Growing evidence indicates that microRNAs have a significant role in tumor development and may constitute robust biomarkers for cancer diagnosis and prognosis. In this study, we evaluated the ...clinical and functional relevance of microRNA-122 (miR-122) expression in human hepatocellular carcinoma (HCC). We report that miR-122 is specifically repressed in a subset of primary tumors that are characterized by poor prognosis. We further show that the loss of miR-122 expression in tumor cells segregates with specific gene expression profiles linked to cancer progression, namely the suppression of hepatic phenotype and the acquisition of invasive properties. We identify liver-enriched transcription factors as central regulatory molecules in the gene networks associated with loss of miR-122, and provide evidence suggesting that miR-122 is under the transcriptional control of HNF1A, HNF3A and HNF3B. We further show that loss of miR-122 results in an increase of cell migration and invasion and that restoration of miR-122 reverses this phenotype. In conclusion, miR-122 is a marker of hepatocyte-specific differentiation and an important determinant in the control of cell migration and invasion. From a clinical point of view, our study emphasizes miR-122 as a diagnostic and prognostic marker for HCC progression.
T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection, but the repertoire of naturally processed and presented viral epitopes on class I human leukocyte antigen (HLA-I) ...remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post infection using mass spectrometry. We found HLA-I peptides derived not only from canonical open reading frames (ORFs) but also from internal out-of-frame ORFs in spike and nucleocapsid not captured by current vaccines. Some peptides from out-of-frame ORFs elicited T cell responses in a humanized mouse model and individuals with COVID-19 that exceeded responses to canonical peptides, including some of the strongest epitopes reported to date. Whole-proteome analysis of infected cells revealed that early expressed viral proteins contribute more to HLA-I presentation and immunogenicity. These biological insights, as well as the discovery of out-of-frame ORF epitopes, will facilitate selection of peptides for immune monitoring and vaccine development.
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•Time course analysis of HLA-I immunopeptidome in SARS-CoV-2-infected cells•25% of detected HLA-I peptides originated from out-of-frame ORFs in S and N•Some out-of-frame peptides elicited stronger T cell responses than canonical peptides•Early expressed viral proteins dominated HLA-I presentation and immunogenicity
Analysis of the HLA-I peptidome of SARS-CoV-2 infection identifies peptides derived from canonical and out-of-frame ORFs in viral S and N protein that are not captured by current vaccines and yield potent T cell responses in a mouse model as well as individuals with COVID-19.
Two related Rho GTPase-activating proteins, DLC-1 (deleted in liver cancer 1) and DLC-2, are emerging as bona fide tumor suppressor genes that inhibit cancer cell growth. In this report, we ...characterized a gene on chromosome Xq13 that encodes DLC-3 (also known as KIAA0189 and STARD8), a third member of the DLC family. The DLC-3 gene has transcripts with alternative 5' ends, one of which, DLC-3alpha, encodes an 1103-amino acid polypeptide highly similar to DLC-1 and DLC-2. A second isoform (DLC-3beta) would yield a protein lacking the N-terminal sterile alpha motif domain. The DLC-3 gene is widely expressed in normal tissues, but DLC-3 mRNA levels were low or absent in a significant number of breast, ovarian, liver and prostate cancer cell lines. Using a cancer profiling array to compare matched tumor and normal human tissues, downregulation of DLC-3 mRNA was observed in kidney, lung, ovarian, uterine and breast cancer samples. By quantitative reverse transcriptase-polymerase chain reaction, DLC-3 expression was reduced in primary prostate carcinomas relative to normal prostate tissue. Transfection of human breast and prostate cancer cells with a DLC-3alpha expression vector inhibited cell proliferation, colony formation and growth in soft agar. These results indicate that deregulation of DLC-3 may contribute to breast and prostate tumorigenesis.
The WWOX (WW-domain containing oxidoreductase) is a candidate tumour suppressor gene spanning the same chromosome region, 16q23, as the second most common fragile site (FS), FRA16D. Deletions ...detected by comparative genomic hybridisation (CGH) and loss of heterozygosity at microsatellite markers on chromosome 16q are common in many human cancers including hepatocellular carcinoma (HCC). The development of human HCC is closely associated with exposure to oncogenic viruses and chemical carcinogens, agents known to frequently target common FS. We examined the status of WWOX genomic DNA, RNA and protein in 18 cell lines derived from human HCC and found recurrent alterations of the gene. Loss of DNA copy-number confined to band 16q23 was detected by CGH in several cell lines. Although homozygous deletions of the WWOX gene were not detected, WWOX mRNA expression was absent or lower in 60% of cell lines. The occurrence of aberrant WWOX reverse transcription-PCR products with deletion of exons 6-8 correlated significantly with altered WWOX expression. All of the cell lines showing mRNA downregulation had a decreased or undetectable level of WWOX protein as demonstrated by Western blotting with antibody to WWOX. Furthermore, 13 out of the 18 cell lines expressed decreased levels or no WWOX protein when compared with normal liver. These results show that WWOX gene is frequently altered in HCC and raise the possibility that this gene is implicated in hepatocarcinogenesis.
