Clinical experience with the novel histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in patients with relapsed lymphoma

Preclinical studies indicate that vorinostat (suberoylanilide hydroxamic acid or SAHA) inhibits histone deacetylase (HDAC) activity, increases acetylated histones H2a, H2b, H3, and H4, and thereby induces differentiation and apoptosis in a variety of tumour cell lines, including murine erythroleukaemia, human bladder transitional cell carcinoma, and human breast adenocarcinoma. On the basis of these favourable preclinical findings, vorinostat has been selected as a candidate for clinical development with the potential to treat patients with selected malignances, including Hodgkin's disease and non-Hodgkin's lymphomas. Phase I clinical trials in patients with haematological malignances and solid tumours showed that both intravenous (i.v.) and oral formulations of vorinostat are well tolerated, can inhibit HDAC activity in peripheral blood mononuclear cells and tumour tissue biopsies, and produce objective tumour regression and symptomatic improvement with little clinical toxicity. The dose-limiting toxicities (DLT) of i.v. vorinostat were primarily haematologic and were rapidly reversible within 4–5 days of therapy cessation. In contrast, the DLT for oral vorinostat were primarily non-haematologic (including dehydration, anorexia, diarrhoea, fatigue) and were also rapidly reversible, usually within 3 days. Further research is warranted to optimise the dosing schedule for vorinostat, particularly with respect to dose, timing of administration, and duration of therapy, and to fully delineate the mechanism(s) of antitumour effect of vorinostat in various types of malignances. Several phase II studies are currently ongoing in patients with haematological malignances and solid tumours

Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys

We transplanted kidneys from α1,3-galactosyltransferase knockout (GalT-KO) pigs into six baboons using two different immunosuppressive regimens, but most of the baboons died from severe acute humoral xenograft rejection. Circulating induced antibodies to non-Gal antigens were markedly elevated at rejection, which mediated strong complement-dependent cytotoxicity against GalT-KO porcine target cells. These data suggest that antibodies to non-Gal antigens will present an additional barrier to transplantation of organs from GalT-KO pigs to humans. © 2005 Nature Publishing Group

Urinary biomarker concentrations of captan, chlormequat, chlorpyrifos and cypermethrin in UK adults and children living near agricultural land

There is limited information on the exposure to pesticides experienced by UK residents living near agricultural land. This study aimed to investigate their pesticide exposure in relation to spray events. Farmers treating crops with captan, chlormequat, chlorpyrifos or cypermethrin provided spray event information. Adults and children residing ≤100 m from sprayed fields provided first-morning void urine samples during and outwith the spray season. Selected samples (1–2 days after a spray event and at other times (background samples)) were analysed and creatinine adjusted. Generalised Linear Mixed Models were used to investigate if urinary biomarkers of these pesticides were elevated after spray events. The final data set for statistical analysis contained 1518 urine samples from 140 participants, consisting of 523 spray event and 995 background samples which were analysed for pesticide urinary biomarkers. For captan and cypermethrin, the proportion of values below the limit of detection was greater than 80%, with no difference between spray event and background samples. For chlormequat and chlorpyrifos, the geometric mean urinary biomarker concentrations following spray events were 15.4 μg/g creatinine and 2.5 μg/g creatinine, respectively, compared with 16.5 μg/g creatinine and 3.0 μg/g creatinine for background samples within the spraying season. Outwith the spraying season, concentrations for chlorpyrifos were the same as those within spraying season backgrounds, but for chlormequat, lower concentrations were observed outwith the spraying season (12.3 μg/g creatinine). Overall, we observed no evidence indicative of additional urinary pesticide biomarker excretion as a result of spray events, suggesting that sources other than local spraying are responsible for the relatively low urinary pesticide biomarkers detected in the study population

Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma

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The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

Association study of genetic variants of pro-inflammatory chemokine and cytokine genes in systemic lupus erythematosus

BACKGROUND: Several lines of evidence suggest that chemokines and cytokines play an important role in the inflammatory development and progression of systemic lupus erythematosus. The aim of this study was to evaluate the relevance of functional genetic variations of RANTES, IL-8, IL-1α, and MCP-1 for systemic lupus erythematosus. METHODS: The study was conducted on 500 SLE patients and 481 ethnically matched healthy controls. Genotyping of polymorphisms in the RANTES, IL-8, IL-1α, and MCP-1 genes were performed using a real-time polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. RESULTS: No significant differences between SLE patients and healthy controls were observed when comparing genotype, allele or haplotype frequencies of the RANTES, IL-8, IL-1α, and MCP-1 polymorphisms. In addition, no evidence for association with clinical sub-features of SLE was found. CONCLUSION: These results suggest that the tested functional variation of RANTES, IL-8, IL-1α, and MCP-1 genes do not confer a relevant role in the susceptibility or severity of SLE in the Spanish population

