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BACKGROUND & AIMS: Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex-determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. METHODS: Hepatocyte-specific Sry knock-in (KI), Sry knockout (KO), and Sry KI with platelet-derived growth factor receptor α (Pdgfrα) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation for 2 weeks or carbon tetrachloride treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. RESULTS: Compared to females, the severity of toxin- or cholestasis-induced liver fibrosis is similarly increased in castrated and uncastrated male mice. Among all Y chromosome-encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. Sry KI mice developed exacerbated liver fibrosis, whereas Sry KO mice had alleviated liver fibrosis, compared to age- and sex-matched control mice after bile duct ligation or administration of carbon tetrachloride. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate Pdgfrα expression, and promote HMGB1 (high mobility group box 1) release and subsequent HSC activation. Pdgfrα KO or treatment with the SRY inhibitor DAX1 in Sry KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. CONCLUSIONS: SRY is a strong pro-fibrotic factor and accounts for the sex disparity observed in liver fibrosis, suggesting its critical role as a potentially sex-specific therapeutic target for prevention and treatment of the disease. IMPACT AND IMPLICATION: We identified that a male-specific gene, sex-determining region Y gene (SRY), is a strong pro-fibrotic gene that accounts for the sex disparity observed in liver fibrosis. As such, SRY might be an appropriate target for surveillance and treatment of liver fibrosis in a sex-specific manner. Additionally, SRY might be a key player in the sexual dimorphism observed in hepatic pathophysiology more generally.
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Células Estrelladas Hepáticas , Hepatocitos , Cirrosis Hepática , Proteína de la Región Y Determinante del Sexo , Animales , Femenino , Masculino , Ratones , Tetracloruro de Carbono/toxicidad , Tetracloruro de Carbono/efectos adversos , Colestasis/genética , Colestasis/metabolismo , Colestasis/fisiopatología , Modelos Animales de Enfermedad , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Ratones Noqueados , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Caracteres Sexuales , Proteína de la Región Y Determinante del Sexo/genética , Proteína de la Región Y Determinante del Sexo/metabolismoRESUMEN
BACKGROUND: Increased level of serum cholic acid (CA) is often accompanied with decreased CYP2E1 expression in hepatocellular carcinoma (HCC) patients. However, the roles of CA and CYP2E1 in hepatocarcinogenesis have not been elucidated. This study aimed to investigate the roles and the underlying mechanisms of CYP2E1 and CA in HCC cell growth. METHODS: The proteomic analysis of liver tumors from DEN-induced male SD rats with CA administration was used to reveal the changes of protein expression in the CA treated group. The growth of CA-treated HCC cells was examined by colony formation assays. Autophagic flux was assessed with immunofluorescence and confocal microscopy. Western blot analysis was used to examine the expression of CYP2E1, mTOR, AKT, p62, and LC3II/I. A xenograft tumor model in nude mice was used to examine the role of CYP2E1 in CA-induced hepatocellular carcinogenesis. The samples from HCC patients were used to evaluate the clinical value of CYP2E1 expression. RESULTS: CA treatment significantly increased the growth of HCC cells and promoted xenograft tumors accompanied by a decrease of CYP2E1 expression. Further studies revealed that both in vitro and in vivo, upregulated CYP2E1 expression inhibited the growth of HCC cells, blocked autophagic flux, decreased AKT phosphorylation, and increased mTOR phosphorylation. CYP2E1 was involved in CA-activated autophagy through the AKT/mTOR signaling. Finally, decreased CYP2E1 expression was observed in the tumor tissues of HCC patients and its expression level in tumors was negatively correlated with the serum level of total bile acids (TBA) and gamma-glutamyltransferase (GGT). CONCLUSIONS: CYP2E1 downregulation contributes to CA-induced HCC development presumably through autophagy regulation. Thus, CYP2E1 may serve as a potential target for HCC drug development.
