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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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Clinicopathological and prognostic value of S100A4 expression in non-small cell lung cancer: a meta-analysis.
Zhang, J, Gu, Y, Liu, X, Rao, X, Huang, G, Ouyang, Y
Bioscience reports. 2020;(7)
Abstract
BACKGROUND Numerous published studies have shown that S100A4 is frequently overexpressed in various human cancers. However, the association between S100A4 expression and prognosis or clinicopathological parameters in non-small cell lung cancer (NSCLC) remains unclear. Therefore, a meta-analysis was performed to identify the significance of S100A4 in NSCLC. METHODS Systematic literature search was conducted using PubMed, Embase, Web of Science, the Cochrane Library, the Chinese National Knowledge Infrastructure database (CNKI), and the Wanfang database to obtain relevant articles. A combined hazard ratio (HR) and its corresponding 95% confidence interval (CI) were used to evaluate the association between S100A4 expression and prognosis in NSCLC patients. Pooled odds ratio (OR) and 95% CI were calculated to assess the association between S100A4 expression and clinicopathological features in NSCLC. RESULTS NSCLC patients with overexpression of S100A4 had a worse prognosis than patients with low expression of S100A4 (HR = 1.77, 95% CI: 1.55-2.02, P<0.001). Additionally, overexpression of S100A4 was significantly correlated to patients' age (OR = 0.67, 95% CI: 0.49-0.91, P=0.010), tumor differentiation (OR = 2.20, 95% CI: 1.69-2.85, P<0.001), lymph node metastasis (LNM) (OR = 3.70, 95% CI: 2.25-6.06, P<0.001), Tumor-Node-Metastasis (TNM) stage (OR = 3.08, 95% CI: 2.10-4.53, P<0.001), and pathological subtype (OR = 1.77, 95% CI: 1.09-2.88, P=0.020). However, there was no association between S100A4 expression and other clinicopathological features in NSCLC, including gender, tumor size, and smoking. CONCLUSION S100A4 overexpression was associated with tumor progression and poor prognosis in NSCLC patients. Hence, S100A4 might serve as a potential prognostic biomarker in NSCLC.
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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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Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker.
Parada, CA, Osbun, JW, Busald, T, Karasozen, Y, Kaur, S, Shi, M, Barber, J, Adidharma, W, Cimino, PJ, Pan, C, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020;(1):193-205
Abstract
PURPOSE Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short. EXPERIMENTAL DESIGN Mass spectrometry (MS)-based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables. RESULTS The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas. CONCLUSIONS RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.
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Investigation of Potential Genetic Biomarkers and Molecular Mechanism of Ulcerative Colitis Utilizing Bioinformatics Analysis.
Zhang, J, Wang, X, Xu, L, Zhang, Z, Wang, F, Tang, X
BioMed research international. 2020;:4921387
Abstract
OBJECTIVES To reveal the molecular mechanisms of ulcerative colitis (UC) and provide potential biomarkers for UC gene therapy. METHODS We downloaded the GSE87473 microarray dataset from the Gene Expression Omnibus (GEO) and identified the differentially expressed genes (DEGs) between UC samples and normal samples. Then, a module partition analysis was performed based on a weighted gene coexpression network analysis (WGCNA), followed by pathway and functional enrichment analyses. Furthermore, we investigated the hub genes. At last, data validation was performed to ensure the reliability of the hub genes. RESULTS Between the UC group and normal group, 988 DEGs were investigated. The DEGs were clustered into 5 modules using WGCNA. These DEGs were mainly enriched in functions such as the immune response, the inflammatory response, and chemotaxis, and they were mainly enriched in KEGG pathways such as the cytokine-cytokine receptor interaction, chemokine signaling pathway, and complement and coagulation cascades. The hub genes, including dual oxidase maturation factor 2 (DUOXA2), serum amyloid A (SAA) 1 and SAA2, TNFAIP3-interacting protein 3 (TNIP3), C-X-C motif chemokine (CXCL1), solute carrier family 6 member 14 (SLC6A14), and complement decay-accelerating factor (CD antigen CD55), were revealed as potential tissue biomarkers for UC diagnosis or treatment. CONCLUSIONS This study provides supportive evidence that DUOXA2, A-SAA, TNIP3, CXCL1, SLC6A14, and CD55 might be used as potential biomarkers for tissue biopsy of UC, especially SLC6A14 and DUOXA2, which may be new targets for UC gene therapy. Moreover, the DUOX2/DUOXA2 and CXCL1/CXCR2 pathways might play an important role in the progression of UC through the chemokine signaling pathway and inflammatory response.
