 63.3%; p=0.9), clinical pregnancy (54.6% and 56.1%; p=0.8) and live birth rates (47.7% and 46.6%; p=0.7) per embryo-transfer were similar between conventional versus random groups. Similar results were obtained in recipients receiving vitrified eggs. Euploidy rate was also comparable. Conclusions There were no notable variations in clinical outcomes using oocytes obtained from random-start protocols and those proceeding from conventional ovarian stimulation in oocyte donation treatments. However, luteal-phase stimulation seems to require longer stimulation and higher FSH consumption. Our results indicate that random-start stimulation strategy does not impair the potential of the oocyte yield or clinical outcomes in oocyte donation cycles

DNA synthesis determines the binding mode of the human mitochondrial single-stranded DNA-binding protein

[EN] Single-stranded DNA-binding proteins (SSBs) play a key role in genome maintenance, binding and organizing single-stranded DNA (ssDNA) intermediates. Multimeric SSBs, such as the human mitochondrial SSB (HmtSSB), present multiple sites to interact with ssDNA, which has been shown in vitro to enable them to bind a variable number of single-stranded nucleotides depending on the salt and protein concentration. It has long been suggested that different binding modes might be used selectively for different functions. To study this possibility, we used optical tweezers to determine and compare the structure and energetics of long, individual HmtSSB¿DNA complexes assembled on preformed ssDNA and on ssDNA generated gradually during `in situ¿ DNA synthesis. We show that HmtSSB binds to preformed ss-DNA in two major modes, depending on salt and protein concentration. However, when protein binding was coupled to strand-displacement DNA synthesis, only one of the two binding modes was observed under all experimental conditions. Our results reveal a key role for the gradual generation of ssDNA in modulating the binding mode of a multimeric SSB protein and consequently, in generating the appropriate nucleoprotein structure for DNA synthetic reactions required for genome maintenance.We are grateful to Prof. M. Salas laboratory (CBMSO-CSIC) for generously providing the Phi29 DNA polymerase and to Juan P. García Villaluenga (UCM) for useful discussions. Spanish Ministry of Economy and Competitiveness [MAT2015-71806-R to J.R.A-G, FIS2010-17440, FIS2015-67765-R to F.J.C., BFU2012-31825, BFU2015-63714-R to B.I.]; Spanish Ministry of Education, Culture and Sport [FPU13/02934 to J.J., FPU13/02826 to E.B-H.]; National Institutes of Health [GM45925 to L.S.K.]; University of Tampere (to G.L.C.); Programa de Financiacion Universidad Complutense de Madrid-Santander Universidades [CT45/15-CT46/15 to F.C.]. Funding for open access charge: Spanish Ministry of Economy and Competitiveness [BFU2015-63714-R].Morin, J.; Cerrón, F.; Jarillo, J.; Beltran-Heredia, E.; Ciesielski, G.; Arias-Gonzalez, JR.; Kaguni, L.... (2017). DNA synthesis determines the binding mode of the human mitochondrial single-stranded DNA-binding protein. Nucleic Acids Research. 