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Autofagia , Carcinoma Hepatocelular , Proliferación Celular , Ácido Cólico , Citocromo P-450 CYP2E1 , Neoplasias Hepáticas , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inducido químicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inducido químicamente , Humanos , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP2E1/genética , Masculino , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Ratas , Proliferación Celular/efectos de los fármacos , Ratones , Ratas Sprague-Dawley , Transducción de Señal , Proteómica/métodos , Modelos Animales de Enfermedad , Ratones DesnudosRESUMEN
The selective cleavage of C-N bonds in N-containing compounds holds significant research value in organic synthesis, particularly for the synthesis of promising polynitrogen species. For instance, the discovery of the cyclo-pentazolate (cyclo-N5-) anion in 2017 as a result of cleavage of the C-N bond has sparked interest within the field of high energy density materials. However, previous methods using ferrous glycinate and m-chloroperoxybenzoic acid generated the cyclo-N5- anion in a low yield of 19.5% after 24 hours, and the mechanism remained unclear. In this study, we developed an efficient catalytic system comprising Mn (II) tetraphenylporphyrin and cumyl hydroperoxide. This system enables the cyclo-N5- anion to be produced from 3,5-dimethyl-4-hydroxyphenylpentazole in 35.4% yield in 4 hours. Characterization of Mn(IV)-oxo porphyrins, â¢CH3, and â¢C8H8ON5 radicals provides evidence for the mechanism whereby the cyclo-N5- anion forms. Our study underscores the competitive potential of radical-initiated selective C-N bonds cleavage in N-arylazoles and opens avenues for further exploration in this field.
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BACKGROUND: Blood clots are composed of aggregated fibrin and platelets, and thrombosis is the body's natural response to repairing injured blood vessels or stopping bleeding. However, when this process is activated abnormally, such as in a mechanical blood pump, it can lead to excessive thrombus formation. Therefore, how to avoid or reduce the probability of thrombus formation is an important indicator of the stable operation of a blood pump. METHODS: In this paper, Lagrangian particle tracking trajectories are simulated to study platelet transport in a blood pump. The design of the thrombus blood pump was optimized using an orthogonal design method based on three factors: inlet angle, outlet angle, and blade number. The effect of blood pump pressure, rotational speed, impeller outlet angle, inlet angle, and number of blades on thrombus formation was analysed using Fluent software. The thrombogenic potential was derived by analyzing the trajectory and flow parameters of platelet particles in the blood pump, as well as the statistical parameters of residence time and stress accumulation thrombus in the platelet pump. RESULTS: When the impeller inlet angle is 30°, the outlet angle is 20°, and the number of blades is 6, the probability of thrombus formation is minimized in the orthogonal design method, aligning with the requirements for blood pump performance. CONCLUSIONS: These design parameters serve as a numerical guideline for optimizing the geometry of the semi-open impeller in blood pumps and provide a theoretical foundation for subsequent in vitro experiments.
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Plaquetas , Corazón Auxiliar , Trombosis , Trombosis/etiología , Trombosis/prevención & control , Humanos , Corazón Auxiliar/efectos adversos , Modelos Cardiovasculares , Simulación por Computador , Diseño de EquipoRESUMEN
African swine fever (ASF) is a viral hemorrhagic disease that affects domestic pigs and wild boar and is caused by the African swine fever virus (ASFV). The ASFV virion contains a long double-stranded DNA genome, which encodes more than 150 proteins. However, the immune escape mechanism and pathogenesis of ASFV remain poorly understood. Here, we report that the pyroptosis execution protein gasdermin D (GSDMD) is a new binding partner of ASFV-encoded protein S273R (pS273R), which belongs to the SUMO-1 cysteine protease family. Further experiments demonstrated that ASFV pS273R-cleaved swine GSDMD in a manner dependent on its protease activity. ASFV pS273R specifically cleaved GSDMD at G107-A108 to produce a shorter N-terminal fragment of GSDMD consisting of residues 1 to 107 (GSDMD-N1-107). Interestingly, unlike the effect of GSDMD-N1-279 fragment produced by caspase-1-mediated cleavage, the assay of LDH release, cell viability, and virus replication showed that GSDMD-N1-107 did not trigger pyroptosis or inhibit ASFV replication. Our findings reveal a previously unrecognized mechanism involved in the inhibition of ASFV infection-induced pyroptosis, which highlights an important function of pS273R in inflammatory responses and ASFV replication.
