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  • BMJ Publishing Group  (20)
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  • 1
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    Interferon-microRNA signalling drives liver precancerous lesion formation and hepatocarcinogenesis (2016)
    BMJ Publishing Group
    In: Gut
    Details
    Publication Date: 2016-06-04
    Description: Objective Precancerous lesion, a well-established histopathologically premalignant tissue with the highest risk for tumourigenesis, develops preferentially from activation of DNA damage checkpoint and persistent inflammation. However, little is known about the mechanisms by which precancerous lesions are initiated and their physiological significance. Design Laser capture microdissection was used to acquire matched normal liver, precancerous lesion and tumour tissues. miR-484 –/– , Ifnar1 –/– and Tgfbr2 hep mice were employed to determine the critical role of the interferon (IFN)–microRNA pathway in precancerous lesion formation and tumourigenesis. RNA immunoprecipitation (RIP), pull-down and chromatin immunoprecipitation (ChIP) assays were applied to explore the underlying mechanisms. Results miR-484 is highly expressed in over 88% liver samples clinically. DEN-induced precancerous lesions and hepatocellular carcinoma were dramatically impaired in miR-484 –/– mice. Mechanistically, ectopic expression of miR-484 initiates tumourigenesis and cell malignant transformation through synergistic activation of the transforming growth factor-β/Gli and nuclear factor-B/type I IFN pathways . Specific acetylation of H3K27 is indispensable for basal IFN-induced continuous transcription of miR-484 and cell transformation. Convincingly, formation of precancerous lesions were significantly attenuated in both Tgfbr2 hep and Ifnar1 –/– mice. Conclusions These findings demonstrate a new protumourigenic axis involving type I IFN–microRNA signalling, providing a potential therapeutic strategy to manipulate or reverse liver precancerous lesions and tumourigenesis.
    Keywords: Editor's choice, Hepatic cancer
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 2
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    IGFBP-5 overexpression as a poor prognostic factor in patients with urothelial carcinomas of upper urinary tracts and urinary bladder (2013)
    BMJ Publishing Group
    Details
    Publication Date: 2013-06-22
    Description: Background Urothelial carcinoma (UC) is prevalent worldwide. Dysregulation of cell growth is a critical event of tumorigenesis and has not been assessed systemically in UC. We thus assessed the published transcriptome of urinary bladder urothelial carcinoma (UBUC) and identified insulin-like growth factor-binding protein-5 (IGFBP-5) as the most significantly upregulated gene associated with the regulation of cell growth. Moreover, validated by using public domain data set, IGFBP-5 expression also significantly predicted worse outcome. IGFBP-5 is one of the binding proteins that regulate insulin-like growth factors (IGFs) and its significance has not been comprehensively evaluated in UCs. Methods Using immunohistochemistry, we evaluated the IGFBP-5 expression status and its associations with clinicopathological features and survival in 340 cases of upper urinary tract urothelial carcinoma (UTUC) and 295 cases of UBUC. Western blot analysis was used to evaluate IGFBP-5 protein expression in human urothelial cell (HUC) lines. Results IGFBP-5 overexpression was significantly associated with advanced pT stage (p〈0.001), high histological grade (UTUC, p〈0.001; UBUC, p=0.035), lymph node metastasis (UTUC, p=0.006; UBUC, p=0.004), vascular invasion (UTUC, p〈0.001; UBUC, p=0.003), perineural invasion (UTUC, p=0.034; UBUC, p=0.021) and frequent mitosis (UTUC, p〈0.001; UBUC, p=0.023). IGFBP-5 overexpression also independently predicted poor disease-specific survival and metastasis-free survival in both groups of patients. Western blot analysis showed IGFBP-5 protein as overexpressed in human urothelial cancer cell lines and not in normal urothelial cancer cells. Conclusions IGFBP-5 plays an important role in tumour progression in UC. Its overexpression is associated with advanced tumour stage and conferred poorer clinical outcome.
