RESUMEN
Objective: To evaluate the clinical efficacy and safety of oral mifepristone (10 mg/day) versus placebo in the preoperative treatment of uterine fibroids. Methods: This study was a multi-center, randomized, double-blind, placebo, parallel controlled trial. A total of 132 patients with uterine fibroids were randomly divided into study group and control group, with 66 cases in each group. The patients in the study group orally took 1 tablet/day of mifepristone (dose of 10 mg/tablet), the patients in the control group orally took 1 tablet/day of placebo, and both groups were treated for 3 months. The primary efficacy evaluation indicators were the change rate of maximum fibroid volume; the secondary efficacy evaluation indicators included amenorrhea rate, improvement of subjective symptoms and anemia; the safety evaluation indicators included the analysis of adverse events and changes in laboratory biochemical indicators. Results: At the end of treatment, the maximum leiomyoma volume was reduced by 25.97% (95%CI: -34.79%--15.95%) in the study group and reduced by 1.51% (95%CI: -13.03%-11.54%) in the control group. The change rate of the maximum leiomyoma volume before and after treatment in the study group was significantly greater than that in the control group, and the difference in the change rate of the maximum leiomyoma volume between the two groups was -24.84% (95%CI: -36.56%--10.94%), which was much higher than the 10% superiority threshold goal set by this study within the 95%CI interval. At the end of treatment, the complete amenorrhea rate [84% (52/62)], dysmenorrhea elimination rate [98% (61/62)], and menstrual blood loss disappearance rate [87% (54/62)] in the study group were significantly higher than those in the control group (all P<0.05). At the end of treatment, the mean hemoglobin [(131±13) g/L], red blood cell count [(4.5±0.4)×1012/L] and hematocrit (0.39±0.03) in the study group were significantly increased compared with the baseline, and the differences had statistical significance (all P<0.05); after treatment, the differences in the above three indicators between the two groups had statistical significance (all P<0.01). The serum estradiol level in the study group was significantly lower than that in the control group at the end of treatment, and the difference was statistically significant (P<0.01). There were no significant differences in follicle-stimulating hormone and cortisol levels before and after treatment between the two groups (P>0.05). The overall incidences of any adverse event were not significantly different between the two groups (all P>0.05). Abdominal pain was the most common adverse event in the study group [9% (6/65)], but the incidence was not significantly increased compared with the control group [3% (2/64); P>0.05]. Conclusion: Compared with placebo, oral mifepristone 10 mg/day is significantly superior to placebo in reducing the size of uterine fibroids and improving anemia, without significant adverse reactions, and could be used as a drug treatment for patients with of uterine fibroids before surgery.
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Leiomioma , Neoplasias Uterinas , Método Doble Ciego , Dismenorrea , Femenino , Humanos , Leiomioma/tratamiento farmacológico , Leiomioma/cirugía , Menstruación , Mifepristona , Resultado del Tratamiento , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/cirugíaRESUMEN
Objective: To analyze the application of difficulty degree index (DDI) in predicting patients's fertility outcome after laparoscopic myomectomy. Methods: A retrospective study was carried out on 118 patients with subserous myoma or intramural myoma undergoing laparoscopic myomectomy from January 2005 to December 2014. The rate of post-operative pregnancy, delivery outcome and disease recurrence were investigated. Logistic regression analysis was used to analyze the impact of DDI, the age of patients undergoing surgery, presence of infertility history etc, on the patients' reproductive outcome following the surgery. Results: Follow-up for 1 to 10 years,118 cases were included in the study, the rate of post-operative pregnancy, live birth, vaginal delivery were 72.9% (86/118) , 52.5% (62/118) and 24.2% (15/62) respectively. No cases of uterine rupture and obstetric complications occurred. Univariate analysis showed that the independent variables of post-operative pregnancy rate were DDI, patient's age at the time of surgery, presence of infertility history and myoma recurrence (all P<0.05) . In multivariate analysis, the factors of post-operative pregnancy rate were DDI (OR=3.131, 95%CI:1.012-8.894) , patient's age at the time of surgery (OR=2.722, 95%CI:1.048-7.067) and presence of infertility history (OR=8.509, 95%CI: 2.102-34.445) . Conclusions: DDI could be applied to predict post-operative pregnancy rate, with the increasing of DDI the post-operative pregnancy rate decreasing. The patients with high DDI scores, age>35 years old or presence of infertility history should get ready for pregnancy positively.