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Virus de la Fiebre Porcina Africana , Fiebre Porcina Africana , Proteasas de Cisteína , Proteínas de Unión a Fosfato , Proteínas Citotóxicas Formadoras de Poros , Proteínas Virales , Fiebre Porcina Africana/virología , Virus de la Fiebre Porcina Africana/enzimología , Virus de la Fiebre Porcina Africana/metabolismo , Animales , Proteasas de Cisteína/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Piroptosis , Sus scrofa , Porcinos , Proteínas Virales/metabolismoRESUMEN
African swine fever is a severe animal infectious disease caused by African swine fever virus (ASFV), and the morbidity and mortality associated with virulent ASFV isolates are as high as 100%. Previous studies showed that the ability of ASFV to antagonize IFN production is closely related to its pathogenicity. Here, we report that ASFV HLJ/18 infection induced low levels of type I IFN and inhibited cGMP-AMP-induced type I IFN production in porcine alveolar macrophages that were isolated from specific pathogen-free Landrace piglets. Subsequently, an unbiased screen was performed to screen the ASFV genes with inhibitory effects on the type I IFN production. ASFV pI215L, a viral E2 ubiquitin-conjugating enzyme, was identified as one of the strongest inhibitory effectors on the production of type I IFN. Knockdown of pI215L expression inhibited ASFV replication and enhanced IFN-ß production. However, inhibition of type I IFN production by pI215L was independent of its E2 enzyme activity. Furthermore, we found that pI215L inhibited type I IFN production and K63-linked polyubiquitination of TANK-binding kinase 1 through pI215L-binding RING finger protein 138 (RNF138). ASFV pI215L enhanced the interaction between RNF138 and RNF128 and promoted RNF138 to degrade RNF128, which resulted in reduced K63-linked polyubiquitination of TANK-binding kinase 1 and type Ð IFN production. Taken together, our findings reveal a novel immune escape mechanism of ASFV, which provides a clue to the design and development of an immune-sensitive attenuated live vaccine.
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Virus de la Fiebre Porcina Africana/inmunología , Nucleotidiltransferasas/inmunología , Proteínas Serina-Treonina Quinasas/inmunología , Ubiquitina-Proteína Ligasas/inmunología , Células Cultivadas , Células HEK293 , Humanos , Transducción de Señal/inmunología , UbiquitinaciónRESUMEN
Diallyl sulfide (DAS), as a major component of garlic extracts, has been shown to inhibit growth of hepatocellular carcinoma cells (HCC), but the underlying mechanism is still elusive. In this study, we aimed to explore the involvement of autophagy in DAS-induced growth inhibition of HepG2 and Huh7 hepatocellular carcinoma cells. We studied growth of DAS-treated HepG2 and Huh7 cells using the MTS and clonogenic assays. Autophagic flux was examined by immunofluorescence and confocal microscopy. The expression levels of autophagy-related proteins AMPK, mTOR, p62, LC3-II, LAMP1, and cathepsin D in the HepG2 and Huh7 cells treated with DAS as well as the tumors formed by HepG2 cells in the nude mice in the presence or absence of DAS were examined using western blotting and immunohistochemistry analysis. We found that DAS treatment induced activation of AMPK/mTOR, and accumulation of LC3-II and p62 both in vivo and in vitro. DAS inhibited autophagic flux through blocking the fusion of autophagosomes with lysosomes. Furthermore, DAS induced an increase in lysosomal pH and inhibition of Cathepsin D maturation. Co-treatment with an autophagy inhibitor (Chloroquine, CQ) further enhanced the growth inhibitory activity of DAS in HCC cells. Thus, our findings indicate that autophagy is involved in DAS-mediated growth inhibition of HCC cells both in vitro and in vivo.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Catepsina D/metabolismo , Ratones Desnudos , Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia , Serina-Treonina Quinasas TOR/metabolismo , Lisosomas/metabolismoRESUMEN
BACKGROUND: Lactose maldigestion or intolerance affects a large number of individuals worldwide. If lactose is hydrolyzed by the ß-galactosidase enzyme during the fermentation process, lactose-intolerant individuals can consume milk products without experiencing diarrhea, flatulence, or other symptoms. RESULTS AND CONCLUSION: We isolated and characterized Streptococcus thermophilus, which exhibits high ß-galactosidase activity. This was then used as a starter culture with Lactobacillus delbrueckii subsp. bulgaricus in yogurt to determine the effects of different starter ratios and fermentation temperatures on its organoleptic and physical properties. The ß-galactosidase activity of the isolated strain was 2.60 units mg-1 . The optimal temperature was 42 °C for St. thermophilus to acidify yogurt faster than at other temperatures and it was effective in hydrolyzing the lactose in the media and yogurt. The lactic acid bacteria (LAB) population in 37 °C fermented yogurt was higher than in the other samples, but the starters St. thermophilus and Lb. bulgaricus with a ratio of 2:1 used lactose more effectively than other sample ratios. The lactose content decreased significantly at 37 °C, where it was ~50% hydrolyzed. The acceptability of the sensory properties of yogurt was unaffected by relative lower fermentation temperatures (30 and 37 °C), despite using different ratios of St. thermophilus and Lb. bulgaricus as starter cultures. © 2023 Society of Chemical Industry.
