Elicitor-induced activation of the potato pathogenesis-related gene PR-10a requires a 30-bp promoter sequence termed the ERE (elicitor response element) that is bound by the nuclear factor PBF-2 ( PR-10a binding factor 2). In this study, PBF-2 has been purified to near homogeneity from elicited tubers through a combination of anion-exchange and DNA affinity chromatography. Evidence demonstrates that inactive PBF-2 is stored in the nuclei of fresh tubers and becomes available for binding to the ERE upon elicitation. A protein with an apparent molecular mass of 24 kD (p24) is a DNA binding component of PBF-2. A cDNA encoding p24 has been cloned and encodes a novel protein with a potential transcriptional activation domain that could also act as a single-stranded DNA binding domain. Both PBF-2 and the cDNA-encoded protein bind with high affinity to the single-stranded form of the ERE in a sequence-specific manner. The inverted repeat sequence of the ERE, TGACAnnnnTGTCA, is critical for binding of this factor in vitro and for PR-10a expression in vivo, supporting the role of PBF-2 as a transcriptional regulator. INTRODUCTIONPlants defend themselves against fungal pathogens by a variety of mechanisms, including preexisting physical barriers and inducible defenses (Lamb et al., 1989). Attack by an avirulent strain of pathogen results in a rapid localized necrosis at the site of infection (termed the hypersensitive response), which contributes to pathogen limitation (Keen, 1992). With a few exceptions, deployment of the inducible defenses requires massive gene induction (Lamb et al., 1989). Despite the importance of transcriptional activation during the plant defense response, very little is known about the players involved and the exact mechanisms that lead to defense gene induction.PR (pathogenesis-related) genes are among the best characterized genes induced by pathogens. Heterogeneous in structure and function, PR genes are subdivided into 11 groups (Van Loon et al., 1994). Although the function of certain PR proteins is unknown, some display in vitro antifungal properties (Schlumbaum et al., 1986;Vigers et al., 1991;Ponstein et al., 1994;Niderman et al., 1995). Genes of the PR-10 group are present in numerous dicots (Somssich et al., 1988;Breiteneder et al., 1989;Matton and Brisson, 1989;Walter et al., 1990) and monocots (Warner et al., 1992;Moons et al., 1997). Evidence is accumulating that some PR-10 proteins might possess ribonuclease activity (Moiseyev et al., 1994;Bufe et al., 1996;Swoboda et al., 1996). More recently, structural and sequential homology between the PR-10 proteins and a group of latex proteins has been described (Osmark et al., 1998). Genes of the PR-10 group encode small, primarily acidic intracellular proteins with molecular masses ranging from 15 to 18 kD and have been shown to be transcriptionally regulated (Linthorst, 1991).In only two cases have cis elements and their trans -acting factors been characterized in the promoters of PR-10 genes. These studies revealed that the processes of tr...

ClinicalTrials.gov identifier: NCT00213135; EudraCT number: 2004-005148-28.

Objective: To estimate the cost-utility of dasatinib versus high-dose imatinib (HDI, imatinib 800mg/day) for chronic myelogenous leukemia (CML) in patients with resistance to imatinib at standard doses. Methods: We adapted to the Canadian setting a Markov model with a monthly cycle length that followed hypothetical patients until death. Cost effectiveness was evaluated during three phases of CML: chronic (86% of Ontario patients in 2006), accelerated (9%) and blast crisis (5%). Efficacy of dasatinib and HDI (cytogenetic and hematologic response) and adverse events (AEs) were taken from randomized trials. Canadian costs of medications, laboratory tests, professional fees, hospitalizations, and AEs were obtained from published sources. Societal utility scores were estimated from a Canadian time trade-off study. Analyses were performed from the perspective of the Ontario Ministry of Health. Costs (2006 CDN$) and outcomes (QALYs) were discounted at 5% annually after the first year. Univariate and probabilistic sensitivity analyses were carried out to quantify uncertainty for the incremental cost-effectiveness ratios (ICERs). Results: Dasatinib dominated HDI in chronic phase patients with additional QALYs (3.92 vs. 3.47) and a lower lifetime cost ($379,678 vs. $444,934). The ICERs of dasatinib vs. HDI in accelerated and blast phase were $88,098/QALY and $173,922/QALY respectively. The higher cost/QALY of dasatinib in the advanced phases is explained primarily by the increased predicted survival of dasatinib patients and therefore the longer duration of drug therapy for these patients. Parameters with the greatest influence on results were the time horizon, drug costs and utility values. The interpretation of results remained robust in univariate and probabilistic sensitivity analyses. Conclusion: From an economic perspective dasatinib is an attractive treatment choice for the majority of imatinib resistant CML patients and provides better value for money than HDI.