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Fertilidad , Infertilidad Femenina/etiología , Laparoscopía/métodos , Leiomioma/cirugía , Miomectomía Uterina , Neoplasias Uterinas/cirugía , Parto Obstétrico , Femenino , Humanos , Infertilidad Femenina/cirugía , Laparoscopía/efectos adversos , Leiomioma/complicaciones , Nacimiento Vivo , Recurrencia Local de Neoplasia , Embarazo , Resultado del Embarazo , Índice de Embarazo , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias Uterinas/complicaciones , Rotura UterinaRESUMEN
Objective: To investigate and predict the behavioral intention and mode of the protective equipment utilization selection of the workers who used Benzene, the Theory of Planned Behavior (TPB) was applied to establish the behavioral model to enhance the theoretical foundation for long-term intervention. Methods: Questionnaires were used to survey the 707 workers, and all the behaviors of using protective equipment were investigated. Evaluate the relationships between each variable and obtain the influence affects by structural equation model. Results: The investigation showed that 38.47% of the total workers (272 cases) used whole body protection, 13.58% used partially, and 16.69% didn't use any body protection. There were significant difference between the varying degrees in the four dimensions (behavioral attitude, perceived behavior control, subjective norm, and behavioral intention) (P<0.01) . The results of structural equation model revealed that perceived behavior control was the most important influencing factor, subjective norm, positive attitude, negative attitude were the other three respects in sequence. The path co-efficient were 0.600ã0.215ã0.141 and 0.046 respectively. Conclusion: The study show that the theory of planned behavior can effectively explain the behavioral intention and behavior of protective equipment utilization. Therefore, combining the subjective initiative of individuals with the supervision of enterprises, In order to effectively enhance the protective equipment utilization of benzene workers.
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Benceno/toxicidad , Intención , Equipos de Seguridad , Actitud , Actitud Frente a la Salud , Humanos , Control Interno-Externo , Modelos Psicológicos , Equipos de Seguridad/estadística & datos numéricos , Encuestas y CuestionariosAsunto(s)
Endometriosis , Preservación de la Fertilidad , Femenino , Humanos , Consenso , Fertilidad , ChinaRESUMEN
It has been reported that interleukin-10 (IL-10) promoter genes (1082 A/G, 819 T/C, 592 A/C) are associated with nasopharyngeal carcinoma (NPC). However, the results remain controversial and ambiguous. To resolve inconsistencies in published data, we performed a meta-analysis to ascertain the association between IL-10 polymorphisms and NPC risk. Two case-control studies and two cohort studies were quantitatively analyzed to evaluate IL-10 promoter gene polymorphisms and NPC risk. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated for each genetic model and allelic comparison. A random-effect model or a fixed-effect model was used to calculate the overall combined risk estimates. Overall, the variant genotypes (AA and AG) of the IL-10-1082 A/G polymorphism were associated with elevated risk of NPC compared with the GG homozygote (AG vs GG: OR = 1.77; 95%CI = 1.39-2.26; AG + GG vs AA: OR = 1.78; 95%CI = 1.42-2.22); no significant associations were observed in allelic contrast and the recessive model. Strong positive association was seen in the cohort studies but not in the case-control studies. No statistically significant association was detected between IL-10-819 T/C and IL-10-592 A/C polymorphisms and NPC. Additionally, publication bias was not found. Based on the current evidence, this meta-analysis suggests that IL-1082 A/G polymorphism may increase the risk of NPC, but IL-10-819 T/C and IL-10-592 A/C polymorphisms do not. Further multicenter studies that are better controlled are required to confirm these findings.