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Lactobacillus delbrueckii , Lactosa , Humanos , Animales , Streptococcus thermophilus , Yogur , Diarrea , Fermentación , Leche , beta-GalactosidasaRESUMEN
OBJECTIVES: To identify the role and mechanism of a male specific gene, SRY, in I/R-induced hepatic injury. BACKGROUND: Males are more vulnerable to I/R injury than females. However, the mechanism of these sex-based differences remains poorly defined. METHODS: Clinicopathologic data of patients who underwent hepatic resection were identified from an international multi-institutional database. Liver specific SRY TG mice were generated, and subjected to I/R insult with their littermate WT controls in vivo. In vitro experiments were performed by treating primary hepatocytes from TG and WT mice with hypoxia/reoxygen-ation stimulation. RESULTS: Clinical data showed that postoperative aminotransferase level, incidence of overall morbidity and liver failure were markedly higher among 1267 male versus 508 female patients who underwent hepatic resection. SRY was dramatically upregulated during hepatic I/R injury. Overexpression of SRY in male TG mice and ectopic expression of SRY in female TG mice exacerbated liver I/R injury compared with WTs as manifested by increased inflammatory reaction, oxidative stress and cell death in vivo and in vitro. Mechanistically, SRY interacts with Glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin, and promotes phosphorylation and degradation of ß-catenin, leading to suppression of the downstream FOXOs, and activation of NF-κBand TLR4 signaling. Furthermore, activation of ß-catenin almost completely reversed the SRYoverexpression-mediated exacerbation of hepatic I/R damage. CONCLUSIONS: SRY is a novel hepatic I/R mediator that promotes hepatic inflammatory reaction, oxidative stress and cell necrosis via inhibiting Wnt/ß-catenin signaling, which accounts for the sex-based disparity in hepatic I/R injuries.
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Hepatopatías , Daño por Reperfusión , Proteína de la Región Y Determinante del Sexo/metabolismo , Animales , Apoptosis , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Isquemia , Hígado/patología , Hepatopatías/metabolismo , Masculino , Ratones , Caracteres Sexuales , beta CateninaRESUMEN
BACKGROUND: This study aims to evaluate the efficacy and safety of the modified application of COOK Cervical Ripening Balloon (CCRB) for induction of labor (IOL) at term in primipara. METHODS: A total of 227 singleton full-term pregnancies with indications of IOL were enrolled and randomly divided into the control and study groups in our hospital from January 2021 to December 2021. In the control group, a conventional method was used. Both the uterine and vaginal balloons were filled to 80 mL and removed after 12 h. In the study group, a modified method was used. The uterine and vaginal balloons were filled to 120 mL and 40 mL respectively. Light traction was given to help CCRB to be discharged after 12 h placement. Oxytocin was administered in both groups after CCRB was discharged before labor starting. The improved Bishop scores, duration of labor, and spontaneous delivery rate were evaluated in the two groups. RESULTS: The improved Bishop scores in the study group were 3.06 ± 0.97 at 12 h placement of CCRB and 4.37 ± 0.87 when CCRB was discharged, which were significantly higher compared to the control group (2.52 ± 0.79, p < 0.05). Duration of the first stage of labor and the full labor in the study group were significantly shorter than those in the control group ((6.17 ± 2.85) h vs. (7.27 ± 2.90) h, p = 0.010; (7.07 ± 3.18) h vs. (8.09 ± 3.11) h, p = 0.028). No difference in spontaneous delivery rate between the two groups was observed. But the delivery rate within 24 h between the two groups was significantly different (79.79% vs. 55.91%, p < 0.05). For the cases with initial Bishop scores ≤ 3, the improved score was significantly increased, the first stage of labor and the full labor were significantly shorter in the study group than those in the control group (p < 0.05). Those results were not observed in cases with initial Bishop scores of 4-6. CONCLUSIONS: The modified application of CCRB could benefit cervical ripening, shorten the duration of labor, especially for cases with poor cervical maturity, and improve the delivery rate within 24 h. TRIAL REGISTRATION: Retrospectively registered: ChiCTR2200058270. Registered 04/04/2022.
