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PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.
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Adenosina Desaminase , Peptídeos e Proteínas de Sinalização Intercelular , Humanos , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estudos de Coortes , Estudos Retrospectivos , MutaçãoRESUMO
OBJECTIVE: To estimate the incidence of thromboembolism in children with primary nephrotic syndrome with Meta-analysis. METHODS: Relevant studies published from January 1, 1980 to December 31, 2021 were retrieved from Pubmed, Web of science, Cochrane library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database(VIP) and Wangfang Database. Quality evaluation of the literatures included was conducted according to Agency for Healthcare Research and Quality(AHRQ) assessment tool, followed by data extraction and Meta-analysis with software RevMan 5.3. RESULTS: A total of seven studies involving 3675 subjects were included. The overall prevalence was 4.9% with 95% CI of 2.83 to 7.05.However, a significant heterogeneity (P < 0.001) was observed with I2 = 89%. The prevalence of venous thromboembolism was 3.3% with 95% CI of 1.7 to 4.9. The prevalence of arterial thromboembolism was 0.5% with 95% CI of 0.2 to 1.4. CONCLUSION: Children with nephrotic syndrome are prone to thromboembolism, and it may lead to disability or death, therefore prevention measures is critical to decreasing the prevalence of thromboembolism.
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Síndrome Nefrótica , Tromboembolia , Humanos , Criança , Incidência , China , PrevalênciaRESUMO
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematologic malignancies and non-malignant disorders, such as aplastic anemia, fanconi anemia, and certain immune deficiencies. Post-transplantation kidney injury is a common complication and involves a wide spectrum of structural abnormalities, including glomerular (MSPGN, mesangial proliferative glomerulonephritis; FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; MCD, minimal change disease), vascular (TMA, thrombotic microangiopathy), and/or tubulointerstitial (TIN, tubulointerstitial nephritis; ATI, acute tubular injury). Renal biopsy is the gold-standard examination for defining multiple etiologies of kidney impairment. Although kidney injury following HSCT has been studied, little is known about the effects of allo-HSCT on renal pathology in pediatric patients. METHODS: We retrospectively analyzed renal biopsy specimens from children with kidney injury after allo-HSCT and correlated results with clinical data in the last 10 years. RESULTS: Among 25 children (18 males and 7 females), three patients had proteinuria indicating nephrotic syndrome (24-hour urinary total protein/weight > 50 mg/kg/d), nine patients had severely reduced estimated glomerular filtration rate (eGFR < 30 ml/min/1.73 m2) and four patients received kidney replacement therapy (KRT). The main pathologies identified from kidney biopsies were MSPGN (n = 12), FSGS (n = 12), MPGN (n = 5), TMA (n = 4), MCD (n = 3), diffuse glomerular fibrosis (DGF, n = 2), ATI and TIN, in isolation or combined with other pathologies. The median follow-up time was 16.5 (0.5 ~ 68.0) months. Three patients died of recurrent malignancy and/or severe infection, one child developed to end-stage renal disease (ESRD), six patients (24%) had elevated serum creatinine (SCr > 100µmol/l) and nine patients (36%) still had proteinuria. CONCLUSIONS: This study evaluates histomorphologic findings from kidney biopsies of pediatric recipients following allo-HSCT. Detailed evaluation of renal biopsy samples is helpful to elucidate the nature of renal insult, and may potentially identify treatable disease processes.
