Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers

Chronic viral hepatitis is the most important risk factor for progression to hepatocellular carcinoma (HCC). To identify genetic risk factors for progression to HCC in individuals with chronic hepatitis C virus (HCV), we analyzed 467,538 SNPs in 212 Japanese individuals with chronic HCV with HCC and 765 individuals with chronic HCV without HCC. We identified one intronic SNP in the DEPDC5 locus on chromosome 22 associated with HCC risk and confirmed the association using an independent case-control population (710 cases and 1,625 controls). The association was highly significant when we analyzed the stages separately as well as together (rs1012068, P(combined) = 1.27 × 10(-13), odds ratio = 1.75). The significance level of the association further increased after adjustment for gender, age and platelet count (P = 1.35 × 10(-14), odds ratio = 1.96). Our findings suggest that common variants within the DEPDC5 locus affect susceptibility to HCC in Japanese individuals with chronic HCV infection.     

Cytotoxicity of new cytochalasans fromChaetomium globosum

Zusammenfassung Nachweis, dass CHCl₃-Rohextrakte aus Myzelien und Filtraten der Zuchtmedien vonChaetomium globosum Kunze ex Fries einen akuten toxischen Effect auf HeLa-Zellen in vitro, sowie auf Mäuse zeigten. Chaetoglobosine die aus Mycelium-Rohextrakt isoliert wurden und chemisch zu den Cytochalasanen gehören, induzierten in HeLa-Zellen eine Polynukleierung und multipolare Kernverteilung. Auch beim Chaetogobosin wird eine Mikrofilament-Schädigung angenommen.     

Hypertrophy of pulmonary arteries and arterioles with cor pulmonale in rats induced by seneciphylline,a pyrrolizidine alkaloid

Summary Seneciphylline, one of the hepatotoxic pyrolizidine alkaloids, induced, as do also monoclotaline, etc., a marked arterial and arteriolar hypertrophy of the lung of young Wistar rats a month after a single s. c. injection of 50–80 mg/kg. Cor pulmonale with leftward shift of the ventricular septum was also noted.     

Loss of Siglec-14 reduces the risk of chronic obstructive pulmonary disease exacerbation

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. COPD exacerbation, or episodic worsening of symptoms, often results in hospitalization and increased mortality rates. Airway infections by new bacterial strains, such as nontypeable Haemophilus influenzae (NTHi), are a major cause of COPD exacerbation. NTHi express lipooligosaccharides that contain sialic acids, and may interact with Siglec-14, a sialic acid recognition protein on myeloid cells that serves as an activating signal transduction receptor. A null allele polymorphism in SIGLEC14 may attenuate the inflammatory responses to NTHi by eliminating Siglec-14 expression. We asked if the loss of Siglec-14 attenuates the inflammatory response by myeloid cells against NTHi, and if the SIGLEC14-null polymorphism has any effect on COPD exacerbation. We found that NTHi interacts with Siglec-14 to enhance proinflammatory cytokine production in a tissue culture model. Inhibitors of the Syk tyrosine kinase suppress this response. Loss of Siglec-14, due to SIGLEC14-null allele homozygosity, is associated with a reduced risk of COPD exacerbation in a Japanese patient population. Taken together, Siglec-14 and its downstream signaling pathway facilitate the “infection–inflammation–exacerbation” axis of COPD disease progression, and may represent promising targets for therapeutic intervention.     

A galaxy at a redshift z = 6.96

When galaxy formation started in the history of the Universe remains unclear. Studies of the cosmic microwave background indicate that the Universe, after initial cooling (following the Big Bang), was reheated and reionized by hot stars in newborn galaxies at a redshift in the range 6 < z < 14 (ref. 1). Though several candidate galaxies at redshift z > 7 have been identified photometrically, galaxies with spectroscopically confirmed redshifts have been confined to z < 6.6 (refs 4-8). Here we report a spectroscopic redshift of z = 6.96 (corresponding to just 750 Myr after the Big Bang) for a galaxy whose spectrum clearly shows Lyman-alpha emission at 9,682 A, indicating active star formation at a rate of approximately 10M(o) yr(-1), where M(o) is the mass of the Sun. This demonstrates that galaxy formation was under way when the Universe was only approximately 6 per cent of its present age. The number density of galaxies at z approximately 7 seems to be only 18-36 per cent of the density at z = 6.6.     

Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ～50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.     

Pummerer-type Functionalization of Aryl and Alkenyl Selenoxides

Heteroatom-stabilized carbenium ions have been widely recognized as potential electrophilic reagents. However, in contrast with the extensive works on thionium ion series, the highly labile character of selenoxide functionalities has caused serious limitation in the synthetic use in spite of their wide potentiality as synthetic equivalents of electrophilic selonium ions. In this paper, novel generation of selonium ions and the synthetic uses of the species for Pummerer-type α-functionalization and for cycloaddition by using the novel dienophilic behavior of π-conjugated selonium cations.     

Toxic metabolites ofAspergillus candidus

Zusammenfassung Zwei neue Toxine wurden aus den Mycelien und dem Zuchtmedium eines Schimmelpilzes,Aspergillus candidus, sowie aus dem experimentell mit demselben Pilz verschimmelten polierten Reis isoliert. Die beiden Substanzen sind sowohl chemisch als auch toxikologisch voneinander völlig verschieden.     

Syntheses and Reactions of Novel Oxidized Variants of Sterically-Crowded Chalcogenocarbonyl Compounds

1 Introduction d-Camphor and their derivatives have been widely used as chiral auxiliaries and synthons for organic synthesis, and our attempts are focused onto the new functionalization of these skeletons through the generation of oxidized variants of thiones and selones through in situ generation of novel oxidized variants of bornane-2-thiones and selones. In this paper, a novel generation and chemical conversion of these reactive intermediates are presented.1Introductiond-Camphor andtheir d…