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Maduración Cervical , Oxitócicos , Cateterismo/métodos , Cuello del Útero , Femenino , Humanos , Trabajo de Parto Inducido/métodos , Oxitócicos/uso terapéutico , Oxitocina/farmacología , EmbarazoRESUMEN
Fiber-like (1D) core-crystalline micelles of uniform length can be obtained in protocols involving multiple steps from block copolymers (BCPs) in which crystallization of the core-forming polymer drives the self-assembly. Here we report a systematic study that shows that adding small amounts (<5 w/w%) of a homopolymer corresponding to the core-forming block of the BCP enables uniform 1D micelles (mean lengths Ln = 0.6 to 9.7 µm) to be obtained in a single step, simply by heating the mixture in a selective solvent followed by slow cooling. A series of poly(ferrocenyldimethylsilane) (PFS) BCPs with different corona-forming blocks and different compositions as well as PFS homopolymers of different lengths were examined. Dye labeling and confocal fluorescence microscopy showed that the homopolymer ends up in the center of the micelle, signaling that it served as the initial seed for epitaxial micelle growth. The rate of unimer addition was strongly enhanced by the length of the PFS block, and this enabled more complex structures to be formed in one-pot self-assembly experiments from mixtures of two or three BCPs with different PFS block lengths. Furthermore, BCP mixtures that included PFS-b-PI (PI = polyisoprene) and PFS-b-PDMS with similar PFS block lengths resulted in simultaneous addition to growing micelles, resulting in a patchy block that could be visualized by staining the vinyl groups of the PI with Pt nanoparticles. This approach also enabled scale up, so that uniform 1D micelles of controlled architecture can be obtained at concentrations of 10 w/w % solids or more.
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BACKGROUND: Laparoscopic pancreatoduodenectomy (LPD) is a minimally invasive technique widely developed in the last few decades. Although magnetic compression anastomosis (magnamosis) is used during cholangiojejunostomy, its applicability in LPD has not yet been reported. Herein, we evaluated the feasibility and effectiveness of magnamosis in LPD. METHODS: Between January 2018 and December 2019, seven patients who underwent laparoscopic magnetic compression choledochojejunostomy (LMC-CJ) or laparoscopic magnetic compression pancreatojejunostomy (LMC-PJ) in LPD were enrolled. After LPD, a parent magnet with or without a drainage tube was placed in the proximal bile duct and pancreatic duct of each patient. Daughter magnets were introduced to couple with the parent magnets at the desired sites. A close postoperative surveillance of magnet movements was performed. Various relevant data were collected, and all patients were followed up until February 2020. RESULTS: LPD was successfully completed in all seven patients, of which seven underwent LMC-CJ and two received LMC-PJ. The median time needed for completion of LMC-CJ was 11 min (range, 8-16). The cost time for the two cases of LMC-PJ was 12 and 15 min, respectively. After a median time of 50 d (range, 40-170) postoperation, all magnets were expelled. No leakages of LMC-CJ or LMC-PJ were observed after operation. After a median follow-up period of 11 mo (range, 4-18), there was no incidence of anastomotic stricture.
