Citations

The SCN5A-encoded cardiac sodium channel underlies excitability in the heart, and dysfunction of sodium current ( INa) can cause fatal ventricular arrhythmia in maladies such as long QT syndrome, Brugada syndrome (BrS), and sudden infant death syndrome (SIDS). The gene GPD1L encodes the glycerol phosphate dehydrogenase 1-like protein with homology to glycerol phosphate dehydrogenase (GPD1), but the function for this enzyme is unknown. Mutations in GPD1L have been associated with BrS and SIDS and decrease INa through an unknown mechanism. Using a heterologous expression system, we show that GPD1L associated with SCN5A and that the BrS- and SIDS-related mutations in GPD1L caused a loss of enzymatic function resulting in glycerol-3-phosphate PKC-dependent phosphorylation of SCN5A at serine 1503 (S1503) through a GPD1L-dependent pathway. The direct phosphorylation of S1503 markedly decreased INa. These results show a function for GPD1L in cell physiology and a mechanism linking mutations in GPD1L to sudden cardiac arrest. Because the enzymatic step catalyzed by GPD1L depends upon nicotinamide adenine dinucleotide, this GPD1L pathway links the metabolic state of the cell to INa and excitability and may be important more generally in cardiac ischemia and heart failure.

We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2saturation). In protocol 1 ( n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 ( n = 10), subjects received intra-arterial phentolamine (α-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml·min−1·100 mmHg−1) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (ΔFVC; change from normoxic baseline) during hypoxic exercise with saline was 172 ± 29 and 314 ± 34 ml·min−1·100 mmHg−1(10% and 20%, respectively). Aminophylline administration did not affect ΔFVC during hypoxic exercise at 10% (190 ± 29 ml·min−1·100 mmHg−1, P = 0.4) or 20% (287 ± 48 ml·min−1·100 mmHg−1, P = 0.3). In protocol 2, ΔFVC due to hypoxic exercise with phentolamine infusion was 313 ± 30 and 453 ± 41 ml·min−1·100 mmHg−1(10% and 20% respectively). ΔFVC was similar at 10% (352 ± 39 ml·min−1·100 mmHg−1, P = 0.8) and 20% (528 ± 45 ml·min−1·100 mmHg−1, P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, ΔFVC to exogenous adenosine was reduced by aminophylline administration in both protocols ( P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans.

AbstractWe performed a pooled analysis of data on atopic disease and risk of non–Hodgkin lymphoma (NHL) from 13 case-control studies, including 13,535 NHL cases and 16,388 controls. Self-reported atopic diseases diagnosed 2 years or more before NHL diagnosis (cases) or interview (controls) were analyzed. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were computed in two-stage random-effects or joint fixed-effects models, and adjusted for age, sex, and study center. When modeled individually, lifetime history of asthma, hay fever, specific allergy (excluding hay fever, asthma, and eczema), and food allergy were associated with a significant reduction in NHL risk, and there was no association for eczema. When each atopic condition was included in the same model, reduced NHL risk was only associated with a history of allergy (OR, 0.80; 95% CI, 0.68–0.94) and reduced B-cell NHL risk was associated with history of hay fever (OR, 0.85; 95% CI, 0.77–0.95) and allergy (OR, 0.84; 95% CI, 0.76–0.93). Significant reductions in B-cell NHL risk were also observed in individuals who were likely to be truly or highly atopic—those with hay fever, allergy, or asthma and at least one other atopic condition over their lifetime. The inverse associations were consistent for the diffuse large B-cell and follicular subtypes. Eczema was positively associated with lymphomas of the skin; misdiagnosis of lymphoma as eczema is likely, but progression of eczema to cutaneous lymphoma cannot be excluded. This pooled study shows evidence of a modest but consistent reduction in the risk of B-cell NHL associated with atopy. [Cancer Res 2009;69(16):6482–9]

It remains to be determined whether systemic insulin replacement normalizes synthesis rates of different plasma proteins and whether there are differential effects on various plasma proteins. We tested a hypothesis that insulin deprivation differentially affects individual plasma protein synthesis and that systemic insulin treatment may not normalize synthesis of all plasma proteins. We measured synthesis rates of 41 plasma proteins in seven each of type 1 diabetic (T1DM) and nondiabetic participants (ND) using [ ring-13C6]phenylalanine as a tracer. T1DM were studied while on chronic insulin treatment and during 8 h insulin deprivation. Insulin treatment normalized glucose levels, but plasma insulin levels were higher during insulin treatment than during insulin deprivation in T1DM and ND. Individual plasma proteins were purified by affinity chromatography and two-dimensional gel electrophoresis. Only 41 protein gel spots from over 300 were chosen based on their protein homogeneity. Insulin deprivation and hyperglycemia either significantly increased ( n = 12) or decreased ( n = 12) synthesis rates of 24 of 41 plasma proteins in T1DM compared with ND. Insulin treatment normalized synthesis rates of 13 of these 24 proteins, which were altered during insulin deprivation. However, insulin treatment significantly altered the synthesis of 14 additional proteins. In conclusion, acute insulin deprivation caused both a decrease and increase in synthesis rates of many plasma proteins with various functions. Moreover, chronic systemic insulin treatment not only did not normalize synthesis of all plasma proteins but also altered synthesis of several additional proteins that were unaltered during insulin deprivation.