    Keywords: Immunology (including allergy)
    Print ISSN: 0021-9746
    Electronic ISSN: 1472-4146
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 3
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    Utility of bone marrow examination for workup of fever of unknown origin in patients with HIV/AIDS (2015)
    BMJ Publishing Group
    Details
    Publication Date: 2015-02-17
    Description: Aims The utility of bone marrow aspiration and biopsy (BMAB) as a diagnostic tool in patients with HIV/AIDS and fever of unknown origin (FUO) is a subject of debate. Because highly active antiretroviral therapy has reduced incidence of opportunistic infections, it is important to reassess the efficacy of BMAB for this diagnostic purpose. To our knowledge, no such studies have been performed in Harris County which has the highest incidence of HIV in the state of Texas. Methods We reviewed all BMABs from patients with HIV/AIDS and FUO or persistent cytopenia(s) from 2007 to 2011. Results Of 57 evaluable patients, BMAB was positive in 24 samples by acid fast bacilli (AFB) or Gomori methenamine silver (GMS) stains (17.5%), presence of granuloma and/or lymphohistiocytic aggregates (31.6%), culture (21.0%) or a combination. Cultures demonstrated Mycobacterium avium/intracellulare (4), M tuberculosis (2), M gordonae (1), Histoplasma capsulatum (3) and Cryptococcus neoformans (2). There were three cases in which a pathogen was grown in culture but that had a negative of ‘direct examination’ on tissue sections (negative AFB and GMS special stains, no morphological evidence of granuloma/lymphohistiocytic infiltrates). Conclusions This study supports the use of diagnostic BMAB as a rapid decision-making tool in patients with HIV and FUO in the proper clinical setting. BMAB demonstrated infection-related evidence prior to positive bone marrow culture in 75% of cases. Special stains and blood cultures had similar diagnostic yield, but BMAB offers faster results. Thus, this procedure assists in clinical decision making and the refinement of treatment in a more timely manner.
    Keywords: Sexual transmitted infections (viral), Immunology (including allergy), HIV/AIDS, Clinical diagnostic tests
    Print ISSN: 0021-9746
    Electronic ISSN: 1472-4146
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 4
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    {alpha}-Methylacyl-CoA racemase (AMACR) serves as a prognostic biomarker for the early recurrence/metastasis of HCC (2014)
    BMJ Publishing Group
    Details
    Publication Date: 2014-10-17
    Description: Aims Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it is still lacking effective prognostic biomarkers so far. Previous results of the iTRAQ-based quantitative proteomics study (iTRAQ-2DLC-MS/MS) have shown that α-methylacyl-CoA racemase (AMACR) might be a promising prognostic biomarker for the early recurrence/metastasis of hepatocellular carcinoma (HCC). Here a large-scale cohort clinical study was performed to evaluate its prognostic potential. Methods HCC samples from patients (n=158) were used for the construction of tissue microarray. The expression level of AMACR was determined by immunohistochemical staining. A large-scale cohort clinical study between the expression of AMACR and some major clinical parameter has been performed to assess the prognostic potential of AMACR for the early recurrence/metastasis of HCC. Results Some important clinical parameters such as α-fetoprotein, tumour numbers, dissemination to regional lymph nodes, tumour capsule and portal vein tumour thrombosis are significantly associated with the low expression of AMACR. The expression of AMACR was an independent factor for the survival of patients with HCC. The median survival time was 17 months in the low-expression group compared with 45 months in the high-expression group. Conclusions This study reveals that the AMACR might be a potential prognostic marker for predicting early recurrence/metastasis of HCC after hepatectomy.
    Keywords: Open access, Immunology (including allergy), Hepatic cancer
    Print ISSN: 0021-9746
    Electronic ISSN: 1472-4146
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 5
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    Lymphocyte subsets contribute to the degree of lobulitis and ductitis in sclerosing lymphocytic lobulitis of the breast (2016)
    BMJ Publishing Group
    Details
    Publication Date: 2016-05-20
    Description: Aims Sclerosing lymphocytic lobulitis (SLL) of the breast is characterised by lymphocytic lobulitis, ductitis, vasculitis and dense keloidal fibrosis with epithelioid fibroblasts. However, the subsets of the infiltrating lymphocytes and their contribution to disease progression have not been fully explored. Methods CD20, CD3, CD4, CD8 and regulatory T (Treg) lymphocytes were evaluated in the epithelial and vascular areas in SLL. The relationship between the lymphocyte subset in different regions and the degree of inflammation was analysed. Results Lymphocytic infiltration was mainly located in peri-lobular, peri-ductal and peri-vascular areas. No significant differences between CD20 and CD3 lymphocytes were found in peri-epithelial areas. However, there were more intra-ductal/lobular epithelial CD3 than CD20 lymphocytes (p〈0.001). For T lymphocyte subsets, more CD4 than CD8 lymphocytes were found in the peri-lobular/vascular regions (p≤0.026); but an opposite trend was seen in the intra-ductal/lobular regions (p〈0.001). In the peri-lobular/vascular regions, generally, different lymphocyte subsets correlated with each other. Interestingly, in the peri-ductal region, only CD4 lymphocytes showed significant correlations with all other subsets (p≤0.020). Regarding their relationship with the degree of inflammation, significant positive correlations were observed for all subsets in peri-vascular/lobular regions (p≤0.045). Only regulatory T cells, but not the others, at the peri-ductal region showed significant correlation with the degree of inflammation at all three regions (p≤0.014). Conclusions In addition to B lymphocyte subsets, T lymphocyte subsets could be involved differently in SLL. CD4 lymphocytes may have a pivotal role in recruiting other subsets to the inflamed site, and triggered the cascade of inflammatory changes resulting in fibrosis.