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Interleucina-10/genética , Neoplasias Nasofaríngeas/genética , Carcinoma , Estudios de Casos y Controles , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Carcinoma Nasofaríngeo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Factores de RiesgoRESUMEN
The purpose of this meta-analysis was to determine whether genetic variants of the interleukin-1ß[+3954 C>T (rs1143634)] (IL-1ß +3954 C>T) gene polymorphisms were associated with orthodontic external apical root resorption (EARR). A meta-analysis was carried out using data entered into the PubMed and Embase electronic databases before October 5, 2012. A total of 7 studies were identified for meta-analysis. The strength of the relationship between IL-1ß +3954 C>T polymorphism and the risk of EARR was assessed using odds ratio (OR). The studies provided overall OR estimates for EARR. Overall, the variant genotypes (CC and CT) of the IL-1ß +3954 C>T polymorphism were unassociated with EARR risk compared with the TT homozygote [CC vs TT, OR = 1.28, 95% confidence interval (95%CI) = 0.27-6.08; CT vs TT, OR = 0.74, 95%CI = 0.11-5.02]. Similarly, no associations were found in the dominant and recessive models (dominant model, OR = 1.08, 95%CI = 0.24-4.86; recessive model, OR = 1.85, 95%CI = 0.87-3.93). No publication bias was found, and no association was apparent between the IL-1ß +3954 C>T polymorphism and risk of EARR in orthodontic treatment patients. Further multicenter and better-controlled studies are required to confirm these findings.
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Interleucina-1beta/genética , Polimorfismo de Nucleótido Simple , Resorción Radicular/genética , Estudios de Casos y Controles , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Ortodoncia Correctiva/efectos adversos , Anomalías Dentarias/terapia , Resultado del TratamientoRESUMEN
OBJECTIVE: The outbreak of SARS-CoV-2 in 2020 has become the world's largest public health event, causing global attention and concern. Despite national efforts to control this emerging infectious disease, it still cannot be contained. China, which reported the disease early, was able to control the outbreak quickly, but there is the problem of imported infections abroad. This review aims to summarize SARS-CoV-2 detected on the outer packaging of imported cold chain food and lead to the transmission of novel coronavirus. MATERIALS AND METHODS: We reviewed information on SARS-COV-2 detected on the outer packaging of imported cold chain food and relevant literature. We searched the following databases: PubMed, Web of Science, EMBASE and CNKI. search terms were "2019 nCoV", "SARS-CoV-2", "COVID-19", "cold-chain", "item surface", "spread", "people". RESULTS: We found that SARS-CoV-2 survives on the surface of cold-chain food for a long period of time and these active viruses can be transmitted to humans. CONCLUSIONS: We believe that while strictly preventing and controlling the importation of infected patients, we should strengthen the management of imported cold-chain food and its workers to prevent the transmission of SARS-CoV-2 to humans on the surface of cold-chain food objects.
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Embalaje de Alimentos , Conservación de Alimentos , Refrigeración , SARS-CoV-2/aislamiento & purificación , China , Humanos , Propiedades de SuperficieRESUMEN
OBJECTIVE: Circular RNAs (circRNAs) have been proved to play a vital role in tumorigenesis and progression. Nevertheless, the potential mechanism of circRNAs in prostate cancer (PC) remains unclear. In the present study, we aimed to investigate the exact role of circ_0004417 in the progression of prostate cancer. PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of circ_0004417 in primary PC tissues and cell lines. In vitro experiments were conducted to explore the function of circ_0004417 in PC progression, including cell counting kit-8 (CCK-8) assay, colony formation assay and transwell assay. Furthermore, the regulatory function of circ_0004417 on miRNA, p-Akt and E-cadherin was investigated to elucidate the potential mechanisms. RESULTS: Circ_0004417 was significantly down-regulated in PC tissues and cells (p<0.05). Functional experiments proved that circ_0004417 overexpression markedly inhibited the proliferation and invasion of PC cells (p<0.05). In addition, the results demonstrated that circ_0004417 served as a sponge for miR-1228 and regulated expressions of p-Akt and E-cadherin. CONCLUSIONS: Circ_0004417 inhibits the progression of prostate cancer through sponging miR-1228. All our findings suggest that circ_0004417 can be used as a potential therapeutic target for PC.
