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Purpose: The aim is to investigate the application value of dermoscopy combined with reflectance confocal microscopy (RCM) in assessing vitiligo disease activity and treatment response. Patients and Methods: We enrolled 279 patients with vitiligo and evaluated the disease activity by Vitiligo Disease Activity (VIDA) score, dermoscopy, RCM and dermoscopy combined with RCM respectively. The sensitivity and specificity of different assessment techniques were compared with VIDA score by the differences and consistency. The different characteristics of dermoscopy and RCM with different treatment responses were also analyzed. Results: The results showed that the sensitivity and specificity of dermoscopy combined RCM were higher than RCM or dermoscopy alone (P values less than 0.05). In the repigmentation process, leukotrichia, pigment network absent and perilesional hyperpigmentation under dermoscopy at the baseline suggested a poor treatment response, while the incompletely disappearing pigment rings under RCM and perifollicular hyperpigmentation under dermoscopy indicated a good treatment response. We also found the proportion of patients with telangiectasia, increased pigment at the lesions and around the hair follicles was significantly higher in the good treatment response group than that in the poor one by dermoscopy (χ2 = 4.423, 32.471, 4.348, P = 0.035 0.000, 0.037) and by RCM the proportion of patients with both increased pigment granules and dendritic melanocytes in the good treatment response group was higher than that in the poor one (χ2 = 38.215, 5.283, P = 0.000, 0.022, respectively). Conclusion: With the higher sensitivity and specificity than dermoscopy or RCM alone, a combination of dermoscopy and RCM may be a new more accurate measure to assess the vitiligo disease activity and the treatment response.
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BACKGROUND: The surgical step-up approach often requires multiple debridements and might not be suitable for infected pancreatic necrosis (IPN) patients with various abscesses or no safe route for percutaneous catheter drainage (PCD). This case-control study aimed to investigate the safety and effectiveness of one-step laparoscopic pancreatic necrosectomy (LPN) in treating IPN. METHODS: This case-control study included IPN patients undergoing one-step LPN or surgical step-up in our center from January 2015 to December 2020. The short-term and long-term complications after surgery, length of hospital stay, and postoperative ICU stays in both groups were analyzed. Univariate and multivariate logistic regression analyses were performed to explore the risk factors of major complications or death. RESULTS: A total of 53 IPN patients underwent one-step LPN and 37 IPN patients underwent surgical step-up approach in this study. There was no significant difference in the incidence of death, major complications, new-onset diabetes, or new-onset pancreatic exocrine insufficiency between the two groups. However, the length of hospital stay in the one-step LPN group was significantly shorter than that in the surgical step-up group. Univariate regression analysis showed that the surgical approach (one-step/step-up) was not the risk factor for major complications or death. Multivariate logistic regression analysis indicated that computed tomography (CT) severity index, American Society of Anesthesiologists (ASA) class IV, and white blood cell (WBC) were the significant risk factors for major complications or death. CONCLUSION: One-step LPN is as safe and effective as the surgical step-up approach for treating IPN patients, and reduces total hospital stay.
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Rationale: Hypoxia has been proved to contribute to aggressive phenotype of cancers, while functional and regulatory mechanism of long noncoding RNA (lncRNA) in the contribution of hypoxia on pancreatic cancer (PC) tumorigenesis is incompletely understood. The aim of this study was to uncover the regulatory and functional roles for hypoxia-induced lncRNA-MTA2TR (MTA2 transcriptional regulator RNA, AF083120.1) in the regulation of PC tumorigenesis. Methods: A lncRNA microarray confirmed MTA2TR expression in tissues of PC patients. The effects of MTA2TR on proliferation and metastasis of PC cells and xenograft models were determined, and the key mechanisms by which MTA2TR promotes PC were further dissected. Furthermore, the expression and regulation of MTA2TR under hypoxic conditions in PC cells were assessed. We also assessed the correlation between MTA2TR expression and PC patient clinical outcomes. Results: We found that metastasis associated protein 2 (MTA2) transcriptional regulator lncRNA (MTA2TR) was overexpressed in PC patient tissues relative to paired noncancerous tissues. Furthermore, we found that depletion of MTA2TR significantly inhibited PC cell proliferation and invasion both in vitro and in vivo. We further demonstrated that MTA2TR transcriptionally upregulates MTA2 expression by recruiting activating transcription factor 3 (ATF3) to the promoter area of MTA2. Consequentially, MTA2 can stabilize the HIF-1α protein via deacetylation, which further activates HIF-1α transcriptional activity. Interestingly, our results revealed that MTA2TR is transcriptionally regulated by HIF-1α under hypoxic conditions. Our clinical samples further indicated that the overexpression of MTA2TR was correlated with MTA2 upregulation, as well as with reduced overall survival (OS) in PC patients. Conclusions: These results suggest that feedback between MTA2TR and HIF-1α may play a key role in regulating PC tumorigenesis, thus potentially highlighting novel avenues PC treatment.
