M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis

BACKGROUND: The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. METHODS: M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. RESULTS: M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity. CONCLUSIONS: This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy

Role of β-Catenin in Post-Meiotic Male Germ Cell Differentiation

Though roles of β-catenin signaling during testis development have been well established, relatively little is known about its role in postnatal testicular physiology. Even less is known about its role in post-meiotic germ cell development and differentiation. Here, we report that β-catenin is highly expressed in post-meiotic germ cells and plays an important role during spermiogenesis in mice. Spermatid-specific deletion of β-catenin resulted in significantly reduced sperm count, increased germ cell apoptosis and impaired fertility. In addition, ultrastructural studies show that the loss of β-catenin in post-meiotic germ cells led to acrosomal defects, anomalous release of immature spermatids and disruption of adherens junctions between Sertoli cells and elongating spermatids (apical ectoplasmic specialization; ES). These defects are likely due to altered expression of several genes reportedly involved in Sertoli cell-germ cell adhesion and germ cell differentiation, as revealed by gene expression analysis. Taken together, our results suggest that β-catenin is an important molecular link that integrates Sertoli cell-germ cell adhesion with the signaling events essential for post-meiotic germ cell development and maturation. Since β-catenin is also highly expressed in the Sertoli cells, we propose that binding of germ cell β-catenin complex to β-catenin complex on Sertoli cell at the apical ES surface triggers a signaling cascade that regulates post-meiotic germ cell differentiation

The 2014 ALMA Long Baseline Campaign: An Overview

A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to make accurate images with resolutions of tens of milliarcseconds, which at submillimeter (submm) wavelengths requires baselines up to ~15 km. To develop and test this capability, a Long Baseline Campaign (LBC) was carried out from September to late November 2014, culminating in end-to-end observations, calibrations, and imaging of selected Science Verification (SV) targets. This paper presents an overview of the campaign and its main results, including an investigation of the short-term coherence properties and systematic phase errors over the long baselines at the ALMA site, a summary of the SV targets and observations, and recommendations for science observing strategies at long baselines. Deep ALMA images of the quasar 3C138 at 97 and 241 GHz are also compared to VLA 43 GHz results, demonstrating an agreement at a level of a few percent. As a result of the extensive program of LBC testing, the highly successful SV imaging at long baselines achieved angular resolutions as fine as 19 mas at ~350 GHz. Observing with ALMA on baselines of up to 15 km is now possible, and opens up new parameter space for submm astronomy