Prognostic Impacts of Angiopoietins in NSCLC Tumor Cells and Stroma: VEGF-A Impact Is Strongly Associated with Ang-2

INTRODUCTION: Angiopoietins and their receptor Tie-2 are, in concert with VEGF-A, key mediators in angiogenesis. This study evaluates the prognostic impact of all known human angiopoietins (Ang-1, Ang-2 and Ang-4) and their receptor Tie-2, as well as their relation to the prognostic expression of VEGF-A. METHODS: 335 unselected stage I-IIIA NSCLC-patients were included and tissue samples of respective tumor cells and stroma were collected in tissue microarrays (TMAs). Immunohistochemistry (IHC) was used to semiquantitatively evaluate the expression of markers in duplicate tumor and stroma cores. PRINCIPAL FINDINGS: In univariate analyses, low tumor cell expression of Ang-4 (P = 0.046) and low stromal expressions of Ang-4 (P = 0.009) and Ang-2 (P = 0.017) were individually associated with a poor survival. In the multivariate analysis, low stromal Ang-2 (HR 1.88; CI 95% 1.15-3.08) and Ang-4 (HR 1.47, CI 95% 1.02-2.11, P = 0.04) expressions were independently associated with a poor prognosis. In patients with high tumor cell expression of Ang-2, a concomitantly high tumor VEGF-A expression mediated a dramatic survival reduction (P<0.001). In the multivariate analysis of patients with high Ang-2 expression, high tumor VEGF-A expression appeared an independent poor prognosticator (HR 6.43; CI 95% 2.46-16.8; P<0.001). CONCLUSIONS: In tumor cells, only Ang-4 expression has prognostic impact in NSCLC. In tumor stroma, Ang-4 and Ang-2 are independently associated with survival. The prognostic impact of tumor cell VEGF-A in NSCLC appears strongly associated with a concomitantly high tumor cell expression of Ang-2

Electrotonic Signals along Intracellular Membranes May Interconnect Dendritic Spines and Nucleus

Synapses on dendritic spines of pyramidal neurons show a remarkable ability to induce phosphorylation of transcription factors at the nuclear level with a short latency, incompatible with a diffusion process from the dendritic spines to the nucleus. To account for these findings, we formulated a novel extension of the classical cable theory by considering the fact that the endoplasmic reticulum (ER) is an effective charge separator, forming an intrinsic compartment that extends from the spine to the nuclear membrane. We use realistic parameters to show that an electrotonic signal may be transmitted along the ER from the dendritic spines to the nucleus. We found that this type of signal transduction can additionally account for the remarkable ability of the cell nucleus to differentiate between depolarizing synaptic signals that originate from the dendritic spines and back-propagating action potentials. This study considers a novel computational role for dendritic spines, and sheds new light on how spines and ER may jointly create an additional level of processing within the single neuron

CRITICAL REVIEW OF THE TAXONOMIC STATUS OF MEDITERRANEAN PHYLLIDIA OPISTHOBRANCHIA NUDIBRANCHIA DORIDOIDEA

Volume: 24Start Page: 205End Page: 21

Multiple clinical profiles of families with the short QT syndrome

Aims Short QT syndrome (SQTS) is a rare cardiac channelopathy characterized by a shortened corrected QT (QTc)-interval that can lead to ventricular arrhythmias and sudden cardiac death. The aim of this study was to investigate the clinical phenotypes and long-term outcomes of three families harbouring genetic mutations associated with the SQTS. Methods and results Clinical data included medical history, physical examination, 12-lead ECG, 24-h Holter-ECG, and transthoracic echocardiography from three index patients and their first-degree relatives. Next generation clinical exome sequencing and genetic cascade screening were performed in index patients and their relatives, respectively. Two index patients experienced malignant ventricular arrhythmias and one patient suffered from arrhythmogenic syncope during a median follow-up period of 8 years. They all had genetic mutations associated with the SQTS. Two mutations were found in the KCNH2 gene, and one in the CACNA2D gene. One patient had an additional SCN10A variant. Alive and mutation-positive family members had short QTc-intervals, but no further phenotypic manifestations. None of the mutation-negative family members had an abnormal ECG or any symptoms. In all patients with shortened QTc-intervals, the QTc-interval had a low long-term variability and QTc shortening always remained detectable by 12-lead ECG. Conclusion This study shows the variety of phenotypic manifestations in different families with SQTS. It further emphasizes the importance of a 12-lead ECG for early diagnosis, and the utility of next generation sequencing for the identification of mutations associated with the SQTS

Long-term follow-up of patients with isolated left ventricular noncompaction: role of electrocardiography in predicting poor outcome

BACKGROUND: Abnormal baseline electrocardiograms (ECGs) are common in patients with isolated left ventricular noncompaction (IVNC). Whether certain electrocardiographic parameters are associated with a poor clinical outcome, however, remains elusive. The present study was therefore designed to comprehensively assess the predictive value of baseline ECG findings in patients newly diagnosed with IVNC. METHODS AND RESULTS: 74 patients diagnosed with IVNC were included in the analysis. During follow-up, 8 patients (11%) died of a cardiovascular cause or underwent heart transplantation (primary outcome measure). On univariate analysis, several variables, including repolarization abnormalities (ST segment elevation/depression, T-wave inversion) in the inferior leads (5-year estimator: 67.1 ± 10.7% vs. 98 ± 2.2%; P = 0.001), an increase in PQ- (hazard ratio (HR) 1.032, P=0.004) and QTc-duration (HR 1.037, P=0.001), were predictive of cardiovascular death or heart transplantation. On multivariate analysis, only PQ- and QTc-duration and the presence of repolarization abnormalities in the inferior leads remained significantly predictive of a poor outcome. CONCLUSIONS: PQ duration, QTc duration, and repolarization abnormalities in the inferior leads are independently predictive of a poor prognosis in IVNC. Further prospective studies are required to conclusively investigate the usefulness of baseline ECG parameters for risk stratification in patients with IVNC