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Anastomosis Quirúrgica/métodos , Imanes , Pancreaticoduodenectomía/métodos , Anciano , Anciano de 80 o más Años , Anastomosis Quirúrgica/estadística & datos numéricos , Estudios de Factibilidad , Femenino , Humanos , Laparoscopía , Masculino , Persona de Mediana Edad , Pancreaticoduodenectomía/estadística & datos numéricos , Estudios RetrospectivosRESUMEN
BACKGROUND: Cholangiojejunostomy (CJ) is a popular operation; however, no specific anastomotic device is available. A novel magnamosis device for CJ was developed in 2017; here, we evaluated the feasibility and safety of the device. METHODS: Between January 2017 and December 2019, 23 patients who underwent CJ using a novel magnamosis device were enrolled. For the CJ: the parent magnet was placed in the proximal duct, and the purse-string suture was tightened over the rod of the parent magnet. The magnamosis device was introduced into the jejunum, and the mandrel penetrated the jejunum at the anastomotic site, before insertion into the rod of the parent magnet. After rotating the knob, the distance between two magnets was shortened enough to achieve coupling. RESULTS: Sixteen patients (69.6%) underwent open CJ, while 7 (30.4%) underwent laparoscopic CJ; 21 patients (91.3%) underwent choledochojejunostomy, and 2 (8.7%) underwent right or left hepatic duct jejunostomy. The mean time for completion of CJ was 9.2±2.5 min; it was significantly shorter for open CJ than for the laparoscopic way (8±1.2 min vs. 11.8±2.5 min, P<0.05). Only one patient (4.3%) suffered bile leakage after operation and was cured by conservative treatment. The magnets were discharged with a postoperative duration of 66.7±47.2 days, with a 100% expulsion rate. After a median follow-up of 15 months, only one patient (4.3%) developed inflammatory anastomotic stricture. CONCLUSION: The novel magnamosis device is a simple, safe, and effective modality for CJ.
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Yeyunostomía , Laparoscopía , Anastomosis Quirúrgica , Coledocostomía , Humanos , ImanesRESUMEN
Although early detection and systemic therapies have improved the diagnosis and clinical cure rate of breast cancer, breast cancer remains the most frequently occurring malignant cancer in women due to a lack of sufficiently effective treatments. Thus, to develop potential targeted therapies and thus benefit more patients, it is helpful to understand how cancer cells work. ZIC family members have been shown to play important roles in neural development and carcinogenesis. In our study, we found that ZIC2 is downregulated in breast cancer tissues at both the mRNA and protein levels. Low expression of ZIC2 was correlated with poor outcome in breast cancer patients and serves as an independent prognostic marker. Furthermore, overexpression of ZIC2 repressed, whereas knockdown of ZIC2 promoted, cell proliferation and colony formation ability in vitro and tumor growth in vivo. Using ChIP-seq and RNA-seq analysis, we screened and identified STAT3 as a potential target for ZIC2. ZIC2 bound to the STAT3 promoter and repressed the promoter activities of STAT3. ZIC2 knockdown induced the expression of STAT3, increasing the level of phosphorylated STAT3. These results suggest that ZIC2 regulates the transcription of STAT3 by directly binding to the STAT3 promoter. Additionally, interfering STAT3 with siRNAs or inhibitors abrogated the oncogenic effects induced by decreased ZIC2. Taken together, our results indicate that ZIC2 serves as a useful prognostic marker in breast cancer and acts as a tumor suppressor by regulating STAT3, implying that STAT3 inhibitors might provide an alternative treatment option for breast cancer patients with ZIC2 downregulation.
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Neoplasias de la Mama/patología , Regulación hacia Abajo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Secuenciación de Inmunoprecipitación de Cromatina , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Ratones , Trasplante de Neoplasias , Fosforilación , Pronóstico , Regiones Promotoras Genéticas , Análisis de Secuencia de ARN , Transducción de SeñalRESUMEN
BACKGROUND: There is no epidemiological evidence on the effects of maternal exposure to ambient particulate matter 10 µm or less in diameter (PM10) and anencephaly risk in offspring. METHODS: We conducted a population-based case-control study in Liaoning Province, China. The case group consisted of 663 cases with anencephaly and the control group consisted of 7950 healthy infants from the Maternal and Child Health Certificate Registry of Liaoning Province that were born between 2010 and 2015. Daily PM10 concentrations were obtained from 77 monitoring stations located within the study area. A multivariable logistic regression model was established to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Maternal PM10 exposure was significantly associated with an increased risk of anencephaly at three months before conception (highest versus lowest tertile: OR = 1.74, 95% CI: 1.29-2.34; per 10 µg/m3 increment: OR = 1.13, 95% CI: 1.06-1.20) and three months after conception (highest versus lowest tertile: OR = 1.93, 95% CI: 1.44-2.60; per 10 µg/m3 increment: OR = 1.01, 95% CI: 0.95-1.08). The evaluation of shorter exposure windows revealed similar associations for PM10 exposure from the third month before pregnancy to the third month after pregnancy. CONCLUSIONS: Maternal PM10 exposure is positively associated with anencephaly risk during the critical period of neural system development.
