Dihydrofolate Reductase Gene Variations in Susceptibility to Disease and Treatment Outcomes

Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF). THF is needed for the action of folate-dependent enzymes and is thus essential for DNA synthesis and methylation. The importance of this reaction is demonstrated by the effectiveness of antifolate medications used to treat cancer by inhibiting DHFR, thereby depleting THF and slowing DNA synthesis and cell proliferation. Due to the pivotal role that DHFR plays in folate metabolism and cancer treatment, changes in the level of DHFR expression can affect susceptibility to a variety of diseases dependent on folate status such as spina bifida and cancer. Likewise, variability in DHFR expression can affect sensitivity to anti-cancer drugs such as the folate antagonist methotrexate. Alterations in DHFR expression can be due to polymorphisms in the DHFR gene. Several variations have recently been described in DHFR, including promoter polymorphisms, the 19-bp deletion allele and variations in 3’UTR. These polymorphisms seem to be functional, affecting mRNA levels through various interesting mechanisms, including regulation through RNA interference. Several groups have assessed the association of these polymorphisms with folate levels, risk of cancer and spina bifida as well as the outcome of diseases treated with MTX. The latter may lead to different treatment schedules, improving treatment efficacy and/or allowing for a reduction in drug side effects. This review will summarize present knowledge regarding the predictive potential of DHFR polymorphisms in disease and treatment

Problems of singers in opera plays

Masteroppgave i utøvende musikk 2006 - Høgskolen i Agder, KristiansandProblems of singers in opera plays deals with two aspects, vocal and stage-acting in two operas W.A.Mozart “Don Giovanni” and G.Donizetti “L’elisir D’amore”. It is written in the English language by Stevica Krajinovic and it is 43 pages long. It is a master thesis from the Agder University College, the Conservatory of Music in Kristiansand Norway, the classical department. The Thesis is divided into eight sections. The First section is an introduction with methods and aim. In the second section I am writing about the history and significance of opera including evolution of the opera and comments about Mozart and Donizetti through history written by Geoffrey Riggs. In the third section I try to explore different kinds of problems which are present in different operas. In the fourth section I start to investigate the Vocal aspect and possible solutions including some knowledge and techniques. In the fifth section I investigate the second problem, Stage-acting aspect and possible solutions. In the sixth section I start to explore the main problem, relations between Vocal and Stageacting aspects in two operas “Don Giovanni” by Mozart and “L’elisire D’amore” by Donizetti. In the Seventh section I give my conclusions

Phosphodiesterase Type 4D Gene Polymorphism: Association with the Response to Short-Acting Bronchodilators in Paediatric Asthma Patients

Short-acting b2-adrenergic receptor agonists are commonly used bronchodilators for symptom relief in asthmatics. The aim of this study was to test whether genetic variants in PDE4D gene, a key regulator of b2-adrenoceptor-induced cAMP turnover in airway smooth muscle cells, affect the response to short-acting b2-agonists. Bronchodilator responsiveness was assessed in 133 asthmatic children by % change in baseline forced expiratory volume in one second (FEV1) after administration of albuterol. The analyses were performed in patients with airway obstruction (FEV1/FVC ratio below 90%, n = 93). FEV1  % change adjusted for baseline FEV1 values was significantly different between genotypes of rs1544791 G/A polymorphism (P = 0.006) and −1345 C/T (rs1504982) promoter variation (P = 0.03). The association remained significant with inclusion of age, sex, atopy, and controller medication into multivariate model (P = 0.004 and P = 0.02, resp.). Our work identifies new genetic variants implicated in modulation of asthma treatment, one of them (rs1544791) previously associated with asthma phenotype

DHFR (dihydrofolate reductase)

Dihydrofolate reductase (DHFR) is a member of the reductase enzyme family, which is ubiquitously expressed in all organisms. Levels of this enzyme peak at the G1/S cell cycle boundary. Autoregulation, through DHFR-RNA interactions, has also been reported. DHFR catalyzes the NADPH dependent reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) needed for several one-carbon transfer reactions in purine and pyrimidine synthesis (Jensen et al 1997, Klon et al 2002). It is also the only enzyme that reduces folic acid, a synthetic vitamin not found in nature, to dihydrofolate (Banka et al. 2011). Reduction of DHFR enzymatic activity diminishes the THF pool inside the cell which slows DNA synthesis and cell proliferation eventually leading to cell death (Assaraf et al 2007, Klon et al 2002, Morales et al 2009). DHFR inhibition is essential to the action of antifolate medications used to treat cancer and some inflammatory diseases. Changes in DHFR expression can affect susceptibility to a variety of diseases dependent on folate status such as spina bifida and cancer. Likewise, human DHFR (hDHFR) has become a major drug target in anticancer therapy (Klon et al 2002, Sharif-Askari et al 2010)

