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1.
Clin Genet ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31328266

RESUMO

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

2.
J Pathol ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30430578

RESUMO

Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. Multiple mutations in later-occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions.

3.
Oncol Lett ; 14(1): 217-223, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28693156

RESUMO

The aim of the present study was to identify the appropriate DNA sequence and design high-quality primers for methylation-specific polymerase chain reaction (MSP). These primers may be used to examine and identify patients with early-stage epithelial ovarian carcinoma (EOC). Opioid binding protein/cell adhesion molecule like (OPCML), Runt-related transcription factor 3 and tissue factor pathway inhibitor 2 were selected as possible molecular markers. MSP primer sets were designed to monitor the methylation of the three markers. Free circulating DNA (fcDNA) from 194 patients with epithelial ovarian carcinoma and healthy donors were templates in the nested MSP. OPCML MSP was effective with respect to screening methylated fcDNA. One-way ANOVA P-values indicated that the difference in cancer antigen 125 (CA125), a biomarker for EOC diagnosis, level between early EOC and healthy donors was not significant. The methylation of OPCML was significantly altered in early-stage EOC compared with healthy donors (P<0.0001), and this supported the hypothesis that specific fcDNA methylation was able to distinguish patients with early-stage EOC from healthy donors. With respect to detecting early EOC, compared with the results of the CA125 test, MSP increased the κ coefficient from 0.140 to 0.757. Therefore, OPCML combined with fcDNA may be used to establish an improved clinical assay compared with the current CA125 test.

4.
Zhonghua Er Ke Za Zhi ; 52(7): 516-20, 2014 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-25224057

RESUMO

OBJECTIVE: To investigate the levels and functions of CD4(+)CD25(+) regulatory T cells and specific transcription factor Foxp3 and Th17 cells related cytokine in peripheral blood mononuclear cells (PBMC) and renal tissues, and explore their roles in pathogenesis of Henoch-Schonlein purpura nephropathy (HSPN) in children. METHOD: From March, 2011 to March, 2013, 30 cases of HSPN children underwent renal biopsy and were treated in Guiyang Children's Hospital were enrolled into this study. Ten healthy children who underwent health check up were enrolled as blood sample control group. The normal kidney tissue specimens were taken from 5 children who underwent surgery for urologic disorders were used as renal sample control group. The circulating proportions of CD4(+)CD25(+) regulatory T cells in PBMC of 30 cases of HSPN children and 10 cases of control group were determined by flow cytometry, respectively.Reverse transcription-polymerase chain reaction (RT-PCR) were used to analyze the mRNA expressions of IL-17, IL-1ß and Foxp3 in PBMC. The expression of IL-17 and IL-1ß in renal tissue of HSPN and control group were measured by immunohistochemistry. CD4(+)CD25(+) regulatory T cells, Foxp3, IL-17, IL-1ß expression were analyzed and compared in HSPN group and control groups respectively. RESULT: Thirty cases of HSPN pathological classification were as follows: type I was found in 0 case; type II in 9 cases; type III in 16 cases; type IV in 5 cases; type V in 0 case. The circulating proportions of CD4(+)CD25(+)/CD4(+)T cells and the CD4(+)CD25(+)Foxp3(+)Treg/CD4(+)T cells level were (5.84 ± 0.78)%, (1.01 ± 0.46) % in HSPN groups were substantially lower than those in control group. All these two differences had statistical significance (t = 27.200, 33.260, P < 0.05). The mRNA levels of IL-17, IL-1ß in HSPN groups (0.86 ± 0.01,0.71 ± 0.01) were higher than those in control group (t = 25.000, 31.840, all P < 0.05). Foxp3 mRNA expression in HSPN groups (0.24 ± 0.02) were significantly lower than those in control group (t = 21.690, P < 0.05). Protein expression of IL-17 and IL-1ß in renal tissues of HSPN children (13.31 ± 0.54, 11.56 ± 0.28) were significantly stronger than those in the control group (t = 27.6, 14.0, all P < 0.01). The highest level of protein expression of IL-17 and IL-1ß in renal biopsy of HSPN was in type IV (IV>III>II, F = 545.800, 262.500, all P < 0.01). CONCLUSION: The disorder of quantity and function of CD4(+)CD25(+) regulatory T cells, and increase in levels of IL-17, IL-1ß (cytokine related to Th17 cells) may play important roles in pathogenesis of HSPN in children; increased protein expression of IL-17, IL-1ß in renal tissue may contribute to the development of renal pathological damage in HSPN children.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Interleucina-17/metabolismo , Nefrite/patologia , Púrpura de Schoenlein-Henoch/patologia , Linfócitos T Reguladores/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Humanos , Interleucina-17/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Rim/metabolismo , Rim/patologia , Masculino , Nefrite/etiologia , Nefrite/imunologia , Púrpura de Schoenlein-Henoch/complicações , Púrpura de Schoenlein-Henoch/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Células Th17/imunologia
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