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Glomerulonefrite Membranoproliferativa , Glomerulonefrite Membranosa , Glomerulosclerose Segmentar e Focal , Transplante de Células-Tronco Hematopoéticas , Nefropatias , Criança , Feminino , Humanos , Masculino , Biópsia/efeitos adversos , Glomerulonefrite Membranoproliferativa/complicações , Glomerulonefrite Membranoproliferativa/patologia , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/patologia , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Rim/patologia , Proteinúria/complicações , Estudos RetrospectivosRESUMO
BACKGROUND: Disorders of the metabolism and absorption of vitamin B12 can lead to decrease in activity of methionine synthetase and methylmalonate coenzyme A mutase (MMUT), which results in increased levels of methylmalonic acid and homocysteine in blood and urine. Often, combined methylmalonic acidemia (MMA) and homocysteinemia is misdiagnosed due to a lack of specific symptoms. The clinical manifestations are diverse, but proteinuria as the initial presentation is rare. CASE PRESENTATION: Two cases of MMA with homocysteinemia in children are reported. Proteinuria were a primary presenting symptom, followed by anemia and neurologic symptoms (frequent convulsions and unstable walking, respectively). Screening of amino acids and acyl carnitine in serum showed that the propionyl carnitine:acetylcarnitine ratio increased. Profiling of urinary organic acids by gas chromatography-mass spectrometry revealed high levels of methylmalonic acid. Homocysteine content in blood was increased. Comprehensive genetic analyses of peripheral blood-derived DNA demonstrated heterozygous variants of methylmalonic aciduria type C and homocystinuria (MMACHC) and amnionless (AMN) genes in our two patients, respectively. After active treatment, the clinical manifestations in Case 1 were relieved and urinary protein ceased to be observed; Case 2 had persistent proteinuria and was lost to follow-up. CONCLUSIONS: Analyses of the organic acids in blood and urine suggested MMA combined with homocysteinemia. In such diseases, reports of renal damage are uncommon and proteinuria as the initial presentation is rare. Molecular analysis indicated two different genetic causes. Although the pathologic mechanisms were related to vitamin B12, the severity and prognosis of renal lesions were different. Therefore, gene detection provides new insights into inherited metabolic diseases.
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Erros Inatos do Metabolismo dos Aminoácidos/complicações , Hiper-Homocisteinemia/complicações , Proteinúria/diagnóstico , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/genética , Aminoácidos/sangue , Sequência de Bases , Carnitina/análogos & derivados , Carnitina/sangue , Pré-Escolar , DNA/sangue , DNA/genética , Cromatografia Gasosa-Espectrometria de Massas , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/genética , Masculino , Ácido Metilmalônico/urina , Proteinúria/etiologiaRESUMO
BACKGROUND: The long-term prognosis of Henoch-Schönlein purpura (HSP) depends on the severity of renal involvement, and crescent formation is considered an important risk factor for poor prognosis of Henoch-Schönlein purpura nephritis (HSPN). The objective of this study was to evaluate factors affecting crescent formation in children with HSPN. METHODS: Demographic factors, clinical characteristics, and laboratory data of children with HSPN with or without crescents were retrospectively analyzed. Univariate and multivariate logistic regression analyses were used to determine the risk factors of crescent formation in HSPN. RESULTS: A total of 191 children with HSPN were enrolled in the study. There were 107 (56%) males and 84 (44%) females, with a median age of 7 years (range: 2 years-15 years). International Study of Kidney Disease in Children (ISKDC) grading was used to divide subjects into two groups: those without glomerular crescent formation (ISKDC grades I-II, n = 146 cases) and those with glomerular crescent formation (ISKDC grades III-V, n = 45 cases). Logistic regression analysis showed that higher urinary white blood cell (WBC) count (OR = 3.300; 95% CI, 1.119-9.739; P = 0.0306) and higher urinary microalbumin/creatinine ratio (ACR) (OR = 25.053; 95% CI, 1.354-463.708; P = 0.0305) were independent risk factors for the formation of crescents in HSPN. The area under the receiver operating characteristic curve of urinary WBC and ACR were 0.753 and 0.698 respectively, with the Hosmer and Lemeshow goodness-of-fit test (P = 0.0669, P > 0.05). CONCLUSION: These results suggest that higher urinary WBC count and ACR should be strictly monitored for children with HSPN. Adequate clinical intervention for these risk factors may limit or prevent renal crescent formation.
