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1.
Ann Surg Oncol ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32040699

RESUMO

BACKGROUND: Most previous risk-prediction models for gastrointestinal stromal tumors (GISTs) were based on Western populations. In the current study, we collected data from 23 hospitals in Shandong Province, China, and used the data to examine prognostic factors in Chinese patients and establish a new recurrence-free survival (RFS) prediction model. METHODS: Records were analyzed for 5285 GIST patients. Independent prognostic factors were identified using Cox models. Receiver operating characteristic curve analysis was used to compare a novel RFS prediction model with current risk-prediction models. RESULTS: Overall, 4216 patients met the inclusion criteria and 3363 completed follow-up. One-, 3-, and 5-year RFS was 94.6% (95% confidence interval [CI] 93.8-95.4), 85.9% (95% CI 84.7-87.1), and 78.8% (95% CI 77.0-80.6), respectively. Sex, tumor location, size, mitotic count, and rupture were independent prognostic factors. A new prognostic index (PI) was developed: PI = 0.000 (if female) + 0.270 (if male) + 0.000 (if gastric GIST) + 0.350 (if non-gastric GIST) + 0.000 (if no tumor rupture) + 1.259 (if tumor rupture) + 0.000 (tumor mitotic count < 6 per 50 high-power fields [HPFs]) + 1.442 (tumor mitotic count between 6 and 10 per 50 HPFs) + 2.026 (tumor mitotic count > 10 per 50 HPFs) + 0.096 × tumor size (cm). Model-predicted 1-, 3-, and 5-year RFS was S(12, X) = 0.9926exp(PI), S(36, X) = 0.9739exp(PI) and S(60, X) = 0.9471exp(PI), respectively. CONCLUSIONS: Sex, tumor location, size, mitotic count, and rupture were independently prognostic for GIST recurrence. Our RFS prediction model is effective for Chinese GIST patients.

2.
Mol Med Rep ; 21(2): 575-582, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31789423

RESUMO

The present study aimed to explore the role of fibroblast growth factor 2 (FGF2) in the development and prognosis of gastric cancer (GC). The relationship between FGF2 mRNA expression levels and the clinical characteristics of GC was investigated using microarray data from four GC cohorts involving 726 patients obtained from the Gene Expression Omnibus. The results of the present study indicated that FGF2 expression levels were an independent factor affecting the prognosis of GC. The primary functions of FGF2 were related to cell adhesion and angiogenesis, and patients with high levels of FGF2 expression had poorer TNM staging and prognosis; these differences were statistically significant. In terms of immune infiltration, a higher extent of M2 macrophage intrusion was observed in patients with higher levels of FGF2. However, the degree of infiltration by dendritic and CD4+ T cells was lower, and this difference was statistically significant. Multivariate Cox proportional hazards model analysis revealed that age, TNM staging and FGF2 expression levels were independent prognostic factors for GC. In summary, FGF2 expression was demonstrated to be an independent prognostic factor in GC, and higher levels of FGF2 may promote the progression of this malignancy.

3.
PLoS Comput Biol ; 15(12): e1007510, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31790389

RESUMO

Quantifying cell-type proportions and their corresponding gene expression profiles in tissue samples would enhance understanding of the contributions of individual cell types to the physiological states of the tissue. Current approaches that address tissue heterogeneity have drawbacks. Experimental techniques, such as fluorescence-activated cell sorting, and single cell RNA sequencing are expensive. Computational approaches that use expression data from heterogeneous samples are promising, but most of the current methods estimate either cell-type proportions or cell-type-specific expression profiles by requiring the other as input. Although such partial deconvolution methods have been successfully applied to tumor samples, the additional input required may be unavailable. We introduce a novel complete deconvolution method, CDSeq, that uses only RNA-Seq data from bulk tissue samples to simultaneously estimate both cell-type proportions and cell-type-specific expression profiles. Using several synthetic and real experimental datasets with known cell-type composition and cell-type-specific expression profiles, we compared CDSeq's complete deconvolution performance with seven other established deconvolution methods. Complete deconvolution using CDSeq represents a substantial technical advance over partial deconvolution approaches and will be useful for studying cell mixtures in tissue samples. CDSeq is available at GitHub repository (MATLAB and Octave code): https://github.com/kkang7/CDSeq.