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Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Pancreáticas/genética , ARN Largo no Codificante/metabolismo , Acetilación , Factor de Transcripción Activador 3/metabolismo , Animales , Hipoxia de la Célula/genética , Línea Celular Tumoral , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Neoplasias Pancreáticas/patología , Pronóstico , Regiones Promotoras Genéticas , Estabilidad Proteica , ARN Largo no Codificante/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transcripción GenéticaRESUMEN
The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.
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Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/genética , ARN Largo no Codificante/fisiología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Animales , Hipoxia de la Célula , Línea Celular Tumoral , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/fisiología , Humanos , Factor 1 Inducible por Hipoxia/genética , Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Metástasis Linfática , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/fisiopatología , Neoplasias Pancreáticas/secundario , ARN Largo no Codificante/metabolismo , Transcripción Genética , Proteína 1 de Unión a la Caja Y/genética , Proteína 1 de Unión a la Caja Y/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismoRESUMEN
Migration and invasion inhibitory protein (MIIP) is recently identified as an inhibitor in tumor development. However, the regulatory mechanism and biological contributions of MIIP in pancreatic cancer (PC) have been not elucidated. In this study, we demonstrated a negative feedback of MIIP and hypoxia-induced factor-1α (HIF-1α), which was mediated by a hypoxia-induced microRNA. Compared with paracarcinoma tissues, MIIP was downregulated in PC tissues. Overexpression of MIIP significantly impeded the proliferation and invasion of PC cells both in vitro and in mouse xenograft models. We further verified MIIP was downregulated under hypoxia in a HIF-1α-mediated manner. Interestingly, although MIIP promoter containing two putative hypoxia response elements (HREs), the chromatin immunoprecipitation (ChIP) and luciferase reporter assays did not support an active interaction between HIF-1α and MIIP promoter. Meanwhile, microRNA array revealed a hypoxia-induced microRNA, miR-646, impaired stability of MIIP mRNA and consequently inhibited its expression by targeting the coding sequence (CDS). Coincidently, knockdown of miR-646 significantly repressed proliferation and invasion ability of PC cells both in vitro and in vivo by upregulating MIIP expression. Besides, ChIP and luciferase reporter assays further validated that HIF-1α activated transcription of miR-646 in hypoxia condition. Therefore, these results suggested HIF-1α indirectly regulated MIIP expression in post-transcriptional level through upregulating miR-646 transcription. Conversely, our results further revealed that MIIP suppressed deacetylase ability of histone deacetylase 6 (HDAC6) to promote the acetylation and degradation of HIF-1α, by which impairing HIF-1α accumulation. What is more, a specific relationship between downregulated MIIP and upregulated miR-646 expression was validated in PC samples. Moreover, the dysregulated miR-646 and MIIP expression was correlated with advanced tumor stage, lymphatic invasion, metastasis and shorter overall survival in PC patients. Together, our results highlight that the reciprocal loop of HIF-1α/miR-646/MIIP might be implemented as an applicable target for pancreatic cancer therapy.
