RESUMEN
Background: Metronidazole (MTZ) is among the first-line drugs against the human gastric pathogen Helicobacter pylori (H. pylori). MTZ is used as a prodrug that is activated by an oxygen-insensitive enzyme NADPH nitroreductase (RdxA). Loss-of-function mutations in rdxA make H. pylori MTZ resistant; however, experimental proof is lacking. Methods: We collected 139 gastric biopsy samples from patients suspected of H. pylori infection in Shanghai, and amplified Hp-specific rdxA gene from 134 samples. All these rdxA genes were sequenced and phylogenetically compared. The effect of mutations on RdxA function was measured by expressing them in Escherichia coli DH5α by using the MTZ sensitivity test. Results: In total, 134 gastric biopsy samples were identified as H. pylori positive. Of the 134 samples, 74 and 6 had point mutations at the various sites or promoter region of rdxA, generating truncated and extended fused proteins, respectively. The remaining 54 were full-length with single nucleotide variation (SNV) compared with the wild-type RdxA from H. pylori, with 49 clustering with hpEastAsia, 3 with hpEurope, and 2 with hpNEAfrica. All 134 rdxA were expressed in E. coli DH5α; 22 and 112 resultant strains showed MTZ-sensitive and MTZ-resistant phenotypes, respectively. Comparative analysis of single nucleotide polymorphisms (SNPs) in the functional and inactivated RdxA revealed 14 novel mutations in RdxA, 5 of which conferred MTZ resistance: S18F, D59S, L62I, S79N, and A187V. Conclusion: The occurrence of MTZ resistance induced by site-mutation of RdxA in patients with H. pylori infection was 83.6% (112/134) in the Shanghai region. The major form of loss-of-function mutation was truncation of RdxA translation at a rate of 58/112 (51.8%). Molecular detection reliably determined the resistance of H. pylori to MTZ. Thus, the functional mutants involved in MTZ resistance facilitate clinical diagnosis and medication based on sequence analysis.
RESUMEN
There has been interested in the microRNAs' roles in pancreatic cancer (PC) cell biology, particularly in regulating pathways related to tumorigenesis. The study aimed to explore the hub miRNAs in PC and underlying mechanisms by bioinformatics and fundamental experiments. RNA datasets collected from the Gene Expression Omnibus were analysed to find out differentially expressed RNAs (DERNAs). The miRNA-mRNA and protein-protein interaction (PPI) networks were built. The clinicopathological features and expressions of hub miRNAs and hub mRNAs were explored. Dual-luciferase reporter gene assay was performed to assess the interaction between microRNA and target gene. RT-qPCR and western blot were employed to explore RNA expression. The roles of RNA were detected by CCK-8 test, wound healing, transwell, and flow cytometry experiment. We verified 40 DEmiRNAs and 1613 DEmRNAs, then detected a total of 69 final functional mRNAs (FmRNAs) and 23 DEmiRNAs. In the miRNA-mRNA networks, microRNA-130b (miR-130b) was the hub RNA with highest degrees. Clinical analysis revealed that miR-130b was considerably lower expressed in cancerous tissues than in healthy ones, and patients with higher-expressed miR-130b had a better prognosis. Mechanically, miR-130b directly targeted MET in PC cells. Cell functional experiments verified that miR-130b suppressed cell proliferation, migration, promoted apoptosis, and inhibited the PI3K/Akt pathway by targeting MET in PC cells. Our findings illustrated the specific molecular mechanism of miR-130b regulating PC progress. The miR-130b/MET axis may be an alternative target in the therapeutic intervention of PC and provide an opportunity to deepen our understanding of the pathogenesis of PC.