4.
BMC Cancer ; 19(1): 1196, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805970

RESUMO

BACKGROUND: NF1(Neurofibromatosis type 1) is an autosomal dominant genetic disorder. Patients with NF1 have an increased risk of developing benign or malignant tumours, such as gastrointestinal stromal tumours (GISTs). However, the coexistence of NF1, GIST and colon cancer is very rare, and few cases have been reported in the literature. CASE PRESENTATION: We admitted a case of a 64-year-old man with type 1 neurofibromatosis, GISTs, and ascending colon cancer. This case was characterized by café-au-lait macules, discrete cutaneous neurofibromas, nodular neurofibromas, multiple jejunal tumours, and ascending colon cancer. Laparoscopic exploration revealed ascending colon cancer and multiple jejunal tumours. Laparoscopic right hemicolectomy and local excision of the jejunal tumours were performed successfully. The pathological results confirmed moderate differentiated adenocarcinoma of the ascending colon with multiple jejunal GISTs (low risk, very low risk). Moreover, the immunohistochemistry results of multiple jejunal GISTs suggest that NF1 is positive. Whole-exome sequencing (WES) of colon cancer revealed mutations in more than 20 genes, including KRAS, PIK3CA, APC, SMAD4, etc. The results of whole-exome sequencing (WES) of jejunal GISTs revealed an NF1 mutation and no KIT or PDGFR gene mutation. CONCLUSION: We report a rare case of simultaneous NF1, GIST and colon adenocarcinoma. For patients with NF1, benign and/or malignant tumours are often combined. Therefore, these patients should undergo regular physical examinations so that early detection and early treatment can be achieved.

5.
Cancer Manag Res ; 11: 9793-9800, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819617

RESUMO

Purpose: The Controlling Nutritional Status (CONUT) score is a recently developed measure that is calculated using the serum albumin level, total cholesterol level, and lymphocyte counts. The aim of this study was to examine whether the CONUT score can predict post-operative outcomes in elderly patients undergoing curative gastrectomy. Patients and methods: Pre-operative CONUT scores were evaluated from August 2014 to September 2016 in 357 gastric cancer patients who were scheduled to undergo curative gastrectomy. The patients were divided into three groups according to pre-operative CONUT scores: normal, light, moderate, and severe. We then calculated the association between the patient's CONUT score and post-operative complications. Results: CONUT scores were statistically associated with age (P = 0.015), body mass index (P < 0.001), pre-operative hemoglobin level (P < 0.001), tumor-node-metastasis stage (P < 0.001), surgical method (P = 0.036), and post-operative complications (P < 0.001). Multivariate analysis showed that age and the CONUT score were independent predictors of post-operative complications and 1-year survival. Conclusion: CONUT scores can be used to predict post-operative complications and 1-year survival in elderly gastric cancer patients undergoing curative gastrectomy. They can also be used to classify the nutritional status of patients, which can be helpful for pre-and post-operative nutritional management.

6.
BMC Genomics ; 20(1): 1021, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31881847

RESUMO

BACKGROUND: Tumor purity is the percent of cancer cells present in a sample of tumor tissue. The non-cancerous cells (immune cells, fibroblasts, etc.) have an important role in tumor biology. The ability to determine tumor purity is important to understand the roles of cancerous and non-cancerous cells in a tumor. METHODS: We applied a supervised machine learning method, XGBoost, to data from 33 TCGA tumor types to predict tumor purity using RNA-seq gene expression data. RESULTS: Across the 33 tumor types, the median correlation between observed and predicted tumor-purity ranged from 0.75 to 0.87 with small root mean square errors, suggesting that tumor purity can be accurately predicted υσινγ expression data. We further confirmed that expression levels of a ten-gene set (CSF2RB, RHOH, C1S, CCDC69, CCL22, CYTIP, POU2AF1, FGR, CCL21, and IL7R) were predictive of tumor purity regardless of tumor type. We tested whether our set of ten genes could accurately predict tumor purity of a TCGA-independent data set. We showed that expression levels from our set of ten genes were highly correlated (ρ = 0.88) with the actual observed tumor purity. CONCLUSIONS: Our analyses suggested that the ten-gene set may serve as a biomarker for tumor purity prediction using gene expression data.