Objectives: Succinic acid as endogenous metabolite, has a wide range of applications in medical care. We conduct research on the development of new medicines based on succinic acid, ascorbic acid and rutin for the prevention and treatment of influenza. A systematic review was carried out to perform a qualitative assessment of succinic acid adding in the various medicines and to determine of their pharmacological action. MethOds: MEDLINE®, EMBASE®, Scopus, Cochrane Library databases and clinical trials registers between 1966 and Jun 2015 were performed. To analyze the RCT were selected and Review on the Study of the pharmacological action of drugs, which include succinic acid. Quality of evidence was assessed and each article was rated of quality. Results: Our study included 29 articles (23 RCT and 6 Review). The evidence varied in terms of: scope and years of research, type of treatment, study duration, sample size (< 100 to> 500 patients). Generally, the mean age of included patients was middle. For pharmacological properties and by relevance RCT are grouped as follows: antigypoxic action were 7 RCT (2003-2013 years), improve iron absorption in the gastrointestinal tract -6 RCT (1966( -1974( ), hepatoprotective -4 RCT (2013( -2014. One RCT proves the efficiency of succinic acid used in gastroenterology (a combination with omeprazole, 2012), depression (2013), in transplantation (1993) at menopause (2008), renal failure (2013), to improve body temperature during surgery (2007). Analysis of Review opens the new prospects for the use of succinic acid in cancer, diabetes and hepatitis C treatment. cOnclusiOns: A comprehencive overview of these studies estimated the evidence of succinic acid addition of the drugs. Succinic acid as endogenous metabolite, is a part of drugs of different pharmacological actions. These clinical trial results have been retrieved and give the possibility to develop of new drugs with succinic acid also in Ukraine.

INTRODUCTION:The Innovative Medicines Initiative, IMI-GetReal project aimed to explore incorporation of robust methods for real-world data (RWD) collection and synthesis earlier in the medicines development process, both by pharmaceutical companies and healthcare decision makers. The focus was on the potential use of RWD, alone or in combination with randomized controlled trials (RCTs), to demonstrate effectiveness of new interventions. Four case studies were conducted in multiple disease areas to examine methods for predicting drug effectiveness and the perspectives of different stakeholders on these methods. This study aimed to identify practical obstacles in accessing and using RWD and RCT data for effectiveness research conducted as part of these case studies.METHODS:Qualitative content analysis was conducted to identify and characterize key issues relating to accessing and analysing study data from external sources, both RWD and RCTs.RESULTS:Accessing RWD from registries proved difficult due to multiple reasons, including: complex and non-transparent application procedures, resistance from registry owners to discuss applications and datasets not being research-ready within project timeframes. There were also issues with the RWD eventually accessed, including a lack of individual participant data (IPD) and incomplete data. Where access to IPD from RCTs was obtainable, there were restrictions imposed on how it could be used. For example, it could not be used to target analysis on an individual product, but rather explore methodologies for data synthesis in a product-anonymised setting. This condition encouraged additional data sharing by other stakeholders.CONCLUSIONS:Despite the collaborative, multi-stakeholder nature of IMI-GetReal and proper disclosures with data owners, access to data proved challenging. Such barriers to data accessibility can delay effectiveness research, restrict opportunities for the development of methods incorporating RWD and diminish the potential use of RWD in decision making. Where data is intended to be used for this purpose, sufficient attention should be paid to these potential barriers.