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MicroARNs/metabolismo , Neoplasias de la Próstata/metabolismo , ARN Circular/metabolismo , Proliferación Celular , Células Cultivadas , Humanos , Masculino , MicroARNs/genética , Neoplasias de la Próstata/patología , ARN Circular/genéticaRESUMEN
OBJECTIVE: This study aimed to explore the mechanism of propofol in alleviating neuronal oxidative damage. MATERIALS AND METHODS: The neuron cells were randomly assigned to normal group (NOR), model group (MOD), and propofol administration group (MED). A 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to detect the viability of neuron cells, reverse transcription PCR (RT-PCR) assay to determine the gene expression of Fis and Mfn1, and Western blot assay to determine the protein expression of Caspase-3, Caspase-9, Bax, Bcl-2, and COX-2. RESULTS: According to the results of cell proliferation rate, under normal circumstances, neuron cells would have some programmed death and weak apoptosis, while after hypoxia-reoxygenation, the apoptosis rate of neuron cells gradually increased with the increase of culture time, which was significantly higher than that of the NOR. After the addition of propofol, the overall apoptosis rate of neuron cells slowly increased, significantly lower than that in the MOD and close to that in the NOR. Compared with the NOR, the ROS content in the MOD was significantly reduced, and compared with the MOD, the ROS content in the MED significantly recovered. Furthermore, the RT-PCR results showed that compared with the NOR, the expression of mitochondrial fusion protein (Mfnl) in the MOD group declined significantly, and the expression of mitochondrial fission protein 1 (Fis1) increased significantly, while after the addition of propofol, the expression of Mfnl and Fis1 was closed to that in the NOR. WB results showed that compared with the NOR, the expression of apoptosis proteins (Caspase-3, Caspase-9, Bax, and COX-2) in the MOD increased significantly, and the expression of Bcl-2 reduced significantly (all p<0.05), and the addition of propofol improved the expression of corresponding proteins. CONCLUSIONS: Propofol could alleviate hypoxic neuronal injury by inhibiting high levels of mitochondrial fusion and fission.
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Hipnóticos y Sedantes/farmacología , Hipoxia/tratamiento farmacológico , Dinámicas Mitocondriales/efectos de los fármacos , Neuronas/efectos de los fármacos , Propofol/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Hipoxia/metabolismo , Hipoxia/patología , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Semenogelin 1 (SEMG1) is an important secretory protein in spermatozoa involved in the formation of a gel matrix encasing ejaculated spermatozoa. Previous studies show that the SEMG1 gene is highly expressed in spermatozoa from patients with asthenozoospermia (AZS); however, the underlying molecular mechanisms are not yet clear. OBJECTIVES: To study the molecular mechanism of high expression of SEMG1 gene and its potential roles in AZS. MATERIALS AND METHODS: Western blot and real-time PCR were used to detect the expression levels of SEMG1 protein and mRNA in the ejaculated spermatozoa from normozoospermic males and AZS patients. Bioinformatics analysis was used to predict miRNAs targeting for SEMG1 3'-untranslated region detection of the expression levels of all the candidate miRNAs in ejaculatory spermatozoa in AZS patients or normozoospermic volunteers. Luciferase reporter assays were performed to confirm it can directly bind to SEMG1. Correlation of miR-525-3p and SEMG1 mRNA expression with clinical sperm parameters were also analyzed. Finally, we conducted a follow-up study of reproductive history about all the subjects. RESULTS: SEMG1 mRNA and protein level were significantly higher in AZS patients compared to that in normozoospermic volunteers (p < 0.001). Subsequently, microRNA-525-3p (miR-525-3p) which was predicted as a candidate regulator of SEMG1 was found lower expressed in ejaculatory spermatozoa in AZS patients (p = 0.0074). Luciferase experiment revealed that microRNA-525-3p could directly target SEMG1 3'-untranslated region and suppress its expression. Importantly, our retrospective follow-up study showed that both low miR-525-3p expression and high SEMG1 expression level was significantly associated with low progressive sperm motility, abnormal sperm morphology, and infertility. DISCUSSION AND CONCLUSION: The elevated expression of SEMG1 and reduced expression of miR-525-3p are associated with AZS and male infertility. Our study provides a potential therapeutic target for the treatment of male infertility or for male contraception.
