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PURPOSE: This research evaluates the effect of balloon pulmonary angioplasty (BPA) on cardiac electrophysiological changes in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Involving a retrospective analysis of 39 CTEPH patients (average age 61 ± 11), who had at least two BPAs and paired ECGs pre- and post-surgery, we examined changes in ECG indicators of right ventricular hypertrophy and their correlation with hemodynamic results. RESULTS: BPA yielded marked improvements in cardiac function and hemodynamics. ECG parameters, specifically the Lewis criteria and Butler-Leggett score, correlated strongly with hemodynamics and were predictive of a mean pulmonary arterial pressure (mPAP) ≥ 35mmHg. Notably, QRS complex axis normalization was observed in 25 patients, with 14 fully normalizing (range - 30° to + 90°). The qR pattern in V1 vanished in 9 cases, and 75% of the patients in qR pattern in V1 group had QRS complex electrical axis completely returned to normal range. The qR V1 group had higher mPAP and pulmonary vascular resistance (PVR), and lower cardiac output and index compared to the non-qR V1 group, alongside a higher Butler-Leggett score. CONCLUSIONS: BPA enhances cardiac function and hemodynamics in CTEPH patients, with certain ECG measures such as Lewis criteria and Butler-Leggett score reflecting the severity of hemodynamic impairment. The reversal of QRS axis deviation and the disappearance of the qR pattern in lead V1 may serve as valuable indicators for assessing post-BPA satisfaction in CTEPH patients.
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Angioplastia com Balão , Eletrocardiografia , Hipertensão Pulmonar , Embolia Pulmonar , Humanos , Estudos Retrospectivos , Pessoa de Meia-Idade , Masculino , Angioplastia com Balão/métodos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/cirurgia , Hipertensão Pulmonar/terapia , Feminino , Embolia Pulmonar/fisiopatologia , Embolia Pulmonar/complicações , Idoso , Doença Crônica , Hemodinâmica/fisiologia , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/cirurgiaRESUMO
BACKGROUND: Approximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC. AIM: To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC. METHODS: We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC. RESULTS: We found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions (n = 5) were the most common, followed by FGFR2, BRAF, MET, FGFR3, RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10), have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA. Consistent with the results of detection using the targeted sequencing fusion panel, the results of FISH (fluorescence in situ hybridization) confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09, respectively. Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification (P = 0.02); however, there were no significant differences between fusion-positive and fusion-negative patients in age, sex, MSI status, and TMB. CONCLUSION: We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.
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This research investigated heating uniformity and pasteurization of canned pineapple using radio frequency (RF) energy. Experiments were conducted in a 6 kW, 27.12 MHz pilot-scale RF system. Results showed that the temperature difference was more than 16°C, and the standard deviation was 4.38°C at the end of heating when using RF heating alone. Water bath-assisted RF (WRF) heating effectively improved the heating uniformity, the temperature difference was less than 7°C and the standard deviation was 2.52°C at the end of heating in the condition of electrode gap (210 mm), chord length of the fruit block (26 mm), and the initial temperature of sugar solution (80°C). When the total number of colonies reached 4-log reduction, water bath (WB) heating alone needed 660 s, and WRF heating needed 180 s. Vitamin C, hardness, and color of fruit blocks were well preserved using WRF heating compared with WB alone. PRACTICAL APPLICATION: This study shows that the pasteurization of canned food by radio frequency heating can achieve better food quality than the traditional pasteurization methods. Therefore, this research can promote the application of radio frequency heating technology in canned food pasteurization.
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Ananas , Pasteurização , Calefação/métodos , Temperatura Alta , Pasteurização/métodos , Ondas de Rádio , ÁguaRESUMO
Digestive system malignancies, the most common types of cancer and a major cause of death in the worldwide, are generally characterized by high morbidity, insidious symptoms and poor prognosis. NLRP3 inflammasome, the most studied inflammasome member, is considered to be crucial in tumorigenesis. In this paper, we reviewed its pro-tumorigenic and anti-tumorigenic properties in different types of digestive system malignancy depending on the types of cells, tissues and organs involved, which would provide promising avenue for exploring new anti-cancer therapies.