7.
Invest Ophthalmol Vis Sci ; 60(13): 4416-4424, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639828

RESUMO

Purpose: Lenses have an intracellular hydrostatic pressure gradient to drive fluid from central fiber cells to surface epithelial cells. Pressure is regulated by a feedback control system that relies on transient receptor potential vanilloid (TRPV)1 and TRPV4 channels. The ciliary muscle transmits tension to the lens through the zonules of Zinn. Here, we have examined if ciliary muscle tension influenced the lens intracellular hydrostatic pressure gradient. Methods: We measured the ciliary body position and intracellular hydrostatic pressures in mouse lenses while pharmacologically causing relaxation or contraction of the ciliary muscle. We also used inhibitors of TRPV1 and TRPV4, in addition to phosphoinositide 3-kinase (PI3K) p110α knockout mice and immunostaining of phosphorylated protein kinase B (Akt), to determine how changes in ciliary muscle tension resulted in altered hydrostatic pressure. Results: Ciliary muscle relaxation increased the distance between the ciliary body and the lens and caused a decrease in intracellular hydrostatic pressure that was dependent on intact zonules and could be blocked by inhibition of TRPV4. Ciliary contraction moved the ciliary body toward the lens and caused an increase in intracellular hydrostatic pressure and Akt phosphorylation that required intact zonules and was blocked by either inhibition of TRPV1 or genetic deletion of the p110α catalytic subunit of PI3K. Conclusions: These results show that the hydrostatic pressure gradient within the lens was influenced by the tension exerted on the lens by the ciliary muscle through the zonules of Zinn. Modulation of the gradient of intracellular hydrostatic pressure in the lens could alter the water content, and the gradient of refractive index.


Assuntos
Corpo Ciliar/metabolismo , Cristalino/metabolismo , Ligamentos/metabolismo , Músculo Liso/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Técnica Indireta de Fluorescência para Anticorpo , Pressão Hidrostática , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Midriáticos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Pilocarpina/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Tropicamida/farmacologia
8.
Cancer Med ; 8(11): 5000-5011, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31293053

RESUMO

PURPOSE: This study aimed to investigate the characteristics of colonic neuroendocrine neoplasms (NENs) and to validate the prognostic value of the European Neuroendocrine Tumor Society (ENETS) and American Joint Committee on Cancer (AJCC) 8th staging systems. METHODS: A total of 167 and 1248 patients with colonic NENs from 12 medical centers across China and from the Surveillance, Epidemiology, and End Results (SEER) cancer registry in the United States, respectively, were reviewed. Patients were staged according to the ENETS and AJCC 8th staging systems. RESULTS: Clinicopathological features of colonic NENs in the Chinese cohort and SEER cohort were significantly distinct. In both the Chinese cohort and the SEER cohort, colonic neuroendocrine carcinoma (NEC) and mixed adeno-neuroendocrine carcinoma (MANEC) were more frequent in the midgut than in the hindgut. Tumors originating from the midgut tended to be larger and at a more advanced stage than those from the hindgut. The AJCC 8th staging system and the ENETS system appeared to have similar prognostic ability for colonic NEC/MANEC. CONCLUSIONS: Our study revealed that tumors originating from the midgut and the hindgut shared different clinicopathological features. The AJCC 8th staging system and the ENETS system appeared to have similar prognostic ability for colonic NEC/MANEC.