RESUMEN
Helicobacter pylori (H. pylori) infection is a major cause of gastric diseases. Currently, bismuth-based quadruple therapy is widely adopted for eradicating H. pylori infection. However, this first-line strategy faces several challenges such as drug resistance, intestinal dysbacteriosis, and patients' poor compliance. To overcome these problems, an all-in-one therapeutic platform (CLA-Bi-ZnO2@Lipo) that composed of liposomes loading clarithromycin (CLA), Bi, and ZnO2 hybrid nanoparticles was developed for eradicating multidrug-resistant (MDR) H. pylori. The in vitro and in vivo results showed that CLA-Bi-ZnO2@Lipo could target the infection-induced inflammatory mucosa through liposome mediated nanoparticle-tissue surface charge interaction and quickly respond to the gastric acid environment to release CLA, Bi3+, Zn2+, and H2O2. By oral administration per day, the acid triggered decomposition of CLA-Bi-ZnO2@Lipo could significantly increase intragastric pH to 6 within 30 min; The released CLA, Zn2+, and H2O2 further exerted synergistical anti-bacterial effects in which a â¼2 order higher efficacy in reducing MDR H. pylori burden was achieved in comparison with standard quadruple therapy (p < 0.05); The released Zn2+ and Bi3+ could also alleviate mucosal inflammation. Most importantly, the CLA-Bi-ZnO2@Lipo exhibited superior biosafety and nearly no side effects on intestinal flora. Overall, this study developed a highly integrated and safe anti-MDR H. pylori agent which had great potential to be used as an alternative treatment for MDR H. pylori eradication.
Asunto(s)
Antibacterianos , Bismuto , Claritromicina , Infecciones por Helicobacter , Helicobacter pylori , Liposomas , Helicobacter pylori/efectos de los fármacos , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Animales , Bismuto/química , Bismuto/uso terapéutico , Bismuto/farmacología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Claritromicina/farmacología , Claritromicina/uso terapéutico , Liposomas/química , Nanopartículas/química , Óxido de Zinc/química , Óxido de Zinc/farmacología , Humanos , Ratones , Peróxido de Hidrógeno/metabolismo , MasculinoRESUMEN
Background: We conducted an assessment of 2'-O-methylated (2'OMe) microRNAs (miRNAs) present in the circulation of individuals suffering from pancreatic ductal adenocarcinoma (PDAC). Subsequently, we devised a set of circulating 2'OMe miRNAs that can be utilized for the screening of PDAC patients within a group at increased risk. Methods: A four-step, multicenter research was carried out. The initial screening phase involved analyzing 10 samples from patients with pancreatic ductal adenocarcinoma (PDAC) and 10 specimens from donors who were in good health. RNA sequencing was performed on these specimens after pre-treatment via NaIO4. The instruction and confirmation phases involved the use of 2'OMe miRNA profiling and multivariate analysis to examine applicant 2'OMe miRNAs in a sample of 248 individuals. In a prospective registration population of 135 individuals, a clinical screening panel was created and confirmed. The performance of individual 2'OMe miRNAs or the biomarker panel was evaluated using the receiver operating characteristic curve. Results: Abnormal circulating 2'OMe miRNAs were detected in individuals suspected of pancreatic ductal adenocarcinoma (PDAC). A circulating panel of 3-2'OMe miRNAs, namely miR-28-3p, miR-143-3p, and miR-151a-3p, was subsequently identified. These miRNAs continually exhibited up-regulation in plasma samples of patients with pancreatic ductal adenocarcinoma (PDAC). The panel's area under the curve (AUC) was 1.0 in the experimental group and 0.928 in the verification cohort when comparing PDAC patients in all clinical stages to normal controls. During the application study, both the specificity and sensitivity were found to be 75.00% and 89.72% respectively, with an AUC value of 0.868. In the comparison between early-stage (I-II) PDAC patients and control subjects, the panel demonstrated an AUC of 1.0 in the training cohort and 0.924 in the validation population. In the application group the AUC was 0.810 (95% CI 0.729-0.876) in comparison to the high-risk symptomatic group. Conclusion: Abnormal circulating 2'OMe miRNAs were detected in individuals with pancreatic ductal adenocarcinoma (PDAC). Consequently, we devised a 2'OMe miRNA biological marker panel that holds promise as an initial detection tool for PDAC.
