Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia

<p>Abstract</p> <p>Background</p> <p>To elucidate the genes involved in the neoplastic transformation of B cells, global gene expression profiles were generated using Affymetrix U74Av2 microarrays, containing 12,488 genes, for four different groups of mouse B-cell lymphomas and six subtypes of pristane-induced mouse plasma cell tumors, three of which developed much earlier than the others.</p> <p>Results</p> <p>Unsupervised hierarchical cluster analysis exhibited two main sub-clusters of samples: a B-cell lymphoma cluster and a plasma cell tumor cluster with subclusters reflecting mechanism of induction. This report represents the first step in using global gene expression to investigate molecular signatures related to the role of cooperating oncogenes in a model of Myc-induced carcinogenesis. Within a single subgroup, e.g., ABPCs, plasma cell tumors that contained typical T(12;15) chromosomal translocations did not display gene expression patterns distinct from those with variant T(6;15) translocations, in which the breakpoint was in the <it>Pvt-1 </it>locus, 230 kb 3' of c-<it>Myc</it>, suggesting that c-<it>Myc </it>activation was the initiating factor in both. When integrated with previously published Affymetrix array data from human multiple myelomas, the IL-6-transgenic subset of mouse plasma cell tumors clustered more closely with MM1 subsets of human myelomas, slow-appearing plasma cell tumors clustered together with MM2, while plasma cell tumors accelerated by v-Abl clustered with the more aggressive MM3-MM4 myeloma subsets. Slow-appearing plasma cell tumors expressed <it>Socs1 </it>and <it>Socs2 </it>but v-<it>Abl</it>-accelerated plasma cell tumors expressed 4–5 times as much. Both v-<it>Abl</it>-accelerated and non-v-<it>Ab</it>l-associated tumors exhibited phosphorylated STAT 1 and 3, but only v-Abl-accelerated plasma cell tumors lost viability and STAT 1 and 3 phosphorylation when cultured in the presence of the v-Abl kinase inhibitor, STI-571. These data suggest that the Jak/Stat pathway was critical in the transformation acceleration by v-Abl and that v-Abl activity remained essential throughout the life of the tumors, not just in their acceleration. A different pathway appears to predominate in the more slowly arising plasma cell tumors.</p> <p>Conclusion</p> <p>Gene expression profiling differentiates not only B-cell lymphomas from plasma cell tumors but also distinguishes slow from accelerated plasma cell tumors. These data and those obtained from the sensitivity of v-Abl-accelerated plasma cell tumors and their phosphorylated STAT proteins indicate that these similar tumors utilize different signaling pathways but share a common initiating genetic lesion, a c-<it>Myc</it>-activating chromosome translocation.</p

Activity and Interactions of Liposomal Antibiotics in Presence of Polyanions and Sputum of Patients with Cystic Fibrosis

BACKGROUND:To compare the effectiveness of liposomal tobramycin or polymyxin B against Pseudomonas aeruginosa in the Cystic Fibrosis (CF) sputum and its inhibition by common polyanionic components such as DNA, F-actin, lipopolysaccharides (LPS), and lipoteichoic acid (LTA). METHODOLOGY:Liposomal formulations were prepared from a mixture of 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) or 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and Cholesterol (Chol), respectively. Stability of the formulations in different biological milieus and antibacterial activities compared to conventional forms in the presence of the aforementioned inhibitory factors or CF sputum were evaluated. RESULTS:The formulations were stable in all conditions tested with no significant differences compared to the controls. Inhibition of antibiotic formulations by DNA/F-actin and LPS/LTA was concentration dependent. DNA/F-actin (125 to 1000 mg/L) and LPS/LTA (1 to 1000 mg/L) inhibited conventional tobramycin bioactivity, whereas, liposome-entrapped tobramycin was inhibited at higher concentrations--DNA/F-actin (500 to 1000 mg/L) and LPS/LTA (100 to 1000 mg/L). Neither polymyxin B formulation was inactivated by DNA/F-actin, but LPS/LTA (1 to 1000 mg/L) inhibited the drug in conventional form completely and higher concentrations of the inhibitors (100 to 1000 mg/L) was required to inhibit the liposome-entrapped polymyxin B. Co-incubation with inhibitory factors (1000 mg/L) increased conventional (16-fold) and liposomal (4-fold) tobramycin minimum bactericidal concentrations (MBCs), while both polymyxin B formulations were inhibited 64-fold. CONCLUSIONS:Liposome-entrapment reduced antibiotic inhibition up to 100-fold and the CFU of endogenous P. aeruginosa in sputum by 4-fold compared to the conventional antibiotic, suggesting their potential applications in CF lung infections

Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma

Cyclooxygenase 2 (Cox-2) is upregulated in colorectal adenomas and carcinomas. Polymorphisms in the Cox-2 gene may influence its function and/or its expression and may modify the protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs), thereby impacting individuals' risk of developing colorectal cancer and response to prevention/intervention strategies. In a nested case–control study, four polymorphisms in the Cox-2 gene (two in the promoter, −663 insertion/deletion, GT/(GT) and −798 A/G; one in intron 5-5229, T/G; one in 3′untranslated region (UTR)-8494, T/C) were genotyped in 726 cases of colorectal adenomas and 729 age- and gender-matched controls in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. There was no significant association between the Cox-2 polymorphisms and adenoma development in the overall population. However, in males, the relatively rare heterozygous genotype GT/(GT) at −663 in the promoter and the variant homozygous genotype G/G at intron 5-5229 appeared to have inverse associations (odds ratio (OR)=0.59, confidence interval (CI): 0.34–1.02 and OR=0.48, CI: 0.24–0.99, respectively), whereas the heterozygous genotype T/C at 3′UTR-8494 had a positive association (OR=1.31, CI: 1.01–1.71) with adenoma development. Furthermore, the haplotype carrying the risk-conferring 3′UTR-8494 variant was associated with a 35% increase in the odds for adenoma incidence in males (OR=1.35, CI: 1.07–1.70), but the one with a risk allele at 3′UTR-8494 and a protective allele at intron 5-5229 had no effect on adenoma development (OR=0.85, CI: 0.66–1.09). Gender-related differences in adenoma risk were also noted with tobacco usage and protective effects of NSAIDs. Our analysis underscores the significance of the overall allelic architecture of Cox-2 as an important determinant for risk assessment

Association of shared decision-making with type of breast cancer surgery: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Although some studies examined the association between shared decision-making (SDM) and type of breast cancer surgery received, it is little known how treatment decisions might be shaped by the information provided by physicians. The purpose of this study was to identify the associations between shared decision making (SDM) and surgical treatment received.</p> <p>Methods</p> <p>Questionnaires on SDM were administered to 1,893 women undergoing primary curative surgery for newly diagnosed stage 0-II localized breast cancer at five hospitals in Korea. Questions included being informed on treatment options and the patient's own opinion in decision-making.</p> <p>Results</p> <p>Patients more likely to undergo mastectomy were those whose opinions were respected in treatment decisions (adjusted odds ratio, aOR), 1.40; 95% confidence interval (CI), 1.14-1.72) and who were informed on chemotherapy (aOR, 2.57; CI, 2.20-3.01) or hormone therapy (aOR, 2.03; CI, 1.77-2.32). In contrast, patients less likely to undergo mastectomy were those who were more informed on breast surgery options (aOR, 0.34; CI, 0.27-0.42). In patients diagnosed with stage 0-IIa cancer, clinical factors and the provision of information on treatment by the doctor were associated with treatment decisions. In patients diagnosed with stage IIb cancer, the patient's opinion was more respected in treatment decisions.</p> <p>Conclusion</p> <p>Our population-based study suggested that women's treatment decisions might be shaped by the information provided by physicians, and that women might request different information from their physicians based on their preferred treatment options. These results might need to be confirmed in other studies of treatment decisions.</p

Choline transporter gene variation is associated with attention-deficit hyperactivity disorder

The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer’s Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Disorder (ADHD). The presynaptic choline transporter (CHT, SLC5A7) is the major, rate-limiting determinant of ACh production in the brain and periphery and is consequently upregulated during tasks that require sustained attention. Given the contribution of central cholinergic circuits to the control of movement and attention, we hypothesized that functional CHT gene variants might impact risk for ADHD. We performed a case-control study, followed by family-based association tests on a separate cohort, of two purportedly functional CHT polymorphisms (coding variant Ile89Val (rs1013940) and a genomic SNP 3’ of the CHT gene (rs333229), affording both a replication sample and opportunities to reduce potential population stratification biases. Initial genotyping of pediatric ADHD subjects for two purportedly functional CHT alleles revealed a 2–3 fold elevation of the Val89 allele (n = 100; P = 0.02) relative to healthy controls, as well as a significant decrease of the 3’SNP minor allele in Caucasian male subjects (n = 60; P = 0.004). In family based association tests, we found significant overtransmission of the Val89 variant to children with a Combined subtype diagnosis (OR = 3.16; P = 0.01), with an increased Odds Ratio for a haplotype comprising both minor alleles. These studies show evidence of cholinergic deficits in ADHD, particularly for subjects with the Combined subtype, and, if replicated, may encourage further consideration of cholinergic agonist therapy in the disorder

