No abstract

Whether aspirin use is protective against cholangiocarcinoma (CCA) remains unclear. We determined the association between aspirin use and other risk factors for each CCA subtype individually. In a hospital-based case-control study, 2395 CCA cases (1169 intrahepatic, 995 perihilar, and 231 distal) seen at the Mayo Clinic, Rochester, MN, from 2000 through 2014 were enrolled. Controls selected from the Mayo Clinic Biobank were matched two to one with cases by age, sex, race, and residence (n 5 4769). Associations between aspirin use, other risk factors, and CCA risk were determined. Aspirin was used by 591 (24.7%) CCA cases and 2129 (44.6%) controls. There was a significant inverse association of aspirin use with all CCA subtypes, with adjusted odds ratios (AORs) of 0.35 (95% confidence interval [CI], 0.29-0.42), 0.34 (95% CI 0.27-0.42), and 0.29 (95% CI 0.19-0.44) for intrahepatic, perihilar, and distal CCA, respectively (P < 0.001 for all). Primary sclerosing cholangitis was more strongly associated with perihilar (AOR 5 453, 95% CI 104-999) than intrahepatic (AOR 5 93.4, 95% CI 27.1-322) or distal (AOR 5 34.0, 95% CI 3.6-323) CCA, whereas diabetes was more associated with distal (AOR 5 4.2, 95% CI 2.5-7.0) than perihilar (AOR 5 2.9, 95% CI 2.2-3.8) or intrahepatic (AOR 5 2.5, 95% CI 2.0-3.2) CCA. Cirrhosis not related to primary sclerosing cholangitis was associated with both intrahepatic and perihilar CCA, with similar AORs of 14. Isolated inflammatory bowel disease without primary sclerosing cholangitis was not associated with any CCA subtype. Conclusions : Aspirin use was significantly associated with a 2.7-fold to 3.6-fold decreased risk for the three CCA subtypes; our study demonstrates that individual risk factors confer risk of different CCA subtypes to different extents.

We have fabricated Mn-doped Bi 2 Te 3 and Sb 2 Te 3 single crystals by the vertical gradient solidification method. The compositions and crystal structures of Bi 2-x Mn x Te 3 and Sb 2-x Mn x Te 3 were determined using Electron Probe Micro-Analyzer (EPMA) and powder X-ray diffraction (XRD) patterns, respectively. Both crystal structures were rhombohedral with smaller lattice constants because of the smaller atomic radius of Mn than those of Bi and Sb. Based on the magnetization measurements, Mn-doped Bi 2 Te 3 and Sb 2 Te 3 compounds have ferromagnetic ordering at T C = 10 and 17 K, respectively.

A fusion between the EML4 (echinoderm microtubule-associated protein-like) and ALK (anaplastic lymphoma kinase) genes was identified in non-small cell lung cancer (NSCLC) in 2007 and there has been rapid progress in applying this knowledge to the benefit of patients. However, we have a poor understanding of EML4 and ALK biology and there are many challenges to devising the optimal strategy for treating EML4-ALK NSCLC patients. In this review, we describe the biology of EML4 and ALK, explain the main features of EML4-ALK fusion proteins and outline the therapies that target EML4-ALK. In particular, we highlight the recent advances in our understanding of the structures of EML proteins, describe the molecular mechanisms of resistance to ALK inhibitors and assess current thinking about combinations of ALK drugs with inhibitors that target other kinases or Hsp90.

Prominence, the expression of informational weight within utterances, can be signaled by prosodic highlighting ( head-prominence, as in English) or by position (as in Korean edge-prominence). Prominence confers processing advantages, even if conveyed only by discourse manipulations. Here we compared processing of prominence in English and Korean, using a task that indexes processing success, namely recognition memory. In each language, participants’ memory was tested for target words heard in sentences in which they were prominent due to prosody, position, both or neither. Prominence produced recall advantage, but the relative effects differed across language. For Korean listeners the positional advantage was greater, but for English listeners prosodic and syntactic prominence had equivalent and additive effects. In a further experiment semantic and phonological foils tested depth of processing of the recall targets. Both foil types were correctly rejected, suggesting that semantic processing had not reached the level at which word form was no longer available. Together the results suggest that prominence processing is primarily driven by universal effects of information structure; but language-specific differences in frequency of experience prompt different relative advantages of prominence signal types. Processing efficiency increases in each case, however, creating more accurate and more rapidly contactable memory representations.