9.
Mol Med Rep ; 20(2): 1196-1202, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173209

RESUMO

In order to examine the inhibitory effects of microRNA (miR)­26b­5p on thyroid cancer (TC), the clinicopathological features and pathological tissues of 67 patients were collected. The expression levels of miR­26b­5p were detected in TC and paracarcinoma tissues by quantitative polymerase chain reaction, and the association between miR­26b­5p expression and the clinicopathological features of the patients was analyzed using t­test or one­way analysis of variance. In addition, B­CPAP TC cells were infected with a lentivirus to induce miR­26b­5p overexpression and proliferation was detected by Cell Counting kit­8. Subsequently, migration and invasion were detected by Transwell and Matrigel assays, respectively, and the molecular mechanism of action was investigated by western blotting. The results demonstrated that the expression levels of miR­26b­5p were significantly lower in TC tissues compared with paracarcinoma tissues (P<0.01), and miR­26b­5p was associated with lymph node metastasis (P<0.05). In addition, overexpression of miR­26b­5p inhibited the proliferation, invasion and migration of B­CPAP cells. Western blot analysis demonstrated that the protein expression levels of phosphorylated glycogen synthase kinase­3ß (pGsk­3ß) were decreased, and the expression of ß­catenin was decreased in B­CPAP cells overexpressing miR­26b­5p. These results demonstrated that miR­26b­5p may exert antitumor activity. In addition, at the molecular level, these effects may be associated with the Gsk­3ß/ß­catenin pathway.


Assuntos
Proliferação de Células , Glicogênio Sintase Quinase 3 beta/metabolismo , MicroRNAs/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , beta Catenina/genética , Adolescente , Adulto , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/fisiologia , Pessoa de Meia-Idade , Fosforilação , Processamento de Proteína Pós-Traducional , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/fisiopatologia , Adulto Jovem
10.
PLoS One ; 14(6): e0218067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31199813

RESUMO

Due to the poor prognosis of advanced metastatic melanoma, it is crucial to find early biomarkers that help identify which melanomas will metastasize. By comparing the gene expression data from primary and cutaneous melanoma samples from The Cancer Genome Atlas (TCGA), we identified GPC6 among a set of genes whose expression levels can distinguish between primary melanoma and regional cutaneous/subcutaneous metastases. Glypicans are thought to play a role in tumor growth by regulating the signaling pathways of Wnt, Hedgehogs, fibroblast growth factors (FGFs), and bone morphogenetic proteins (BMPs). We showed that GPC6 expression was up-regulated in a melanoma cell line compared to normal melanocytes and in metastatic melanoma compared to primary melanoma. Furthermore, GPC6 expression was positively correlated with genes largely involved in cell adhesion and migration in both melanoma samples and in RNA-seq samples from other TCGA tumors. Our results suggest that GPC6 may play a role in tumor metastatic progression. In TCGA melanoma samples, we also showed that GPC6 expression was negatively correlated with miR-509-3p, which has previously been shown to function as a tumor suppressor in various cancer cell lines. We overexpressed miR-509-3p in A375 melanoma cells and showed that GPC6 expression was significantly suppressed. This result suggested that GPC6 was a putative target of miR-509-3p in melanoma. Together, our findings identified GPC6 as an early biomarker for melanoma metastatic progression, one that can be regulated by miR-509-3p.

11.
Cancer Invest ; 37(3): 174-184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30982362

RESUMO

As important factors in the tumor microenvironment, interleukin-6 (IL-6) and integrin ανß6 play significant roles in accumulating mutations that drive the progression and metastatic capacities of cancer. The aim of this study was to investigate the expression of IL-6 and integrin ανß6, their clinical significance, as well as their correlation in the colon cancer tissues of 145 cases using immunohistochemistry. Our results showed that IL-6 and integrin ανß6 are indicators of cancer progression and poor prognosis in patients with colon cancer. Moreover, their relationship may provide clues for further studies on how the tumor microenvironment mediates the development of colon cancer, as well as strategies for the identification of novel therapeutic targets in the prevention and treatment of colon cancer.