Self-similar extinction for a diffusive Hamilton-Jacobi equation with critical absorption

International audienceThe behavior near the extinction time is identified for non-negative solutions to the diffusive Hamilton-Jacobi equation with critical gradient absorption ∂_t u − ∆_p u + |∇u|^{p−1} = 0 in (0, ∞) × R^N , and fast diffusion 2N/(N + 1) < p < 2. Given a non-negative and radially symmetric initial condition with a non-increasing profile which decays sufficiently fast as |x| → ∞, it is shown that the corresponding solution u to the above equation approaches a uniquely determined separate variable solution of the form U (t, x) = (T_e − t)^{1/(2−p)} f_* (|x|), (t, x) ∈ (0, T_e) × R^N , as t → T_e , where T_e denotes the finite extinction time of u. A cornerstone of the convergence proof is an underlying variational structure of the equation. Also, the selected profile f_* is the unique non-negative solution to a second order ordinary differential equation which decays exponentially at infinity. A complete classification of solutions to this equation is provided, thereby describing all separate variable solutions of the original equation. One important difficulty in the uniqueness proof is that no monotonicity argument seems to be available and it is overcome by the construction of an appropriate Pohozaev functional

What are the competences in information system required by managers? Curriculum development for management and public administration degrees

[EN] This paper analyzes the competences required by executives to manage information system, and consequently, the competences that must define the information system subjects in non-technical degrees, degrees, such as Public Administration or Business Management. This work reviews the literature about business managers competences on Information Technologies (IT) and compares the theory with the traditional body of knowledge about information systems taught at business schools. By analyzing the executives function, their role in the information system management, and, above, all the importance of their decisions in the effective integration of IT in business processes, this work proposes specific development in seven knowledge areas that facilitate the acquisition of these types of executive competencesDevece Carañana, CA.; Peris-Ortiz, M.; Rueda Armengot, C. (2016). What are the competences in information system required by managers? Curriculum development for management and public administration degrees. Technology, Innovation and Education. 2(10):1-9. doi:10.1186/s40660-016-0016-2S19210Bassellier G, Benbasat I (2004) Business competence of IT professionals: conceptual development and influence on IT-business partnerships. MIS Q 28(4):673–694Bassellier G, Reich BH, Benbasat I (2001) Information technology competence of business managers: a definition and research model. J Manag Inf Syst 17(4):159–182Bassellier G, Benbasat I, Reich BH (2003) The influence of business managers’ IT competence on championing IT. Inf Syst Res 14(4):317–336Bettiol M, Di Maria E, Finotto V (2012) Marketing in SMEs: the role of entrepreneurial sensemaking. Int Entrep Manag J 8(2):223–248Boyatzis RE (1982) The competent manager a model for effective performance. Wiley, New YorkBoynton AC, Zmud RW, Jacobs GC (1994) The influence of IT management practice on IT use in large organizations. MIS Q 18(3):299–318Broadbent M, Weill P (1993) Improving business and information strategy alignment: learning from the banking industry. IBM Syst J 32(1):162–179Brown CV, Magill SL (1994) Alignment of the IS functions with the enterprise: toward a model of antecedents. MIS Q 18(4):371–403Busch EA, Jarvenpaa SL, Tractinsky N, Glick WH (1991) External versus internal perspectives in determining a firm’s progressive use of information technology. Proceedings of the 12th International Conference on Information Systems, New York, 1991:239–250Camisón C (2002) On the relevance of industry, competitive scope, strategic group, size and distinctive competences construct on explaining of organizational performance. Universitat jaume I, Castellón (Working Paper 1–02,Research Group on Strategy, Knowledge Management and Organizational Learning)Castanias RP, Helfat CE (1991) Managerial resources and rents. J Manag 17:155–171Cegarra-Navarro JG, Sánchez-Vidal ME, Cegarra-Leiva D (2011) Balancing exploration and