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Telaprevir (TVR) is typically a poorly soluble drug with an extremely low bioavailability of 1.7%. Polymorph modifications cannot improve the solubility of TVR because it only has a single unsolvated crystalline form. Co-crystals also provide limited bioavailability enhancement for TVR. Thus, in this study, we increased the solubility and dissolution rate of TVR through formulations of TVR-polymer solid dispersions. Three solid dispersions of TVR were successfully prepared by co-milling with polyvinylpyrrolidone K30 (PVP), polyethylene glycol 6000, and hydroxypropyl methylcellulose (HPMC), which were characterized by different techniques. According to X-ray powder diffraction and differential scanning calorimetry results, TVR presented in amorphous form in all solid dispersions. The fourier transform infrared spectra results indicated that TVR may connect with polymers through the N-H···O or O-H···O hydrogen bonds, which were verified by molecular docking. TVR-PVP and TVR-HPMC displayed a good stability at conventional RH levels, and their thermostabilities were better than those of milled TVR. Among the three solid dispersions, TVR-HPMC showed significant solubility and dissolution rate advantages in different media. Moreover, TVR-HPMC displayed the same anticancer efficacy with crystalline TVR and presented no toxic side effects to normal liver cells. Thus, TVR-HPMC showed potential application value.
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Fenômenos Químicos , Composição de Medicamentos/métodos , Oligopeptídeos/farmacologia , Varredura Diferencial de Calorimetria , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Polímeros/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Dabrafenib is a novel targeted antimelanoma drug. The present work explored the binding mechanism of dabrafenib-human serum albumin (HSA) and the effect on the esterase-like activity and antioxidant activity of HSA by using 19F NMR, spectroscopy methods, and molecular dynamics simulation. The results of 19F NMR, fluorescence, and time-resolved fluorescence spectroscopy revealed that dabrafenib spontaneously binds to the subdomain IIIA of the HSA by hydrophobic action and forms a static complex. The binding affects the esterase-like activity of HSA but not its antioxidant activity. According to the results of molecular dynamics simulation, dabrafenib interacts with Arg410 and Tyr411, which are the key residue associated with the esterase-like activity of HSA. Meanwhile, dabrafenib does not interact with Cys34, the key residue associated with the antioxidant activity of HSA. The results of circular dichroism spectroscopy and molecular dynamics simulation show that the conformation of HSA is not affected by the binding of dabrafenib. This study can provide useful information for understanding the pharmacokinetic properties of dabrafenib.
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Antineoplásicos/farmacocinética , Esterases/metabolismo , Imidazóis/farmacocinética , Oximas/farmacocinética , Albumina Sérica Humana/metabolismo , Antineoplásicos/química , Sítios de Ligação , Dicroísmo Circular , Cisteína/metabolismo , Esterases/química , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/química , Simulação de Dinâmica Molecular , Oximas/química , Ligação Proteica , Albumina Sérica Humana/química , Espectrometria de FluorescênciaRESUMO
Prolyl hydroxylase 3 (PHD3) is widely accepted as a tumor suppressor; however, the expression of PHD3 in various cancer types remains controversial. The present study aimed to investigate the association between PHD3 expression and the clinicopathological features of gastric cancer using reverse transcriptionquantitative polymerase chain reaction and immunohistochemistry. The effects of PHD3 in gastric cancer cell lines were assessed using western blot analysis and transwell migration assays. The present results revealed that PHD3 expression was increased in adjacent noncancerous tissue compared with in gastric cancer tissue, and PHD3 overexpression was correlated with the presence of welldifferentiated cancer cells, early cancer stage classification and the absence of lymph node metastasis. In vitro experiments demonstrated that PHD3 may act as a negative regulator of hypoxiainducible factor1α and vascular endothelial growth factor, both of which participate in tumor angiogenesis. In conclusion, the present results suggested that PHD3 may act as a tumor suppressor in gastric cancer. Therefore, the targeted regulation of PHD3 may have potential as a novel therapeutic approach for the treatment of patients with gastric cancer.