RESUMEN
BACKGROUND: Few studies have been conducted to explore the expression of tumor necrosis factor receptor-associated factor 6 in eosinophilic gastroenteritis patients. Therefore, the expression profile of tumor necrosis factor receptor-associated factor 6 in the gastrointestinal tract of eosinophilic gastroenteritis patients and its associations with clinical features were explored in this study. METHODS: Thirty-four eosinophilic gastroenteritis patients who presented in Ruijin Hospital from December 2012 to May 2019 and had accepted gastrointestinal endoscopic examinations were recruited. Medical records and endoscopic biopsies were collected, and the prognosis was followed up by telephone. Healthy persons were selected as the control group. Hematoxylin and eosin and immunohistochemical staining were performed in both eosinophilic gastroenteritis patients and healthy persons. The final results were analyzed by skilled pathologists, and mean optical density values of tumor necrosis factor receptor-associated factor 6 were calculated by Image J software. Final results were analyzed by Statistical Package for the Social Sciences software 22.0. RESULTS: Thirty-four patients (mean age: 25.56 ± 21.14 years, 61.76% males) were recruited for this study. There was no significant difference in tumor necrosis factor receptor-associated factor 6 mean optical density values of gastric tissues in eosinophilic gastroenteritis patients and healthy people (0.22 ± 0.16 vs. 0.14 ± 0.05, P > .05). Eosinophilic gastroenteritis patients had a significantly lower level of intestinal tumor necrosis factor receptor-associated factor 6 mean optical density values than that of healthy people (0.16 ± 0.05 vs. 0.23 ± 0.06, P < .05). Intestinal tumor necrosis factor receptor-associated factor 6 mean optical density values negatively linearly correlated with serum interleukin-10 level (r = -0.618, P = .043 < .05). There were no differences between eosinophilic gastroenteritis patients with or without relapse regarding the expression level of intestinal tumor necrosis factor receptor-associated factor 6 (P = .227 > .05). CONCLUSION: Patients with eosinophilic gastroenteritis might have a deficiency of intestinal tumor necrosis factor receptor-associated factor 6 compared to healthy controls.
Asunto(s)
Enteritis , Masculino , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Femenino , Pronóstico , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis TumoralRESUMEN
INTRODUCTION: Centrally mediated abdominal pain syndrome (CAPS) is characterized by severe abdominal pain. Diagnosis of CAPS is still an exclusionary diagnosis, there remain no effective diagnostic biomarkers so far. Duloxetine is the major pharmacotherapy of CAPS, while some CAPS patients do not respond to duloxetine treatment. However, there is a lack of molecular markers to predict the efficacy of duloxetine. In our pilot study, we have found differential expression profiles of serum miRNAs between CAPS patients and healthy controls. Our study aims to explore the clinical characteristics, specific miRNAs in serum as diagnostic biomarkers of CAPS and predictive biomarkers of the efficacy of duloxetine. METHODS/DESIGN: In this prospective cohort study, we plan to enroll 430 participants including 215 CAPS patients and 215 healthy controls. The CAPS group takes duloxetine 30 mg per day as an initial dose. Patients will have 24-week medication period and follow up at week 0, 4, 12, 24 and 36. Blood samples will be obtained from patients at every visits and health controls at the initial visit and a series of questionnaires will be completed by the participants. The primary end points are: The differential expression of miRNAs between CAPS groups and healthy control groups at baseline. The changes in abdominal pain scores before and after duloxetine treatment in patients with CAPS and their relationship with the changes in miRNAs. The secondary end point is the changes in scores of depression, anxiety, sleep quality and quality of life before and after duloxetine treatment in patients with CAPS and their relationship with changes in miRNAs. DISCUSSION: Findings of study will provide the reliable basis for diagnosis and the predictor of duloxetine efficacy of CAPS. Importantly, findings grant patients a chance to benefit from treatment.
Asunto(s)
Dolor Abdominal , Calidad de Vida , Humanos , Clorhidrato de Duloxetina/uso terapéutico , Proyectos Piloto , Estudios Prospectivos , Dolor Abdominal/tratamiento farmacológicoRESUMEN
BACKGROUND: New onset diabetes mellitus demonstrates a roughly correlation with pancreatic cancer (PaC), which is unique in PaC and was named as PaC-induced DM, but the inner mechanism remains unclear. Exosomes mediate intercellular communication and bearing microRNAs might be direct constituent of effect in target cells. METHODS AND RESULTS: The isolated exosomes from PaC cells were used to treat pancreatic ß cells or the primary mice islets, and the glucose stimulated insulin secretions were measured. We validated the exosomal miR-19a from PaC cells to be an important mediator in the down regulation of insulin secretion by targeting Neurod1, the validated gene involved in insulin secretion, by using the quantitative real-time PCR, western blot, and promoter luciferase activity. The relative insulin, cAMP and Ca2+ expressions were also assayed to verify the inverse correlation between cancerous miR-19a and pancreatic islets Neurod1. CONCLUSIONS: Our study indicated that signal changes between cancer cells and ß cells via exosomes might be important in the pathogenesis of PaC-induced DM and supplemented the pathogenesis of PaC-induced DM and provide a possible access of PaC screening strategy.