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Astenozoospermia/genética , Astenozoospermia/metabolismo , MicroARNs/biosíntesis , Proteínas de Secreción de la Vesícula Seminal/biosíntesis , Espermatozoides/metabolismo , Adulto , Regulación de la Expresión Génica/genética , Humanos , Masculino , MicroARNs/genética , Proteínas de Secreción de la Vesícula Seminal/genéticaRESUMEN
Exosomes are membranous nanovesicles of endocytic origin that carry and transfer regulatory bioactive molecules and mediate intercellular communication between cells and tissues. Although seminal exosomes have been identified in human seminal plasma, their exact composition and possible physiologic function remain unknown. The objective of this study was to perform a comprehensive proteomics analysis of exosomes derived from human seminal plasma. Seminal exosomes were isolated and purified from 12 healthy donors using a 30% sucrose cushion-based exosome-isolation protocol, followed by characterization by western blot, transmission electron microscopy, and nanoparticle tracking analysis before performing extensive liquid chromatography tandem mass spectrometry proteomics analysis. The identified proteins were analyzed by bioinformatics analysis, and seminal exosomes-associated proteins were selectively validated by western blot. A total of 1474 proteins were identified in all seminal exosomes samples, with Gene Ontology analysis demonstrating that these identified seminal exosomes-associated proteins were mostly linked to 'exosomes,' 'cytoplasm,' and 'cytosol.' Bioinformatics analysis indicated that these proteins were mainly involved in biologic processes, including metabolism, energy pathways, protein metabolism, cell growth and maintenance, and transport. Of these identified proteins, PHGDH, LGALS3BP, SEMG1, ACTB, GAPDH, and the exosomal-marker protein ALIX were validated by western blot. This study provided a more comprehensive description of the seminal exosomes proteome and could also be a resource for further screening of biomarkers and comparative proteomics studies, including those associated with male infertility and prostate cancer.
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Proteoma , Semen/metabolismo , Adulto , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Bases de Datos de Proteínas , Exosomas/metabolismo , Humanos , Masculino , Análisis de Semen , Espectrometría de Masas en TándemRESUMEN
Large cohort studies have revealed a close relationship between cognitive impairment and cardiovascular diseases, although the mechanism underlying this relationship remains incompletely understood. In this study, using a transgenic (Tg) mouse model of cardiac-specific over-expression of microRNA-1-2 (miR-1-2), we observed that microRNA-1 (miR-1) levels were increased not only in the heart but also in the hippocampus and blood, whereas its levels did not change in the skeletal muscle of Tg mice compared with age-matched wild-type (WT) mice. Six-month-old Tg mice showed cognitive impairment compared with age-matched WT mice, as assessed using the Morris Water Maze test. The brain-derived neurotrophic factor (BDNF) level and cyclic AMP-responsive element-binding protein (CREB) phosphorylation were also significantly reduced in the hippocampi of the Tg mice, as evaluated by Western blot. Further examination showed that BDNF protein expression was down- or up-regulated by miR-1 over-expression or inhibition, respectively, and was unchanged by binding site mutations or miRNA-masks for the 3'UTR of Bdnf, indicating that this gene is a potential target of miR-1. Knockdown of miR-1 by hippocampal stereotaxic injection of an anti-miR-1 oligonucleotide fragment carried by a lentivirus vector (lenti-pre-AMO-miR-1) led to up-regulation of BDNF expression and prevented the reduction in cognitive performance in the Tg mice without affecting cardiac function. Our findings demonstrate that cardiac over-expression of miR-1 also induces behavioral abnormalities that may be associated, at least in part, with the down-regulation of BDNF expression in the hippocampus. This study definitely contributes to the understanding of the relationship between cardiovascular disease and cognitive impairment.