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Carcinogénesis/genética , Proteínas Portadoras/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , MicroARNs/fisiología , Neoplasias Pancreáticas/genética , Adulto , Anciano , Animales , Proliferación Celular/genética , Células Cultivadas , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Hipoxia Tumoral/genéticaRESUMEN
Centrosomal protein 55 (CEP55) is a microtubule-bundling protein that participants in cell mitosis. It is overexpressed in several solid tumours and promotes the growth and invasion of cancer cells. However, the role of CEP55 in pancreatic cancer (PANC) remains unclear. Herein, upregulated expression of CEP55 (associated with poor prognosis) was detected in PANC using quantitative real-time reverse transcription PCR, western blotting, and immunohistochemistry. Cell migration, colony formation, wound-healing, and Transwell matrix penetration assays, revealed that upregulation of CEP55 promoted PANC cells proliferation, migration, and invasion in vitro, whereas knockdown of CEP55 attenuated it. In an in vivo murine model, CEP55 overexpression accelerated PANC cells tumourigenicity, together with upregulation of the protein levels of invasion-related proteins matrix metalloproteinase (MMP)2, MMP9, and proliferation-related protein Cyclin D1. Downregulation of CEP55 had the reverse effect. Moreover, the nuclear factor κB (NF-κB)/IκBα signalling pathway, which was activated in CEP55-transduced PANC cells and inhibited in CEP55-silenced PANC cells, contributed to CEP55-mediated PANC cell aggressiveness. This study provided new insights into the oncogenic roles of CEP55 and the mechanism by which the NF-κB pathway is hyperactivated in patients with PANC, indicating that CEP55 is a valuable prognostic factor and a potential therapeutic target in PANC.
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Proteínas de Ciclo Celular/metabolismo , FN-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Transducción de Señal , Carcinogénesis/genética , Carcinogénesis/patología , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Invasividad Neoplásica , Proteínas Nucleares/genética , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Supervivencia , Regulación hacia Arriba/genéticaRESUMEN
Extracellular acid can have important effects on cancer cells. Acid-sensing ion channels (ASICs), which emerged as key receptors for extracellular acidic pH, are differently expressed during various diseases and have been implicated in underlying pathogenesis. This study reports that ASIC1 and ASIC3 are mainly expressed on membrane of pancreatic cancer cells and upregulated in pancreatic cancer tissues. ASIC1 and ASIC3 are responsible for an acidity-induced inward current, which is required for elevation of intracellular Ca2+ concentration ([Ca2+]i). Inhibition of ASIC1 and ASIC3 with siRNA or pharmacological inhibitor significantly decreased [Ca2+]i and its downstream RhoA during acidity and, thus, suppressed acidity-induced epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. Meanwhile, downregulating [Ca2+]i with calcium chelating agent BAPTA-AM or knockdown of RhoA with siRNA also significantly repressed acidity-induced EMT of pancreatic cancer cells. Significantly, although without obvious effect on proliferation, knockdown of ASIC1 and ASIC3 in pancreatic cancer cells significantly suppresses liver and lung metastasis in xenograft model. In addition, ASIC1 and ASIC3 are positively correlated with expression of mesenchymal marker vimentin, but inversely correlated with epithelial marker E-cadherin in pancreatic cancer cells. In conclusion, this study indicates that ASICs are master regulator of acidity-induced EMT. In addition, the data demonstrate a functional link between ASICs and [Ca2+]i/RhoA pathway, which contributes to the acidity-induced EMT.
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Canales Iónicos Sensibles al Ácido/metabolismo , Ácidos/farmacología , Calcio/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pancreáticas/patología , Transducción de Señal/efectos de los fármacos , Proteína de Unión al GTP rhoA/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Femenino , Técnicas de Silenciamiento del Gen , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Neoplasias Pancreáticas/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
[This corrects the article DOI: 10.1038/srep08087.].
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In the present study, we investigated the effects of hydroxyethyl starch (HES) 130/0.4 on serum pro-inflammatory variables, immunologic variables, fluid balance (FB)-negative(-) rate and renal function in severe acute pancreatitis (SAP) patients. From October, 2007 to November, 2008, a total of 120 SAP patients were enrolled in this retrospective study. Fifty-nine patients in the HES group received 6% HES 130/0.4 combined with crystalloid solution for fluid resuscitation (HES group). In the control group, 61 patients received only crystalloid solution after admission. Interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF)-α levels in serum were measured on days 1, 2, 4 and 8. The peripheral blood CD4+CD8+ T lymphocyte rates, serum BUN and Cr values were also measured on days 1, 4 and 8. Patients with FB(-) rates were recorded from day 1 to 8. Interaction term analysis (hospital stay and fluid resuscitation methods) based on mixed-effects regression model revealed significantly lower levels of IL-1 and TNF-α in the HES group compared with the control group. The difference in curve's risk ratio was not significant for IL-6, CD4+CD8+ T lymphocyte rate, BUN and Cr values (P>0.05). In the HES group, we detected a significantly higher rate of patients with FB(-) from day 4 to 8 (P<0.05). Thus, HES 130/0.4 resuscitation could decrease the IL-1 and IL-8 levels, shorten the duration of positive FB, and preserve the patient's immune status as well as renal function during the early phase of SAP.