45(12):7237-7248. https://doi.org/10.1093/nar/gkx395S723772484512Shereda, R. D., Kozlov, A. G., Lohman, T. M., Cox, M. M., & Keck, J. L. (2008). SSB as an Organizer/Mobilizer of Genome Maintenance Complexes. Critical Reviews in Biochemistry and Molecular Biology, 43(5), 289-318. doi:10.1080/10409230802341296Flynn, R. L., & Zou, L. (2010). Oligonucleotide/oligosaccharide-binding fold proteins: a growing family of genome guardians. Critical Reviews in Biochemistry and Molecular Biology, 45(4), 266-275. doi:10.3109/10409238.2010.488216Murzin, A. G. (1993). OB(oligonucleotide/oligosaccharide binding)-fold: common structural and functional solution for non-homologous sequences. The EMBO Journal, 12(3), 861-867. doi:10.1002/j.1460-2075.1993.tb05726.xKozlov, A. G., Weiland, E., Mittal, A., Waldman, V., Antony, E., Fazio, N., … Lohman, T. M. (2015). Intrinsically Disordered C-Terminal Tails of E. coli Single-Stranded DNA Binding Protein Regulate Cooperative Binding to Single-Stranded DNA. Journal of Molecular Biology, 427(4), 763-774. doi:10.1016/j.jmb.2014.12.020Kuznetsov, S. V., Kozlov, A. G., Lohman, T. M., & Ansari, A. (2006). Microsecond Dynamics of Protein–DNA Interactions: Direct Observation of the Wrapping/Unwrapping Kinetics of Single-stranded DNA around the E.coli SSB Tetramer. Journal of Molecular Biology, 359(1), 55-65. doi:10.1016/j.jmb.2006.02.070Lohman, T. M., & Ferrari, M. E. (1994). Escherichia Coli Single-Stranded DNA-Binding Protein: Multiple DNA-Binding Modes and Cooperativities. Annual Review of Biochemistry, 63(1), 527-570. doi:10.1146/annurev.bi.63.070194.002523Maier, D., Farr, C. L., Poeck, B., Alahari, A., Vogel, M., Fischer, S., … Schneuwly, S. (2001). Mitochondrial Single-stranded DNA-binding Protein Is Required for Mitochondrial DNA Replication and Development in Drosophila melanogaster. Molecular Biology of the Cell, 12(4), 821-830. doi:10.1091/mbc.12.4.821Ruhanen, H., Borrie, S., Szabadkai, G., Tyynismaa, H., Jones, A. W. E., Kang, D., … Yasukawa, T. (2010). Mitochondrial single-stranded DNA binding protein is required for maintenance of mitochondrial DNA and 7S DNA but is not required for mitochondrial nucleoid organisation. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1803(8), 931-939. doi:10.1016/j.bbamcr.2010.04.008Farr, C. L., Matsushima, Y., Lagina, A. T., Luo, N., & Kaguni, L. S. (2004). Physiological and Biochemical Defects in Functional Interactions of Mitochondrial DNA Polymerase and DNA-binding Mutants of Single-stranded DNA-binding Protein. Journal of Biological Chemistry, 279(17), 17047-17053. doi:10.1074/jbc.m400283200Van Tuyle, G. C., & Pavco, P. A. (1985). The rat liver mitochondrial DNA-protein complex: displaced single strands of replicative intermediates are protein coated. The Journal of Cell Biology, 100(1), 251-257. doi:10.1083/jcb.100.1.251Clayton, D. A. (1982). Replication of animal mitochondrial DNA. Cell, 28(4), 693-705. doi:10.1016/0092-8674(82)90049-6Farr, C. L., Wang, Y., & Kaguni, L. S. (1999). Functional Interactions of Mitochondrial DNA Polymerase and Single-stranded DNA-binding Protein. Journal of Biological Chemistry, 274(21), 14779-14785. doi:10.1074/jbc.274.21.14779Korhonen, J. A., Gaspari, M., & Falkenberg, M. (2003). TWINKLE Has 5′ → 3′ DNA Helicase Activity and Is Specifically Stimulated by Mitochondrial Single-stranded DNA-binding Protein. Journal of Biological Chemistry, 278(49), 48627-48632. doi:10.1074/jbc.m306981200Miralles Fusté, J., Shi, Y., Wanrooij, S., Zhu, X., Jemt, E., Persson, Ö., … Falkenberg, M. (2014). In