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1.
Ultrasensitive Nanopore Sensing of Mucin 1 and Circulating Tumor Cells in Whole Blood of Breast Cancer Patients by Analyte-Triggered Triplex-DNA Release.
Sun, K, Chen, P, Yan, S, Yuan, W, Wang, Y, Li, X, Dou, L, Zhao, C, Zhang, J, Wang, Q, et al
ACS applied materials & interfaces. 2021;(18):21030-21039
Abstract
The characterization of circulating tumor cells (CTCs) by liquid biopsy has a great potential for precision medicine in oncology. Here, a universal and tandem logic-based strategy is developed by combining multiple nanomaterials and nanopore sensing for the determination of mucin 1 protein (MUC1) and breast cancer CTCs in real samples. The strategy consists of analyte-triggered signal conversion, cascaded amplification via nanomaterials including copper sulfide nanoparticles (CuS NPs), silver nanoparticles (Ag NPs), and biomaterials including DNA hydrogel and DNAzyme, and single-molecule-level detection by nanopore sensing. The amplification of the non-DNA nanomaterial gives this method considerable stability, significantly lowers the limit of detection (LOD), and enhances the anti-interference performance for complicated samples. As a result, the ultrasensitive detection of MUC1 could be achieved in the range of 0.0005-0.5 pg/mL, with an LOD of 0.1 fg/mL. Moreover, we further tested MUC1 as a biomarker for the clinical diagnosis of breast cancer CTCs under double-blind conditions on the basis of this strategy, and MCF-7 cells could be accurately detected in the range from 5 to 2000 cells/mL, with an LOD of 2 cells/mL within 6 h. The detection results of the 19 clinical samples were highly consistent with those of the clinical pathological sections, nuclear magnetic resonance imaging, and color ultrasound. These results demonstrate the validity and reliability of our method and further proved the feasibility of MUC1 as a clinical diagnostic biomarker for CTCs.
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2.
FOLFOX treatment response prediction in metastatic or recurrent colorectal cancer patients via machine learning algorithms.
Lu, W, Fu, D, Kong, X, Huang, Z, Hwang, M, Zhu, Y, Chen, L, Jiang, K, Li, X, Wu, Y, et al
Cancer medicine. 2020;(4):1419-1429
Abstract
Early identification of metastatic or recurrent colorectal cancer (CRC) patients who will be sensitive to FOLFOX (5-FU, leucovorin and oxaliplatin) therapy is very important. We performed microarray meta-analysis to identify differentially expressed genes (DEGs) between FOLFOX responders and nonresponders in metastatic or recurrent CRC patients, and found that the expression levels of WASHC4, HELZ, ERN1, RPS6KB1, and APPBP2 were downregulated, while the expression levels of IRF7, EML3, LYPLA2, DRAP1, RNH1, PKP3, TSPAN17, LSS, MLKL, PPP1R7, GCDH, C19ORF24, and CCDC124 were upregulated in FOLFOX responders compared with nonresponders. Subsequent functional annotation showed that DEGs were significantly enriched in autophagy, ErbB signaling pathway, mitophagy, endocytosis, FoxO signaling pathway, apoptosis, and antifolate resistance pathways. Based on those candidate genes, several machine learning algorithms were applied to the training set, then performances of models were assessed via the cross validation method. Candidate models with the best tuning parameters were applied to the test set and the final model showed satisfactory performance. In addition, we also reported that MLKL and CCDC124 gene expression were independent prognostic factors for metastatic CRC patients undergoing FOLFOX therapy.
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Non-genetic biomarkers and colorectal cancer risk: Umbrella review and evidence triangulation.
Zhang, X, Gill, D, He, Y, Yang, T, Li, X, Monori, G, Campbell, H, Dunlop, M, Tsilidis, KK, Timofeeva, M, et al
Cancer medicine. 2020;(13):4823-4835
Abstract
Several associations between non-genetic biomarkers and colorectal cancer (CRC) risk have been detected, but the strength of evidence and the direction of associations are not confirmed. We aimed to evaluate the evidence of these associations and integrate results from different approaches to assess causal inference. We searched Medline and Embase for meta-analyses of observational studies, meta-analyses of randomized clinical trials (RCTs), and Mendelian randomization (MR) studies measuring the associations between non-genetic biomarkers and CRC risk and meta-analyses of RCTs on supplementary micronutrients. We repeated the meta-analyses using random-effects models and categorized the evidence based on predefined criteria. We described each MR study and evaluated their credibility. Seventy-two meta-analyses of observational studies and 18 MR studies on non-genetic biomarkers and six meta-analyses of RCTs on micronutrient intake and CRC risk considering 65, 42, and five unique associations, respectively, were identified. No meta-analyses of RCTs on blood level biomarkers have been found. None of the associations were classified as convincing or highly suggestive, three were classified as suggestive, and 26 were classified as weak. For three biomarkers explored in MR studies, there was evidence of causality and seven were classified as likely noncausal. For the first time, results from both observational and MR studies were integrated by triangulating the evidence for a wide variety of non-genetic biomarkers and CRC risk. At blood level, lower vitamin D, higher homeostatic model assessment-insulin resistance, and human papillomavirus infection were associated with higher CRC risk while increased linoleic acid and oleic acid and decreased arachidonic acid were likely causally associated with lower CRC risk. No association was found convincing in both study types.
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Sino-European Differences in the Genetic Landscape and Clinical Presentation of Pheochromocytoma and Paraganglioma.