Asunto(s)
Diabetes Mellitus , Exosomas , Células Secretoras de Insulina , MicroARNs , Neoplasias Pancreáticas , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diabetes Mellitus/metabolismo , Exosomas/genética , Exosomas/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismoRESUMEN
New-onset diabetes mellitus has a rough correlation with pancreatic cancer (PaC), but the underlying mechanism remains unclear. This study aimed to explore the exosomal microRNAs and their potential role in PaC-induced ß-cell dysfunction. The pancreatic ß cells were treated with isolated exosomes from PaC cell lines, SW1990 and BxPC-3, before measuring the glucose-stimulated insulin secretion (GSIS), validating that SW1990 and BxPC-3 might disrupt GSIS of both ß cell line MIN6 and primary mouse pancreatic islets. The difference in expression profiles between exosomes and exosome-free medium of PaC cell lines was further defined, revealing that miR-19a secreted by PaC cells might be an important signaling molecule in this process. Furthermore, adenylyl cyclase 1 (Adcy1) and exchange protein directly activated by cAMP 2 (Epac2) were verified as the direct targets of exogenous miR-19a, which was involved in insulin secretion. These results indicated that exosomes might be an important mediator in the pathogenesis of PaC-DM, and miR-19a might be the effector molecule. The findings shed light on the pathogenesis of PaC-DM.
Asunto(s)
Adenilil Ciclasas/metabolismo , Exosomas/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , MicroARNs/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Línea Celular Tumoral , Humanos , Secreción de Insulina , Células Secretoras de Insulina/fisiología , Neoplasias Pancreáticas/fisiopatologíaRESUMEN
BACKGROUND: The microRNA miR-221-3p has previously been found to be an underlying biomarker of pancreatic cancer. However, the mechanisms of miR-221-3p underlying its role in pancreatic cancer pathogenesis, proliferation capability, invasion ability, drug resistance and apoptosis and the clinicopathological value of miR-221-3p have not been thoroughly studied. METHODS: Based on microarray and miRNA-sequencing data extracted from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), relevant literature, and real-time quantitative PCR (RT-qPCR), we explored clinicopathological features and the expression of miR-221-3p to determine its clinical effect in pancreatic cancer. Proliferation, migration, invasion, apoptosis and in vitro cytotoxicity tests were selected to examine the roles of mir-221-3p. In addition, several miR-221-3p functional analyses were conducted, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein-protein interaction (PPI) network analyses, to examine gene interactions with miR-221-3p. RESULTS: The findings of integrated multi-analysis revealed higher miR-221-3p expression in pancreatic cancer tissues and blood than that in para-carcinoma samples (SMD of miR-221-3p: 1.52; 95% CI 0.96, 2.08). MiR-221-3p is related to survival both in pancreatic cancer and pancreatic ductal adenocarcinoma patients. Cell experiments demonstrated that miR-221-3p promotes pancreatic cancer cell proliferation capability, migration ability, invasion ability, and drug resistance but inhibits apoptosis. Further pancreatic cancer bioinformatics analyses projected 30 genes as the underlying targets of miR-221-3p. The genes were significantly distributed in diverse critical pathways, including microRNAs in cancer, viral carcinogenesis, and the PI3K-Akt signalling pathway. Additionally, PPI indicated four hub genes with threshold values of 5: KIT, CDKN1B, RUNX2, and BCL2L11. Moreover, cell studies showed that miR-221-3p can inhibit these four hub genes expression in pancreatic cancer. CONCLUSIONS: Our research revealed that pancreatic cancer expresses a high-level of miR-221-3p, indicating a potential miR-221-3p role as a prognosis predictor in pancreatic cancer. Moreover, miR-221-3p promotes proliferation capacity, migration ability, invasion ability, and drug resistance but inhibits apoptosis in pancreatic cancer. The function of miR-221-3p in the development of pancreatic cancer may be mediated by the inhibition of hub genes expression. All these results might provide an opportunity to extend the understanding of pancreatic cancer pathogenesis.