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Transcriptome Alterations in Liver Metastases of Colorectal Cancer After Acquired Resistance to Cetuximab.
Li, Z, Chen, Y, Ren, WU, Hu, S, Tan, Z, Wang, Y, Chen, Y, Zhang, J, Wu, J, Li, T, et al
Cancer genomics & proteomics. 2019;(3):207-219
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Abstract
BACKGROUND/AIM: Cetuximab in combination with chemotherapy is recommended as first-line therapy for metastatic colorectal cancer (mCRC) with wild-type RAS. However, drug resistance to cetuximab exists widely in mCRC and reduces the prognosis of patients. Although some genomic alterations have been demonstrated to drive acquired resistance to cetuximab, the overall compendium of inherent molecular mechanisms is still incomplete. MATERIALS AND METHODS Four liver metastasis biopsies were collected from two mCRC patients who were treated with cetuximab in combination with 5-fluororacil plus leucovorin and oxaliplatin (FOLFOX) regimen. RESULTS Transcriptomic analysis revealed global gene expression alterations between paired samples prior to treatment and after acquired resistance. Further bioinformatics analysis discovered differentially expressed protein-coding genes/lncRNAs/miRNAs, potential miRNA-mRNA regulatory networks and lncRNA-mRNA competing endogenous RNA network, which may be potential biomarkers or play roles during the process of acquired resistance to cetuximab. CONCLUSION Our study contributes to deciphering the molecular mechanisms of acquired resistance to cetuximab.
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Circulating Leptin and Branched Chain Amino Acids-Correlation with Intraductal Papillary Mucinous Neoplasm Dysplastic Grade.
Yip-Schneider, MT, Simpson, R, Carr, RA, Wu, H, Fan, H, Liu, Z, Korc, M, Zhang, J, Schmidt, CM
Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2019;(5):966-974
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Abstract
BACKGROUND The most common type of mucinous pancreatic cyst that may progress to pancreatic cancer is intraductal papillary mucinous neoplasm (IPMN). Low-risk IPMN with low-/moderate-grade dysplasia may be safely watched, whereas high-risk IPMN with high-grade dysplasia or invasive components should undergo resection. However, there is currently no reliable means of making this distinction. We hypothesize that blood concentrations of insulin resistance biomarkers may aid in the differentiation of low- and high-risk IPMN. METHODS Plasma/serum was collected from consented patients undergoing pancreatic resection. IPMN diagnosis and dysplastic grade were confirmed by surgical pathology. The study included 235 IPMN (166 low/moderate grade, 39 high grade, 30 invasive). Circulating levels of leptin, branched chain amino acids (BCAA), and retinol-binding protein-4 (RBP-4) were measured by enzyme-linked immunoassay and correlated with surgical pathology. RESULTS Circulating leptin levels (mean ± SE) were significantly higher in patients with low/moderate IPMN than in high-grade/invasive IPMN (15,803 ± 1686 vs. 10,275 ± 1228 pg/ml; p = 0.0086). Leptin levels were positively correlated with BMI (r = 0.65, p < 0.0001) and were higher in females (p < 0.0001). Stratified analysis showed that mean leptin levels were significantly different between low/moderate and high/invasive IPMNs only in females (24,383 ± 2748 vs. 16,295 ± 2040 pg/ml; p = 0.020). Conversely, circulating BCAA levels were lower in low/moderate IPMN than in high-grade/invasive IPMN (0.38 ± 0.007 vs. 0.42 ± 0.01 mM; p = 0.011). No significant differences in RBP-4 levels were observed. CONCLUSIONS Circulating leptin in females and BCAA correlates with IPMN dysplastic grade and, if combined with clinical characteristics, have the potential to improve clinical decision-making.