Vivo Occupancy of Mitochondrial Single-Stranded DNA Binding Protein Supports the Strand Displacement Mode of DNA Replication. PLoS Genetics, 10(12), e1004832. doi:10.1371/journal.pgen.1004832Oliveira, M. T., & Kaguni, L. S. (2011). Reduced Stimulation of Recombinant DNA Polymerase γ and Mitochondrial DNA (mtDNA) Helicase by Variants of Mitochondrial Single-stranded DNA-binding Protein (mtSSB) Correlates with Defects in mtDNA Replication in Animal Cells. Journal of Biological Chemistry, 286(47), 40649-40658. doi:10.1074/jbc.m111.289983Williams, A. J., & Kaguni, L. S. (1995). Stimulation ofDrosophilaMitochondrial DNA Polymerase by Single-stranded DNA-binding Protein. Journal of Biological Chemistry, 270(2), 860-865. doi:10.1074/jbc.270.2.860Bogenhagen, D. F., Wang, Y., Shen, E. L., & Kobayashi, R. (2003). Protein Components of Mitochondrial DNA Nucleoids in Higher Eukaryotes. Molecular & Cellular Proteomics, 2(11), 1205-1216. doi:10.1074/mcp.m300035-mcp200BARAT-GUERIDE, M., DUFRESNE, C., & RICKWOOD, D. (1989). Effect of DNA conformation on the transcription of mitochondrial DNA. European Journal of Biochemistry, 183(2), 297-302. doi:10.1111/j.1432-1033.1989.tb14928.xYang, C., Curth, U., Urbanke, C., & Kang, C. (1997). Crystal structure of human mitochondrial single-stranded DNA binding protein at 2.4 Å resolution. Nature Structural Biology, 4(2), 153-157. doi:10.1038/nsb0297-153Raghunathan, S., Ricard, C. S., Lohman, T. M., & Waksman, G. (1997). Crystal structure of the homo-tetrameric DNA binding domain of Escherichia coli single-stranded DNA-binding protein determined by multiwavelength x-ray diffraction on the selenomethionyl protein at 2.9-A resolution. Proceedings of the National Academy of Sciences, 94(13), 6652-6657. doi:10.1073/pnas.94.13.6652CURTH, U., URBANKE, C., GREIPEL, J., GERBERDING, H., TIRANTI, V., & ZEVIANI, M. (1994). Single-stranded-DNA-binding proteins from human mitochondria and Escherichia coli have analogous physicochemical properties. European Journal of Biochemistry, 221(1), 435-443. doi:10.1111/j.1432-1033.1994.tb18756.xOverman, L. B., & Lohman, T. M. (1994). Linkage of pH, Anion and Cation Effects in Protein-Nucleic Acid Equilibria. Journal of Molecular Biology, 236(1), 165-178. doi:10.1006/jmbi.1994.1126Bhattacharyya, B., George, N. P., Thurmes, T. M., Zhou, R., Jani, N., Wessel, S. R., … Keck, J. L. (2013). Structural mechanisms of PriA-mediated DNA replication restart. Proceedings of the National Academy of Sciences, 111(4), 1373-1378. doi:10.1073/pnas.1318001111Carlini, L. E., Porter, R. D., Curth, U., & Urbanke, C. (1993). Viability and preliminary in vivo characterization of site directed mutants of Escherichia coli single-stranded DNA-binding protein. Molecular Microbiology, 10(5), 1067-1075. doi:10.1111/j.1365-2958.1993.tb00977.xGriffith, J. D., Harris, L. D., & Register, J. (1984). Visualization of SSB-ssDNA Complexes Active in the Assembly of Stable RecA-DNA Filaments. Cold Spring Harbor Symposia on Quantitative Biology, 49(0), 553-559. doi:10.1101/sqb.1984.049.01.062Morrical, S. W., & Cox, M. M. (1990). Stabilization of recA protein-ssDNA complexes by the single-stranded DNA binding protein of Escherichia coli. Biochemistry, 29(3), 