RESUMEN
Pancreatic ductal adenocarcinoma (PanCa) is an extremely lethal disease characterized by mutations of p53 in up to 70% of cases. Our previous studies have confirmed that hyperglycemia may be the first clinical manifestation for the early diagnosis of PanCa. In this article, we showed that targeted knockdown of TG2 or p53 in tumor cells led to decreased cell survival in response to glucose deprivation, while this phenomenon was abolished by combined inhibition of TG2 and p53. We observed that inhibition of TG2 or p53 sensitized glucose deprivation resistance through an intracellular reactive oxygen species (ROS) pathway and the induction of Bcl-2. Moreover, to understand whether pancreatic cancer cells with TG2 and p53 combined interference had possible effects on pancreatic ß cells, we performed studies comparing pancreatic cancer cells with TG2 and p53 combined interference and pancreatic ß cells. We discovered that the supernatant of pancreatic cancer cells withTG2 and p53 combined interference decreased cell survival in pancreatic ß cells. Following the creation of an orthotopic pancreatic cancer mouse model, we revealed glucose tolerance abnormalities in the pancreatic cancer mouse model with TG2 and p53 combined interference, indicating a possible mechanism for damage of ßcells in pancreatic cancer. Taken together, our findings establish roles for TG2 and p53 in response to glucose deprivation in pancreatic cancer cells. The relationship between TG2 and p53 suggests a possible mechanism for glucose tolerance abnormalities-associated pancreatic cancer and could have therapeutic potential for cancer treatment and diagnosis.
RESUMEN
BACKGROUNDS AND AIMS: This study aimed to compare the esophageal motility between gastroesophageal reflux disease (GERD) patients with typical symptoms but without globus sensation and GERD patients only with globus symptoms. METHODS: A total of 57 consecutive GERD patients diagnosed by endoscopy or by 24-hour pH monitoring between May 2013 and September 2015 were included retrospectively into the study. The patients were grouped based on the presence or absence of globus. Thirty patients presented with typical reflux symptoms but without globus were assigned to the typical GERD group and 27 patients only with globus symptom were assigned to the globus GERD group. All patients underwent esophageal high resolution manometry (HRM) and the differences in esophageal motility between the two groups were analyzed. RESULTS: The globus GERD group showed a significantly greater lower esophageal sphincter (LES) length, LES basal pressure and upper esophageal sphincter (UES) residual pressure than that of the typical GERD group (3.47 ± 0.76 vs. 2.65 ± 0.62 cm, 21.71 ± 9.68 vs. 16.04 ± 8.49 mmHg, 7.30 ± 4.42 vs. 4.12 ± 2.92 mmHg, all p < 0.05). There was no significant difference between the two groups in terms of the distal wave amplitude, mean wave duration, distal contractile integral (DCI), contractile front velocity (CFV), distal latency (DL), integrated relaxation pressure (IRP) and UES basal pressure. The incidence of esophageal dysmotility in the globus GERD group (33.3%) was higher than in the typical GERD group (23.3%). There was no significant difference in esophageal acid exposure of the non-erosive gastroesophageal reflux disease (NERD) patients between the two groups. CONCLUSIONS: Globus GERD patients have a higher UES residual pressure, longer LES length, higher LES basal pressure and greater esophageal dysmotility than typical GERD patients. HRM is useful in evaluating esophageal motility of GERD patients.
Asunto(s)
Trastornos de Deglución/complicaciones , Trastornos de la Motilidad Esofágica/etiología , Reflujo Gastroesofágico/complicaciones , Adolescente , Adulto , Anciano , Trastornos de Deglución/fisiopatología , Trastornos de la Motilidad Esofágica/fisiopatología , Esfínter Esofágico Inferior/fisiopatología , Esfínter Esofágico Superior/fisiopatología , Femenino , Reflujo Gastroesofágico/fisiopatología , Humanos , Masculino , Manometría , Persona de Mediana Edad , Estudios Retrospectivos , Sensación , Adulto JovenRESUMEN
BACKGROUND: Although the relationship between non-O blood types and the risk of exocrine pancreatic cancer has been demonstrated, the association between ABO blood types and sporadic pancreatic neuroendocrine tumor (PNET) has not been reported thus far. METHODS: This hospital-based, case-control study included 387 patients with PNET and 542 age- and sex-matched controls. Unconditional multivariable logistic regression analysis was performed to estimate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs). The relationship between ABO blood types and clinicopathologic features was also analyzed. RESULTS: After adjusting for age, sex, smoking status, alcohol drinking, and first-degree family history of any cancer, the AORs (95% CI) of functional PNET were 0.87 (0.59-1.28) for blood type A, 0.86 (0.58-1.28) for blood type B, and 0.71 (0.39-1.26) for blood type AB compared with subjects with blood type O. A similar ABO blood-type distribution was observed among cases with non-functional PNETs compared with controls. On comparing blood type B with non-B blood type, cases with non-functional PNETs had marginally higher rates of lymph node invasion (P = 0.047), distant metastasis (P = 0.044), and advanced European Neuroendocrine Tumor Society Stage (P = 0.040). CONCLUSIONS: There is no association between the ABO blood group and the development of functional and non-functional PNETs. The ABO blood types are not associated with the clinicopathologic features in patients with functional and non-functional PNETs.