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Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolil Hidroxilases/metabolismo , Neoplasias Gástricas/patologia , Adulto , Idoso , Linhagem Celular , Movimento Celular , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prolil Hidroxilases/química , Prolil Hidroxilases/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: We aimed to systematically assess the effect of adipose tissue-derived stem cell (ADSC) therapy and its influential factors on the treatment of erectile dysfunction (ED) in rats. METHODS: Two authors independently searched for published studies through PubMed and EMBASE from study inception until August 31, 2016. A meta-analysis was used to combine the effect estimate from the published studies. A subgroup analysis was performed to identify the effect of some influential factors. The pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated by a fixed-effects or random-effects model analysis. RESULTS: Twenty studies with a total of 248 rats were included in this meta-analysis. The pooled analysis showed that ADSC therapy significantly increased the ratio of intracavernous pressure and mean arterial pressure (ICP/MAP; SMD 3.46, 95% CI 2.85-4.06; P < 0.001) compared to control therapy. The levels of neuronal nitric oxide synthase (nNOS; SMD 6.37, 95% CI 4.35-8.39; P < 0.001), the cavernous smooth muscle content (CSMC; SMD 3.65, 95% CI 2.65-4.65; P < 0.001), the ratio of cavernous smooth muscle and collagen (CSM/collagen; SMD 4.16, 95% CI 2.59-5.72; P < 0.001), and the cyclic guanosine monophosphate (cGMP; SMD 7.12, 95% CI 2.76-11.48; P = 0.001) were higher following ADSC therapy than following control therapy. Subgroup analysis showed that ADSCs modified by growth or neurotrophic factors significantly recovered erectile function (P < 0.001) compared with ADSC therapy. CONCLUSION: The adequate data indicated that ADSC therapy recovered erectile function and regenerated cavernous structures in ED rats, and ADSCs modified by some growth and neurotrophic factors accelerated the recovery of erectile function and cavernous structures in ED rats.
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Tecido Adiposo/citologia , Disfunção Erétil/fisiopatologia , Disfunção Erétil/terapia , Transplante de Células-Tronco , Animais , Pressão Arterial , Colágeno/metabolismo , GMP Cíclico/metabolismo , Disfunção Erétil/metabolismo , Masculino , Músculo Liso , Óxido Nítrico Sintase Tipo I/metabolismo , Ereção Peniana , RatosRESUMO
BACKGROUND: Numerous epidemiological studies have evaluated the association between the CDH1 -160C/A polymorphism and the risk of breast cancers. However, these studies have yielded conflicting results. To derive a more precise estimation of this association, this meta-analysis was conducted. METHODS: A comprehensive search using the keywords "CDH1," "E-Cadherin," "polymorphism," "SNP," and "variant" combined with "breast," "cancer," "tumor," or "carcinomas" was conducted. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were appropriately calculated using a fixed effect or random effect model. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 checklist was used for this meta-analysis. RESULTS: Four publications including five studies were identified. It was found that the CDH1 -160C/A polymorphism was significantly associated with breast cancer risk in the dominant model (CA + AA vs. CC: OR = 1.207, 95 % CI = 1.031-1.412, P = 0.019). CONCLUSIONS: Our meta-analysis demonstrated that the -160C/A polymorphism in the CDH1 gene might contribute to breast cancer susceptibility. Further investigations using a much larger sample including different ethnicities are still needed to verify this association.
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Neoplasias da Mama/genética , Caderinas/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Antígenos CD , Feminino , Humanos , Fatores de RiscoRESUMO
MicroRNA (miR)-145-5p has been reported to function as a suppressor of cancer and plays an important role in cancer invasiveness. Epithelial-mesenchymal transition (EMT) is an important process in cancer invasion and migration. However, the involvement of miR-145-5p in EMT in human gastric cancer (GC) remains unclear. In this study, we aimed to investigate the molecular mechanisms by which miR-145-5p regulates EMT in GC invasiveness. We used quantitative real-time polymerase chain reaction to investigate the miR-145-5p expression level in GC and matched normal tissues. The effects of miR-145-5p on GC cell invasion and migration abilities were evaluated using Transwell models. The relationships among miR-145-5p and zinc-finger E-box binding homeobox 2 (ZEB2), E-cadherin, and N-cadherin were analyzed by quantitative real-time polymerase chain reaction and Western blot analyses. miR-145-5p levels in primary GC tissues obtained from 60 patients were significantly downregulated, compared to those in paired normal tissues. Lauren classification, depth of tumor invasion, lymph node metastasis, lymphatic invasion, and tumor-node-metastasis stage were associated with miR-145-5p expression. miR-145-5p inhibits the expression of the candidate target gene ZEB2 to delay the invasion and migration of GC cells. ZEB2 acts as transcriptional repressor of E-cadherin, while miR-145-5p is known to suppress N-cadherin directly to regulate EMT. Therefore, we concluded that miR-145-5p may target N-cadherin and ZEB2 directly to influence EMT.