Assuntos
Antígenos de Neoplasias/biossíntese , Neoplasias do Colo/metabolismo , Integrinas/biossíntese , Interleucina-6/biossíntese , Microambiente Tumoral , Neoplasias do Colo/patologia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico
12.
J Cancer Res Ther ; 15(2): 437-441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964123

RESUMO

Objective: The objective of the study was to evaluate the usefulness of large-section cytokeratin 20 (CK20) staining technique in the detection of infiltration on the distal wall and mesangial metastasis in patients with middle and lower rectal cancer. Materials and Methods: A total of 62 patients with rectal cancer in the middle and lower segment were studied on large slices stained with CK20. Logistic regression was used to analyze the clinicopathologic factors related to distal low and middle rectal cancer metastasis to the mesorectum and rectal wall. Results: Two types of distal metastasis of the tumor were observed in the rectal wall in 18% (11/62) of the patients: submucosal invasion and muscularis propria invasion. The extent of distal metastasis to the rectal wall was around 0.5-1.0 cm. Four types of distal metastasis occurred in the mesorectum: lymph node invasion, blood and lymphatic vessel invasion, perineural invasion, and isolated neoplastic microfoci. Distal metastasis to the mesorectum was observed in 24% (15/62) of the patients. The extent of metastasis to the mesorectum was around 0.5-4.0 cm. Another three patients with microcapillary invasion in the distal mesorectum were observed by immunohistochemistry, as it was difficult to determine the spread by conventional hematoxylin and eosin staining. Conclusion: The large-section CK20 staining technique is useful for the detection of infiltration on the distal wall and mesangial metastasis in patients with middle and lower rectal cancer.


Assuntos
Queratina-20/metabolismo , Neoplasias Retais/metabolismo , Neoplasias Retais/patologia , Reto/metabolismo , Reto/patologia , Biomarcadores , Seguimentos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias Retais/mortalidade
13.
Oncol Lett ; 17(3): 2599-2606, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30854035

RESUMO

Musashi 2 (MSI2), a marker of stem and progenitor cells, has been identified as an oncogene. Various investigations have revealed that MSI2 is differently expressed in several types of blood cancer and solid cancers. However, its expression and biological functions in gastric cancer (GC) remain unclear. In the present study, MSI2 mRNA and protein expression were assessed in GC tissue samples. The associations between MSI2 mRNA expression and the clinicopathological characteristics of patients with GC were analyzed, and the effect of MSI2 on the prognosis of patients with GC was verified. The biological functions of MSI2 in GC cells were assessed using gain-of-function assays in vitro. The results revealed that MSI2 was overexpressed in the majority of GC tissue samples, although this difference was not significant. MSI2 mRNA expression levels were associated with invasion depth, tumor-node-metastasis stage, degree of differentiation and tumor size (P<0.05), but were not associated with sex, age, tumor location or human epidermal growth factor receptor 2 expression. Increased MSI2 expression resulted in a poorer prognosis in patients with GC (χ2=4.221; P=0.040). In vitro assays revealed that MSI2 promoted MKN-28 cell proliferation, migration and invasion, and promoted tube formation in HUVECs. Although no significance of MSI2 expression was found, its oncogenic functions in the GC cell line indicated that MSI2 may be a potential oncogene that may serve as a biomarker for GC diagnosis and prognosis with verification from a larger sample and more GC cell lines.