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Enfermedades Cardiovasculares/complicaciones , Trastornos del Conocimiento/metabolismo , MicroARNs/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Enfermedades Cardiovasculares/metabolismo , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/sangre , MicroARNs/genética , Músculo Esquelético/metabolismo , Miocardio/metabolismoRESUMEN
Peptide YY (PYY) is a gut hormone that inhibits secretion and promotes absorption and growth in the intestinal epithelium. We have performed structure-activity studies with the active site, N-alpha-Ac-PYY(22-36)-NH(2), for interaction with intestinal PYY receptors. Investigation of aromatic substitutions at position 27 resulted in analogues that exhibited potent in vitro antisecretory potencies with N-alpha-Ac-[Trp(27)]PYY(22-36)-NH(2) exhibiting even greater potency than intact PYY. In vivo studies in dogs revealed that this analogue also promoted intestinal absorption of water and electrolytes during continuous intravenous and intraluminal infusion. Investigations carried out to identify features that would enhance stability revealed that incorporation of Trp(30) increased affinity for PYY receptors. A "CH(2)-NH" scan revealed that incorporation of reduced bonds at position 28-29 or 35-36 imparted greater receptor affinity. In general, disubstituted analogues designed based on the results of single substitutions exhibited good receptor affinity with N-alpha-Ac-[Trp(27),CH(2)-NH(35-36)]PYY(22-36)-NH(2) having the greatest affinity (IC(50) = 0.28 nM). Conservative multiple substitutions with Nle-->Leu and Nva-->Val also imparted good affinity. An analogue designed to encompass most of the favored substitutions, N-alpha-Ac-[Nle(24,28),Trp(30),Nva(31), CH(2)-NH(35-36)]PYY(22-36)-NH(2), exhibited a proabsorptive effect in dogs comparable to, but longer lasting than, that of intact hormone. Selected analogues also exhibited good antisecretory potencies in rats with N-alpha-Ac-[Trp(30)]PYY(22-36)-NH(2) being even more potent than PYY. However, the potencies did not correlate well with the PYY receptor affinity or the proabsorptive potencies in dogs. These differences could be due to species effects and/or the involvement of multiple receptors and neuronal elements in controlling the in vivo activity of PYY compounds. PYY(22-36) analogues exhibited good affinity for neuronal Y2 receptors but poor affinity for Y1 receptors. Also, crucial analogues in this series hardly bound to Y4 and Y5 receptors. In summary, we have developed PYY(22-36) analogues which, via interacting with intestinal PYY receptors, promoted potent and long-lasting proabsorptive and antisecretory effects in in vivo models. These compounds or analogues based on them may have useful clinical application in treating malabsorptive disorders observed under a variety of conditions.
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Intestinos/efectos de los fármacos , Fragmentos de Péptidos/síntesis química , Péptido YY/síntesis química , Animales , Línea Celular , Colon/efectos de los fármacos , Colon/metabolismo , Perros , Íleon/efectos de los fármacos , Íleon/metabolismo , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Péptido YY/química , Péptido YY/farmacología , Ratas , Receptores de Neuropéptido Y/metabolismo , Relación Estructura-ActividadRESUMEN
BACKGROUND: Peptide YY (PYY), a 36 amino acid enteric hormone, is known to decrease pancreatic exocrine and endocrine function. Previous studies with BIM-43004-1, a modified PYY(22-36) Y2 receptor agonist, have revealed diminished mitochondrial activity in pretreated pancreatic cancer cells in vitro. We investigated the effects of both PYY and BIM-43004-1 on pancreatic cancer growth in vivo. METHODS: The 100,000 to 150,000 human pancreatic cancer cells, Mia PaCa-2, were orthotopically transplanted into 48 male athymic mice. After 1 week animals were treated with either PYY or BIM-43004-1 at 200 pmol/kg/hr via miniosmotic pumps for 2, 3, or 4 weeks. Paired controls received saline solution. At death tumor size and mass were measured. Receptor binding studies and intracellular cyclic adenosine monophosphate (cAMP) levels were measured in vitro. RESULTS: All mice had significant human cancer growth within the pancreas by histologic sections at 2, 3, and 4 weeks. Tumor mass was decreased by 60.5% in BIM-43004-1 treated mice and 27.1% in PYY treated mice. Receptor binding studies revealed binding of [125I]-BIM-43004-1 and displacement of ligand on competitive addition of nonradioactive BIM-43004-1. K dissociation constant of 4.5 nmol and 27,000 receptors per cell were quantitated by receptor binding studies. In BIM-43004-1 treated pancreatic cells a 52.5% decrease in intracellular cAMP levels was noted, whereas a 15.3% decrease was seen in PYY treated cells. CONCLUSIONS: BIM-43004-1, a novel Y2 synthetic agonist, specifically binds to human pancreatic cancer cells, decreases intracellular cAMP levels, and suppresses tumor growth in vivo. Adjuvant hormonal treatment with this Y2 receptor analog may be beneficial in the treatment of patients with pancreatic adenocarcinoma.