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Contaminantes Atmosféricos , Contaminación del Aire , Anencefalia , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/análisis , Anencefalia/inducido químicamente , Anencefalia/epidemiología , Estudios de Casos y Controles , Niño , China/epidemiología , Femenino , Humanos , Lactante , Exposición Materna/efectos adversos , Material Particulado/análisis , Material Particulado/toxicidad , EmbarazoRESUMEN
BACKGROUND: Magnetic compression anastomosis (MCA) is a revolutionary minimally invasive method to perform choledochocholedochostomy in patients with benign biliary stricture (BBS). We conducted MCA for the treatment of severe BBS that could not be treated by conventional methods. PATIENTS AND METHODS: Patients with BBSs that could not be treated using conventional treatments were included. All patients underwent percutaneous transhepatic biliary drainage (PTBD) before MCA, and underwent cholangiography via simultaneous PTBD and endoscopic retrograde cholangiopancreatography (ERCP). The MCA device consisted of a parent and a daughter magnet. The daughter magnet was delivered via the PTBD route to the proximal end of the obstruction, and the parent magnet was delivered via ERCP to the distal end of the obstruction. After recanalization, the MCA device was removed, and biliary stenting (or PTBD) was performed for at least 6 months. RESULTS: Of the 9 patients (age 49 ± 12.9 years), 6 had undergone orthotopic liver transplantation. MCA was successful in all 9 patients. The stricture length was 3 ± 1.7 mm, and recanalization occurred after 16.3 ± 13.2 days. Multiple plastic stents (4 patients), fully covered self-expandable metallic stents (4 patients), or PTBD (1 patient) was used after recanalization. Two mild adverse events occurred (cholangitis, 1 patient; biliary bleeding, 1 patient), but were resolved with conservative treatment. Stents were retrieved after > 6 months, and no stenosis occurred during 2-66 months of stent-free follow-up. CONCLUSION: The MCA technique is a revolutionary method for choledochocholedochostomy in patients with severe BBS unresponsive to conventional procedures.
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Procedimientos Quirúrgicos del Sistema Biliar/métodos , Coledocostomía/métodos , Colestasis/cirugía , Imanes , Complicaciones Posoperatorias/cirugía , Stents , Adulto , Anastomosis Quirúrgica/instrumentación , Anastomosis Quirúrgica/métodos , China , Colangiopancreatografia Retrógrada Endoscópica/métodos , Coledocostomía/instrumentación , Colestasis/etiología , Drenaje/métodos , Femenino , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiologíaRESUMEN
BACKGROUND: Laparoscopic splenectomy (LS) has been proven to be a safe and advantageous procedure. To ensure that resections of appropriate difficulty are selected, an objective preoperative grading of difficulty is required. We aimed to develop a predictive difficulty grading of LS based on intraoperative complications. METHODS: A total of 272 non-traumatic patients who underwent LS were identified from a regional medical center. Patients were randomized into a training cohort (n = 222) and a validation cohort (n = 50). Data on demographics, medical and surgical history, operative and pathological characteristics, and postoperative outcome details were collected. Univariate and multivariate analyses of risk factors for intraoperative complications were performed to develop a difficulty scoring system. The Spearman correlation coefficient was used to evaluate the relationship between the difficulty grading score and intraoperative outcomes. Receiver operating characteristic (ROC) curve was used to evaluate the discriminatory power of this scoring system. RESULTS: Three preoperative factors (spleen weight, esophagogastric varices, and INR) had a significant effect on operative time, bleeding, and conversion to open surgery. We created a difficulty grading score with three levels of difficulty: low (≤ 4 points), medium (5-6 points), and high (≥ 7 points), based on the three preoperative parameters. The correlation was highly significant (P < 0.01) according to Spearman's correlation. The area under the ROC curve was 0.695 (95% CI 0.630-0.755). The external validation showed significant correlations with the present model, with an AUC of 0.725 (95% CI 0.580-0.842). The comparison between our difficulty score and the previous grading system in the 272-patient cohort presented a significant difference in the AUC (0.701, 95% CI 0.643-0.755 vs. 0.644, 95% CI 0.584-0.701, P = 0.0452). CONCLUSION: The present difficulty scoring system, based on preoperative factors, has good performance in predicting the risk of intraoperative complications of LS and could be helpful for enabling appropriate case selection with respect to the current experience of a surgeon.