exploitation of knowledge through an unlearning context: an empirical investigation in SMEs. Manag Decis 49(7):1099–1119Chan YE, Reich BH (2007) IT alignment: what have we learned? J Inf Tech 22:297–315Chan YE, Sabherwal R, Thatcher JB (2006) Antecedents and outcomes of strategic IS alignment: an empirical investigation. IEEE Trans Eng Manag 51(3):27–47Croteau AM, Bergeron F (2001) An information technology trilogy: business strategy, technological deployment and organizational performance. J Strateg Inf Syst 10:77–99Crowston K, Myers MD (2004) Information technology and the transformation of industries: three research perspectives. J Strateg Inf Syst 13(1):5–28Dent-Micallef A, Powell T (1998) Technologies de l’information: nécessités stratégiques ou sources d’avantage concurrentiel? Une étude empirique dans le secteur de la distribution aux Etats-Unis. Rev Can Sci Adm 15(1):39–64Devece C (2013) The value of business managers’ ‘information technology’ competence. Serv Ind J 33(7/8):720–733Doll WJ, Torkzadeh G (1987) The relationship of MIS steering committee to size of firm and formalization of mis planning. Commun ACM 30(11):972–978Earl MJ (1996) The risks of outsourcing IT. Sloan Manag Rev 37(3):26–32European Commission (2015) ECTS Users’ Guide 2015. Publications Office of the European Union, Luxembourg. doi: 10.2766/87592Hambrick DC, Brandon G (1988) Executive values. In: Hambrick DC (ed) The executive effect: concepts and methods for studying top managers. JAI Press, GreenwichHambrick DC, Mason PA (1984) Upper echelons: the organization as a reflection of its top managers. Acad Manag Rev 9(2):193–206Hotho S, Champion K (2011) Small businesses in the new creative industries: innovation as a people management challenge. Manag Decis 49(1):29–54Jarvenpaa SL, Ives B (1991) Executive involment and participation in the management of IT. MIS Q 15(2):52–69Lado AA, Wilson MC (1994) Human resource systems and sustained competitive advantage: a competency-based perspective. Acad Manag Rev 19(4):699–727Lado AA, Boyd NG, Wright P (1992) A competency-based model of sustainable competitive advantage: toward a conceptual integration. J Manag 18(1):77–91Lederer AL, Mendelow AL (1988) Information systems planning: top management takes control. Bus Horiz 31(3):73–78Oh W, Pinsonneault A (2007) On the assessment of the strategic value of information technologies: conceptual and analytical approaches. MIS Q 31(2):239–265Osbaldeston M, Barham K (1992) Using management development for competitive advantage. Long Range Plan 25(6):18–24Penrose ET (1959) The theory of the growth of the firm. Basil Blackwell, OxfordReich BH, Benbasat I (1996) Measuring the linkage between business and information technology objectives. MIS Q 20(1):55–81Reich BH, Benbasat I (2000) Factors that influence the social dimension of alignment between business and information techonology objectives. MIS Q 24(1):81–113Riegner C (2007) Word of mouth on the web: the impact of web 2.0 on consumer purchase decisions. J Advert Res 47(4):436–447Rockart JF (1988) The lines takes the leadership. Sloan Manag Rev 29(4):57–64Sabherwal R, Chan YE (2001) Alignment between business and IS strategies: a study of prospectors, analyzers, and defenders. Inf Syst Res 12(1):11–33Sanchez R, Heene A, Thomas H (1996) Towards the theory and practice of competence-based competition. In: Sanchez R, Heene A, Thomas H (eds) Dynamics of competence-based competition: theory and practice in the new strategic management. Elsevier, London, pp 1–35Senge PM (1990) The fifth discipline: the age and practice of the learning organization. Century Business, LondonSiegel DS, Renko M (2012) The role of market and technological knowledge in recognizing entrepreneurial opportunities. Manag Decis 50(5):797–816Stare M, Jaklic A, Kotnik P (2006) Exploiting ICT potential in service firms in transition economies. Serv Ind J 26(3):287–302Swanson EB (1974) Management information systems: appreciation and involvement. Manag Sci 21(2):178–188Torkzadeh G, Xia W (1992) Managing telecommunications by steering committee. MIS Q 16(2):187–199Westley F, Mintzberg H (1989) Visionary leadership and strategic management. Strateg Manag J 10:17–32Yang TT, Li CR (2011) Competence exploration and exploitation in new product development: the moderating effects of environmental dynamism and competitiveness. Manag Decis 49(9):1444–147