Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells

Lymphomas arising from NK or γδ-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n=51), γδ-T-cell lymphomas (n=43) and their cell lines (n=9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of γδ-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy. © 2015 Macmillan Publishers Limited. All rights reserved

Measurement of Cosmic-ray Muon-induced Spallation Neutrons in the Aberdeen Tunnel Underground Laboratory

AbstractMuon-induced neutrons are one of the major backgrounds to various underground experiments, such as dark matter searches, low-energy neutrino oscillation experiments and neutrino-less double beta-decay experiments. Previous experiments on the underground production rate of muon-induced neutrons were mostly carried out either at shallow sites or at very deep sites. The Aberdeen Tunnel experiment aims to measure the neutron production rate at a moderate depth of 611 meters water equivalent. Our apparatus comprises of six layers of plastic-scintillator hodoscopes for tracking the incident cosmic-ray muons, and 760 L of gadolinium-doped liquid-scintillator for both neutron production and detection targets. In this paper, we describe the design and the performance of the apparatus. The preliminary result on the measurement of neutron production rate is also presented

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Histiocytic sarcoma

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A novel method for detecting HIV-I by non-radioactive in situ hybridization: Application of a peptide nucleic acid probe and catalysed signal amplification

A novel in situ hybridization (ISH) method for detecting human immunodeficiency virus-1 (HIV-1) was developed by applying a peptide nucleic acid (PNA) probe and a catalysed signal amplification (CSA) method. The PNA probe used in the present study possessed 15 base sequences of the HIV-1 protease gene, and the 5′ end of the probe was labelled with the fluorescein isothiocyanate (FITC) molecule. The hybridized probe was detected by sequential reactions of the following antibodies and reagents: horseradish peroxidase (HRP)-conjugated anti-FITC antibody, biotinylated tyramide (first amplification), HRP-labelled streptavidin, biotinylated tyramide (second amplification), and streptavidin-conjugated Alexa 488. The signal of Alexa 488 was finally detected by fluorescence microscopy. HIV-1-related dotted signals were clearly obtained in HIV-1 persistently infected cell lines, MOLT4-III_B and ACH-2, and CD4-positive T lymphocytes from AIDS patients. For light microscopy, HRP-labelled streptavidin was reacted instead of streptavidin-conjugated Alexa 488 at the final treatment, followed by diaminobenzidine as chromogen. This method can detect HIV-1 in either blood smear samples or paraffin-embedded autopsy tissue and is useful as a sensitive non-radioactive method for in situ hybridization. Copyright © 2001 John Wiley & Sons, Ltd