Influence of amyloglucosidase in bread crust properties

Enzymes are used in baking as a useful tool for improving the processing behavior or properties of baked products. A number of enzymes have been proposed for improving specific volume, imparting softness, or extend the shelf life of breads, but scarce studies have been focused on bread crust. The aim of this study was to determine the use of amyloglucosidase for modulating the properties of the bread crust and increase its crispness. Increasing levels of enzyme were applied onto the surface of two different partially bake breads (thin and thick crust bread). Amyloglucosidase treatment affected significantly (P<0.05) the color of the crust and decreased the moisture content and water activity of the crusts. Mechanical properties were modified by amyloglucosidase, namely increasing levels of enzyme promoted a decrease in the force (Fm) required for crust rupture and an increase in the number of fracture events (Nwr) related to crispy products. Crust microstructure analysis confirmed that enzymatic treatment caused changes in the bread crust structure, leading to a disruption of the structure, by removing the starchy layer that covered the granules and increasing the number of voids, which agree with the texture fragility.Authors acknowledge the financial support of Spanish Ministry of Economy and Sustainability (Project AGL2011-23802), the European Regional Development Fund (FEDER), Generalitat Valenciana (Project Prometeo 2012/064) and the Consejo Superior de Investigaciones Cientificas (CSIC). R. Altamirano-Fortoul would like to thank her grant to CSIC. The authors also thank Forns Valencians S. A. (Spain) for supplying commercial frozen partially baked breads.Altamirano Fortoul, RDC.; Hernando Hernando, MI.; Molina Rosell, MC. (2014). Influence of amyloglucosidase in bread crust properties. Food and Bioprocess Technology. 7(4):1037-1046. https://doi.org/10.1007/s11947-013-1084-xS1037104674Altamirano-Fortoul R, Hernando I & Rosell CM (2013) Texture of bread crust: puncturing settings effect and its relationship to microstructure. Journal of Texture Studies. doi: 10.1111/j.1745-4603.2012.00368.x .Altamirano-Fortoul, R., Le Bail, A., Chevallier, S., & Rosell, C. M. (2012). Effect of the amount of steam during baking on bread crust features and water diffusion. Journal of Food Engineering, 108, 128–134.Altamirano-Fortoul R & Rosell CM (2010) Alternatives for extending crispiness of crusty breads. In Proceedings of International Conference on Food Innovation, FoodInnova, 25–29 October 2010, Valencia, Spain. ISBN978-84-693-5011-.9.Arimi, J. M., Duggan, E., O’sullivan, M., Lyng, J. G., & O’riordan, E. D. (2010). Effect of water activity on the crispiness of a biscuit (crackerbread): mechanical and acoustic evaluation. Food Research International, 43, 1650–1655.Castro-Prada, E. M., Primo-Martin, C., Meinders, M. B. J., Hamer, R. J., & Van Vliet, T. (2009). Relationship between water activity, deformation speed, and crispness characterization. Journal of Texture Studies, 40, 127–156.Esveld, D. C., Van Der Sman, R. G. M., Van Dalen, G., Van Duynhoven, J. P. M., & Meinders, M. B. J. (2012). Effect of morphology on water sorption in cellular solid foods. Part I: Pore Scale Network Model. Journal of Food Engineering, 109, 301–310.Goedeken, D. L., & Tong, C. H. (1993). Permeability measurements of porous food materials. Journal of Food Science, 58, 1329–1331.Gondek, E., Lewicki, P. P., & Ranachowski, Z. (2006). Influence of water activity on the acoustic properties of breakfast cereals. Journal of Texture Studies, 37, 497–515.Guerrieri, N., Eynard, L., Lavelli, V., & Cerletti, P. (1997). Interactions of protein and starch studied through amyloglucosidase action. Cereal Chemistry, 74, 846–850.ICC. (1994). Standard methods of the International Association for Cereal Science and Technology. Vienna: Austria.Heenan, S. P., Dufour, J. P., Hamid, N., Harvey, W., & Delahunty, C. M. (2008). The sensory quality of fresh bread: descriptive attributes and consumer perceptions. Food Research International, 41, 989–997.Heiniö, R. L., Nordlund, E., Poutanen, K., & Buchert, J. (2012). Use of enzymes to elucidate the factors contributing to bitterness in rye flavor. Food Research International, 45, 31–38.Hug-Iten, S., Escher, F., & Conde-Petit, B. (2003). Staling of bread: role of amylose and amylopectin and influence of starch-degrading enzymes. Cereal Chemistry., 80(6), 