A novel method for quantification of sulfolane (a metabolite of busulfan) in plasma by gas chromatography-tandem mass spectrometry

The role of busulfan (Bu) metabolites in the adverse events seen during hematopoietic stem cell transplantation and in drug interactions is not explored. Lack of availability of established analytical methods limits our understanding in this area. The present work describes a novel gas chromatography-tandem mass spectrometric assay for the analysis of sulfolane (Su) in plasma of patients receiving high-dose Bu. Su and Bu were extracted from a single 100 μL plasma sample by liquid-liquid extraction. Bu was separately derivatized with 2,3,5,6-tetrafluorothiophenolfluorinated agent. Mass spectrometric detection of the analytes was performed in the selected reaction monitoring mode on a triple quadrupole instrument after electronic impact ionization. Bu and Su were analyzed with separate chromatographic programs, lasting 5min each. The assay for Su was found to be linear in the concentration range of 20-400ng/mL. The method has satisfactory sensitivity (lower limit of quantification, 20ng/mL) and precision (relative standard deviation less than 15%) for all the concentrations tested with a good trueness (100 ± 5%). This method was applied to measure Su from pediatric patients with samples collected 4h after dose 1 (n = 46), before dose 7 (n = 56), and after dose 9 (n = 54) infusions of Bu. Su (mean ± SD) was detectable in plasma of patients 4h after dose 1, and higher levels were observed after dose 9 (249.9 ± 123.4ng/mL). This method may be used in clinical studies investigating the role of Su on adverse events and drug interactions associated with Bu therapy. Figure Overall sample preparation procedure for quantification of sulfolane and busulfan in plasma from patients receiving higher doses of busulfa

A 2‐year dyadic longitudinal study of mothers' and fathers' marital adjustment when caring for a child with cancer

Objective Studies examining interrelationships within parental couples confronted with pediatric cancer are scarce. This study explored dyadic longitudinal associations between both partners' family functioning and mood at diagnosis, and marital adjustment 2 years later. Method Parents of children (n = 47 couples) with acute lymphoblastic leukemia (ALL) completed the Family Well‐Being Assessment and Profile of Mood States‐Bipolar Form at diagnosis, and the Locke–Wallace Marital Adjustment Test 2 years post diagnosis. Multilevel linear models using the actor–partner interdependence model (APIM) and controlling for baseline marital adjustment were conducted to evaluate within subject and dyadic longitudinal effects. Results For mothers, better marital adjustment 2 years post diagnosis was associated with perception of greater family support and less role conflict and role overload at diagnosis. For fathers, better marital adjustment 2 years post‐diagnosis was associated with perception of less role conflict, greater role ambiguity, and being more tired at diagnosis, as well as their partner's perception of less role conflict at diagnosis. Conclusions These findings highlight the importance of considering both partners' perspectives in understanding marital adjustment across treatment phases in parents of children with ALL. Early interventions for couples should be tailored to meet each partner's needs in order to foster resilience within the couple

Could we use parent report as a valid proxy of child report on anxiety, depression, and distress? : a systematic investigation of father–mother–child triads in children successfully treated for leukemia

Background Systematic assessment of emotional distress is recommended in after care. Yet, it is unclear if parent report may be used as a proxy of child report. The aim of this study was to assess agreements and differences and explore possible moderators of disagreement between child and parent ratings. Methods Sixty‐two young survivors treated for acute lymphoblastic leukemia (9–18 years) and both parents responded to the Beck Youth Inventory (anxiety and depression) and the distress rating scale on the child's status. Parents completed the Brief Symptom Inventory‐18 on their own psychological status. Systematic analyses of agreement and differences were performed. Results Mother–child and father–child agreements were fair on anxiety, depression, and distress (median intraclass correlation coefficient = 0.37). Differences between parents and children were medium sized (median d = 0.55) with parents giving higher scores than their children on anxiety, depression, and distress. Mothers reported distress more frequently than fathers (39 vs. 17%) when children reported none. The child being female and lower parental income were associated with lower agreement in fathers when rating child distress. Higher levels of parental psychological symptoms were consistently associated with lower agreement. Conclusions Parent–child differences when rating adolescent survivors’ difficulties may be more important than previously thought. Parent report probably cannot be considered as a valid proxy of older child report on such internalized domains as anxiety, depression, or distress in the after‐care clinic. Parents’ report is also likely to be influenced by their own mood, a factor that should be corrected for when using their report