Jiang, J, Zhang, J, Pang, Y, Bechmann, N, Li, M, Monteagudo, M, Calsina, B, Gimenez-Roqueplo, AP, Nölting, S, Beuschlein, F, et al
The Journal of clinical endocrinology and metabolism. 2020;(10)
Abstract
CONTEXT Pheochromocytomas and paragangliomas (PPGLs) are characterized by distinct genotype-phenotype relationships according to studies largely restricted to Caucasian populations. OBJECTIVE To assess for possible differences in genetic landscapes and genotype-phenotype relationships of PPGLs in Chinese versus European populations. DESIGN Cross-sectional study. SETTING 2 tertiary-care centers in China and 9 in Europe. PARTICIPANTS Patients with pathologically confirmed diagnosis of PPGL, including 719 Chinese and 919 Europeans. MAIN OUTCOME MEASURES Next-generation sequencing performed in tumor specimens with mutations confirmed by Sanger sequencing and tested in peripheral blood if available. Frequencies of mutations were examined according to tumor location and catecholamine biochemical phenotypes. RESULTS Among all patients, higher frequencies of HRAS, FGFR1, and EPAS1 mutations were observed in Chinese than Europeans, whereas the reverse was observed for NF1, VHL, RET, and SDHx. Among patients with apparently sporadic PPGLs, the most frequently mutated genes in Chinese were HRAS (16.5% [13.6-19.3] vs 9.8% [7.6-12.1]) and FGFR1 (9.8% [7.6-12.1] vs 2.2% [1.1-3.3]), whereas among Europeans the most frequently mutated genes were NF1 (15.9% [13.2-18.6] vs 6.6% [4.7-8.5]) and SDHx (10.7% [8.4-13.0] vs 4.2% [2.6-5.7]). Among Europeans, almost all paragangliomas lacked appreciable production of epinephrine and identified gene mutations were largely restricted to those leading to stabilization of hypoxia inducible factors. In contrast, among Chinese there was a larger proportion of epinephrine-producing paragangliomas, mostly due to HRAS and FGFR1 mutations. CONCLUSIONS This study establishes Sino-European differences in the genetic landscape and presentation of PPGLs, including ethnic differences in genotype-phenotype relationships indicating a paradigm shift in our understanding of the biology of these tumors.
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5.
S100A1 promotes cell proliferation and migration and is associated with lymph node metastasis in ovarian cancer.
Tian, T, Li, X, Hua, Z, Ma, J, Liu, Z, Chen, H, Cui, Z
Discovery medicine. 2017;(127):235-245
Abstract
S100A1 is a calcium-binding protein belonging to the family of S100 proteins, and is highly expressed in ovarian cancer. However, its role in ovarian cancer has not yet been fully elucidated. In this study, we examined S100A1 expression in ovarian cancer tissues and normal tissue controls and analyzed the correlation between S100A1 expression and clinicopathological parameters. We found that S100A1 expression was significantly upregulated in ovarian cancer tissues compared with fallopian and normal ovarian epithelium tissues and was significantly associated with lymph node metastasis and International Federation of Gynecology and Obstetrics (FIGO) stages and tumor grades. We then investigated the biological functions of S100A1 in ovarian cancer by cell proliferation, fluorescence-activated cell sorting (FACS), and migration and invasion assays. The results indicated that S100A1 enhanced the ovarian cancer cell proliferation and migration. Together, our findings demonstrated that S100A1 plays an important role in the malignancy of ovarian cancer, and serves as a useful marker for the detection of ovarian malignancy.
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6.
Folate Receptor-Positive Circulating Tumor Cell Detected by LT-PCR-Based Method as a Diagnostic Biomarker for Non-Small-Cell Lung Cancer.
Chen, X, Zhou, F, Li, X, Yang, G, Zhang, L, Ren, S, Zhao, C, Deng, Q, Li, W, Gao, G, et al
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2015;(8):1163-71
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Abstract
INTRODUCTION To investigate the diagnostic performance of folate receptor-positive circulating tumor cells in distinguishing non-small-cell lung cancer (NSCLC) from lung benign disease by using a novel ligand-targeted polymerase chain reaction (PCR) detection technique. METHODS Circulating tumor cells were enriched from 3-ml peripheral blood by immunomagnetic depletion of leukocytes and then labeled with a conjugate of a tumor-specific ligand folic acid and a synthesized oligonucleotide. After washing off free conjugates, the stripped bound conjugates were analyzed by quantitative PCR. RESULTS Seven hundred fifty-six participants (473 patients with NSCLC, 227 patients with lung benign disease, and 56 healthy donors) were randomly assigned to a training set and a test set. The circulating tumor cell (CTC) levels in patients with NSCLC were significant higher than those with lung benign disease (p < 0.001) and healthy donors (p < 0.001). Compared with carcinoembryonic antigen, neuron-specific enolase, and Cyfra21-1, CTCs displayed the highest area under the receiver operating characteristic curve (training set, 0.815; validation set, 0.813) in the diagnosis of NSCLC, with a markedly sensitivity (training set, 72.46%; validation set, 76.37%) and specificity (training set, 88.65%; validation set, 82.39%). The model combining CTCs with carcinoembryonic antigen, neuron-specific enolase, and Cyfra21-1 was more effective for the diagnosis of NSCLC than tumor makers alone (sensitivity and specificity in the training set, 84.21% and 83.91%; validation set, 88.78% and 87.36%, respectively). In addition, the CTC levels were higher in patients with stage III/IV NSCLC compared with those with stage I/II disease. CONCLUSION Ligand-targeted PCR technique was feasible and reliable for detecting folate receptor-positive CTCs in patients with NSCLC, and CTC levels could be used as a useful biomarker for the diagnosis of NSCLC.