Asunto(s)
Laparoscopía/métodos , Cuidados Preoperatorios/métodos , Esplenectomía/métodos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Magnetic compression anastomosis is a feasible and effective method for bilioenteric anastomosis (BEA) in animal model. The objective of the present study was to report our initial clinical experience in laparoscopically magnetic compression bilioenteric anastomosis (LMC-BEA). METHODS: Patients with obstructive jaundice who were candidates for LMC-BEA were prospectively enrolled from 2013 to 2015. All the procedures were performed laparoscopically. A mother magnet and drainage tube were placed in the proximal bile duct and tightened by a purse suture after dissection of the common bile duct. The drainage tube was introduced into the jejunal lumen at the anastomotic site and guided a daughter magnet to approximate the mother magnet. The two magnets mated at the anastomotic site. All the patients were routinely followed up for magnets discharge till the end of the study. RESULTS: In total, four patients with malignant obstructive jaundice and one patient with benign biliary stricture were included. The median age was 70 y (range, 49-74 y). The median time for LMC-BEA was 12 min (range, 8-15 min). A complete anastomosis was confirmed after a median time of 21 d (range, 5-25 d) postoperatively by cholangiography via drainage tube. The magnets were expulsed around 41 d after surgery (range, 12-47 d) postoperatively. With a median follow-up of 313 d (range, 223-1042 d), no complications associated with magnetic anastomosis was documented, such as bile leakage or anastomotic stricture. CONCLUSIONS: Magnetic compression is a promising alternate method for laparoscopic BEA. Among the five patients undergoing LMC-BEA, no one developed anastomotic complications.
Asunto(s)
Conductos Biliares/cirugía , Ictericia Obstructiva/cirugía , Yeyuno/cirugía , Laparoscopía/métodos , Estomas Quirúrgicos/efectos adversos , Anciano , Anastomosis Quirúrgica/efectos adversos , Anastomosis Quirúrgica/instrumentación , Anastomosis Quirúrgica/métodos , Fuga Anastomótica/epidemiología , Fuga Anastomótica/etiología , Constricción Patológica/epidemiología , Constricción Patológica/etiología , Femenino , Estudios de Seguimiento , Humanos , Laparoscopía/efectos adversos , Laparoscopía/instrumentación , Imanes , Masculino , Persona de Mediana Edad , Tempo Operativo , Datos Preliminares , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Microplastics were demonstrated to be an environmental sink for hydrophobic organic pollutants, while they can also serve as a potential source of such pollutants. In this study, the sorption and release of bisphenol A in marine water were investigated through laboratory experiments. Sorption and desorption isotherms were developed, and the results reveal that sorption and desorption depend on the crystallinity, elasticity, and hydrophobicity of the polymer concerned. The adsorption and partition of bisphenol A can be quantified using a dual-mode model of the sorption mechanisms. Polyamide and polyurethane were found to exhibit the highest sorption capacity for bisphenol A, and it was almost irreversible, probably due to hydrogen bonding. Polyethylenes and polypropylene exhibited high and reversible sorption without noticeable desorption hysteresis. Glassy polystyrene, poly(vinyl chloride), poly(methyl methacrylate), and poly(ethylene terephthalate) exhibited low sorption capacity and only partial reversibility. Low-density polyethylene and polycarbonate microplastic particles were for the first time proved to be a persistent source releasing bisphenol A into aquatic environments. Salinity, pH, coexisting estrogens, and water chemistry influence the sorption/desorption behaviors to different degrees. Plastic particles can serve as transportation vectors for bisphenol A, which may constitute an ecological risk.