Objective: To summarize the role of pharmacotherapy in the management of phenylketonuria (PKU) and to review the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and safety profile of sapropterin for this indication. Data Sources: A literature search was conducted using MEDLINE (1966–May 2009), International Pharmaceutical Abstracts (1970–May 2009), and Cochrane database (2008) for the following key words: sapropterin, tetrahydrobiopterin, phenylketonurias, and phenylalanine. Study Selection and Data Extraction: English-language studies involving humans examining the role of tetrahydrobiopterin (BH4) in the management of PKU were reviewed to evaluate the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and safety profile for sapropterin. All Phase 2 and 3 randomized controlled trials assessing the safety and efficacy of sapropterin were included in this literature evaluation. Data Synthesis: Sapropterin represents the only Food and Drug Administration–approved medication for BH4-responsive PKU, marking an important advance in the treatment of this condition. Among individuals with hyperphenylalaninemia and some residual phenylalanine hydroxylase function, sapropterin can enhance activity of this enzyme to decrease serum phenylalanine concentrations. Sapropterin has been compared with placebo in one Phase 2 and one Phase 3 clinical trial, demonstrating significantly better response rates. Based on available studies, this agent appears to be safe and well tolerated, with adverse event rates similar to those of placebo. However, additional studies are warranted to assess the long-term safety and efficacy of sapropterin therapy. Conclusions: Sapropterin offers a promising therapeutic option for select individuals with BH4-responsive PKU, although long-term data are limited evaluating its safety and efficacy in traditional clinical practice settings. When considering sapropterin therapy, clinicians must consider factors such as cost and patient adherence to drug therapy and/or diet.

Abstract Acquired platinum resistance is a serious problem in the treatment of ovarian carcinomas. However, the mechanism of the drug resistance has not been elucidated. Here, we show functional significance of restoration of BRCA2 protein by secondary BRCA2 mutations in acquired drug resistance of BRCA2-mutated ovarian carcinoma. Three ovarian cancer cell lines (PEO1, PEO4, and PEO6) were derived from a BRCA2 mutation [5193C&gt;G (Y1655X)] carrier with ovarian carcinoma with acquired cisplatin resistance and a secondary BRCA2 mutation [5193C&gt;T (Y1655Y)] that canceled the inherited mutation. PEO1 was BRCA2 deficient and sensitive to cisplatin and a poly(ADP-ribose) polymerase inhibitor, AG14361, whereas PEO4 was resistant. PEO4 and PEO6, derived from ascites at the time of relapse with cisplatin resistance, had the secondary mutation and were BRCA2 proficient. In vitro cisplatin/AG14361 selection of PEO1 led to restoration of BRCA2 due to another secondary BRCA2 mutation. BRCA2 depletion sensitized BRCA2-restored PEO1 clones and PEO4 to cisplatin/AG14361. Thus, restoration of BRCA2 due to secondary BRCA2 mutation is involved in acquired drug resistance of BRCA2-mutated ovarian carcinoma. [Cancer Res 2009;69(16):6381–6]

Abstract The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum insulin-like growth factor (IGF)-I levels and mammary tumor (MT) development was investigated. Ten-week-old MMTV-TGF-α female mice were assigned to ad libitum–fed (AL; AIN-93M diet), ICR [3-week 50% caloric restriction using AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3 weeks of daily 100% AL consumption of AIN-93M (∼75% of AL for each 6-week cycle)], and CCR (calorie and nutrient intake matched for each 6-week ICR cycle) groups. Half of the mice from each group were sacrificed at 79 (end of restriction) or 82 (end of refeeding) weeks of age. Serum was obtained at euthanasia and in cycles 1, 3, 5, 8, and 11. MT incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice. ICR-Restricted mice had significantly lower terminal serum IGF-I and IGF-I/IGF binding protein-3 (IGFBP-3) ratio than CCR, ICR-Refed, and AL mice. There were no differences in terminal IGFBP-3. Final body, internal, and mammary fat pad weights correlated positively with IGF-I and negatively with IGFBP-3. Few changes were found for protein expression of IGF-IRα and IGFBP-3 in mammary tissue and MTs. During the study, IGF-I levels of ICR-Restricted mice were reduced, whereas refeeding allowed partial recovery. For all groups, elevated IGF-I levels preceded MT detection, although not all values were significant versus mice without MTs. However, the specific role of IGF-I in the protective effect of calorie restriction remains to be determined. These results confirm that ICR prevents MT development to a greater extent than CCR.

AbstractUnlike in meiosis where recombination near telomeres is repressed, subtelomeric regions appear to recombine with each other frequently in vegetative cells with no detrimental consequences. To test whether or not such recombination is prevented in the core of chromosomes for maintenance of genome stability, we measured allelic homologous recombination (HR) along chromosome arms and between different ectopic locations. We found that there is an increase of recombination at telomeres in wild-type cells compared with sequences at proximal subtelomeric and interstitial regions of the genome. We also screened for mutations that result in an increase in HR between a telomeric sequence and a more internal sequence, which normally exhibit very low rates of HR. YKU80 was hit most frequently in our screen, and we show that the yKu heterodimer specifically represses HR in the vicinity of telomeres. This repression of HR is not explained solely by the role of yKu in maintaining telomere length, silencing, or tethering to the nuclear periphery. Analysis of mutant strains harboring deleted core X sequences revealed a role for this subtelomeric element in preventing telomeric recombination. Furthermore, core X bestowed this protection as part of the same pathway as yKu. Our findings implicate a role for both yKu and core X in stabilizing the genome against recombination events involving telomeric sequences.