    Keywords: Immunology (including allergy), Inflammation, Vascularitis
    Print ISSN: 0021-9746
    Electronic ISSN: 1472-4146
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 6
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    Elevated expression of ASCL2 is an independent prognostic indicator in lung squamous cell carcinoma (2016)
    BMJ Publishing Group
    Details
    Publication Date: 2016-03-18
    Description: Aims ASCL2, a basic helix-loop-helix (bHLH) transcription factor, is putatively involved in tumour progression. This study aimed to evaluate ASCL2 expression level in non-small-cell carcinoma (NSCLC) and assess its prognostic value for patients. Methods ASCL2 protein expression was detected by immunohistochemistry (IHC cohort) in 79 cases of squamous cell carcinoma (SCC) and 67 cases of adenocarcinoma (AC). Kaplan–Meier analysis and Cox regression analysis were performed to evaluate the prognostic significance of ASCL2. The same analyses were conducted in a cohort (n=790) from The Cancer Genome Atlas database (TCGA) to validate the expression pattern and prognostic value of ASCL2. Results ASCL2 expression levels were significantly increased in SCC compared with normal lung tissue (p〈0.001) and AC (p=0.008). High ASCL2 expression was associated with advanced tumour-node-metastasis (TNM) stage (p=0.023) and worse differentiation status (p=0.001) in SCC, but a positive correlation between ASCL2 expression level and advanced TNM stage (p=0.016) was observed in AC. Kaplan–Meier analysis showed that ASCL2 was prognostic in SCC (p=0.004) but not in AC (p=0.183). Multivariable Cox regression analysis indicated that elevated expression of ASCL2 was an independent prognostic factor (HR 2.764; p=0.030) in SCC patients. The expression pattern and prognostic significance of ASCL2 in SCC and AC were validated using the TCGA cohort. Conclusions Elevated expression of ASCL2 may identify an aggressive subgroup in SCC and serve as an independent prognostic indicator in these patients.
    Keywords: Immunology (including allergy)
    Print ISSN: 0021-9746
    Electronic ISSN: 1472-4146
    Topics: Medicine
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  • 7
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    Comparison of MRI with liver-specific contrast agents and multidetector row CT for the detection of hepatocellular carcinoma: a meta-analysis of 15 direct comparative studies (2013)
    BMJ Publishing Group
    In: Gut
    Details
    Publication Date: 2013-09-15
    Description: We read with great interest the paper by Tremosini et al 1 which prospectively assessed the diagnostic performance of a panel of markers (glypican 3, heat shock protein 70, and glutamine synthetase) for small (〈20 mm) hepatocellular carcinoma (HCC) in patients with cirrhosis. This study showed that the panel of markers is a useful diagnostic approach for the diagnosis of small HCC. It had a high specificity (100%) but a relatively low sensitivity (60%) when at least two of the markers (regardless of which) were positive. To diagnose HCC, some useful, non-invasive imaging tests, such as CT and MRI, can also be used. The guidelines recently updated by the American Association for the Study of Liver Diseases (AASLD) state that a non-invasive diagnosis of HCC can be made if a lesion 〉10 mm has a typical vascular enhancement pattern in 4-phase multidetector row CT (MDCT) or dynamic contrast enhanced...