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Over the past decades, cancer has become one of the toughest challenges for health professionals. The epidemiologists are increasingly directing their research efforts on various malignant tumor worldwide. Of note, incidence of cancers is on the rise more quickly in developed countries. Indeed, great endeavors have to be made in the control of the life-threatening disease. As we know it, pancreatic cancer (PC) is a malignant disease with the worst prognosis. While little is known about the etiology of the PC and measures to prevent the condition, so far, a number of risk factors have been identified. Genetic factors, pre-malignant lesions, predisposing diseases and exogenous factors have been found to be linked to PC. Genetic susceptibility was observed in 10% of PC cases, including inherited PC syndromes and familial PC. However, in the remaining 90%, their PC might be caused by genetic factors in combination with environmental factors. Nonetheless, the exact mechanism of the two kinds of factors, endogenous and exogenous, working together to cause PC remains poorly understood. The fact that most pancreatic neoplasms are diagnosed at an incurable stage of the disease highlights the need to identify risk factors and to understand their contribution to carcinogenesis. This article reviews the high risk factors contributing to the development of PC, to provide information for clinicians and epidemiologists.
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Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Sistema del Grupo Sanguíneo ABO/genética , Consumo de Bebidas Alcohólicas/fisiopatología , Diabetes Mellitus/genética , Diabetes Mellitus/patología , Humanos , Incidencia , Obesidad/genética , Obesidad/patología , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pancreatitis Crónica/genética , Pancreatitis Crónica/patología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Pronóstico , Factores de Riesgo , Fumar/fisiopatología , Análisis de Supervivencia , Neoplasias PancreáticasRESUMEN
Locally advanced pancreatic cancer is associated with a very poor prognosis. This study was performed to evaluate whether patients with locally advanced pancreatic cancer benefit from (125)I seed implantation. This retrospective study included 224 patients with locally advanced pancreatic cancer, with 137 patients (61.2%) in the implantation (IP) group and 87 (38.9%) in the non-implantation (NIP) group. The survival status, complications and objective curative effects were compared between the groups. The average operative time in the IP group was significantly longer than that in the NIP group (243±51 vs. 214±77 min). The tumor response rates were 9.5% and 0 at the 2nd month after surgery in the IP and NIP groups, respectively (P<0.05). The IP group exhibited a trend toward pain relief at the 6th month after surgery. The global health status scores of the IP group were higher than those of the NIP group at the 3rd and 6th month after surgery. The median survival time in the IP group was significantly longer than that in the NIP group. In conclusion, patients with locally advanced pancreatic cancer can benefit from (125)I seed implantation in terms of local tumor control, survival time, pain relief and quality of life.
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Stents Liberadores de Fármacos/efectos adversos , Radioisótopos de Yodo/administración & dosificación , Neoplasias Pancreáticas/radioterapia , Radiofármacos/administración & dosificación , Adulto , Anciano , Femenino , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Calidad de Vida , Radiofármacos/uso terapéutico , Análisis de SupervivenciaRESUMEN
Recent studies indicate that long non-coding RNAs (lncRNAs) play crucial roles in numerous cancers, while their function in pancreatic cancer is rarely elucidated. The present study identifies a functional lncRNA and its potential role in tumorigenesis of pancreatic cancer. Microarray co-assay for lncRNAs and mRNAs demonstrates that lncRNA-NUTF2P3-001 is remarkably overexpressed in pancreatic cancer and chronic pancreatitis tissues, which positively correlates with KRAS mRNA expression. After downregulating lncRNA-NUTF2P3-001, the proliferation and invasion of pancreatic cancer cell are significantly inhibited both in vitro and vivo, accompanying with decreased KRAS expression. The dual-luciferase reporter assay further validates that lncRNA-NUTF2P3-001 and 3'UTR of KRAS mRNA competitively bind with miR-3923. Furthermore, miR-3923 overexpression simulates the inhibiting effects of lncRNA-NUTF2P3-001-siRNA on pancreatic cancer cell, which is rescued by miR-3923 inhibitor. Specifically, the present study further reveals that lncRNA-NUTF2P3-001 is upregulated in pancreatic cancer cells under hypoxia and CoCl2 treatment, which is attributed to the binding of hypoxia-inducible factor-1α (HIF-1α) to hypoxia response elements (HREs) in the upstream of KRAS promoter. Data from pancreatic cancer patients show a positive correlation between lncRNA-NUTF2P3-001 and KRAS, which is associated with advanced tumor stage and worse prognosis. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumor oncogene KRAS and implicate that lncRNA-NUTF2P3-001 and miR-3923 can be applied as novel predictors and therapeutic targets for pancreatic cancer.