654–661.Jakubczyk, E., Marzec, A., & Lewicki, P. P. (2008). Relationship between water activity of crisp bread and its mechanical properties and structure. Polish Journal of Food and Nutrition Sciences, 58(1), 45–51.Luyten, A., Pluter, J. J., & Van Vliet, T. (2004). Crispy/crunchy crusts of cellular solid foods: a literature review with discussion. Journal of Texture Studies, 35, 445–492.Potter, N. N., & Hotchkiss, J. H. (1998). Food dehydration and concentration. In N. N. Potter & J. H. Hotchkiss (Eds.), Food Science (5th ed.). New York: Aspen Publishers.Primo-Martin, C., Van de Pijpekamp, A., Van Vliet, T., Jongh, H. H. J., Plijter, J. J., & Hamer, R. J. (2006). The role of the gluten network in the crispness of bread crust. Journal of Cereal Science, 43, 342–352.Primo-Martin, C., Sozer, N., Hamer, R. J., & Van Vliet, T. (2009). Effect of water activity on fracture and acoustic characteristics of a crust model. Journal of Food Engineering, 90, 277–284.Roudaut, G., Dacremont, C., & Le Meste, M. (1998). Influence of water on the crispness of cereal-based foods: acoustic, mechanical, and sensory studies. Journal of Texture Studies, 29, 199–213.Roudaut, G., Dacremont, C., Pamies, B. V., Colas, B., & Le Meste, M. (2002). Crispness: a critical review on sensory and material science approaches. Trends in Food Science and Technology, 13, 217–227.Rojas JA (2000) Uso combinado de hidrocoloides y alfa-amilasa como mejorantes en panificación. Dissertation PhD Thesis. Universidad Politécnica de ValenciaRosell, C. M. (2007). Vitamin and mineral fortification of bread. In B. Hamaker (Ed.), Technology of functional cereal products. Cambridge: Woodhead Publishing Ltd.Rosell, C. M. (2011). The science of doughs and bread quality. In V. R. Preedy, R. R. Watson, & V. B. Patel (Eds.), Flour and breads and their fortification in health and disease prevention (pp. 3–14). London: Academic.Rosell CM, Altamirano-Fortoul R & Hernando I (2011) Mechanical properties of bread crust by puncture test and the effect of sprayed enzymes. In: Proceedings of 6th International Congress Flour. Bread’11, 8th Croatian Congress of Cereal Technologist, 12–14 October 2011, Opatija, Croatia. ISSN 1848–2562.Sahlström, S., & Brathen, E. (1997). Effects of enzyme preparations for baking, mixing time and resting time on bread quality and bread staling. Food Chemistry, 58, 75–80.Sharma K & Singh J (2010) Enzymes in baking industry. Panesar, P.S.; Marwaha, S.S and Chopra, H.K. (Eds), Enzymes in food processing, fundamentals and potential applications, IK International Publishing House Pvt. Ltd, New Delhi, India.Stokes, D. J., & Donald, A. M. (2000). In situ mechanical testing of dry and hydrated breadcrumb in the environmental scanning electron microscope (ESEM). Journal of Materials Science, 35, 599–607.Tsukakoshi, Y., Naito, S., & Ishida, N. (2008). Fracture intermittency during a puncture test of cereal snacks and its relation to porous structure. Food Research International, 41, 909–917.Van Benschop CHM, Terdu AG & Hille JDR (2012) Baking enzyme composition as SSL replacer. Patent No.US2012164272.Van Eijk JH (1991) Retarding the firming of bread crumb during storage. Patent No. US5023094.Van Hecke, E., Allaf, K., & Bouvier, J. M. (1998). Texture and structure of crispy-puffed food products—part II: mechanical properties in puncture. Journal of Texture Studies, 29, 617–632.Vanin, F. M., Lucas, T., & Trystram, G. (2009). Crust formation and its role during bread baking. Trends in Food Science and Technology, 20, 333–343.Van Nieuwenhuijzen, N. H., Primo-Martin, C., Meinders, M. B. J., Tromp, R. H., Hamer, R. J., & Van Vliet, T. (2008). Water content or water activity: what rules crispy behavior in bread crust? Journal of Agricultural and Food Chemistry, 56, 6432–6438.Van Oort, M. (2010). Enzymes in bread making. In R. J. Whitehurst & M. Van Oort (Eds.), Enzymes in food technology (2nd ed.). Iowa: Wiley-Blackwell.Vidal, F.D., Guerrety, A.B. (1979) Antistaling agent for bakery products. Patent No. US54160848.Wählby, U., & Skjoldebrand, C. (2002). Reheating characteristic of crust formed on buns, and crust formation. Journal of Food Engineering, 53, 177–184.Würsch, P., & Gumy, D. (1994). Inhibition of amylopectin retrogradation by partial beta-amylosis. Carbohydrate Research, 256, 129–137.Xiong, X., Narsimhan, G., & Okos, M. R. (1991). Effect of composition and pore structure on binding energy and effective diffusivity of moisture in porous foods. Journal of Food Engineering, 15, 187–208

