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INTRODUCTION AND OBJECTIVES: Cholangiocarcinoma (CCA) is characterized by early distant invasion and metastasis, whereas the underlying mechanism is still obscure. Increasing evidence shows that collagen type Ι alpha 1 (COL1A1) is a gene associated with the progression of multiple diseases. Here, we attempted to investigate the role of COL1A1 in CCA. MATERIALS AND METHODS: The expression of COL1A1 between tumor tissues and adjacent normal tissues obtained from CCA patients was detected by Western blot and immunofluorescence, followed by analysis of its clinical significance. Then, the biological effects of COL1A1 overexpression or knockdown on CCA cells were evaluated in vitro and in vivo. Finally, molecular mechanism of COL1A1 in regulating the invasion and metastasis of CCA cells was determined by a series of experiments. RESULTS: COL1A1 expression was significantly higher in CCA pathological tissues than in corresponding adjacent normal tissues. Analysis of 83 CCA patients showed that higher expression of COL1A1 was correlated with poorer patient prognosis. Notably, overexpression or knockdown experiments revealed that COL1A1 contributed to the migration and invasion, as well as epithelial-to-mesenchymal transition (EMT), in CCA cells. Further investigations demonstrated that matrix metalloproteinase-2 (MMP2) promoted COL1A1 upregulation via the integrin alpha â ¤ pathway, therefore affecting ECM remodelling and inducing EMT in CCA cells. Moreover, COL1A1 expression was positively related to PD-1 and PD-L1 in CCA, and COL1A1 increased PD-L1 expression by activating the NF-κB pathway. CONCLUSIONS: COL1A1 plays an important role in regulating CCA progression and may act as a promising biomarker and therapeutic target for CCA.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Colangiocarcinoma/patología , Regulación Neoplásica de la Expresión Génica , Integrina alfaV/genética , Integrina alfaV/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismoRESUMEN
BACKGROUND: Studies show higher rates of dissatisfaction with antireflux surgery (ARS) outcomes in patients with chronic constipation. This suggests a relationship between colonic dysmotility and suboptimal surgical outcome. However, due to limitations in technology, there is no objective data available examining this relationship. The wireless motility capsule (WMC) is a novel technology consisting of an ingestible capsule equipped with pH, temperature, and pressure sensors, which provide information regarding regional and whole gut transit times, pH and motility. The aim of this study was to assess the impact of objective regional and whole gut motility data on the outcomes of ARS. STUDY DESIGN: This was a retrospective review of patients who underwent WMC testing before ARS. Transit times, motility, and pH data obtained from different gastrointestinal tract regions were used in analysis to determine factors that impact surgical outcome. A favorable outcome was defined as complete resolution of the predominant reflux symptom and freedom from antisecretory medications. RESULTS: The final study population consisted of 48 patients (fundoplication [n = 29] and magnetic sphincter augmentation [n = 19]). Of those patients, 87.5% were females and the mean age ± SD was 51.8 ± 14.5 years. At follow-up (mean ± SD, 16.8 ± 13.2 months), 87.5% of all patients achieved favorable outcomes. Patients with unfavorable outcomes had longer mean whole gut transit times (92.0 hours vs 55.7 hours; p = 0.024) and colonic transit times (78.6 hours vs 47.3 hours; p = 0.028), higher mean peak colonic pH (8.8 vs 8.15; p = 0.009), and higher mean antral motility indexes (310 vs 90.1; p = 0.050). CONCLUSIONS: This is the first study to demonstrate that objective colonic dysmotility leads to suboptimal outcomes after ARS. WMC testing can assist with preoperative risk assessment and counseling for patients seeking ARS.