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Identification of Candidate Biomarkers in Malignant Ascites from Patients with Hepatocellular Carcinoma by iTRAQ-Based Quantitative Proteomic Analysis.
Zhang, J, Liang, R, Wei, J, Ye, J, He, Q, ChunlingYuan, , Ye, J, Li, Y, Liu, Z, Lin, Y
BioMed research international. 2018;:5484976
Abstract
Almost all the patients with hepatocellular carcinoma (HCC) at advanced stage experience pathological changes of chronic liver cirrhosis, which generally leads to moderate ascites. Recognition of novel biomarkers in malignant ascites could be favorable for establishing a diagnosis for the HCC patients with ascites, and even predicting prognosis, such as risk of distant metastasis. To distinguish the proteomic profiles of malignant ascites in HCC patients from those with nonmalignant liver cirrhosis, an iTRAQ pipeline was built up to analyze the differentially distributed proteins in the malignant ascites from HCC patients (n=10) and benign ascites from hepatic decompensation (HD) controls (n=9). In total, 112 differentially distributed proteins were identified, of which 69 proteins were upregulated and 43 proteins were downregulated (ratio <0.667 or >1.3, respectively) in the malignant ascites. Moreover, 19 upregulated proteins (including keratin 1 protein and rheumatoid factor RF-IP20, ratio>1.5) and 8 downregulated proteins (including carbonic anhydrase 1, ratio<0.667) were identified from malignant ascites samples. Functional categories analyses indicated that membrane proteins, ion regulation, and amino acid metabolism are implicated in the formation of HCC malignant ascites. Pathways mapping revealed that glycolysis/gluconeogenesis and complement/coagulation cascades are the mostly affected cell life activities in HCC malignant ascites, suggesting the key factors in these pathways such as Enolase-1 and fibrinogen are potential ascitic fluid based biomarkers for diagnosis and prognosis for HCC.
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The Immunohistochemical Evaluation of Solid Pseudopapillary Tumors of the Pancreas and Pancreatic Neuroendocrine Tumors Reveals ERO1Lβ as a New Biomarker.
Xie, J, Zhu, Y, Chen, H, Shi, M, Gu, J, Zhang, J, Shen, B, Deng, X, Zhan, X, Peng, C
Medicine. 2016;(2):e2509
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Solid pseudopapillary tumor of the pancreas (SPTP) is a class of low-grade malignant tumors that carry a favorable prognosis after surgery. Our group has reported that dysfunctions in the endoplasmic reticulum (ER) protein processing pathway may play a role in tumor development. However, alterations of this pathway in other pancreatic tumors had not been well investigated. In this study, we collected 35 SPTP and pancreatic neuroendocrine tumor (PNET) specimens and described the clinicopathological features of them. We performed immunohistochemistry (IHC) for 6 representative proteins (ERO1Lβ, TRAM1, GRP94, BIP, P4HB, and PDIA4) involved in the ER pathway in both SPTP and PNET specimens. We compared the IHC scoring results of tumors and matched normal pancreas tissues and demonstrated that these proteins were downregulated in SPTP specimens. Five of these proteins (TRAM1, GRP94, BIP, P4HB, and PDIA4) did not display significant changes between PNET and normal pancreas tissue. However, ERO1Lβ was upregulated in PNET tissues compared to the normal tissues, which could be used as a pathological biomarker in the future.