Human umbilical cord mesenchymal stromal cells (hUC-MSCs) of Wharton's jelly origin undergo adipogenic, osteogenic, and chondrogenic differentiation in vitro. Recent studies have consistently shown their therapeutic potential in various human disease models. However, the biological effects of major pregnancy complications on the cellular properties of hUC-MSCs remain to be studied. In this study, we compared the basic properties of hUC-MSCs obtained from gestational diabetes mellitus (GDM) patients (GDM-UC-MSCs) and normal pregnant women (N-UC-MSCs). Assessments of cumulative cell growth, MSC marker expression, cellular senescence, and mitochondrial function-related gene expression were performed using a cell count assay, senescence-associated b-galactosidase staining, quantitative real-time reverse transcription-polymerase chain reaction, immunoblotting, and cell-based mitochondrial functional assay system. When compared with N-UCMSCs, GDM-UC-MSCs showed decreased cell growth and earlier cellular senescence with accumulation of p16 and p53, even though they expressed similar levels of CD105, CD90, and CD73 MSC marker proteins. GDM-UC-MSCs also displayed significantly lower osteogenic and adipogenic differentiation potentials than N-UC-MSCs. Furthermore, GDM-UC-MSCs exhibited a low mitochondrial activity and significantly reduced expression of the mitochondrial function regulatory genes ND2, ND9, COX1, PGC-1a, and TFAM. Here, we report intriguing and novel evidence that maternal metabolic derangement during gestation affects the biological properties of fetal cells, which may be a component of fetal programming. Our findings also underscore the importance of the critical assessment of the biological impact of maternal-fetal conditions in biological studies and clinical applications of hUC-MSCs.

This study investigates whether the learning of prosodic cues to word boundaries in speech segmentation is more difficult if the native and second/foreign languages (L1 and L2) have similar (though non-identical) prosodies than if they have markedly different prosodies (Prosodic-Learning Interference Hypothesis). It does so by comparing French, Korean, and English listeners’ use of fundamental-frequency (F0) rise as a cue to word-final boundaries in French. F0 rise signals phrase-final boundaries in French and Korean but word-initial boundaries in English. Korean-speaking and English-speaking L2 learners of French, who were matched in their French proficiency and French experience, and native French listeners completed a visual-world eye-tracking experiment in which they recognized words whose final boundary was or was not cued by an increase in F0. The results showed that Korean listeners had greater difficulty using F0 rise as a cue to word-final boundaries in French than French and English listeners. This suggests that L1–L2 prosodic similarity can make the learning of an L2 segmentation cue difficult, in line with the proposed Prosodic-Learning Interference Hypothesis. We consider mechanisms that may underlie this difficulty and discuss the implications of our findings for understanding listeners’ phonological encoding of L2 words.

Human umbilical cord mesenchymal stem cells (hUC-MSCs), originating in Wharton’s jelly, are multipotent stem cells that home to damaged tissues and can modulate the immune system. We examined whether administering extracts of MSCs (MSC-Ex) instead of MSCs could augment the beneficial effects of MSC therapy by overcoming the low homing efficiency of MSCs systemically administered in inflammatory bowel diseases (IBD). Dextran sodium sulfate-induced colitis model was established in C57BL/6 mice, and MSC-Ex was administered intraperitoneally. MSC-Ex reduced colitis, disease activity index (DAI), and histological colitis scores, and increased the body weight. Treatment with MSC-Ex completely blocked the induction of inflammatory cytokines, which were strongly detected in mice with colitis. MSC-Ex shifted the macrophage functional phenotype from M1 to M2 by decreasing the levels of MCP1, CXCL9, and iNOS, but increasing the levels of IL-10, LIGHT, CCL1, and Arg-1. MSC-Ex recovered the destruction of the epithelial barrier in the differentiated Caco-2 cells in vitro. Treatment with MSC-Ex was more potent than that with MSC in reducing DAI, the histological score, and nitrite levels. These data strongly support that MSC-Ex treatment can be a potent approach to overcome severe refractory IBD.