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Endoscopía Capsular , Procedimientos Quirúrgicos del Sistema Digestivo , Femenino , Humanos , Masculino , Tránsito Gastrointestinal , Motilidad Gastrointestinal , Colon/cirugíaRESUMEN
OBJECTIVE: To evaluate the impact of MSA on lower esophageal sphincter (LES) and esophageal body using high resolution impedance manometry. BACKGROUND: MSA is an effective treatment in patients with gastroesophageal reflux disease, but there is limited data on its impact on esophageal functional physiology. METHODS: Patients who underwent MSA were approached 1-year after surgery for objective foregut testing consists of upper endoscopy, esophagram, high resolution impedance manometry, and esophageal pH-monitoring. Postoperative data were then compared to the preoperative measurements. RESULTS: A total of 100 patients were included in this study. At a mean follow up of 14.9(10.1) months, 72% had normalization of esophageal acid exposure. MSA resulted in an increase in mean LES resting pressure [29.3(12.9) vs 25(12.3), P < 0.001]. This was also true for LES overall length [2.9(0.6) vs 2.6(0.6), P = 0.02] and intra-abdominal length [1.2(0.7) vs 0.8(0.8), P < 0.001]. Outflow resistance at the EGJ increased after MSA as demonstrated by elevation in intrabolus pressure (19.6 vs 13.5 mmHg, P < 0.001) and integrated relaxation pressure (13.5 vs 7.2, P < 0.001). MSA was also associated with an increase in distal esophageal body contraction amplitude [103.8(45.4) vs 94.1(39.1), P = 0.015] and distal contractile integral [2647.1(2064.4) vs 2099.7(1656.1), P < 0.001]. The percent peristalsis and incomplete bolus clearance remained unchanged ( P = 0.47 and 0.08, respectively). CONCLUSIONS: MSA results in improvement in the LES manometric characteristics. Although the device results in an increased outflow resistance at the EGJ, the compensatory increase in the force of esophageal contraction will result in unaltered esophageal peristaltic progression and bolus clearance.
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Líquidos Corporales , Reflujo Gastroesofágico , Humanos , Unión Esofagogástrica/cirugía , Reflujo Gastroesofágico/cirugía , Impedancia Eléctrica , Monitorización del pH EsofágicoRESUMEN
Bombyx mori gloverin A2 (BMGlvA2) is an induced antimicrobial insect protein isolated from Bombyx mori. This study was conducted to explore the effect and potential mechanisms of BMGlvA2 on inflammatory responses and cellular functions in intestinal epithelial cells (IPEC-J2) exposure to enterotoxigenic E. coli (ETEC). IPEC-J2 cells pretreated with or without BMGlvA2 (12.5 µg/mL) were challenged by ETEC K88 (1×106 CFU/well) or culture medium. We show that BMGlvA2 pretreatment increased the cell viability and improved the distribution and abundance of tight junction protein ZO-1 in IPEC-J2 cells exposure to ETEC (P < 0.05). Interestingly, BMGlvA2 not only decreased the expression levels of inflammatory cytokines such as the tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), but also decreased the expression level of Caspase3 and the apoptosis rate in the ETEC-challenged cells (P < 0.05). Importantly, BMGlvA2 decreased the protein abundances of two critical inflammation-associated signaling proteins, phosphorylated nuclear factor-kappa-B inhibitor alpha (p-IκBα) and phosphorylated nuclear factor-kappa B (p-NF-κB), in the ETEC-challenged cells. These results indicate that BMGlvA2 attenuates ETEC-induced inflammation in the IPEC-J2 cells by regulating the NF-κB signaling pathway, resulting in decreased secretion of inflammatory cytokine and reduced cell apoptosis.
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Bombyx , Escherichia coli Enterotoxigénica , Células Epiteliales/microbiología , Infecciones por Escherichia coli , Péptidos y Proteínas de Señalización Intercelular/farmacología , Animales , Bombyx/química , Línea Celular , Citocinas , Inflamación , Mucosa Intestinal/citología , FN-kappa B/genética , PorcinosRESUMEN
BACKGROUND: The performance and durability of various types of fundoplication are variable when stratified by disease severity. To date, magnetic sphincter augmentation (MSA) has not been evaluated in this context. We designed this study to determine the efficacy of MSA in the treatment of severe GERD. STUDY DESIGN: Guided by previous studies, a DeMeester score (DMS) ≥ 50 was used as a cutoff point to define severe reflux disease. Subjects were divided into 2 groups using this cutoff, and outcomes of severe cases were compared with those with less severe disease (DMS < 50). RESULTS: A total of 334 patients underwent MSA. Patients with severe disease had a higher mean preoperative DMS compared with those with mild to moderate GERD (79.2 [53.2] vs 22.8 [13.7], p < 0.0001). At a mean postoperative follow-up of 13.6 (10.4) months, there was no difference between the mean GERD Health-Related Quality of Life (HRQL) total scores in patients with severe disease compared with those with less severe GERD (8.8 [10] vs 9.2 [10.8], p = 0.9204). Postoperative mean DMS was not different between groups (17.3[23.0] vs 14.1[33.9], p = 0.71), and there was no difference in the prevalence of esophagitis (p = 0.52). Patients with severe disease were less likely to be free from use of proton pump inhibitors after surgery (85% vs 93.1%, p = 0.041). There were similar rates of postoperative dysphagia (10% vs 14%, p = 0.42) and need for device removal (3% vs 5%, p = 0.7463). CONCLUSIONS: MSA is an effective treatment in patients with severe GERD and leads to significant clinical improvement across the spectrum of disease severity, with few objective outcomes being superior in patients with mild-to-moderate reflux disease.