14.
J Hematol Oncol ; 12(1): 16, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764882

RESUMO

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts' clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

15.
Oncol Lett ; 17(2): 1461-1466, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30675200

RESUMO

The incidence of gastric cancer is high, especially in China. The present study aims to provide a novel therapeutic target for gastric cancer. Peripheral blood, cancerous and paracancerous tissues were collected from patients with gastric cancer. T-cell immunoglobulin mucin domain-3 (Tim-3) expression in T-cells was measured and the correlation between Tim-3 expression and the T staging of gastric cancer was analyzed. The levels of T-cell secreted interferon (IFN)-γ and tumor necrosis factor (TNF)-α were assessed following Tim-3 signaling pathway activation. A nude mouse model of gastric cancer was established and Tim-3-stimulated T-cells were injected into the mice to evaluate tumor growth. The results of the present study demonstrated that Tim-3 expression levels from the paracancerous and cancerous gastric tissues were significantly increased compared with the peripheral blood, while its expression was significantly increased in cancerous compared with paracancerous gastric tissues. With the T staging of gastric cancer increasing, the expression of Tim-3 gradually increased. The activation of the Tim-3 signaling pathway in T-cells may inhibit IFN-γ and TNF-α secretion, and the results from the nude mice tumor model demonstrated that the inhibitory effect on tumor growth by T-cells was reduced by Tim-3 signaling pathway activation. The expression level of Tim-3 on the surface of tumor infiltrating T-cells in gastric cancer tissue increases significantly and the increased Tim-3 signaling may inhibit the function of T-cells. The results suggest that the increased expression of Tim-3 on T-cells may be involved the development of gastric cancer.

16.
Sci Rep ; 9(1): 19, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631135

RESUMO

Mutations in the gene (GJA1) encoding connexin43 (Cx43) are responsible for several rare genetic disorders, including non-syndromic skin-limited diseases. Here we used two different functional expression systems to characterize three Cx43 mutations linked to palmoplantar keratoderma and congenital alopecia-1, erythrokeratodermia variabilis et progressiva, or inflammatory linear verrucous epidermal nevus. In HeLa cells and Xenopus oocytes, we show that Cx43-G8V, Cx43-A44V and Cx43-E227D all formed functional gap junction channels with the same efficiency as wild-type Cx43, with normal voltage gating and a unitary conductance of ~110 pS. In HeLa cells, all three mutations also localized to regions of cell-cell contact and displayed a punctate staining pattern. In addition, we show that Cx43-G8V, Cx43-A44V and Cx43-E227D significantly increase membrane current flow through formation of active hemichannels, a novel activity that was not displayed by wild-type Cx43. The increased membrane current was inhibited by either 2 mM calcium, or 5 µM gadolinium, mediated by hemichannels with a unitary conductance of ~250 pS, and was not due to elevated mutant protein expression. The three Cx43 mutations all showed the same gain of function activity, suggesting that augmented hemichannel activity could play a role in skin-limited diseases caused by human Cx43 mutations.


Assuntos
Conexina 43/genética , Conexina 43/metabolismo , Junções Comunicantes/metabolismo , Mutação de Sentido Incorreto , Dermatopatias/genética , Dermatopatias/patologia , Animais , Condutividade Elétrica , Células Epiteliais , Células HeLa , Humanos , Oócitos , Xenopus
17.
Hum Mutat ; 40(2): 217-229, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30431684

RESUMO

Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in the Xenopus oocyte expression system and by molecular modeling analysis. Compound heterozygous mutations in the GJB2 gene were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. The p.Asn176Asp missense mutation was demonstrated to significantly reduce the cell-cell gap junction channel activity and increase the nonjunctional hemichannel activity in the Xenopus oocyte expression system. Molecular modeling analyses of the mutant Cx26 protein revealed significant changes in the structural characteristics and electrostatic potential of the Cx26, either in hemichannel or gap junction conformation. Thus, association of a new syndrome of an autosomal recessive disorder of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma with mutations in GJB2, expands the phenotypic spectrum of the GJB2-associated disorders. The findings attest to the complexity of the clinical consequences of different mutations in GJB2.