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Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , MicroARNs/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , ARN Largo no Codificante/biosíntesis , Animales , Carcinogénesis/genética , Hipoxia de la Célula/fisiología , Línea Celular Tumoral , Proliferación Celular/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN Largo no Codificante/genéticaRESUMEN
The purpose of this study was to investigate the etiology, pathological characteristics, management and prognosis of chronic pancreatitis in the Chinese population. The clinical data of 142 patients with chronic pancreatitis were retrospectively studied. All patients were of Chinese nationality and hospitalized from January 2008 to December 2011. Their ages ranged from 14 to 76 years, with a mean of 43 years. Of 142 patients, there were 72 cases of obstructive chronic pancreatitis (50.70%), 19 cases of alcoholic chronic pancreatitis (13.38%), 14 cases of autoimmune pancreatitis (9.86%) and 37 cases of undetermined etiology (26.06%). Pathologically, the average inflammatory mass diameter was 3.8 ± 3.3 cm, biliary obstruction occurred in 36 cases, gall stones in 70 cases, calcification in 88 cases, ductal dilatation in 61 cases, side branch dilatation in 32 cases, ductal irregularity in 10 cases, lymphocytic inflammation in 23 cases, obliterative phlebitis in 14 cases, extra pancreatic lesion in 19 cases and fibrosis in 142 cases. Location of pancreatic lesion in the region of head (n=97), neck (n=16), body (n=12), tail (n=15) and whole pancreas (n=2) influenced the choice of surgical procedures. Ninety-four patients (66.20%) received surgical treatment and 33.80% received other treatments. After operation, 80.85% of 94 patients experienced decreased pain, and 8.51% of 94 showed recovery of endocrine function but with a complication rate of 12.77%. All the operations were performed successfully. According to the pain scale of European Organization for Research and Treatment of Cancer (QLQ-C30) a decrease from 76 ± 22 to 14 ± 18 was observed. Etiology, pathological characteristics, management and prognosis of chronic pancreatitis in the Chinese population vary from others.
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Enfermedades Autoinmunes/epidemiología , Colestasis/epidemiología , Pancreatitis Alcohólica/epidemiología , Pancreatitis Crónica/patología , Pancreatitis Crónica/terapia , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes/terapia , China/epidemiología , Colestasis/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pancreatitis Alcohólica/terapia , Pancreatitis Crónica/etiología , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Recent studies have indicated the possible function of miR-217 in tumorigenesis. However, the roles of miR-217 in colorectal cancer (CRC) are still largely unknown. METHODS: We examined the expression of miR-217 and AEG-1 in 50 CRC tissues and the corresponding noncancerous tissues by qRT-PCR. The clinical significance of miR-217 was analyzed. CRC cell lines with miR-217 upregulation and AEG-1 silencing were established and the effects on tumor growth in vitro and in vivo were assessed. Dual-luciferase reporter gene assays were also performed to investigate the interaction between miR-217 and AEG-1. RESULTS: Our data demonstrated that miR-217 was significantly downregulated in 50 pairs of colorectal cancer tissues. MiR-217 expression levels were closely correlated with tumor differentiation. Moreover, decreased miR-217 expression was also associated with shorter overall survival of CRC patients. MiR-217 overexpression significantly inhibited proliferation, colony formation and invasiveness of CRC cells by promoting apoptosis and G0/G1 phase arrest. Interestingly, ectopic miR-217 expression decreased AEG-1 expression and repressed luciferase reporter activity associated with the AEG-1 3'-untranslated region (UTR). AEG-1 silencing resulted in similar biological behavior changes to those associated with miR-217 overexpression. Finally, in a nude mouse xenografted tumor model, miR-217 overexpression significantly suppressed CRC cell growth. CONCLUSIONS: Our findings suggest that miR-217 has considerable value as a prognostic marker and potential therapeutic target in CRC.
