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  • Genetics Society of America (GSA)  (2)
  • Rockefeller University Press  (2)
  • BMJ Publishing  (1)
  • Cold Spring Harbor Laboratory Press  (1)
  • 2015-2019  (6)
  • 1
    Publication Date: 2018-03-06
    Description: Drug resistance to approved systemic therapies in estrogen receptor–positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance. FGF2-driven drug resistance in anti-estrogen–sensitive and –resistant models, including patient-derived xenografts, was reverted by neutralizing FGF2 or FGFRs. A transcriptomic signature of FGF2 signaling in primary tumors predicted shorter recurrence-free survival independently of age, grade, stage, and FGFR amplification status. These findings delineate FGF2 signaling as a ligand-based drug resistance mechanism and highlights an underdeveloped aspect of precision oncology: characterizing and treating patients according to their TME constitution.
    Keywords: Solid Tumors
    Print ISSN: 0022-1007
    Electronic ISSN: 1540-9538
    Topics: Medicine
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  • 2
    Publication Date: 2018-01-28
    Description: Objectives This study aimed to assess the relationship between infection with multiple human papillomavirus (HPV) types and abnormal anal cytology in HIV-infected men. Design An observational, cross-sectional study. Setting A regional referral hospital in Taiwan. Participants In total, 714 HIV-infected men were enrolled between March 2011 and June 2016. Thin preparation anal Pap smears were interpreted according to the 2001 Bethesda System. Thirty-seven types of HPV were detected by reverse line blotting, including 13 oncogenic types and 24 non-oncogenic types. Outcome measures The relationship between anal HPV infection and abnormal anal cytology in people of Asian ethnicity and the coverage efficacy in HPV-vaccinated HIV-infected men. Results On anal cytology, 175 (24.5%) subjects had atypical squamous cells of undetermined significance (ASCUS) or higher grades of dysplasia, including 87 (49.7%) with ASCUS, 73 (41.7%) with low-grade squamous intraepithelial lesions (LSILs) and 15 (8.6%) with high-grade squamous intraepithelial lesions (HSILs). A higher proportion of subjects with those without LSIL/HSIL (93.1% vs 67.3%, P〈0.0001) had multiple HPV types. The odds of having LSIL/HSIL increased with an increasing number of HPV types: the ORs ranged from 1 for no HPV types to 6.96 (95% CI 2.38 to 20.37) for more than five types (P trend 〈0.0001). Multivariate logistic regression analysis showed a significant association between LSIL/HSIL and the number of HPV genotypes present (OR 1.20; 95% CI 1.02 to 1.42, P〈0.05). HPV types covered by the nonavalent HPV vaccine (types 6/11/16/18/31/33/45/52/58) were detected in 70.1% of the patients in this study. Conclusions The odds of having anal LSIL/HSIL are approximately seventimes greater in HIV-infected men with than withoutsix or more types of HPV. Multiple HPV types in HIV-infected patients deserves aggressive follow-up, and HPV vaccination programme require scaling up.
    Keywords: Oncology, Open access
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 3
    Publication Date: 2018-09-18
    Description: The epithelial–mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they coregulate a set of cassette exon events, with the majority showing discordant splicing regulation. Discordant splicing events regulated by hnRNPM show a positive correlation with splicing during EMT; however, concordant events do not, indicating the role of hnRNPM in regulating alternative splicing during EMT is more complex than previously understood. Motif enrichment analysis near hnRNPM–ESRP1 coregulated exons identifies guanine–uridine rich motifs downstream from hnRNPM-repressed and ESRP1-enhanced exons, supporting a general model of competitive binding to these cis -elements to antagonize alternative splicing. The set of coregulated exons are enriched in genes associated with cell migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of coregulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtyping. This study identifies complex modes of interaction between hnRNPM and ESRP1 in regulation of splicing in disease-relevant contexts.
    Print ISSN: 1355-8382
    Electronic ISSN: 1469-9001
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2018-06-01
    Description: Recombination often differs markedly between males and females. Here we present the first analysis of sex-specific recombination in Gasterosteus sticklebacks. Using whole-genome sequencing of 15 crosses between G. aculeatus and G. nipponicus , we localized 698 crossovers with a median resolution of 2.3 kb. We also used a bioinformatic approach to infer historical sex-averaged recombination patterns for both species. Recombination is greater in females than males on all chromosomes, and overall map length is 1.64 times longer in females. The locations of crossovers differ strikingly between sexes. Crossovers cluster toward chromosome ends in males, but are distributed more evenly across chromosomes in females. Suppression of recombination near the centromeres in males causes crossovers to cluster at the ends of long arms in acrocentric chromosomes, and greatly reduces crossing over on short arms. The effect of centromeres on recombination is much weaker in females. Genomic differentiation between G. aculeatus and G. nipponicus is strongly correlated with recombination rate, and patterns of differentiation along chromosomes are strongly influenced by male-specific telomere and centromere effects. We found no evidence for fine-scale correlations between recombination and local gene content in either sex. We discuss hypotheses for the origin of sexual dimorphism in recombination and its consequences for sexually antagonistic selection and sex chromosome evolution.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 5
    Publication Date: 2018-04-03
    Description: Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration–approved drugs to prevent or treat it. We screened 4,385 small molecules in a cochlear cell line and identified 10 compounds that protected against cisplatin toxicity in mouse cochlear explants. Among them, kenpaullone, an inhibitor of multiple kinases, including cyclin-dependent kinase 2 (CDK2), protected zebrafish lateral-line neuromasts from cisplatin toxicity and, when delivered locally, protected adult mice and rats against cisplatin- and noise-induced hearing loss. CDK2-deficient mice displayed enhanced resistance to cisplatin toxicity in cochlear explants and to cisplatin- and noise-induced hearing loss in vivo. Mechanistically, we showed that kenpaullone directly inhibits CDK2 kinase activity and reduces cisplatin-induced mitochondrial production of reactive oxygen species, thereby enhancing cell survival. Our experiments have revealed the proapoptotic function of CDK2 in postmitotic cochlear cells and have identified promising therapeutics for preventing hearing loss.
    Keywords: Neuroscience
    Print ISSN: 0022-1007
    Electronic ISSN: 1540-9538
    Topics: Medicine
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  • 6
    Publication Date: 2018-02-09
    Description: The Hulunbuir short-tailed sheep ( Ovis aries ) is a breed native to China, in which the short-tail phenotype is the result of artificial and natural selection favoring a specific set of genetic mutations. Here, we analyzed the genetic differences between short-tail and normal-tail phenotypes at the genomic level. Selection signals were identified in genome-wide sequences. From 16 sheep, we identified 72,101,346 single nucleotide polymorphisms. Selection signals were detected based on the fixation index and heterozygosity. Seven genomic regions under putative selection were identified, and these regions contained nine genes. Among these genes, T was the strongest candidate as T is related to vertebral development. In T , a nonsynonymous mutation at c.G334T resulted in p.G112W substitution. We inferred that the c.G334T mutation in T leads to functional changes in Brachyury—encoded by this gene—resulting in the short-tail phenotype. Our findings provide a valuable insight into the development of the short-tail phenotype in sheep and other short-tailed animals.
    Electronic ISSN: 2160-1836
    Topics: Biology
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