18.
Iran J Allergy Asthma Immunol ; 17(4): 318-325, 2018 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-30537795

RESUMO

Mir-22-3p is associated with many important biological processes, including neuroprotection, tumorigenesis, and various other tumor progressions. Our study aimed to investigate the roles of Mir-22-3p in chemosensitivity of gastrointestinal stromal tumor (GIST-T1) cells to cisplatin and explore its underlying mechanisms. Mir-22-3p high-expressing cell line was established by transfecting GIST-T1 cell line cells with Mir-22-3p mimic. After treatment with cisplatin (10 µM), Cell counting kits-8 (CCK-8) method was used to detect the cell viability. Flow cytometry was applied to measure the degree of cell apoptosis. Scratch wound healing test was used to detect the migration ability of cells. The protein and mRNA levels of the phosphatase and tensin homolog deleted on chromosome ten (PTEN)/phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway-related factors were analyzed by Western blot and qRT-PCR. The mRNA level of Mir-22-3p was increased in transfected GIST-T1 cells compared with that in control cells. The survival rate and Bcl-2/Bax ratio of GIST-T1 cells treated with both Mir-22-3p analogue and cisplatin were significantly decreased, while the apoptosis rate and protein level of caspase-3 were significantly increased (p<0.05). In addition, the mRNA and protein levels of PTENwere significantly increased in cells treated with both Mir-22-3p analogue and cisplatin (p<0.05), while the expression levels of PI3K and Akt were significantly decreased (p<0.05). Mir-22-3p overexpression can increase the chemosensitivity of cisplatin in human gastrointestinal stromal tumor cells by PTEN/PI3K/Akt pathway.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , MicroRNAs/genética , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
19.
Nucleic Acids Res ; 46(16): 8153-8167, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30107566

RESUMO

p53 transcriptional networks are well-characterized in many organisms. However, a global understanding of requirements for in vivo p53 interactions with DNA and relationships with transcription across human biological systems in response to various p53 activating situations remains limited. Using a common analysis pipeline, we analyzed 41 data sets from genome-wide ChIP-seq studies of which 16 have associated gene expression data, including our recent primary data with normal human lymphocytes. The resulting extensive analysis, accessible at p53 BAER hub via the UCSC browser, provides a robust platform to characterize p53 binding throughout the human genome including direct influence on gene expression and underlying mechanisms. We establish the impact of spacers and mismatches from consensus on p53 binding in vivo and propose that once bound, neither significantly influences the likelihood of expression. Our rigorous approach revealed a large p53 genome-wide cistrome composed of >900 genes directly targeted by p53. Importantly, we identify a core cistrome signature composed of genes appearing in over half the data sets, and we identify signatures that are treatment- or cell-specific, demonstrating new functions for p53 in cell biology. Our analysis reveals a broad homeostatic role for human p53 that is relevant to both basic and translational studies.


Assuntos
Proteínas de Ligação a DNA/genética , Genoma Humano/genética , Transcrição Genética , Proteína Supressora de Tumor p53/genética , DNA Intergênico/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica/genética , Genes/genética , Humanos , Linfócitos , Biossíntese de Proteínas
20.
Sci Rep ; 8(1): 9662, 2018 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-29941866

RESUMO

Fetal germ cell development is regulated by an elaborate combination of cell-extrinsic and cell-intrinsic signals. Here we identify a novel role for the Krüppel-like transcription factor Gli-Similar 3 (Glis3) in male germ cell development in the mouse embryos. Glis3 is expressed in male germ cells during the brief window of time prior to initiation of piRNA-dependent retrotransposon surveillance. Disruption of Glis3 function led to a widespread reduction in retrotransposon silencing factors, aberrant retrotransposon expression and pronounced germ cell loss. Experimental induction of precocious Glis3 expression in vivo before its normal expression resulted in premature expression of several piRNA pathway members, suggesting that GLIS3 is necessary for the activation of the retrotransposon silencing programs. Our findings reveal an unexpected role for GLIS3 in the development of male germ cells and point to a central role for GLIS3 in the control of retrotransposon silencing in the fetal germline.


Assuntos
Feto/citologia , Inativação Gênica , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Retroelementos/genética , Espermatozoides/metabolismo , Testículo/citologia , Transativadores/deficiência , Transativadores/genética , Animais , Sobrevivência Celular/genética , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Masculino , Camundongos , Fenótipo
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