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Biomarcadores de Tumor/biosíntesis , Moléculas de Adhesión Celular/biosíntesis , Neoplasias Colorrectales/genética , MicroARNs/biosíntesis , Anciano , Animales , Apoptosis/genética , Biomarcadores de Tumor/genética , Moléculas de Adhesión Celular/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas de la Membrana , Ratones , MicroARNs/genética , Persona de Mediana Edad , Invasividad Neoplásica/genética , Pronóstico , Proteínas de Unión al ARN , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: 7, 12-dimethylbenzanthracene (DMBA)-induced pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic cancer. However, this model has not been characterized genetically, and in particular, the major genetic alterations in the p16 gene are unknown. METHODS: Lesions of PanIN and pancreatic cancer were induced with DMBA implantation in 40 rats, and control pancreatic tissue was obtained from 10 age-matched rats without exposure to DMBA. Pancreatic tissue was harvested three months after DMBA implantation and DNA was extracted. Homozygous deletions and point mutations of the p16 (exons 1 and 2) gene were detected by PCR amplification and direct sequencing. RESULTS: DMBA implantation in the 40 rats induced 26 PanINs and 9 carcinomas. The overall frequency of p16 alterations in the pancreatic tissue of these rats was 42.86% (15/35), and the changes were point mutations, not homozygous deletions. p16 mutations were present in 30.77% (8/26) of the rats with PanIN and 77.78% (7/9) of the rats with carcinoma (P<0.05). The increasing incidence of p16 alterations was detected in 20.00% (1/5) of PanIN-1, 28.57% (2/7) of PanIN-2 and 35.71% (5/14) of PanIN-3 lesions. CONCLUSION: Our findings indicated that p16 alteration is a common event in the carcinogenesis of this model and that the mutation pattern is analogous to that of human lesions.
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Carcinoma in Situ/genética , Carcinoma/genética , Genes p16 , Neoplasias Pancreáticas/genética , 9,10-Dimetil-1,2-benzantraceno , Animales , Carcinoma/inducido químicamente , Carcinoma/patología , Carcinoma in Situ/inducido químicamente , Carcinoma in Situ/patología , Modelos Animales de Enfermedad , Exones , Masculino , Neoplasias Pancreáticas/inducido químicamente , Neoplasias Pancreáticas/patología , Mutación Puntual , Ratas , Ratas Sprague-DawleyRESUMEN
Accumulating evidences indicate that microRNAs play a vital role in regulating tumor progression. However, the roles of miR-148b in hepatocellular carcinoma (HCC) are still largely unknown. In this study, our data showed that miR-148b was significantly downregulated in 40 pairs of human HCC tissues. Further, the deregulated miR-148b was significantly correlated with larger tumor size, more tumor number, metastasis and worse prognosis in HCC. Overexpression of miR-148b inhibited HCC HepG2 cells proliferation and tumorigenicity. Further, miR-148b induced cells apoptosis by activating caspase- 3 and caspase-9, and induced S phase arrest by regulating cyclinD1 and p21, and also inhibited cell invasion. Data from the dual-luciferase reporter gene assay showed that WNT1 was a direct target of miR-148b, and overexpressed WNT1 inversely correlated with miR-148b levels in HCC tissues. Silencing of WNT1 inhibited the growth of HCC cells, and also induced cells apoptosis and inhibited invasion, which is consistent with the effects of miR-148b overexpression. MiR-148b downregulated expression of WNT1, ß-catenin and C-myc, while upregulated E-cadherin expression. We conclude that the frequently downregulated miR-148b can regulate WNT1/ß-catenin signalling pathway and function as a tumor suppressor in HCC. These findings suggest that miR-148b may serve as a novel therapeutic target for HCC.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , MicroARNs/metabolismo , Vía de Señalización Wnt , Proteína Wnt1/metabolismo , Regiones no Traducidas 3'/genética , Anciano , Animales , Apoptosis/genética , Secuencia de Bases , Western Blotting , Puntos de Control del Ciclo Celular/genética , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , Datos de Secuencia Molecular , Invasividad Neoplásica , Análisis de Supervivencia , TransfecciónRESUMEN