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AMP Cíclico/metabolismo , Hormonas Gastrointestinales/metabolismo , Membranas Intracelulares/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Fragmentos de Péptidos/metabolismo , Receptores de la Hormona Gastrointestinal/fisiología , Animales , Peso Corporal , División Celular/efectos de los fármacos , Hormonas Gastrointestinales/farmacología , Humanos , Masculino , Ratones , Ratones Desnudos , Péptido YY , Péptidos/farmacología , Células Tumorales CultivadasRESUMEN
BACKGROUND: Plasma peptide YY (PYY) levels rise after a meal and have recently been shown to increase small bowel-absorption. The purpose of this study was to determine whether immunoneutralization of PYY would block postprandial absorption in vivo. METHODS: Exteriorized, neurovascularly intact jejunal and ileal segments (25 cm) were created in six mongrel dogs. After a 2-week recovery luminal perfusion with an isotonic buffer, containing [14C]-polyethylene glycol as a volume marker, was used to analyze water and sodium flux after an oral meal. Each meal was accompanied by either intravenous anti-PYY (0.5 mg.kg-1.h-1) or nonspecific immunoglobulin IG (control). PYY antibody binding was determined by radioimmunoassay. RESULTS: Displacement studies showed complete PYY neutralization. In control experiments feeding increased absorption of sodium and water in both segments. PYY immunoneutralization had no effect on jejunal absorption but significantly diminished ileal absorption (p < 0.05). CONCLUSIONS: These results suggest that PYY acts selectively in the ileum to increase postprandial fluid and electrolyte absorption after a meal. Agents directed at PYY-stimulated absorption may prove to be of therapeutic benefit in patients with malabsorptive conditions.
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Hormonas Gastrointestinales/fisiología , Absorción Intestinal , Péptidos/fisiología , Animales , Perros , Femenino , Alimentos , Inmunoglobulinas Intravenosas/inmunología , Péptido YY , Péptidos/inmunologíaRESUMEN
Pancreatic cancer continues to have a dismal prognosis despite multimodality treatment plans. Peptide YY (PYY) is a gut hormone that suppresses pancreatic exocrine and endocrine function. Previous experiments have shown that shortened synthetic PYY(22-36) analog decreases pancreatic cancer cell growth while also decreasing intracellular cyclic adenosine monophosphate. Our purpose was to construct an optimal synthetic PYY analog that binds to pancreatic cancer cells that may be used for imaging and therapy. Biotinylated PYY analogs with lengths ranging from PYY(1-36), PYY(9-36), PYY(14-36), PYY(22-36), and PYY(27-36) were tested with flow cytometry and receptor cross-linking studies to measure cell membrane binding. Growth inhibition studies were also performed using monotetrazolium tests to determine potency of various PYY analogs. Quantitative flow cytometry reveals the highest specific binding of PYY(14-36) to pancreatic cancer cells. Cross-linking studies reveal a receptor on the cell membrane of human pancreatic ductal adenocarcinoma cells. Growth inhibition studies reveal that PYY (14-36) has the highest potency against PANC-1 and MiaPaCa-2 cells. A novel synthetic PYY analog binds to the cell surface of pancreatic cancer cells and has the ability to deliver fluorescent dyes. The strategy of using biotinylated peptides to deliver avidin-dye complexes to cancer cells will allow imaging of pancreatic tumors and delivery of therapeutic agents.
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Carcinoma Ductal Pancreático/metabolismo , Colorantes Fluorescentes , Neoplasias Pancreáticas/metabolismo , Fragmentos de Péptidos/metabolismo , Péptido YY/metabolismo , Receptores de Superficie Celular/metabolismo , Biotinilación , Citometría de Flujo , Humanos , Células Tumorales CultivadasRESUMEN
BACKGROUND: Recent studies have revealed decreased pancreatic cancer cell growth upon administration of peptide YY (PYY). We examined whether adjuvant treatment with PYY or its synthetic analog, BIM-43004, would decrease human pancreatic adenocarcinoma growth. MATERIALS AND METHODS: Human pancreatic ductal adenocarcinomas, MiaPaCa-2 and BxPC-3, were cultured and assessed for growth by MTT assay. Pancreatic cancer cells received 500 pmol of PYY or BIM-43004 for 24 hours prior to 5-fluorouracil (5-FU; 10 micrograms/mL) and leucovorin (40 micrograms/mL) administration. Cell membrane epidermal growth factor (EGF) receptors were analyzed by Western blotting after exposure to peptides and chemotherapy. RESULTS: Cancer cell growth was reduced in all groups receiving hormonal pretreatment (23% PYY/5-FU/leucovorin versus control; 27% BIM-43004/5-FU/leucovorin versus control) as compared with groups receiving 5-FU and leucovorin only (16% versus control). The EGF receptor expression was reduced by 30% in cells treated with PYY/5-FU/leucovorin and by 45% in cells treated with BIM/5-FU/leucovorin as compared with control cells without treatment. CONCLUSION: Human pancreatic cancer cell growth is further decreased when pretreated with PYY or its synthetic analog prior to chemotherapy.