837-843. doi:10.1021/bi00455a034Muniyappa, K., Williams, K., Chase, J. W., & Radding, C. M. (1990). Active nucleoprotein filaments of single-stranded binding protein and recA protein on single-stranded DNA have a regular repeating structure. Nucleic Acids Research, 18(13), 3967-3973. doi:10.1093/nar/18.13.3967Wessel, S. R., Marceau, A. H., Massoni, S. C., Zhou, R., Ha, T., Sandler, S. J., & Keck, J. L. (2013). PriC-mediated DNA Replication Restart Requires PriC Complex Formation with the Single-stranded DNA-binding Protein. Journal of Biological Chemistry, 288(24), 17569-17578. doi:10.1074/jbc.m113.478156Bell, J. C., Liu, B., & Kowalczykowski, S. C. (2015). Imaging and energetics of single SSB-ssDNA molecules reveal intramolecular condensation and insight into RecOR function. eLife, 4. doi:10.7554/elife.08646Suksombat, S., Khafizov, R., Kozlov, A. G., Lohman, T. M., & Chemla, Y. R. (2015). Structural dynamics of E. coli single-stranded DNA binding protein reveal DNA wrapping and unwrapping pathways. eLife, 4. doi:10.7554/elife.08193Zhou, R., Kozlov, A. G., Roy, R., Zhang, J., Korolev, S., Lohman, T. M., & Ha, T. (2011). SSB Functions as a Sliding Platform that Migrates on DNA via Reptation. Cell, 146(2), 222-232. doi:10.1016/j.cell.2011.06.036Pant, K., Karpel, R. L., Rouzina, I., & Williams, M. C. (2004). Mechanical Measurement of Single-molecule Binding Rates: Kinetics of DNA Helix-destabilization by T4 Gene 32 Protein. Journal of Molecular Biology, 336(4), 851-870. doi:10.1016/j.jmb.2003.12.025Pant, K., Karpel, R. L., Rouzina, I., & Williams, M. C. (2005). Salt Dependent Binding of T4 Gene 32 Protein to Single and Double-stranded DNA: Single Molecule Force Spectroscopy Measurements. Journal of Molecular Biology, 349(2), 317-330. doi:10.1016/j.jmb.2005.03.065Robberson, D. L., & Clayton, D. A. (1972). Replication of Mitochondrial DNA in Mouse L Cells and Their Thymidine Kinase- Derivatives: Displacement Replication on a Covalently-Closed Circular Template. Proceedings of the National Academy of Sciences, 69(12), 3810-3814. doi:10.1073/pnas.69.12.3810Ciesielski, G. L., Bermek, O., Rosado-Ruiz, F. A., Hovde, S. L., Neitzke, O. J., Griffith, J. D., & Kaguni, L. S. (2015). Mitochondrial Single-stranded DNA-binding Proteins Stimulate the Activity of DNA Polymerase γ by Organization of the Template DNA. Journal of Biological Chemistry, 290(48), 28697-28707. doi:10.1074/jbc.m115.673707Lázaro, J. M., Blanco, L., & Salas, M. (1995). [5] Purification of bacteriophage φ29 DNA polymerase. DNA Replication, 42-49. doi:10.1016/0076-6879(95)62007-9Ibarra, B., Chemla, Y. R., Plyasunov, S., Smith, S. B., Lázaro, J. M., Salas, M., & Bustamante, C. (2009). Proofreading dynamics of a processive DNA polymerase. The EMBO Journal, 28(18), 2794-2802. doi:10.1038/emboj.2009.219Morin, J. A., Cao, F. J., Lazaro, J. M., Arias-Gonzalez, J. R., Valpuesta, J. M., Carrascosa, J. L., … Ibarra, B. (2012). Active DNA unwinding dynamics during processive DNA replication. Proceedings of the National Academy of Sciences, 109(21), 8115-8120. doi:10.1073/pnas.1204759109Smith, S. B., Cui, Y., & Bustamante, C. (2003). [7] Optical-trap force transducer that operates by direct measurement of light momentum. Biophotonics, Part B, 134-162. doi:10.1016/s0076-6879(03)61009-8Bosco, A., Camunas-Soler, J., & Ritort, F. (2013). Elastic