Citations

The cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of testosterone. Functional changes in this enzyme may influence endogenous hormone exposure, which has been associated with risk of breast cancer. To assess potential associations between two functional polymorphisms CYP2B6_516_G>T (rs3745274) and CYP2B6_785_A>G (rs2279343) and breast cancer risk, we established a specific matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry assay. The GENICA breast cancer case–control study showed associations between the variant genotypes CYP2B6_516_TT and CYP2B6_785_GG and breast cancer risk with odds ratios (ORs) of 1.34 (p = 0.001) and 1.31 (p = 0.002), respectively. A similar effect was observed for carriers of the CYP2B6_516_T allele in a validation study including four independent studies from Germany, Sweden and USA. In a pooled analysis of all five studies involving 4,638 breast cancer cases and 3,594 controls of European ancestry, carriers of the CYP2B6_516_G and the CYP2B6_785_G variant had an increased breast cancer risk with ORs of 1.10 (p = 0.027) and 1.10 (p = 0.031), respectively. We conclude that the genetic variants CYP2B6_516_G and CYP2B6_785_G (designated CYP2B6*6), which are known to decrease activity of the CYP2B6 enzyme, contribute to an increased breast cancer risk.

Glycogen storage diseases are important causes of myopathy and cardiomyopathy. We describe 10 patients from 8 families with childhood or juvenile onset of myopathy, 8 of whom also had rapidly progressive cardiomyopathy, requiring heart transplant in 4. The patients were homozygous or compound heterozygous for missense or truncating mutations in RBCK1, which encodes for a ubiquitin ligase, and had extensive polyglucosan accumulation in skeletal muscle and in the heart in cases of cardiomyopathy. We conclude that RBCK1 deficiency is a frequent cause of polyglucosan storage myopathy associated with progressive muscle weakness and cardiomyopathy. Ann Neurol 2013;74:914–919

AbstractObjectiveThe Suspicion Index (SI) screening tool was developed to identify patients suspected of having Niemann‐Pick disease type C (NP‐C). The SI provides a risk prediction score (RPS) based on NP‐C manifestations within and across domains (visceral, neurological, and psychiatric). The aim of these subanalyses was to further examine the discriminatory power of the SI by age and manifestation–associations by NP‐C suspicion‐level and leading manifestations.MethodsThe original retrospectively collected data were split into three patient age groups, where NP‐C‐positive cases were >16 years (n = 30), 4–16 years (n = 18), and <4 years (n = 23), and patients’ RPS were analyzed by logistic regression. Co‐occurrence of manifestations within groups of suspicion level (low, medium, high) and leading manifestations (presence/absence of ataxia, cognitive decline, psychosis, and splenomegaly) were analyzed descriptively.ResultsNP‐C‐positive cases versus controls showed strong discriminatory power of RPS. Area under the receiver operating characteristic curve was 0.964 (>16 years) and 0.981 (4–16 years) but weaker 0.562 for infants (<4 years). Patients with RPS <70 were characterized by a lack of psychiatric manifestations and low levels of neurological involvement, suggestive of a preneurological phase of the disease. In patients >4 years, prominent leading manifestation–associations were ataxia with dystonia, dysarthria/dysphagia, and cognitive decline. Psychosis was associated with dysarthria/dysphagia but also with cognitive decline and treatment‐resistant psychiatric symptoms.ConclusionsThe SI tool maintains strong discriminatory power in patients >4 years but is not as useful for infants <4 years. The SI is also informative regarding the association and co‐occurrence of manifestations in patients with NP‐C.

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

This white paper, prepared by a working group of the Catholic Medical Association, provides a commentary on a new type of end-of-life document called a POLST form (Physician Orders for Life-Sustaining Treatment) as well as on its model (or “paradigm”) for implementation across the United States. After an introductory section reviewing the origin, goals, and standard defenses of the POLST paradigm and form, the paper offers a critical analysis of POLST, including an analysis of the risks that POLST poses to sound clinical and ethical decision-making. The paper ends with several recommendations to help Catholic healthcare professionals and institutions better address the challenges of end-of-life care with alternatives to POLST.

Abstract Tumor-associated hypoxia has been associated with malignant progression, metastasis and resistance to therapy. We studied the role of oxygen tension (pO2) in modulating the properties of cultured human prostate cancer (CaP) cells. In air, where oxygen tension (pO2) is approximately 20 kPa, cultured CaP cells expressed lower levels of transcripts associated with cancer and urologic disease; reducing pO2 to 2 kPa made these levels comparable to those in surgical CaP specimens suggesting that hypoxically cultured cells, rather than normoxically cultured cells, express genes at levels akin to those in tumor cells in situ. In human primary CaP tissue, transcripts of hypoxia-associated genes DLG7, CCNB1 and HMMR were overexpressed and associated with Gleason score and disease prognosis; this implies the potential prognostic value of these transcripts. While hypoxia affected the CaP cell proteome mostly quantitatively, it did affect expression of tumor–associated antigens and suggested the potential therapeutic relevance of the hypoxic antigenic landscape. Overall, our results suggest that hypoxia modifies cellular properties of cultured CaP cells towards a phenotype more similar to tumor cells in situ. Introduction of pO2 as a variable can constitute a tool for the identification of more effective prognostic biomarkers and development of better therapy for CaP and, possibly, other tumors. Citation Format: Christian R. Gomez, Stanimir Vuk-Pavlovic, Farhad Kosari, Jan Marie Munz, Claire Schreiber, Gaylord Knutson, Cristine Charlesworth, R. Jeffrey Karnes, John Cheville, George Vasmatzis. Prognostic value of hypoxia-associated genes in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C43.

Background— Diastolic dysfunction is frequently seen after myocardial infarction and is characterized by a disproportionate increase in filling pressure during exercise to maintain stroke volume. We hypothesized that sildenafil would reduce filling pressure during exercise in patients with diastolic dysfunction after myocardial infarction. Methods and Results— Seventy patients with diastolic dysfunction and near normal left ventricular ejection fraction on echocardiography were randomly assigned sildenafil 40 mg thrice daily or matching placebo for 9 weeks. Before randomization and after 9 weeks of treatment patients underwent simultaneous echocardiography and right heart catheterization at rest and during exercise. Primary end point was pulmonary capillary wedge pressure, and secondary end points comprised cardiac index and pulmonary arterial pressure at rest and during exercise after 9 weeks. After 9 weeks there were no differences in pulmonary capillary wedge pressure at rest (13±4 versus 13±3 mm Hg, P =0.25) or at peak exercise (35±8 mm Hg versus 31±7 mm Hg, P =0.07). However, with treatment cardiac index increased at rest ( P =0.006) and peak exercise ( P =0.02) in the sildenafil group, and systemic vascular resistance index (resting, P =0.0002; peak exercise, P =0.007) and diastolic blood pressure (resting, P =0.005; peak exercise, P =0.02) were lower in the sildenafil group. Resting left ventricular end-diastolic volume index increased ( P =0.001) within the sildenafil group but was unchanged in the placebo group. Conclusions— Sildenafil did not decrease filling pressure at rest or during exercise in post–myocardial infarction patients with diastolic dysfunction. However, there were effects on secondary end points, which require further studies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov/ct2/show/NCT01046838 . Unique identifier: NCT01046838.