RESUMEN
Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2 However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration-enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)-challenged mice, and protected mice against DSS or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in D prostanoid receptor 1 (DP1)-dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS-induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro-inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro-inflammatory gene expression of macrophages. Moreover, treatment with niacin-containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS-induced colitis in mice by activation of PGD2/DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Niacina/uso terapéutico , Prostaglandina D2/inmunología , Receptores de Prostaglandina/inmunología , Complejo Vitamínico B/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Prostaglandina D2/análisis , Receptores de Prostaglandina/análisisRESUMEN
BACKGROUND/AIMS: Patients with active ulcerative colitis (UC) have elevated levels of activated myeloid-derived leukocytes as a source of inflammatory cytokines. The selective depletion of these leukocytes by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn should alleviate inflammation, promote remission and enhance drug efficacy. However, studies have reported contrasting efficacy outcomes based on patients' baseline demographic variables. This study was undertaken to understand the demographic features of GMA responders and nonresponders. METHODS: This was a multicenter study in China involving four institutions and 34 patients with active UC. Baseline conventional medications were continued without changing the dosage. The treatment efficacy was evaluated based on the endoscopic activity index and the Mayo score. RESULTS: Thirty of the 34 patients completed all 10 GMA treatment sessions. The overall efficacy rate was 70.59%. The receiver operating characteristic analysis showed that the area under the curve was approximately 0.766 for a Mayo score of ≤5.5 with 0.273 specificity and 0.857 sensitivity (Youden index, 0.584) for GMA responders. No GMA-related serious adverse events were observed. CONCLUSIONS: The overall efficacy of GMA in patients with active UC who were taking first-line medications or were corticosteroid refractory was encouraging. Additionally, GMA was well tolerated and had a good safety profile.
Asunto(s)
Colitis Ulcerosa/terapia , Granulocitos , Leucaféresis/métodos , Monocitos , Adsorción , Adulto , China , Colitis Ulcerosa/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVES: ErbB3 (HER3) has been associated with pancreatic cancer progression, but little is known about its regulatory mechanisms. We investigated whether microRNAs (miRNAs) regulate levels of ErbB3 in pancreatic cancer cells. METHODS: We used bioinformatic analyses to search for miRNAs that can potentially target ERBB3. Furthermore, the biological consequences of the targeting of ERBB3 by miR-148a were examined by cell proliferation and migration assays in vitro. RESULTS: We identified an inverse correlation between miR-148a and ErbB3 protein levels in pancreatic cancer tissue samples and cell lines. We identified that miR-148a directly recognizes the 3'-UTR of the ErbB3 transcript and regulates ErbB3 expression. We demonstrated that the repression of ERBB3 by miR-148a suppressed the proliferation and migration of pancreatic cancer cells. In PANC-1 pancreatic cancer cells, the repression of ErbB3 by miR-148a inhibited the phosphorylation of ERK1/2 and AKT, which eventually repressed the proliferation and migration of these cells. CONCLUSIONS: Taken together, the present study provides the first evidence that miR-148a plays a significant role in the suppression of pancreatic tumorigenesis via the inhibition of ErbB3 translation.