Metal-Substituted Microporous Aluminophosphates

This chapter aims to present the zeotypes aluminophosphates (AlPOs) as a complementary alternative to zeolites in the isomorphic incorporation of metal ions within all-inorganic microporous frameworks as well as to discuss didactically the catalytic consequences derived from the distinctive features of both frameworks. It does not intend to be a compilation of either all or the most significant publications involving metal-substituted microporous aluminophosphates. Families of AlPOs and zeolites, which include metal ion-substituted variants, are the dominant microporous materials. Both these systems are widely used as catalysts, in particular through aliovalent metal ions substitution. Here, some general description of the synthesis procedures and characterization techniques of the MeAPOs (metal-contained aluminophosphates) is given along with catalytic properties. Next, some illustrative examples of the catalytic possibilities of MeAPOs as catalysts in the transformation of the organic molecules are given. The oxidation of the hardly activated hydrocarbons has probably been the most successful use of AlPOs doped with the divalent transition metal ions Co2+, Mn2+, and Fe2+, whose incorporation in zeolites is disfavoured. The catalytic role of these MeAPOs is rationalized based on the knowledge acquired from a combination of the most advanced characterization techniques. Finally, the importance of the high specificity of the structure-directing agents employed in the preparation of MeAPOs is discussed taking N,N-methyldicyclohexylamine in the synthesis of AFI-structured materials as a driving force. It is shown how such a high specificity could be predicted and how it can open great possibilities in the control of parameters as critical in catalysis as crystal size, inter-and intracrystalline mesoporosity, acidity, redox properties, incorporation of a great variety of heteroatom ions or final environment of the metal site (surrounding it by either P or Al)

Measurement and interpretation of same-sign W boson pair production in association with two jets in pp collisions at s = 13 TeV with the ATLAS detector

This paper presents the measurement of fducial and diferential cross sections for both the inclusive and electroweak production of a same-sign W-boson pair in association with two jets (W±W±jj) using 139 fb−1 of proton-proton collision data recorded at a centre-of-mass energy of √s = 13 TeV by the ATLAS detector at the Large Hadron Collider. The analysis is performed by selecting two same-charge leptons, electron or muon, and at least two jets with large invariant mass and a large rapidity diference. The measured fducial cross sections for electroweak and inclusive W±W±jj production are 2.92 ± 0.22 (stat.) ± 0.19 (syst.)fb and 3.38±0.22 (stat.)±0.19 (syst.)fb, respectively, in agreement with Standard Model predictions. The measurements are used to constrain anomalous quartic gauge couplings by extracting 95% confdence level intervals on dimension-8 operators. A search for doubly charged Higgs bosons H±± that are produced in vector-boson fusion processes and decay into a same-sign W boson pair is performed. The largest deviation from the Standard Model occurs for an H±± mass near 450 GeV, with a global signifcance of 2.5 standard deviations