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  • 1
    Publication Date: 2018-05-17
    Description: Cholinesterase activity (ChA), the effective biomarker for organophosphate pesticide exposure, is possibly affected by single nucleotide polymorphisms (SNPs) in cell-cycle-related genes. One hundred and eighty workers with long-term exposure to omethoate and 115 healthy controls were recruited to explore the gene–gene and gene–environment interactions. The acetylthiocholine and dithio-bis-(nitrobenzoic acid) method was used to detect the cholinesterase activities in whole blood, erythrocytes and plasma. Genetic polymorphisms were determined by the PCR-RFLP and direct PCR electrophoresis methods. Statistical results showed that the cholinesterase activities of whole blood, erythrocytes and plasma in the exposure group were significantly lower than those in the control group ( p 〈 0.001), and erythrocyte cholinesterase activities were associated with gender, smoking and drinking in the exposure group ( p 〈 0.05). Single-locus analyses showed that there is a statistically significant difference in the ChA among the genotypes CC, CA and AA of the p21 rs1801270 locus in the control group ( p = 0.033), but not in the exposure group. A significant interaction between genes and environmental factors (i.e. p53 , p21 , mdm2, gender, smoking and drinking) affecting ChA was found through a generalized multifactor dimensionality reduction analysis. These obtained markers will be useful in further marker-assisted selection in workers with exposure to omethoate.
    Keywords: molecular biology, genetics, environmental science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 2
    Publication Date: 2018-02-09
    Description: Introduction Circulating tumour DNA (ctDNA) has potential applications in cancer management. Most previous studies about ctDNA focused on advanced stage cancer patients. We have completed a clinical prospective study (NCT02645318) and showed the feasibility and clinical application of ctDNA detection in early stage non-small cell lung cancer (NSCLC) patients. The aim of this study is to investigate the elimination rate of ctDNA level after surgery. This is the first prospective study to evaluate the perioperative dynamic changes of ctDNA in surgical lung cancer patients. Methods and analysis This is a prospective observational study to determine the elimination rate of circulating tumour DNA after surgery. Consecutive patients with suspected lung cancer who undergo curative-intent lung resection will be enrolled. 10 mL blood samples are taken by intravenous puncture. Plasma samples are obtained before surgery (time A) and at a series of scheduled time-points (2 min to 72 hours, time B to F) after tumour resection. DNA is prepared from 4 mL of purified plasma. A multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART) is used to simultaneously detect and quantitate hot spot EGFR, KRAS, BRAF, ERBB2, PIK3CA, TP53, ALK, RET and MET plasma DNA variants. Positive plasma mutations are validated in tumour tissue and normal lung tissue by targeted sequencing. Ethics and dissemination Ethical approval has been obtained from the Peking University People’s Hospital Medical Ethics Committee (2016PHB156-01). Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. Trial registration number NCT02965391 ; Pre-results.
    Keywords: Open access, Oncology
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 3
    Publication Date: 2018-10-03
    Description: Malignant melanoma is an aggressive tumor of the skin and still lacks effective preventive and therapeutic treatments. In melanoma, both the BRAF/MEK/ERK and PI3-K/AKT signaling pathways are constitutively activated through multiple mechanisms, which result in cell-cycle progression and prevention of apoptosis. Therefore, the development of novel strategies for targeting BRAF and PI3K are of utmost importance. In this study, we found that Ashitaba ( Angelica keiskei ) chalcones, 4-hydroxyderricin (4HD) and xanthoangelol (XAG), suppressed melanoma development by directly targeting both BRAFV600E and PI3K, which blocked the activation of downstream signaling. This led to the induction of G 1 phase cell-cycle arrest and apoptosis in melanoma cells. Importantly, 4HD or XAG dramatically attenuated tumor incidence and volume in the BRAF-activated Pten -deficient melanoma mouse model. Our findings suggest that 4HD and XAG are promising chemopreventive or potential therapeutic agents against melanomagenesis that act by targeting both BRAF and PI3K, providing hope for rapid clinical translation. Cancer Prev Res; 11(10); 607–20. ©2018 AACR .