The large Juneau and Stikine icefields (Alaska) lost mass rapidly in the
second part of the 20th century. Laser altimetry, gravimetry and field
measurements suggest continuing mass loss in the early ...21st century. However,
two recent studies based on time series of Shuttle Radar Topographic Mission (SRTM) and
Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) digital elevation
models (DEMs) indicate a slowdown in mass loss after 2000. Here, the
ASTER-based geodetic mass balances are recalculated carefully avoiding the
use of the SRTM DEM because of the unknown penetration depth of the C-band
radar signal. We find strongly negative mass balances from 2000 to 2016
(−0.68 ± 0.15 m w.e. a−1 for the Juneau Icefield and
−0.83 ± 0.12 m w.e. a−1 for the Stikine Icefield), in
agreement with laser altimetry, confirming that mass losses are continuing at
unabated rates for both icefields. The SRTM DEM should be avoided or used
very cautiously to estimate glacier volume change, especially in the North
Hemisphere and over timescales of less than ∼ 20 years.
GTF2IRD1 in Craniofacial Development of Humans and Mice Tassabehji, May; Hammond, Peter; Karmiloff-Smith, Annette ...
Science (American Association for the Advancement of Science),
11/2005, Letnik:
310, Številka:
5751
Journal Article
Recenzirano
Craniofacial abnormalities account for about one-third of all human congenital defects, but our understanding of the genetic mechanisms governing craniofacial development is incomplete. We show that ...GTF2IRD1 is a genetic determinant of mammalian craniofacial and cognitive development, and we implicate another member of the TFII-I transcription factor family, GTF2I, in both aspects. Gtf2ird1-null mice exhibit phenotypic abnormalities reminiscent of the human microdeletion disorder Williams-Beuren syndrome (WBS); craniofacial imaging reveals abnormalities in both skull and jaws that may arise through misregulation of goosecoid, a downstream target of Gtf2ird1. In humans, a rare WBS individual with an atypical deletion, including GTF2IRD1, shows facial dysmorphism and cognitive deficits that differ from those of classic WBS cases. We propose a mechanism of cumulative dosage effects of duplicated and diverged genes applicable to other human chromosomal disorders.
The serotonin (5-HT) receptor subtype mediating inhibition of neurogenic dural inflammation in guinea pigs was investigated using a series of serotonin agonists with differing affinities for the ...5-HT1B, 5-HT1D and 5-HT1F receptors. When agonist potencies for inhibiting neurogenic inflammation were compared with affinities for these receptor subtypes, a significant positive correlation was seen only with the 5-HT1F receptor. The potency of agonists in inhibiting adenylate cyclase in cells transfected with human 5-HT1F receptor was also highly correlated with their potency in the animal model of migraine. In situ hybridization demonstrated 5-HT1F receptor mRNA in guinea pig trigeminal ganglion neurons. These data suggest that the 5-HT1F receptor is a rational target for migraine therapeutics.
The relative effects of antiepileptic drugs (AEDs) on cognition are controversial. We compared the cognitive effects of phenobarbital, phenytoin, and valproate in 59 healthy adults using a ...randomized, double-blind, incomplete-block, crossover design. Cognitive assessments were conducted at baseline, after 1 month on each drug (two AEDs per subject), and at two repeat baselines 11 weeks after each AED treatment. The neuropsychological battery included 12 tests, yielding 22 variables: Choice Reaction Time, P3 Event-Related Potential, Finger Tapping, Lafayette Grooved Pegboard, Selective Reminding Test, Paragraph Memory, Complex Figures, Symbol Digit Modalities Test, Stroop Test, Visual Serial Addition Test, Hopkins Symptom Checklist, and Profile of Mood States. More than one-half of the variables exhibited AED effects when compared with nondrug baselines, and all three AEDs produced some untoward effects. Differential AED effects on cognition were present for approximately one-third of the variables. Phenobarbital produced the worst performance; there was no clinically significant difference between phenytoin and valproate.
Adolescent Bullying and Sleep Difficulties Hunter, Simon C.; Durkin, Kevin; Boyle, James M. E. ...
Europe's journal of psychology,
11/2014, Letnik:
10, Številka:
4
Journal Article
Recenzirano
Odprti dostop
This study evaluated whether adolescents who report having been bullied, being bullies, or report both being a bully and being bullied experience more sleep difficulties than children uninvolved in ...bullying. The study drew upon cognitive theories of insomnia, investigating whether the extent to which young people report worrying about bullying can moderate associations between victimization and sleep difficulties. Participants were 5420 adolescents who completed a self-report questionnaire. Pure Victims (OR = 1.72, 95% CI 1.07, 2.75), Pure Bullies (OR = 1.80, 95% CI 1.16, 2.81), and Bully-Victims (OR = 2.90, 95% CI 1.17, 4.92) were all more likely to experience sleep difficulties when compared to uninvolved young people. The extent to which young people reported worrying about being bullied did not moderate the links between victimization and sleep difficulties. In this way, bullying is clearly related to sleep difficulties among adolescents but the conceptual reach of the cognitive model of insomnia in this domain is questioned.
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