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Esfínter Esofágico Inferior/cirugía , Reflujo Gastroesofágico/cirugía , Laparoscopía , Imanes , Índice de Severidad de la Enfermedad , Adulto , Anciano , Femenino , Estudios de Seguimiento , Fundoplicación , Reflujo Gastroesofágico/diagnóstico , Humanos , Laparoscopía/instrumentación , Laparoscopía/métodos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Calidad de Vida , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Magnetic sphincter augmentation (MSA) is a promising surgical treatment for patients with GERD. The aim of this study was to evaluate the outcomes of MSA in a large cohort of patients with GERD and to determine the factors predicting a favorable outcome. METHODS: This was a retrospective review of prospectively collected data of 553 patients who underwent MSA at our institution in a 5-year period. Preoperative clinical, endoscopic, manometric, and pH data were used in a univariate analysis. This was followed by a regression multivariable analysis to determine the factors predicting a favorable outcome. Favorable outcome was defined as freedom from proton pump inhibitors and ≥50% improvement in Gastroesophageal Reflux Disease-Health-Related Quality of Life (GERD-HRQL) total score. RESULTS: At a mean (SD) follow-up of 10.3 (10.6) months after MSA, 92.7% of the patients were free of proton pump inhibitor use and 84% reported at least 50% improvement in their GERD-HRQL total score. The GERD-HRQL total score was improved from a mean (SD) baseline value of 33.8 (18.7) to 7.2 (9.0) (p < 0.001) and 76.1% of the patients had normalization of their esophageal acid exposure. Independent predictors of a favorable outcome after MSA included age younger than 45 years (odds ratio [OR] 4.2; 95% CI, 1.1 to 15.2; p = 0.0305), male sex (OR 2.5; 95% CI, 1.1 to 5.7; p = 0.0301), GERD-HRQL total score >15 (OR 7.5; 95% CI, 3.3 to 16.8; p < 0.0001), and abnormal DeMeester score (OR, 2.6; 95% CI, 1.1 to 5.7; p = 0.0225). CONCLUSIONS: In this largest single-institution series, we demonstrate that MSA implantation is associated with very good clinical and objective outcomes. Age younger than 45 years, male sex, GERD-HRQL total score >15, and abnormal DeMeester score are the 4 preoperative factors predicting a favorable outcome and can be used in patient counseling and MSA use.
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Esfínter Esofágico Inferior/cirugía , Reflujo Gastroesofágico/cirugía , Laparoscopía/métodos , Imanes , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Laparoscopía/instrumentación , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Calidad de Vida , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
This experiment was conducted to evaluate the effects of dietary protein and net energy (NE) levels on growth performance, nutrient digestibility, nitrogen metabolism, and faecal microbiota of growing-finishing pigs. Eighteen crossed barrows were randomly allocated into one of three dietary treatments: high protein + high NE diet, low protein + high NE diet, and low protein + low NE diet. The whole experiment lasted 90 days and was divided into three phases (phase I: 25-50 kg; phase II: 50-75 kg; phase III: 75-105 kg). All pigs were individually housed in a metabolism cage and subjected to four-day total faeces and urine collection period at the end of each phase. There was no significant difference in growth performance, nutrient digestibility, serum total protein, and albumin concentrations of pigs among the dietary treatments. Compared with the high protein + high NE diet, pigs fed low protein + high NE and low protein + low NE diets had lower N intake, urine N, and total N excretion in each phase. At the end of the experiment, pigs fed the low protein + high NE and low protein + low NE diets had lower blood urea nitrogen, serum NH3-N concentrations, faecal pH value, faecal NH3-N concentration, and faecal Escherichia coli count than those fed the high protein + high NE diet. However, there was no significant difference in all of the above indexes between low protein + high NE and low protein + low NE diets. Decreasing the dietary protein content by 3.5 percentage units has no adverse effects on growth performance and nutrient digestibility of pigs while significantly reduces N excretion and faecal Escherichia coli count. Moreover, further decreasing dietary NE level in the low-protein diet by 0.35-0.5 MJ/kg does not affect growth performance, nutrient digestibility, N excretion, blood profiles, and faecal Escherichia coli count of pigs.(AU)