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Glomerulonefrite , Vasculite por IgA , Nefrite , Criança , Pré-Escolar , Feminino , Humanos , Vasculite por IgA/complicações , Rim , Masculino , Nefrite/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: X-linked lymphoproliferative disease (XLP) is a rare inherited X-linked primary immunodeficiency diseases (PID). One such disease, X-linked inhibitor of apoptosis protein (XIAP) deficiency, is characterized by Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH). However, EBV-HLH with coronary artery dilation and acute renal injury (AKI) in children is unusual. CASE PRESENTATION: We report the case of a young boy aged 17 months with a novel XIAP variant. He was initially diagnosed with EBV-HLH based on the HLH-2004 diagnostic criteria and the condition was accompanied by coronary artery dilation and acute renal injury. The comprehensive genetic analysis of peripheral blood-derived DNA revealed a hemizygous variant of the XIAP gene [c.116G > C(p.G39A)], which was inherited from his mother (heterozygous condition). After combined treatment with rituximab, intravenous immunoglobulin, corticosteroids, antiviral drugs, and mycophenolate mofetil (MMF) in addition to supportive therapy, his clinical manifestations and laboratory indexes were improved. The patient achieved complete remission with MMF treatment in the 8-month follow-up. CONCLUSIONS: We report the [c.116G > C(p.G39A)] variant in the XIAP gene for the first time in a case of XLP-2 associated with EBV-HLH. For male patients with severe EBV-HLH, the possibility of XLP should be considered and molecular genetic testing should be used early in auxiliary diagnosis. Reports of EBV-HLH with coronary artery dilation and AKI in children are rare. In the patients with EBV-HLH, color Doppler echocardiography and urine tests should be monitored regularly. If necessary, renal biopsy can be performed to clarify the pathology. Treatment with rituximab, immunosuppressors and supportive therapy achieved a good effect, but long-term follow-up is required.
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Injúria Renal Aguda , Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/etiologia , Criança , Vasos Coronários , Dilatação , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4/genética , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genéticaRESUMO
BACKGROUND: Pancreatic cancer is a highly aggressive malignant tumor with the lowest survival rate. A better understanding of the molecular mechanisms which contribute to pancreatic cancer occurrence and progression will aid in the development of new approaches to the early diagnosis, prevention, and treatment of this deadly disease. The scaffold protein IQGAP1 shows elevated levels in a variety of cancer types. Currently, we investigated whether or not IQGAP1 is also overexpressed in pancreatic cancer. METHODS: IQGAP1 expression was examined in pancreatic cancer and normal tissues adjacent to cancerous tissues (adjacent tissues) by Western blotting and real-time RT-PCR as well as in paraffin sections of tissue microarray by immunohistochemistry. The correlations between IQGAP1 expression and various clinicopathological characteristics were analyzed. RESULTS: Western blotting and real-time RT-PCR revealed that the levels of IQGAP1 protein and mRNA expression in pancreatic cancer tissues were significantly increased compared with adjacent tissues. Immunohistochemistry analysis on tissue microarray showed that IQGAP1 protein expression was significantly higher in pancreatic cancer (80.0%, 48/60) compared with adjacent tissues (18.3%, 11/60) (P<0.001). Moreover, overexpression of IQGAP1 was shown to be associated with the grades of tumor differentiation (P<0.05). CONCLUSION: The overexpression of IQGAP1 may play an important role in pancreatic cancer occurrence and progression, and IQGAP1 may serve as a novel molecular target for the diagnosis and treatment of pancreatic cancer.
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Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/química , Neoplasias Pancreáticas/química , Proteínas Ativadoras de ras GTPase/análise , Biomarcadores Tumorais/genética , Western Blotting , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Diferenciação Celular , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Análise Serial de Tecidos , Regulação para Cima , Proteínas Ativadoras de ras GTPase/genéticaRESUMO
Objectives: Inflammatory bowel disease (IBD) is a chronic lifelong inflammatory disease. Probiotics such as Bifidobacterium longum are considered to be beneficial to the recovery of intestinal inflammation by interaction with gut microbiota. Our goals were to define the effect of the exclusive use of BAA2573 on dextran sulfate sodium (DSS)-induced colitis, including improvement of symptoms, alleviation of histopathological damage, and modulation of gut microbiota. Methods: In the present study, we pretreated C57BL/6J mice with Bifidobacterium longum BAA2573, one of the main components in an over-the-counter (OTC) probiotic mixture BIFOTO capsule, before modeling with DSS. 16S rDNA sequencing and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based non-targeted metabolomic profiling were performed with the collected feces. Results: We found that pretreatment of Bifidobacterium longum BAA2573 given by gavage significantly improved symptoms and histopathological damage in DSS-induced colitis mice. After the BAA2573 intervention, 57 genera and 39 metabolites were significantly altered. Pathway enrichment analysis demonstrated that starch and sucrose metabolism, vitamin B6 metabolism, and sphingolipid metabolism may contribute to ameliorating colitis. Moreover, we revealed that the gut microbiome and metabolites were interrelated in the BAA2573 intervention group, while Alistipes was the core genus. Conclusion: Our study demonstrates the impact of BAA2573 on the gut microbiota and reveals a possible novel adjuvant therapy for IBD patients.