properties and secondary structure formation of single-stranded DNA at monovalent and divalent salt conditions. Nucleic Acids Research, 42(3), 2064-2074. doi:10.1093/nar/gkt1089Smith, S., Finzi, L., & Bustamante, C. (1992). Direct mechanical measurements of the elasticity of single DNA molecules by using magnetic beads. Science, 258(5085), 1122-1126. doi:10.1126/science.1439819Longley, M. J., Smith, L. A., & Copeland, W. C. (2009). Preparation of Human Mitochondrial Single-Stranded DNA-Binding Protein. Mitochondrial DNA, 73-85. doi:10.1007/978-1-59745-521-3_5Li, K., & Williams, R. S. (1997). Tetramerization and Single-stranded DNA Binding Properties of Native and Mutated Forms of Murine Mitochondrial Single-stranded DNA-binding Proteins. Journal of Biological Chemistry, 272(13), 8686-8694. doi:10.1074/jbc.272.13.8686Jarillo, J., Morín, J. A., Beltrán-Heredia, E., Villaluenga, J. P. G., Ibarra, B., & Cao, F. J. (2017). Mechanics, thermodynamics, and kinetics of ligand binding to biopolymers. PLOS ONE, 12(4), e0174830. doi:10.1371/journal.pone.0174830Bujalowski, W., & Lohman, T. M. (1986). Escherichia coli single-strand binding protein forms multiple, distinct complexes with single-stranded DNA. Biochemistry, 25(24), 7799-7802. doi:10.1021/bi00372a003Thömmes, P., Farr, C. L., Marton, R. F., Kaguni, L. S., & Cotterill, S. (1995). Mitochondrial Single-stranded DNA-binding Protein fromDrosophilaEmbryos. Journal of Biological Chemistry, 270(36), 21137-21143. doi:10.1074/jbc.270.36.21137Rodriguez, I., Lazaro, J. M., Blanco, L., Kamtekar, S., Berman, A. J., Wang, J., … de Vega, M. (2005). A specific subdomain in  29 DNA polymerase confers both processivity and strand-displacement capacity. Proceedings of the National Academy of Sciences, 102(18), 6407-6412. doi:10.1073/pnas.0500597102Kamtekar, S., Berman, A. J., Wang, J., Lázaro, J. M., de Vega, M., Blanco, L., … Steitz, T. A. (2004). Insights into Strand Displacement and Processivity from the Crystal Structure of the Protein-Primed DNA Polymerase of Bacteriophage φ29. Molecular Cell, 16(4), 609-618. doi:10.1016/j.molcel.2004.10.019Chrysogelos, S., & Griffith, J. (1982). Escherichia coli single-strand binding protein organizes single-stranded DNA in nucleosome-like units. Proceedings of the National Academy of Sciences, 79(19), 5803-5807. doi:10.1073/pnas.79.19.5803Hamon, L., Pastre, D., Dupaigne, P., Breton, C. L., Cam, E. L., & Pietrement, O. (2007). High-resolution AFM imaging of single-stranded DNA-binding (SSB) protein--DNA complexes. Nucleic Acids Research, 35(8), e58-e58. doi:10.1093/nar/gkm147Takamatsu, C., Umeda, S., Ohsato, T., Ohno, T., Abe, Y., Fukuoh, A., … Kang, D. (2002). Regulation of mitochondrial D‐loops by transcription factor A and single‐stranded DNA‐binding protein. EMBO reports, 3(5), 451-456. doi:10.1093/embo-reports/kvf099Wang, Y., & Bogenhagen, D. F. (2006). Human Mitochondrial DNA Nucleoids Are Linked to Protein Folding Machinery and Metabolic Enzymes at the Mitochondrial Inner Membrane. Journal of Biological Chemistry, 281(35), 25791-25802. doi:10.1074/jbc.m604501200Brown, T. A. (2005). Replication of mitochondrial DNA occurs by strand displacement with alternative light-strand origins, not via a strand-coupled mechanism. Genes & Development, 19(20), 2466-2476. doi:10.1101/gad.135210

Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma

In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2(-/-)γc(-/-) mice and of murine B220(+)IgM(+) B-cell lymphomas generated in Eμ-MYC and Eμ-MYC-BIM(+/-) transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL

Diagnóstico no invasivo de amiloidosis cardiaca por transtirretina. Caso clínico

La amiloidosis cardiaca por transtirretina se considera en la actualidad la forma más frecuente de amiloidosis cardiaca y su incidencia está aumentando gracias al avance de las técnicas de diagnóstico por imagen. Recientemente se han publicado unos criterios de diagnóstico no invasivo para esta entidad, y se están desarrollando nuevos fármacos para el tratamiento específico de este tipo de amiloidosis cardiaca. Por ello, la amiloidosis cardiaca por transtirretina podría pasar de ser una enfermedad rara a frecuente, y de incurable a potencialmente tratable. Presentamos el caso de un varón de 80 años diagnosticado de amiloidosis cardiaca mediante gammagrafía con 99mTc dicarboxipropano difosfonato (99mTc- DPD) según los nuevos criterios de diagnóstico no invasivo. Amyloidosis due to deposits of transthyretin (ATTR) is currently considered the most frequent form of cardiac amyloidosis and its incidence is increasing thanks to the advances in diagnostic imaging techniques. Some non-invasive diagnostic criteria have recently been published on this entity that due to the development of new drugs for the specific treatment of cardiac ATTR, have prognostic and therapeutic implications. That is why cardiac ATTR could cease to be a rare disease and become a frequent one, and become potentially treatable instead of incurable. We present the case of an 80-year-old male diagnosed with non-hereditary cardiac ATTR by means of gammagraphy with 99mTc diphosfonate scintigraphy (99mTc-DPD) following the new criteria of non-invasive diagnosis

Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas

Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes

Evaluation of different bowel preparations for small bowel capsule endoscopy: a prospective, randomized, controlled study

To obtain an adequate view of the whole small intestine during capsule endoscopy (CE) a clear liquid diet and overnight fasting is recommended. However, intestinal content can hamper vision in spite of these measures. Our aim was to evaluate tolerance and degree of intestinal cleanliness during CE following three types of bowel preparation. PATIENTS AND METHODS: This was a prospective, multicenter, randomized, controlled study. Two-hundred ninety-one patients underwent one of the following preparations: 4 L of clear liquids (CL) (group A; 92 patients); 90 mL of aqueous sodium phosphate (group B; 89 patients); or 4 L of a polyethylene glycol electrolyte solution (group C; 92 patients). The degree of cleanliness of the small bowel was classified by blinded examiners according to four categories (excellent, good, fair or poor). The degree of patient satisfaction, gastric and small bowel transit times, and diagnostic yield were measured. RESULTS: The degree of cleanliness did not differ significantly between the groups (P = 0.496). Interobserver concordance was fair (k = 0.38). No significant differences were detected between the diagnostic yields of the CE (P = 0.601). Gastric transit time was 35.7 +/- 3.7 min (group A), 46.1 +/- 8.6 min (group B) and 34.6 +/- 5.0 min (group C) (P = 0.417). Small-intestinal transit time was 276.9 +/- 10.7 min (group A), 249.7 +/- 13.1 min (group B) and 245.6 +/- 11.6 min (group C) (P = 0.120). CL was the best tolerated preparation. Compliance with the bowel preparation regimen was lowest in group C (P = 0.008). CONCLUSIONS: A clear liquid diet and overnight fasting is sufficient to achieve an adequate level of cleanliness and is better tolerated by patients than other forms of preparation

A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma

The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G(1)-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1-expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1-expressing tumors