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Animales , Masculino , Porcinos/microbiología , Proteínas/efectos adversos , Microbiota , Coliformes , Nitrógeno/análisisRESUMEN
Background: Xylanases are considered one of the most important enzymes in many industries. However, their low thermostability hampers their applications in feed pelleting, pulp bleaching, and so on. The main aim of this work was to improve the thermostability of Trichoderma ressei xylanase 2 (Xyn2) by introducing disulfide bonds between the N-terminal and α-helix and the ß-sheet core. Results: In this work, two disulfide bonds were separately introduced in the Xyn2 to connect the N-terminal and α-helix to the ß-sheet core of Xyn2. The two disulfide bonds were introduced by site-directed mutagenesis of the corresponding residues. The half-life of the mutants Xyn2C1452 (disulfide bond between ß-sheets B2 and B3) and Xyn2C59149 (disulfide bond between ß-sheets A5 and A6) at 60°C was improved by approximately 2.5- and 1.8-fold compared to that of the wild type Xyn2. In addition, the enzyme's resistance to alkali and acid was enhanced. Conclusion: Our results indicated that the connection of the N-terminal and α-helix to the ß-sheet core is due to the stable structure of the entire protein.
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Trichoderma/enzimología , Xilosidasas/metabolismo , Disulfuros/metabolismo , Espectrometría de Masas , Temperatura , Trichoderma/genética , Trichoderma/metabolismo , Xilanos/metabolismo , Xilosidasas/genética , Estabilidad de Enzimas , Cinética , Mutagénesis Sitio-Dirigida , Concentración de Iones de Hidrógeno , MutaciónRESUMEN
BACKGROUND: Health systems may play an important role in identification of patients at-risk of opioid medication overdose. However, standard measures for identifying overdose risk in administrative data do not exist. OBJECTIVE: Examine the association between opioid medication overdose and 2 validated measures of nonmedical use of prescription opioids within claims data. RESEARCH DESIGN: A longitudinal retrospective cohort study that estimated associations between overdose and nonmedical use. SUBJECTS: Adult Pennsylvania Medicaid program 2007-2012 patients initiating opioid treatment who were: nondual eligible, without cancer diagnosis, and not in long-term care facilities or receiving hospice. MEASURES: Overdose (International Classification of Disease, ninth edition, prescription opioid poisonings codes), opioid abuse (opioid use disorder diagnosis while possessing an opioid prescription), opioid misuse (a composite indicator of number of opioid prescribers, number of pharmacies, and days supplied), and dose exposure during opioid treatment episodes. RESULTS: A total of 372,347 Medicaid enrollees with 583,013 new opioid treatment episodes were included in the cohort. Opioid overdose was higher among those with abuse (1.5%) compared with those without (0.2%, P<0.001). Overdose was higher among those with probable (1.8%) and possible (0.9%) misuse compared with those without (0.2%, P<0.001). Abuse [adjusted rate ratio (ARR), 1.52; 95% confidence interval (CI), 1.10-2.10), probable misuse (ARR, 1.98; 95% CI, 1.46-2.67), and possible misuse (ARR, 1.76; 95% CI, 1.48-2.09) were associated with significantly more events of opioid medication overdose compared with those without. CONCLUSIONS: Claims-based measures can be used by health systems to identify individuals at-risk of overdose who can be targeted for restrictions on opioid prescribing, dispensing, or referral to treatment.