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Carcinoma Ductal de Mama/patología , Hormonas Gastrointestinales/farmacología , Neoplasias Pancreáticas/patología , Péptidos/farmacología , Receptores ErbB/análisis , Fluorouracilo/farmacología , Humanos , Leucovorina/farmacología , Péptido YY , Células Tumorales CultivadasRESUMEN
The development of nonbladed obturators with integrated stability sleeves allows for creation of a muscle-splitting dilated laparoscopic port site with minimal abdominal wall defects after removal of trocar sleeves. Our objective was to determine the safety of using nonbladed obturators and not closing laparoscopic fascial port sites. Seventy patients underwent various laparoscopic procedures including the following: seven laparoscopic Roux en Y gastric bypasses, 21 laparoscopic cholecystectomies, 23 laparoscopic hernia repairs, 10 laparoscopic Nissen fundoplications, two laparoscopic appendectomies, two laparoscopic liver biopsies, one laparoscopic common bile duct exploration, one laparoscopic jejunal resection, one laparoscopic low anterior resection, one laparoscopic splenectomy, and one bedside diagnostic laparoscopy. A total of 180 laparoscopic port sites did not undergo fascial closure involving 110 10- to 12-mm ports. One hundred eighty nonbladed trocars were inserted without complication during laparoscopic surgery. In all cases the nonbladed obturator did not cause bleeding or injure viscera. Upon removal of large laparoscopic ports, the fascial defect was less than 6 to 8 mm, and the muscles of the abdominal wall covered the port site defect. The anterior fascial defect did not line up with the posterior fascial defect after removal of CO2 insufflation. No patients have developed ventral incisional hernias in the postoperative period (median follow-up of 11 months). We conclude that the use of nonbladed laparoscopic trocars is a safe technique with the ability to visualize dissection through the abdominal wall layers to create the smallest port dissection without bleeding or cutting muscle fibers. The ability to split the abdominal wall musculature allows the surgeon to forego closure of the small fascial defect.
Asunto(s)
Músculos Abdominales/cirugía , Fasciotomía , Laparoscopios , Técnicas de Sutura , Anastomosis en-Y de Roux/métodos , Animales , Apendicectomía/instrumentación , Apendicectomía/métodos , Biopsia/instrumentación , Biopsia/métodos , Dióxido de Carbono , Colecistectomía Laparoscópica/instrumentación , Colecistectomía Laparoscópica/métodos , Conducto Colédoco/cirugía , Diseño de Equipo , Estudios de Seguimiento , Fundoplicación/instrumentación , Fundoplicación/métodos , Derivación Gástrica/métodos , Hernia Inguinal/cirugía , Humanos , Insuflación/métodos , Yeyuno/cirugía , Laparoscopía/métodos , Seguridad , Esplenectomía/instrumentación , Esplenectomía/métodos , Propiedades de Superficie , PorcinosRESUMEN
Axillary lymphadenectomy in breast conservation surgery is associated with substantial morbidity in either seroma formation or infection. Seroma formation in the axilla requiring aspiration occurs in up to 42 per cent of patients treated without drainage. Prolonged outpatient suction drainage reduces but does not eliminate the incidence of seroma formation, while increasing cost, discomfort, and possibly infection rates. We studied the efficacy of overnight closed suction drainage in patients undergoing breast conservation surgery. Fifty consecutive patients undergoing a standard axillary dissection for breast cancer were studied. The axilla was drained with a 7-French closed suction drain. All drains were removed within 23 hours of surgery and prior to discharge from the outpatient surgical center. Patients were examined by the operating surgeon 7 to 10 days after surgery. One patient (2%) experienced a seroma postoperatively. No infections were observed in all 50 patients, and the remaining 49 patients did not experience visible or symptomatic seromas. The number of lymph nodes removed ranged between 5 and 33 with a mean of 15.5 +/- 0.6. Nine out of 50 (18%) patients had metastatic breast cancer to the axillary lymph nodes. Patients undergoing breast conservation surgery benefit from overnight closed suction drainage of the axilla. This short-term method reduces the incidence and the inherent morbidity of axillary seroma formation.