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Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Ferroptosis is a new form of regulated cell death and targeting ferroptosis provides a novel therapeutic approach for human cancers. Verteporfin (VP) has been identified as a Yes-associated protein (YAP) inhibitor for treatment of several human cancers. However, it remains unclear whether VP exerts anticancer activity by inducing ferroptosis in ESCC cells. In the current study, we found that VP reduced cell viability and led to cell death in ESCC cell lines (KYSE150 and KYSE30) by inhibiting YAP expression. Subsequently, the findings revealed that VP treatment triggered significant ferroptosis events, including accumulation of Fe2+, reactive oxygen species (ROS) and malondialdehyde (MDA), reduction of mitochondrial membrane potential (MMP), glutathione (GSH) and glutathione peroxidase 4 (GPX4) expression. Further study showed that the effects of ESCC cell proliferation and death caused by VP could be reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1). Moreover, VP enhanced the chemosensitivity of ESCC resistant cells to paclitaxel (PTX). And VP combined with PTX can synergistically inhibit cell proliferation and induce cell death by triggering ferroptosis of PTX-resistant cells. All these data suggested that VP suppressed ESCC cell survival and reversed resistance to PTX through inducing ferroptosis, which may provide a promising therapeutic strategy for ESCC.
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PURPOSE: Targeting angiogenesis is an attractive strategy for the effective treatment of cancer. This study aimed to investigate the anti-cancer activities of YAP inhibitor verteporfin (VP) in esophageal squamous cell carcinoma (ESCC) cells through its inhibitory effect on tumor angiogenesis. METHODS: Cell proliferation, apoptosis, migration and invasion abilities were estimated by MTT, colony formation, DAPI staining, wound healing and transwell assays, respectively. Human umbilical vein endothelial cell (HUVEC) tube formation assay and chick embryo chorioallantoic membrane (CAM) model were used to observe angiogenesis in vitro and in vivo. The interactions between ESCC cells and HUVECs were assessed by cell chemotactic migration and adhesion assays. The expression levels of angiogenesis-related molecules were detected by Western blot. RESULTS: We found that VP was potential to inhibit ESCC cell proliferation, migration, invasion and induce apoptosis in the dose-dependent fashion. VP also significantly suppressed proliferation, migration, and tube formation of HUVECs and promoted apoptosis of HUVECs, and reduced angiogenesis in CAM. Moreover, VP inhibited ESCC cell-induced angiogenesis in vitro by decreasing HUVEC chemotactic migration, adhesion and tube formation, and also reduced ESCC cell-induced neovascularization of the CAM in vivo. In addition, VP suppressed the expression of pro-angiogenic molecules such as VEGFA, MMP-2 and ß-catenin in ESCC cells. Furtherly, VP increased the chemosensitivity of ESCC-resistant cells to paclitaxel (PTX). The combination of VP and PTX attenuated the resistant cell-mediated angiogenesis in vitro and in vivo. CONCLUSION: These results reveal for the first time that VP potently inhibits malignant progression and overcomes chemoresistance of ESCC cells via inhibition of tumor angiogenesis. It provides insight into a new strategy for the treatment of ESCC that VP could be a potential drug candidate for targeting tumor angiogenesis.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Embrião de Galinha , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Verteporfina/farmacologia , Verteporfina/uso terapêutico , Neoplasias Esofágicas/patologia , Resistencia a Medicamentos Antineoplásicos , Neovascularização Patológica/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Proliferação de Células , Linhagem Celular Tumoral , Movimento CelularRESUMO
Programmed cell death 1 receptor (PD-1) and its ligands constitute an inhibitory pathway to mediate the mechanism of immune tolerance and provide immune homeostasis. Significantly, the binding partners of PD-1 and its associated ligands are diverse, which facilitates immunosuppression in cooperation with other immune checkpoint proteins. Accumulating evidence has demonstrated the important immunosuppressive role of the PD-1 axis in the tumor microenvironment and in autoimmune diseases. In addition, PD-1 blockades have been approved to treat various cancers, including solid tumors and hematological malignancies. Here, we provide a comprehensive review of the PD-1 pathway, focusing on the structure and expression of PD-1, programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2); the diverse biological functions of PD-1 signaling in health and immune-related diseases (including tumor immunity, autoimmunity, infectious immunity, transplantation immunity, allergy and immune privilege); and immune-related adverse events related to PD-1 and PD-L1 inhibitors.