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Analgésicos Opioides/envenenamiento , Sobredosis de Droga/epidemiología , Revisión de Utilización de Seguros/estadística & datos numéricos , Medicaid/estadística & datos numéricos , Trastornos Relacionados con Opioides/epidemiología , Adolescente , Adulto , Factores de Edad , Comorbilidad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pennsylvania/epidemiología , Farmacias/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Características de la Residencia/estadística & datos numéricos , Estudios Retrospectivos , Factores Sexuales , Factores Socioeconómicos , Estados Unidos , Adulto JovenRESUMEN
Single nucleotide polymorphisms in the promoter region of interleukin-18 (IL-18), an inflammatory cytokine, have been linked to susceptibility to many diseases, including cancer and immune dysfunction. Here, we explored the potential association between the IL-18 -607C/A (rs1946518) promoter region polymorphism and susceptibility to ischemic stroke (IS). This locus was amplified from peripheral blood samples of 386 IS patients (cases) and 364 healthy individuals (controls) by the polymerase chain reaction with sequence-specific primers. Significant differences were observed by the χ2 test in the -607C/A (rs1946518) genotype and allele frequencies between cases and controls (P < 0.05). Furthermore, after excluding for age, gender, smoking status, and hypertension, logistic regression indicated that IS susceptibility of -607C carriers increased 1.6 times (OR = 1.601, 95%CI = 1.148-2.233, P = 0.006) compared to -607A carriers. Additionally, similar increases in IS risk were noted for male patients or patients less than 65 years old. In conclusion, IL-18 -607C/A (rs1946518) promoter polymorphism is associated with IS susceptibility, and the C allele may confer increased IS risk.
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Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Isquemia Encefálica/genética , /genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Accidente Cerebrovascular/genética , Isquemia Encefálica/epidemiología , Genotipo , Predisposición Genética a la Enfermedad/epidemiología , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Fumar , Accidente Cerebrovascular/epidemiologíaRESUMEN
Single nucleotide polymorphisms in the promoter region of interleukin-18 (IL-18), an inflammatory cytokine, have been linked to susceptibility to many diseases, including cancer and immune dysfunction. Here, we explored the potential association between the IL-18 -607C/A (rs1946518) promoter region polymorphism and susceptibility to ischemic stroke (IS). This locus was amplified from peripheral blood samples of 386 IS patients (cases) and 364 healthy individuals (controls) by the polymerase chain reaction with sequence-specific primers. Significant differences were observed by the χ2 test in the -607C/A (rs1946518) genotype and allele frequencies between cases and controls (P < 0.05). Furthermore, after excluding for age, gender, smoking status, and hypertension, logistic regression indicated that IS susceptibility of -607C carriers increased 1.6 times (OR = 1.601, 95%CI = 1.148-2.233, P = 0.006) compared to -607A carriers. Additionally, similar increases in IS risk were noted for male patients or patients less than 65 years old. In conclusion, IL-18 -607C/A (rs1946518) promoter polymorphism is associated with IS susceptibility, and the C allele may confer increased IS risk.
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Isquemia Encefálica/genética , Interleucina-18/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Accidente Cerebrovascular/genética , Adulto , Anciano , Isquemia Encefálica/epidemiología , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Fumar , Accidente Cerebrovascular/epidemiologíaRESUMEN
The doublesex/male abnormal 3 (dsx/mab-3 or DM) domain gene family involved in sexual development encodes putative transcription factors including a DNA-binding homology motif, the DM domain. We used highly degenerate primers to clone and sequence seven distinct DM related transcription factor (Dmrt) genes from the Asian toad (Bufo gargarizans Cantor, 1842). A database search for the cloned sequences revealed the following percentage identity with the homologous Dmrt genes of the human: BgDmrt1 = 97 percent, BgDmrt2 = 97 percent, three isoforms of BgDmrt3 (BgDmrt3a = 93 percent, BgDmrt3b = 95 percent, BgDmrt3c = 100 percent) and two isoforms of BgDmrt5 (BgDmrt5 = 97 percent, BgDmrt5 = 91 percent). Based on DM domain amino acid sequence similarities we constructed a phylogenetic tree which grouped vertebrate and invertebrate Dmrt genes into seven distinct subfamilies. The DM domains of both human and the newly-discovered Bufo gargarizans genes contained two conserved zinc-chelating sites (CCHC and HCCC), except BgDmrt3b, which contained the CCRC and HCCC sites.
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The Sox family of genes shares a high sequence similarity with the HMG box region of the human Y chromosomal gene, SRY. We used highly degenerate primers to clone and sequence seven Eremias breuchleyi Sox genes (EbSox2, EbSox3, EbSox4, EbSox11, EbSox12, EbSox14 and EbSox21). A database search for the cloned sequences revealed the following percentage identity with the homologous human SOX genes: EbSox2 = 96 percent, EbSox3 = 88 percent, EbSox4 = 94 percent, EbSox11 = 99 percent, EbSox12 = 96 percent, EbSox14 = 98 percent, EbSox21 = 97 percent. Cluster analysis indicates that they seem to belong to group B and group C of Sox gene family, respectively.