Tumor growth cascade is a complicated and multistep process with numerous obstacles. Until recently, evidences have shown the involvement of microRNAs (miRNAs) in tumorigenesis and tumor progression of various cancers, including colorectal cancer (CRC). In this study, we explored the role of miR-194 and its downstream pathway in CRC. We acquired data through miRNA microarray profiles, showing that the expression of miR-194 was significantly suppressed in CRC tissues compared with corresponding noncancerous tissues. Decreased miR-194 expression was obviously associated with tumor size and tumor differentiation, as well as TNM stage. Both Kaplan-Meier and multivariate survival analysis showed that downregulated miR-194 was associated with overall survival. Moreover, functional assays indicated that overexpression of miR-194 in CRC cell lines inhibited cell proliferation both in vitro and in vivo. In addition, using dual-luciferase reporter gene assay, we found MAP4K4 was the direct target of miR-194. Silencing of MAP4K4 resulted in similar biological behavior changes to that of overexpression of miR-194. We also observed through Human Gene Expression Array that MDM2 was one of the downstream targets of MAP4K4. Knockdown of MAP4K4 downregulated MDM2 expression through transcription factor c-Jun binding to the -1063 to -1057 bp of the promoter. These results suggest that miR-194, regulating the MAP4K4/c-Jun/MDM2 signaling pathway, might act as a tumor suppressor and serve as a novel target for CRC prevention and therapy.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , MicroARNs/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Regiones no Traducidas 3' , Animales , Apoptosis , Secuencia de Bases , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Regulación hacia Abajo , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Estimación de Kaplan-Meier , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Análisis Multivariante , Trasplante de Neoplasias , Pronóstico , Regiones Promotoras Genéticas , Modelos de Riesgos Proporcionales , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Interferencia de ARN , Transducción de SeñalRESUMEN
High mobility group box 1 protein (HMGB1), a nuclear non-histone DNA-binding protein, is secreted extracellularly during inflammation and is a late mediator of inflammatory responses. The pro-inflammatory activity of recombinant HMGB1 proteins is dependent upon the formation of complexes with other mediators, such as lipopolysaccharide (LPS). This study investigated the influence of heparin on LPS+HMGB1-mediated inflammatory responses in cultured macrophages and a murine sepsis model. HMGB1 promoted the phosphorylation of p38 and ERK1/2. HMGB1 enhanced the induction of the pro-inflammatory cytokine, TNF-α, by LPS in macrophages. Heparin blocked the binding of HMGB1 to the surface of macrophages, and suppressed the phosphorylation of p38 and ERK1/2, but not JNK; TNF-α secretion was also decreased. However, heparin alone did not affect LPS-induced production of TNF-α. Heparin reduced lethality in mice exposed to LPS+HMGB1. To conclude, heparin inhibited LPS-induced HMGB1-amplified inflammatory responses by blocking HMGB1 binding to macrophage surfaces. Heparin could be used therapeutically as an effective inhibitor of HMGB1-associated inflammation.
Asunto(s)
Proteína HMGB1/metabolismo , Heparina/farmacología , Macrófagos/efectos de los fármacos , Sepsis/tratamiento farmacológico , Animales , Línea Celular , Modelos Animales de Enfermedad , Activación Enzimática , Inflamación/inmunología , Lipopolisacáridos/inmunología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Sepsis/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The main treatment strategies for chronic pancreatitis in young patients include therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) intervention and surgical intervention. Therapeutic ERCP intervention is performed much more extensively for its minimally invasive nature, but a part of patients are referred to surgery at last. Historical and follow-up data of 21 young patients with chronic pancreatitis undergoing duodenum-preserving total pancreatic head resection were analyzed to evaluate the outcomes of therapeutic ERCP intervention and surgical intervention in this study. The surgical complications of repeated therapeutic ERCP intervention and surgical intervention were 38% and 19% respectively. During the first therapeutic ERCP intervention to surgical intervention, 2 patients developed diabetes, 5 patients developed steatorrhea, and 5 patients developed pancreatic type B pain. During the follow-up of surgical intervention, 1 new case of diabetes occurred, 1 case of steatorrhea recovered, and 4 cases of pancreatic type B pain were completely relieved. In a part of young patients with chronic pancreatitis, surgical intervention was more effective than therapeutic ERCP intervention on delaying the progression of the disease and relieving the symptoms.