Primary tumor classification according to methylation pattern is prognostic in patients with early stage ER-negative breast cancer

Breast cancer patients with similar clinical stage may experience different disease outcomes. Aberrant DNA methylation of primary breast tumors can have impact on the clinical outcome. This study aimed to assess clinical utility of tumor-specific methylated sequences (MINT17, 31) and tumor-related gene (RARβ2) methylation classification in primary breast tumors. Absolute quantitative assessment of methylated alleles (AQAMA) was used to determine the methylation index (MI) of MINT17, MINT31, and RARß2 in 242 primary tumors of early stage breast cancer patients. Patients were classified into three methylation groups: meth-N, with normal methylation levels of all biomarkers; meth-L, with one biomarker hypermethylation; and meth-H, with hypermethylation of >1 biomarker. Disease outcome of methylation groups was compared during follow-up. MI of all biomarkers was successfully obtained in 237 tumors of which 79 (33%) were classified as meth-N, 86 (36%) as meth-L, and 72 (30%) as meth-H. Meth-H status was a risk factor for distant recurrence (DR) (log-rank P = 0.007) and shorter disease-free survival (DFS) (log-rank P = 0.039). Methylation classification had strongest prognostic value for patients with ER-negative tumors. In multivariate analysis (n = 222), ER-negative meth-H patients had a 4.1-fold increased risk of DR (95% CI 1.80–9.59; meth-N HR 1.0, P = 0.001), a 4.2-fold increased risk of overall recurrence (OR) (95% CI 1.88–9.47; meth-N HR 1.0, P = 0.001), and a 3.1-fold shorter DFS (95% CI 1.57–5.98; meth-N HR 1.0, P = 0.003). Methylation classification of primary breast cancer is an independent prognostic factor for disease outcome in patients with ER-negative tumors. The study’s findings will have to be confirmed in an independent dataset.     

Familiality of postpartum depression in unipolar disorder: results of a family study

OBJECTIVE: The authors previously reported strong evidence for familial aggregation of postpartum (puerperal) psychotic episodes in women with bipolar disorder. The authors here examine whether vulnerability to postpartum triggering of depressive episodes aggregates in families and assess how this aggregation varies with the definition of postpartum onset. METHOD: Postpartum depression occurrence was studied in the female members of 120 sibling pairs recruited at a site within an international multicenter study of sibling pairs with recurrent unipolar depression. Employing a range of definitions of postpartum onset, the authors examined concordance for postpartum episode status between sisters. RESULTS: Episodes of depression with onset within 4 weeks of delivery clustered in families, but there was no significant evidence of familial clustering of broadly defined postpartum depression (onset within 6 months). Among women with a family history of narrowly defined postpartum episodes, 42% experienced depression following their first delivery, whereas only 15% of women with no such family history experienced depression following first delivery. The evidence for familiality maximized with a postpartum onset definition of 6-8 weeks. CONCLUSIONS: These results implicate familial factors in susceptibility to the triggering of narrowly defined postpartum depressive episodes in women with recurrent major depression. They suggest that a postnatal onset definition of within 6-8 weeks of delivery may be optimal in studies of the triggering of depressive illness by childbirth.     

Repeated measurements of contrast sensitivity reveal limits to visual plasticity after early binocular deprivation in humans

Contrast sensitivity improves in visually normal children until 7 years of age and is impaired in children who experienced early visual deprivation from bilateral congenital cataracts. Here, we investigated whether the deficits after early visual deprivation change during childhood by retesting the contrast sensitivity of seven patients treated for bilateral congenital cataract who had been first tested before 7.5 years of age, and of two patients first tested after 11 years of age. For the younger group, contrast sensitivity at low spatial frequencies improved after 1- and 2-year intervals, while their sensitivity at mid and high spatial frequencies did not change. There was no systematic change in the two older patients. The results indicate that early visual input sets up the neural substrate for later improvement in contrast sensitivity at mid and high spatial frequencies. However, there is sufficient plasticity during middle childhood to allow some recovery at low spatial frequencies. The results shed new light on the role of early visual experience and the nature of developmental plasticity.     

Convection-enhanced delivery and systemic mannitol increase gene product distribution of AAV vectors 5, 8, and 9 and increase gene product in the adult mouse brain

The use of recombinant adeno-associated viral (rAAV) vectors as a means of gene delivery to the central nervous system has emerged as a potentially viable method for the treatment of several types of degenerative brain diseases. However, a limitation of typical intracranial injections into the adult brain parenchyma is the relatively restricted distribution of the delivered gene to large brain regions such as the cortex, presumably due to confined dispersion of the injected particles. Optimizing the administration techniques to maximize gene distribution and gene expression is an important step in developing gene therapy studies. Here, we have found additive increases in distribution when 3 methods to increase brain distribution of rAAV were combined. The convection enhanced delivery (CED) method with the step-design cannula was used to deliver rAAV vector serotypes 5, 8 and 9 encoding GFP into the hippocampus of the mouse brain. While the CED method improved distribution of all 3 serotypes, the combination of rAAV9 and CED was particularly effective. Systemic mannitol administration, which reduces intracranial pressure, also further expanded distribution of GFP expression, in particular, increased expression on the contralateral hippocampi. These data suggest that combining advanced injection techniques with newer rAAV serotypes greatly improves viral vector distribution, which could have significant benefits for implementation of gene therapy strategies.     

Design of the REVEAL registry for US patients with pulmonary arterial hypertension

The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) has been designed to meet the need for current information about patients with pulmonary arterial hypertension (PAH). The main objectives of REVEAL are to better define and understand PAH and to assess the consequences of treatment strategies. REVEAL is collecting clinically relevant data from 3500 consecutively enrolled patients with confirmed PAH diagnoses. Outcomes will be evaluated longitudinally and compared according to the baseline classification of PAH. The primary outcome for group comparisons will be survival. Collected data include World Health Organization functional class, 6-minute walk distance, cardiopulmonary exercise testing, pulmonary function test results, hemodynamic measurements, functional status, hospitalizations, and death. REVEAL will be the richest source of data on patients with World Health Organization group I PAH.