Asunto(s)
Neoplasias Pancreáticas , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Humanos , MicroARNsRESUMEN
BACKGROUND: The aim of this study was to identify novel microRNAs for potential use in the diagnosis of pancreatic cancer (PaC). METHODS: A total of 1063 serum samples from 303 patients with PaC were collected, and the expression level of miR-25 was measured using quantitative real-time PCR (qRT-PCR). RESULTS: We found that miR-25 had significant diagnostic value for the differential diagnosis of PaC in normal controls with an AUC (the area under the ROC curve) of 0.915 (95% CI: 0.893-0.937) that was significantly higher compared with an AUC of 0.725 for serum tumor marker carcinoembryonic antigen (CEA) and an AUC of 0.844 for CA19-9. CONCLUSIONS: These data suggest that serum miR-25 has strong potential as a novel biomarker for the early detection of PaC.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Gastrointestinales/diagnóstico , MicroARNs/sangre , Neoplasias Pancreáticas/diagnóstico , Pancreatitis Crónica/diagnóstico , Adulto , Anciano , Área Bajo la Curva , Biomarcadores de Tumor/genética , Antígeno CA-19-9/sangre , Antígeno CA-19-9/genética , Antígeno Carcinoembrionario/sangre , Antígeno Carcinoembrionario/genética , Estudios de Casos y Controles , Diagnóstico Diferencial , Diagnóstico Precoz , Femenino , Neoplasias Gastrointestinales/sangre , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Expresión Génica , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Estadificación de Neoplasias , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pancreatitis Crónica/sangre , Pancreatitis Crónica/genética , Pancreatitis Crónica/patología , Curva ROCRESUMEN
BACKGROUND: New-onset diabetes mellitus in pancreatic cancer has been recognized as a paraneoplastic phenomenon caused by the existence of the tumor. Circulating microRNAs (miRNAs) are emerging as non-invasive biomarkers for the detection of various cancers. In the present study, we hypothesized that a specific serum miRNA profile exists in pancreatic cancer-associated new-onset diabetes mellitus (PaC-DM). METHODS: Initial screening of differentially expressed miRNAs in pooled serum samples from 25 PaC-DM patients, 25 non-cancer new-onset type 2 diabetes mellitus (T2DM) patients, and 25 healthy controls was performed by TaqMan low-density arrays (TLDA). A stem-loop quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was conducted to confirm the relative concentrations of candidate miRNAs in 80 PaC-DM, 85 non-cancer new-onset T2DM patients, and 80 healthy controls. RESULTS: The TLDA identified 16 serum miRNAs that were significantly increased in PaC-DM samples. A combination of six serum miRNAs (miR-483-5p, miR-19a, miR-29a, miR-20a, miR-24, miR-25) was selected by qRT-PCR as a biomarker for PaC-DM. The area under the receiver operating characteristic curve (AUC) for the six-miRNA panel training and validation sets was 0.959 (95% confidence interval [CI] 0.890-1.028) and 0.902 (95% CI 0.844-0.955), respectively. The combination of these six miRNAs enabled the discrimination of PaC-DM from non-cancer new-onset T2DM with an AUC of 0.885 (95% CI 0.784-0.986) and 0.887 (95% CI 0.823-0.952) for the training and validation sets, respectively. CONCLUSION: The six-serum miRNA panel may have potential as a biomarker for the accurate diagnosis and discrimination of PaC-DM from healthy controls and non-cancer new-onset T2DM.
Asunto(s)
Biomarcadores de Tumor/genética , Diabetes Mellitus Tipo 2/genética , Perfilación de la Expresión Génica , MicroARNs/genética , Neoplasias Pancreáticas/complicaciones , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Curva ROC , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Cancer-associated fibroblasts (CAF) are a major constituent of the pancreatic cancer microenvironment and that the meaning is as intended. Pancreatic cancer cells can induce normal fibroblasts to convert into CAF and, reciprocally, CAF promote tumor invasions and proliferations. The mechanism of the conversion from normal fibroblasts (NF) to CAF remains unclear. MicroRNA are short non-coding RNA involved in the post-transcription gene regulation, which have been defined as an imperative controller in tumor invasions, proliferations and colony formations. Microvesicles (MV) have been proved to be an important mediator of intercellular communication and can selectively transport secreted microRNA from a donor cell into a recipient cell. In this study, we isolated primary pancreatic fibroblasts from wild type C57 mice and co-cultured them with pancreatic cancer cell lines, BxPC-3 and SW1990, and observed the conversion from NF to CAF, or at least CAF-like cells. This phenomenon could also be replicated in primary fibroblasts treated with MV separated from a cancer cell media. We identified that miR-155 was upregulated in PaC-derived MV and we confirmed that normal fibroblasts could convert into CAF after MV containing miR-155 had been taken up. TP53INP1 is a target of miR-155 in fibroblasts and a downregulation of TP53INP1 protein levels could contribute to the fibroblasts' activation. These results indicated that pancreatic cancer cells might reprogram normal adjacent fibroblasts into CAF by means of secreted MV containing miR-155. Targeting the circulating microRNA might be a potential therapy for malignant tumors.