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Marsdeniae tenacissimae extract (MTE), commonly known as Xiao-Ai-Ping in China, is a traditional Chinese herb medicine capable of inhibiting proliferation and metastasis and boosting apoptosis in various cancer cells. However, little is known about the contribution of MTE towards tumor angiogenesis and the underlying mechanism. The present study aimed to evaluate the effects of MTE on the proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) and the molecular mechanism. 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, inner salt (MTS) and PI-stained flow cytometry assays revealed that MTE dose-dependently reduced the proliferation of HUVECs by arresting cell cycle at S phase (P < 0.05). Annexin V-FITC/PI-stained flow cytometry confirmed that MTE (160 µL·L-1) enhanced the apoptosis of HUVECs significantly (P < 0.001). Real-time quantitative RT-PCR and Western blot analyses showed an increase in Bax expression and a sharply decline in Bcl-2 expression; caspase-3 was activated simultaneously in a dose-dependent manner (P < 0.05). Further study observed the dose-dependent down-regulation of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2), P2Y6 receptor (P2Y6R), and chemokine (C-C motif) ligand 2 (CCL-2), along with the activation of PKC Δ and up-regulation of p53 in a dose-dependent manner in MTE-treated selected cells (P < 0.05). Collectively, the results from the present study suggested that MTE suppressed the proliferation by attenuating CCL-2-mediated VEGF/VEGFR2 interactions and promoted the apoptosis through PKCΔ-induced p53-dependent mitochondrial pathway in HUVECs, supporting that MTE may be developed as a potent anti-cancer medicine.
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Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Marsdenia/química , Extratos Vegetais/farmacologia , Transdução de Sinais , Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Besides CDH1, few hereditary gastric cancer predisposition genes have been previously reported. In this study, we discovered two germline ATM mutations (p.Y1203fs and p.N1223S) in a Chinese family with a history of gastric cancer by screening 83 cancer susceptibility genes. Using a published exome sequencing dataset, we found deleterious germline mutations of ATM in 2.7% of 335 gastric cancer patients of different ethnic origins. The frequency of deleterious ATM mutations in gastric cancer patients is significantly higher than that in general population (p=0.0000435), suggesting an association of ATM mutations with gastric cancer predisposition. We also observed biallelic inactivation of ATM in tumors of two gastric cancer patients. Further evaluation of ATM mutations in hereditary gastric cancer will facilitate genetic testing and risk assessment.
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Proteínas Mutadas de Ataxia Telangiectasia/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Neoplasias Gástricas/genética , Adulto , Idoso , Sequência de Bases , Saúde da Família , Frequência do Gene , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNARESUMO
BACKGROUND: Several somatic mutation hotspots were recently identified in the telomerase reverse transcriptase (TERT) promoter region in human cancers. Large scale studies of these mutations in multiple tumour types are limited, in particular in Asian populations. This study aimed to: analyse TERT promoter mutations in multiple tumour types in a large Chinese patient cohort, investigate novel tumour types and assess the functional significance of the mutations. METHODS: TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumour types and 799 tumour tissues from Chinese cancer patients. Thymic epithelial tumours, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), telomerase activity by the telomeric repeat amplification protocol (TRAP) assay and promoter activity by the luciferase reporter assay. RESULTS: TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%) and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in gastrointestinal stromal tumour (GIST), thymic epithelial tumours, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. CONCLUSIONS: TERT promoter mutations are frequent in multiple tumour types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumourigenesis, making them potential therapeutic targets.
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Mutação , Neoplasias/genética , Regiões Promotoras Genéticas/genética , Telomerase/genética , Telomerase/metabolismo , Adulto , Povo Asiático/genética , Povo Asiático/estatística & dados numéricos , Sequência de Bases , Análise Mutacional de DNA , Ativação Enzimática/genética , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Humanos , Neoplasias/epidemiologia , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único , Células Tumorais Cultivadas , Regulação para Cima/genéticaRESUMO
In chronic obstructive pulmonary disease (COPD), two major pathological changes that occur are the loss of alveolar structure and airspace enlargement. Type II alveolar epithelial cells (AECII) play a vital role in maintaining alveolar homeostasis and lung tissue repair. Sirtuin 1 (SIRT1), a NAD(+)-dependent histone deacetylase, regulates many pathophysiological processes including inflammation, apoptosis, cellular senescence and stress resistance. The main aim of this study was to investigate whether SRT1720, a pharmacological SIRT1 activator, could protect against AECII apoptosis in rats with emphysema caused by cigarette smoke exposure and intratracheal lipopolysaccharide instillation in vivo. During the induction of emphysema in rats, administration of SRT1720 improved lung function including airway resistance and pulmonary dynamic compliance. SRT1720 treatment up-regulated the levels of surfactant protein (SP)A, SPC, SIRT1 and forkhead box O 3, increased SIRT1 activity, down-regulated the level of p53 and inhibited AECII apoptosis. Lung injury caused by emphysema was alleviated after SRT1720 treatment. SRT1720 could protect against AECII apoptosis in rats with emphysema and thus could be used in COPD treatment.