    Print ISSN: 1940-6207
    Electronic ISSN: 1940-6215
    Topics: Medicine
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  • 4
    ISSN: 1432-0851
    Keywords: Key words. Generation ; Lymphocytes ; Melanoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Metastatic or tumor-draining lymph nodes from six of nine melanoma patients undergoing lymph node dissection for metastatic melanoma generated cytotoxic T cells against autologous melanoma when these lymph node cells were treated by in vitro sensitization and recombinant interleukin-2 (IL-2). During the initial lymphocyte culture (2–6 weeks), cross-reactivity with autologous tumor cells, K562 and Daudi cells was usually noted. Cold-target inhibition assay with K562 and Daudi showed K562/Daudi-associated antigens on melanoma cells. During the later phase of lymphocyte culture with repeated in vitro sensitization (over 6–10 weeks), cytotoxicity was noted against autologous and allogeneic melanoma cells but not against K562, Daudi cells or autologous fibroblasts. Repeated in vitro sensitization resulted in the selection of specific cytotoxic lymphocytes against melanoma. Cold-target inhibition assay with autologous and allogeneic melanoma cells revealed shared and individual antigens. Using blocking monoclonal antibodies, MHC-restricted killing was noted in the autologous system. Further, both the autologous and allogeneic systems could be mediated through adhesion molecules such as ICAM-1 and LFA-3 on melanoma cells and LFA-1 on T cells. This study suggests that a constellation of cytotoxic effector cells and melanoma-associated antigens may be pivotal in tumor killing. Thus, future adoptive immunotherapy should modulate and enhance this complex interaction.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background Asthma is now known to be an inflammatory response caused by the release of inflammatory mediators and cytokines. Tumour necrosis factor (TNF) is a potent cytokine in the inflammation response of the airway, and the polymorphisms of TNF genes have been associated with asthma.Objective This study investigated two variants, TNF-α-308*2 and lymphotoxin (LT)-α-NcoI*1, which may predispose individuals to asthma and atopy pathogenesis.Methods PCR-based assays were performed to determine LT-α-NcoI*1 and TNF-α-308*2 genotypes among our subjects, with 128 atopic asthmatics and 51 non-atopic asthmatics, 55 atopic controls, and 78 non-atopic controls in this genetic case–control study.Results The TNF-α-308*2 polymorphism increased in subjects with atopic asthma vs. non-atopic controls after adjusting for age distribution (adjusted odds ratios, AOR=2.73, 95% confidence interval, CI=1.16–6.64), but was not associated with non-atopic asthma (AOR=2.40, 95% CI=0.81–7.09). LT-α-NcoI*1 did not show an independent association with either atopic asthma or any one phenotype of specific IgE. The synergistic effect between these two genes was conducted, and the interaction between TNF-α-308*2 and LT-α-NcoI*1 polymorphisms was seen for atopic asthma (OR=2.59, 95% CI=1.10–6.10) when compared with all controls.Conclusion We have concluded that TNF-α-308 may be a risk factor for atopic asthma, whereas the LT-α-NcoI polymorphism may modify risk to atopic asthma with TNF-α-308.
    Type of Medium: Electronic Resource
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  • 6
    Publication Date: 2018-12-15
    Description: Purpose: High-grade serous ovarian carcinoma (HGSOC) typically remains undiagnosed until advanced stages when peritoneal dissemination has already occurred. Here, we sought to identify HGSOC-specific alterations in DNA methylation and assess their potential to provide sensitive and specific detection of HGSOC at its earliest stages. Experimental Design: MethylationEPIC genome-wide methylation analysis was performed on a discovery cohort comprising 23 HGSOC, 37 non-HGSOC malignant, and 36 histologically unremarkable gynecologic tissue samples. The resulting data were processed using selective bioinformatic criteria to identify regions of high-confidence HGSOC-specific differential methylation. Quantitative methylation-specific real-time PCR (qMSP) assays were then developed for 8 of the top-performing regions and analytically validated in a cohort of 90 tissue samples. Lastly, qMSP assays were used to assess and compare methylation in 30 laser-capture microdissected (LCM) fallopian tube epithelia samples obtained from cancer-free and serous tubal intraepithelial carcinoma (STIC) positive women. Results: Bioinformatic selection identified 91 regions of robust, HGSOC-specific hypermethylation, 23 of which exhibited an area under the receiver-operator curve (AUC) value ≥ 0.9 in the discovery cohort. Seven of 8 top-performing regions demonstrated AUC values between 0.838 and 0.968 when analytically validated by qMSP in a 90-patient cohort. A panel of the 3 top-performing genes ( c17orf64, IRX2, and TUBB6 ) was able to perfectly discriminate HGSOC (AUC 1.0). Hypermethylation within these loci was found exclusively in LCM fallopian tube epithelia from women with STIC lesions, but not in cancer-free fallopian tubes. Conclusions: A panel of methylation biomarkers can be used to accurately identify HGSOC, even at precursor stages of the disease.