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Doenças Autoimunes , Neoplasias , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Ligantes , Terapia de Imunossupressão , Transdução de Sinais , Doenças Autoimunes/tratamento farmacológico , Microambiente TumoralRESUMO
BACKGROUND: Pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a life-threatening systemic vasculitis featured by liability to renal involvement. However, there are few studies on the risk factors and predictive models for renal outcomes of AAV in children. METHODS: Data from 179 AAV children in multiple centers between January 2012 and March 2020 were collected retrospectively. The risk factors and predictive model of end-stage renal disease (ESRD) in AAV were explored. RESULTS: Renal involvement was the most typical manifestation (95.5%), and the crescent was the predominant pathological lesion (84.9%). The estimated glomerular filtration rate (eGFR) was evaluated in 114 patients, of whom 59.6% developed ESRD, and the median time to ESRD was 3.20 months. The eGFR [P = 0.006, odds ratio (OR) = 0.955, 95% confidence interval (CI) = 0.924-0.987] and the percentages of global glomerulosclerosis (pGGS; P = 0.018, OR = 1.060, 95% CI = 1.010-1.112) were independent risk factors for ESRD of renal biopsy. Based on the pGGS and eGFR at renal biopsy, we developed three risk grades of ESRD and one predictive model. The KaplanâMeier curve indicated that renal outcomes were significantly different in different risk grades (P < 0.001). Compared with serum creatinine at baseline, the predictive model had higher accuracy (0.86 versus 0.58, P < 0.001) and a lower coefficient of variation (0.07 versus 0.92) in external validation. CONCLUSIONS: Renal involvement is the most common manifestation of pediatric AAV in China, of which more than half deteriorates into ESRD. The predictive model based on eGFR at renal biopsy and the pGGS may be stable and accurate in speculating the risk of ESRD in AAV children. Supplementary file 2 (MP4 18937 KB).
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OBJECTIVE: To investigate the genetic structure of X chromosome in Mongolia, Ewenki, Elunchun and Dawoer in Inner Mongolia. METHODS: Nine short tandem repeat (STR) markers on the X chromosome (DXS6789, DXS101, DXS8378, DXS7132, DXS7133, DXS7423, DXS6804, DXS6799 and HPRTB) were analyzed in the four populations from Inner Mongolian (Mongol, Ewenki,Oroqen and Daur) for their genetic diversity, forensic suitability and possible genetic affinities of the populations. Frequencies and other parameters of forensic interest were computed. RESULTS: The results revealed that the nine markers described here have a moderate degree of variability in the population groups. And there are significant differences in the genetic variability among the populations. Genetic distance and cluster analyses show very low genetic distance between Mongol and Han (Xi'an) communities. The results based on genetic distance analyses are consistent with earlier studies based on linguistic as well as immigration history and origin of these populations. CONCLUSION: The nine STR loci studied here were found not only useful in studying genetic variations between populations but also suitable for human identity testing.
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Cromossomos Humanos X/genética , Etnicidade/genética , Variação Genética , Repetições de Microssatélites/genética , China/etnologia , Análise por Conglomerados , Feminino , Humanos , MasculinoRESUMO
Angiogenesis is crucial for the progression of esophageal squamous cell carcinoma (ESCC). Antiangiogenesis by targeting important molecules has been considered as one of the most promising and efficient strategy for cancer therapy. Recent studies have demonstrated that the IQdomain GTPase activating protein 1 (IQGAP1) plays critical roles in tumorigenesis and cancer progression. We previously reported that IQGAP1 is overexpressed in ESCC, and IQGAP1 knockdown can decrease cell proliferation and metastasis ability in vitro and in vivo. However, the effects of IQGAP1 on the angiogenesis of ESCC and its underlying mechanisms remain unknown. In the present study, we found that IQGAP1 overexpression promoted tumor angiogenesis confirmed by human umbilical vascular endothelial cell (HUVEC) tube formation in vitro and chicken embryo chorioallantoic membrane (CAM) assay in vivo. Moreover, IQGAP1 overexpression in ESCC cells increased expression of vascular endothelial growth factor (VEGF) and phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). Meanwhile, we found that levels of AKT and ERK phosphorylation were upregulated in IQGAP1overexpressing cells. Importantly, IQGAP1knockdown cells showed the opposing results. Furthermore, AKT and ERK inhibitors not only significantly decreased VEGF expression and VEGFR2 phosphorylation in IQGAP1overexpressing cells, but also abolished the proangiogenic effect of IQGAP1 overexpression on angiogenesis in the HUVEC tube formation and chicken embryo CAM assay. Taken together, this evidence confirms that IQGAP1 overexpression promotes tumor angiogenesis via the AKT and ERKmediated VEGFVEGFR2 signaling pathway in ESCC, and IQGAP1 may be an attractive therapeutic target for cancer antiangiogenesis treatment.