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Células Epiteliais Alveolares/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ativadores de Enzimas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Lesão Pulmonar/prevenção & controle , Enfisema Pulmonar/tratamento farmacológico , Células Epiteliais Alveolares/fisiologia , Animais , Biomarcadores/metabolismo , Western Blotting , Ativadores de Enzimas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Masculino , Enfisema Pulmonar/complicações , Enfisema Pulmonar/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Resultado do TratamentoRESUMO
BACKGROUND: This study aimed to summarize the potential diagnostic value of serum DKK1 levels in cancer detection. MATERIALS AND METHODS: Serum DKK1 was measured using enzyme-linked immunosorbent assay in a case-control study. Then we performed a meta-analysis and the pooled sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic (sROC) curves were used to evaluate the overall test performance. RESULTS: Serum DKK1 levels were found to be significantly upregulated in gastric cancer as compared to controls. ROC curve analysis revealed an AUC of 0.636, indicating the test has the potential to diagnose cancer with poor accuracy. The summary estimates of the pooled sensitivity, specificity and diagnostic odds ratio in meta-analysis were 0.55 with a 95% confidence interval (CI) (0.53-0.57), 0.86 (95%CI, 0.84-0.88) and 12.25 (95%CI, 5.31-28.28), respectively. The area under the sROC was 0.85. Subgroup analysis revealed that the diagnostic accuracy of serum DKK1 in lung cancer (sensitivity: 0.69 with 95%CI, 0.66-0.74; specificity: 0.95 with 95%CI, 0.92-0.97; diagnostic odds ratio: 44.93 with 95%CI, 26.19-77.08) was significantly higher than for any other cancer. CONCLUSIONS: Serum DKK1 might be useful as a noninvasive method for confirmation of cancer diagnosis, particularly in the case of lung cancer.
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Biomarcadores Tumorais/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Neoplasias/diagnóstico , Neoplasias Gástricas/diagnóstico , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/sangue , Prognóstico , Curva ROC , Neoplasias Gástricas/sangueRESUMO
Increased expression of galectin-1 (Gal-1) in carcinoma-associated fibroblasts (CAFs) has been reported to correlate with progression and prognosis in many cancers. However, rarely have reports sought to determine whether high Gal-1 expression in CAFs in gastric cancer is involved in the tumor process, and the specific mechanism by which it promotes the evolution of gastric cancer is still unknown. In this study, we cultured gastric cancer CAFs, which showed strong expression of Gal-1, and established a co-culture system of CAFs with gastric cancer cells. Specific siRNA and in vitro migration and invasion assays were used to explore the effects of the interaction between Gal-1 expression of CAFs and gastric cancer cells on cell migration and invasion. We found that the overexpression of Gal-1 in CAFs enhanced gastric cancer cell migration and invasion, and these stimulatory effects could be blocked by specific siRNA which reduced the Gal-1 expression level. A set of cancer invasion-associated genes were then chosen to identify the possible mechanism of Gal-1-induced cell invasion. Among these genes, integrin ß1 expression in cancer cells was considered to be associated with Gal-1 expression. Pre-blocking of the integrin ß1 expression in gastric cancer cells with siRNA could interrupt the invasion-promoting effect of CAFs with high Gal-1 expression. Furthermore, immunohistochemical assay confirmed a positive correlation between Gal-1 and integrin ß1 expression. Our results showed that high expression of Gal-1 in CAFs might facilitate gastric cancer cell migration and invasion by upregulating integrin ß1 expression in gastric cancer.