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 7
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    German Medical Science; Düsseldorf, Köln
    In:  51. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie; 20060910-20060914; Leipzig; DOC06gmds412 /20060901/
    Publication Date: 2006-09-25
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 8
    Abstract: Background: Previous studies suggest that a stable end-product of prostaglandin E2, the urinary metabolite PGE-M, is associated with colorectal cancer, and 1 study of relatively small sample size found an association with gastric cancer among women. In the present study we further investigate the PGE-M, Helicobacter pylori, and gastric cancer association. Methods: The present analysis included 359 prospectively ascertained gastric cancer cases and 700 individually matched controls from the Shanghai Women's and Men's Health Studies. Urinary PGE-M was measured by a liquid chromatography/tandem mass spectrometric method. Seropositivity to 15 H. pylori recombinantly expressed fusion proteins was detected by H. pylori multiplex serology. Results: Adjusting for H. pylori, increasing PGE-M was associated with higher risk of gastric cancer (quartile 4 vs 1: odds ratio [OR], 1.76 [95% confidence interval {CI}, 1.17-2.66], Ptrend = .004). This association remained after excluding those diagnosed within 2 years from sample collection (OR, 1.73 [95% CI, 1.12-2.65], Ptrend = .007). However it was no longer present among individuals with 10 or more years of follow-up (2-4.9 years: OR, 3.15 [95% CI, 1.11-8.91]; 5-9.9 years: OR, 2.23 [95% CI, 1.22-4.06]; 〉/=10 years: OR, 0.73 [95% CI, .31-1.70]). Compared to H. pylori-negative individuals with below-median PGE-M levels, H. pylori-positive individuals with above-median PGE-M levels had a 5-fold increase in the odds of gastric cancer (OR, 5.08 [95% CI, 2.47-10.43]). Conclusions: In China, higher PGE-M levels may indicate an increased risk of gastric cancer independent of the risk conferred by H. pylori infection status, particularly for cancers diagnosed within 10 years of sample collection.
    Type of Publication: Journal article published
    PubMed ID: 28402440
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  • 9
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  G-I-N Conference 2012; 20120822-20120825; Berlin; DOCP073 /20120710/
    Publication Date: 2012-07-11
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 10
    Keywords: SIGNAL-TRANSDUCTION ; MAMMALIAN-CELLS ; LIPID RAFTS ; SINGLE-CELL ; reverse transfection ; PROTEIN PALMITOYLATION ; FAMILY KINASES ; CONTENT SCREENING MICROSCOPY ; AUTOMATIC IDENTIFICATION ; COATOMER COMPLEXES
    Abstract: SRC proteins are non-receptor tyrosine kinases that play key roles in regulating signal transduction by a diverse set of cell surface receptors. They contain N-terminal SH4 domains that are modified by fatty acylation and are functioning as membrane anchors. Acylated SH4 domains are both necessary and sufficient to mediate specific targeting of SRC kinases to the inner leaflet of plasma membranes. Intracellular transport of SRC kinases to the plasma membrane depends on microdomains into which SRC kinases partition upon palmitoylation. In the present study, we established a live-cell imaging screening system to identify gene products involved in plasma membrane targeting of SRC kinases. Based on siRNA arrays and a human model cell line expressing two kinds of SH4 reporter molecules, we conducted a genome-wide analysis of SH4-dependent protein targeting using an automated microscopy platform. We identified and validated 54 gene products whose down-regulation causes intracellular retention of SH4 reporter molecules. To detect and quantify this phenotype, we developed a software-based image analysis tool. Among the identified gene products, we found factors involved in lipid metabolism, intracellular transport, and cellular signaling processes. Furthermore, we identified proteins that are either associated with SRC kinases or are related to various known functions of SRC kinases such as other kinases and phosphatases potentially involved in SRC-mediated signal transduction. Finally, we identified gene products whose function is less defined or entirely unknown. Our findings provide a major resource for future studies unraveling the molecular mechanisms that underlie proper targeting of SRC kinases to the inner leaflet of plasma membranes.
    Type of Publication: Journal article published
    PubMed ID: 21795383
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