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Neoplasias Esofágicas/irrigação sanguínea , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Membrana Corioalantoide/metabolismo , Membrana Corioalantoide/patologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Humanos , Fosforilação , Células Tumorais CultivadasRESUMO
OBJECTIVE: To determine the genetic diversity of X-TR loci, and to evaluate the genetic structure X chromosome's of Ewenki nationality and its affinity with other nationalities. METHODS: We chose 9 X-TR (DXS6804, DXS7133, DXS101, DXS6789, DXS6799, DXS7423, HPRTB, DXS8378, DXS7132) as genetic markers from 99 irrelative individules to determine the genetic diversity of Ewenki in Inner Mongolian. Cluster analysis and phylogenic trees was applied to show the genetic distance among the nationalities. RESULTS: We got 51 alleles in the studied population, with the frequency diverse between 0.0109 and 0.6863. Genotype frequency was from 0.0217 to 0.3778. Heterozygosity(H),the power of discrimination(PD) and the polymorphism information conten (PIC) were consistent with the forensic application. Cluster analysis and phylogenic trees revealed that Ewenki nationality had estrangement genetic affinity with the other 3 major nationalities in inner mongolia and Han nationality in Xi'an. CONCLUSION: The genetic information demonstrates that the 9 chosen gene makers were highly informative loci and are suitable for population genetics research and forensic application.
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Cromossomos Humanos X/genética , Marcadores Genéticos/genética , Repetições de Microssatélites/genética , Polimorfismo Genético , China , Análise por Conglomerados , Etnicidade/classificação , Etnicidade/genética , Feminino , Frequência do Gene , Variação Genética , Genótipo , Humanos , Masculino , FilogeniaRESUMO
OBJECTIVE: To study the genetic polymorphism of five STR loci on X-chromosome in 98 Ewenke population of China and establish the related genetic database. METHODS: The sequence variation of DXS7423, DXS7424, DXS7132, DXS7133, DXS6804 loci on X-chromosome were analyzed by PCR following PAG electrophoresis and silver staining. RESULTS: The genetic data of the 5 X-chromosome STRs in Ewenke ethnic group of China is in accordance with Hard-Weinberg equilibrium. CONCLUSION: Five X-STR loci could be used in forensic identification and population genetic research.
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Cromossomos Humanos X/genética , Etnicidade/genética , Frequência do Gene , Polimorfismo Genético/genética , Sequências de Repetição em Tandem , Distribuição de Qui-Quadrado , China/etnologia , DNA/genética , Eletroforese em Gel de Poliacrilamida , Feminino , Medicina Legal , Genética Populacional , Genótipo , Humanos , Masculino , Reação em Cadeia da PolimeraseRESUMO
IQGAP1 is a scaffolding protein that can regulate several distinct signaling pathways. The accumulating evidence has demonstrated that IQGAP1 plays an important role in tumorigenesis and tumor progression. However, the function of IQGAP1 in esophageal squamous cell carcinoma (ESCC) has not been thoroughly investigated. In the present study, we showed that IQGAP1 was overexpressed in ESCC tumor tissues, and its overexpression was correlated with the invasion depth of ESCC. Importantly, by using RNA interference (RNAi) technology we successfully silenced IQGAP1 gene in two ESCC cell lines, EC9706 and KYSE150, and for the first time found that suppressing IQGAP1 expression not only obviously reduced the tumor cell growth, migration and invasion in vitro but also markedly inhibited the tumor growth, invasion, lymph node and lung metastasis in xenograft mice. Furthermore, Knockdown of IQGAP1 expression in ESCC cell lines led to a reversion of epithelial to mesenchymal transition (EMT) progress. These results suggest that IQGAP1 plays crucial roles in regulating ESCC occurrence and progression. IQGAP1 silencing may therefore develop into a promising novel anticancer therapy.