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
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  • 8
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    Cognitive function and plasma BDNF levels among manganese-exposed smelters (2014)
    BMJ Publishing Group
    Details
    Publication Date: 2014-02-07
    Description: Objectives To explore the potential dose–response relationship between manganese (Mn) exposure and cognitive function and also plasma brain-derived neurotrophic factor (BDNF) levels in occupational Mn exposure workers. Methods A total 819 workers were identified from our Mn-exposed workers, and 293 control workers were recruited in the same region. All exposed workers were divided into three groups based on Mn cumulative exposure index. The Montreal Cognitive Assessment (MoCA) test was applied to estimate cognitive function for all subjects. Plasma BDNF levels were determined by ELISA in 248 selected exposed workers and 100 controls. Results Mn-exposed workers had significantly lower MoCA scores than those in the control group (25.62±0.25): those in high-exposure group had the lowest scores (21.33±0.32), compared with the intermediate-exposure group (23.22±0.30) and low-exposure group (23.57±0.23). Mn exposure levels were inversely associated with MoCA total scores, all p〈0.05. A positive correlation was found between plasma BDNF levels and MoCA total scores (r=0.278, p〈0.01). Moreover, compared with the control group (288.7±181.7 pg/mL), BDNF levels were lower in the high-exposure group (127.5±99.8 pg/mL), and in the intermediate-exposure (178.2±138.1 pg/mL) and low-exposure groups (223.4±178.3 pg/mL). Additionally, plasma BDNF levels decreased significantly as Mn exposure levels increased (p trend 〈0.01). Conclusions Mn exposure may be associated with decreased plasma BDNF levels and cognition impairment in this large cross-sectional study.
    Print ISSN: 1351-0711
    Electronic ISSN: 1470-7926
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 9
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    A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma (2014)
    BMJ Publishing Group
    In: Gut
    Details
    Publication Date: 2014-04-08
    Description: Objective Hepatocellular carcinoma (HCC) is a heterogeneous tumour displaying a complex variety of genetic and epigenetic changes. In human cancers, aberrant post-transcriptional modifications, such as alternative splicing and RNA editing, may lead to tumour specific transcriptome diversity. Design By utilising large scale transcriptome sequencing of three paired HCC clinical specimens and their adjacent non-tumour (NT) tissue counterparts at depth, we discovered an average of 20 007 inferred A to I (adenosine to inosine) RNA editing events in transcripts. The roles of the double stranded RNA specific ADAR (Adenosine DeAminase that act on RNA) family members (ADARs) and the altered gene specific editing patterns were investigated in clinical specimens, cell models and mice. Results HCC displays a severely disrupted A to I RNA editing balance. ADAR1 and ADAR2 manipulate the A to I imbalance of HCC via their differential expression in HCC compared with NT liver tissues. Patients with ADAR1 overexpression and ADAR2 downregulation in tumours demonstrated an increased risk of liver cirrhosis and postoperative recurrence and had poor prognoses. Due to the differentially expressed ADAR1 and ADAR2 in tumours, the altered gene specific editing activities, which was reflected by the hyper-editing of FLNB (filamin B, β) and the hypo-editing of COPA (coatomer protein complex, subunit α), are closely associated with HCC pathogenesis. In vitro and in vivo functional assays prove that ADAR1 functions as an oncogene while ADAR2 has tumour suppressive ability in HCC. Conclusions These findings highlight the fact that the differentially expressed ADARs in tumours, which are responsible for an A to I editing imbalance, has great prognostic value and diagnostic potential for HCC.
    Keywords: Cirrhosis, Open access, Hepatic cancer
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
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  • 10
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    Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study (2017)
    BMJ Publishing Group
    In: Gut
    Details
    Publication Date: 2017-12-13
    Description: Objective Proton pump inhibitors (PPIs) is associated with worsening of gastric atrophy, particularly in Helicobacter pylori (HP)-infected subjects. We determined the association between PPIs use and gastric cancer (GC) among HP-infected subjects who had received HP therapy. Designs This study was based on a territory-wide health database of Hong Kong. We identified adults who had received an outpatient prescription of clarithromycin-based triple therapy between year 2003 and 2012. Patients who failed this regimen, and those diagnosed to have GC within 12 months after HP therapy, or gastric ulcer after therapy were excluded. Prescriptions of PPIs or histamine-2 receptor antagonists (H2RA) started within 6 months before GC were excluded to avoid protopathic bias. We evaluated GC risk with PPIs by Cox proportional hazards model with propensity score adjustment. H2RA was used as a negative control exposure. Result Among the 63 397 eligible subjects, 153 (0.24%) developed GC during a median follow-up of 7.6 years. PPIs use was associated with an increased GC risk (HR 2.44, 95% CI 1.42 to 4.20), while H2RA was not (HR 0.72, 95% CI 0.48 to 1.07). The risk increased with duration of PPIs use (HR 5.04, 95% CI 1.23 to 20.61; 6.65, 95% CI 1.62 to 27.26 and 8.34, 95% CI 2.02 to 34.41 for ≥1 year, ≥2 years and ≥3 years, respectively). The adjusted absolute risk difference for PPIs versus non-PPIs use was 4.29 excess GC (95% CI 1.25 to 9.54) per 10 000 person-years. Conclusion Long-term use of PPIs was still associated with an increased GC risk in subjects even after HP eradication therapy.
    Keywords: Gut
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
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