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Fibroblastos/metabolismo , Galectina 1/genética , Integrina beta1/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Feminino , Fibroblastos/patologia , Galectina 1/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Integrina beta1/metabolismo , Masculino , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Gástricas/mortalidade , Carga Tumoral , Regulação para CimaRESUMO
The aim of this study was to discuss the role of c-KIT mutation in the pathogenesis of gastrointestinal stromal tumors (GISTs) and analyze its correlation with proliferation and apoptosis. c-KIT and PDGFRA genotypes were examined by deoxyribonucleic acid sequencing. Immunohistochemistry was performed to determine the expression levels of Kit, Ki-67 (proliferation marker), and apoptotic protease-activating factor (APAF)-1 (apoptosis marker) and the relationship between their three genes. In the 68 cases examined, 44 cases (64.7%) showed mutations in one of the four exons of c-KIT. The mutations were most frequently found in exon 11 (30 cases [44.1%]), followed by exon 9 (ten cases [14.7%]) and exon 13 (four cases [5.9%]). c-KIT mutation showed no association with prognostic factors using the classification of risk of aggressive behavior in GIST proposed by Fletcher et al. No cases had mutated exon 17 of c-KIT, and neither did exon 12, 14, or 18 of PDGFRA in our present study. There was a positive correlation between the expression level of Kit and Ki-67 (R=0.282, P=0.020). Conversely, a negative correlation was found between the expression levels of Kit and APAF1 (R=-0.243, P=0.046). In conclusion, most GISTs with Kit expression showed c-KIT mutation. Kit expression has a positive correlation with Ki-67 and a negative correlation with APAF1, showing that c-KIT is involved in GIST occurrence and development through proliferation promotion and apoptosis inhibition.
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BACKGROUND: Recent studies have shown that miR-199a-5p plays opposite roles in cancer initiation and progression of different cancer types, acting as oncogene for some cancer types but as tumor suppressor gene for others. However, the role and molecular mechanism of miR-199a-5p in gastric cancer are largely unknown. METHODS: In this study, miR-199a-5p expression level in gastric cancer was first analyzed by qPCRand then validated in 103 gastric cancer patients by in situ hybridization (ISH). Gastric cancer cell lines were transfected with miR-199a-5p inhibitor and mimic, and underwent in vitro transwell assays. Target genes (klotho) were identified using Luciferase reporter assay. Immunohistochemical staining was also used to investigate on how miR-199a-5p regulates the tumour-suppressive effects of klotho in gastric cancer. RESULTS: In our present study, we found that miR-199a-5p level was significantly increased in gastric cancer tissues compared to paired normal tissues. We observed that miR-199a-5p could promote migration and invasion of gastric cancer cells. In situ hybridization of miR-199a-5p also confirmed that higher miR-199a-5p expression level was associated with increased likelihood of lymph node metastasis and later TNM stage. Luciferase reporter assay and immunohistochemistry revealed that klotho might be the downstream target of miR-199a-5p. CONCLUSIONS: Our present study suggests that miR-199a-5p acts as an oncogene in gastric cancer and functions by targeting klotho.
Assuntos
Glucuronidase/metabolismo , MicroRNAs/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Glucuronidase/genética , Humanos , Proteínas Klotho , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , MicroRNAs/antagonistas & inibidores , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Reprodutibilidade dos Testes , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Andrographolide has been shown to have anticancer activity on diverse cancer cell lines representing different types of human cancers. The aim of this research was to investigate the anticancer and apoptotic effects of andrographolide on the BGC-823 human gastric cancer cell line. METHODS: Cell proliferation and IC50 were evaluated using MTT assay, cell-cycle analysis with flow cytometry apoptotic effects with Annexin-V/propidium iodide double-staining assay, and morphologic structure with transmission electron microscopy. Immunohistochemistry and reverse-transcription PCR was used to analyze Bcl-2, Bax, and caspase-3 expressions. RESULTS: Andrographolide showed a time- and concentration-dependent inhibitory effects on BGC-823 cell growth. Compared to controls, the number of cells in the G0-G1-phase increased significantly, S and G2-M-phase cells decreased after 48 hours of treatment with andrographolide, and both early and late apoptotic rates increased significantly compared to the controls, all in a concentration-dependent manner. Bax and caspase-3 expressions were markedly increased, and Bcl-2 expression was decreased. CONCLUSIONS: Andrographolide inhibits BGC-823 cell growth and induces BGC-823 cell apoptosis by up-regulating Bax and caspase-3 expressions and down-regulating Bcl-2 expression. Andrographolide may be useful as a potent and selective agent in the treatment of human gastric cancers.