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Group I metabotropic glutamate receptors (mGlu1 and mGlu5) are promising targets for multiple psychiatric and neurodegenerative disorders. Understanding the subtype selectivity of mGlu1 and mGlu5 allosteric sites is essential for the rational design of novel modulators with single- or dual-target mechanism of action. In this study, starting from the deposited mGlu1 and mGlu5 crystal structures, we utilized computational modeling approaches integrating docking, molecular dynamics simulation, and efficient post-trajectory analysis to reveal the subtype-selective mechanism of mGlu1 and mGlu5 to 10 diverse drug scaffolds representing known negative allosteric modulators (NAMs) in the literature. The results of modeling identified six pairs of non-conserved residues and four pairs of conserved ones as critical features to distinguish the selective NAMs binding to the corresponding receptors. In addition, nine pairs of residues are beneficial to the development of novel dual-target NAMs of group I metabotropic glutamate receptors. Furthermore, the binding modes of a reported dual-target NAM (VU0467558) in mGlu1 and mGlu5 were predicted to verify the identified residues that play key roles in the receptor selectivity and the dual-target binding. The results of this study can guide rational structure-based design of novel NAMs, and the approach can be generally applicable to characterize the features of selectivity for other G-protein-coupled receptors.
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Regulación Alostérica/efectos de los fármacos , Compuestos Heterocíclicos/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Sitio Alostérico , Compuestos Heterocíclicos/química , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Receptor del Glutamato Metabotropico 5/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/química , TermodinámicaRESUMEN
Background: Less is known about the sexual life and information seeking of Chinese patients with prostate cancer (PCa) after androgen deprivation therapy (ADT) treatment. Aim: To identify the experiences of sex and information needs among Chinese patients with PCa after ADT treatment. Methods: This qualitative study included 15 Chinese patients with PCa in urology inpatient wards, selected via a purposive sampling method. Semistructured interviews were conducted face-to-face or by telephone regarding sexual experiences and information needs after ADT treatment. Outcomes: Themes and subthemes were assessed among patients with PCa. Results: Two themes and 5 subthemes emerged from the interview data. The first theme was "altered sexual life and attitude" with 3 subthemes: (1) undesirable sexual function and altered sexuality, (2) sexual attitudes and sociocultural cognition, and (3) behavior adjustment and intimacy. The second theme was "scarce information sources" with 2 subthemes: (1) uncertainty and lack of information support and (2) barriers to access sexual information. Clinical Implications: The present findings suggest that the following may help patients with PCa manage treatment and develop appropriate sexual attitudes: a tailored sexual health education program, well-equipped consultations rooms, and information delivery innovations. Strengths and Limitations: Strengths of this study included adding unique evidence among patients with PCa within an Asian context to reveal the understudied topic of sexual health and information needs after ADT treatment. This study was limited in being representative of all Chinese patients with PCa, with different marital statuses, treatment therapies, sexual orientations, and barriers of information seeking. Conclusion: Sexual life and attitude among patients with PCa were affected by their sociocultural cognition and ADT treatment, and most patients received insufficient information and sexual health education from health care providers.
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The efficient electrochemically promoted [3 + 2] annulation of imidazo[1,2-a]pyridines with alkynes using traceless electrons as green reagents has been developed, leading to the synthesis of a large class of polycyclic heteroaromatics in good yields with a broad substrate scope under mild and green conditions. The scaled-up experiment, follow-up procedures, and potential biological applications show the practicability and feasibility of the electrochemical method.
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A facile approach to fabricate antibiofouling membrane was developed by grafting quaternary ammonium compounds (QACs) onto polyvinylidene fluoride (PVDF) membrane via surface-initiated activators regenerated by electron transfer atom-transfer radical-polymerization (ARGET ATRP) method. During the modification process, a hydrophilic silica nanoparticle layer was also immobilized onto the membrane surface as an interlayer through silicification reaction for QAC grafting, which imparted the membrane with favorable surface properties (e.g., hydrophilic and negatively charged surface). The QAC-modified membrane (MQ) showed significantly improved hydrophilicity and permeability mainly due to the introduction of silica nanoparticles and exposure of hydrophilic quaternary ammonium groups instead of long alkyl chains. Furthermore, the coverage of QAC onto membrane surface enabled MQ membrane to have clear antibacterial effect, with an inhibition rate ~99.9% of Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive), respectively. According to the batch filtration test, MQ had better antibiofouling performance compared to the control membrane, which was ascribed to enhanced hydrophilicity and antibacterial activity. Furthermore, the MQ membrane also exhibited impressive stability of QAC upon suffering repeated fouling-cleaning tests. The modification protocols provide a new robust way to fabricate high-performance antibiofouling QAC-based membranes for wastewater treatment.
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Objective: To investigate the quality of life and associated factors in patients with coronary heart disease (CHD) in China. Methods: A cross-sectional study of 25 provinces and cities in China was performed from June to September 2020. A questionnaire was used to collect the socio-demographic and clinical information of patients with CHD, while the European Five-dimensional Quality of Life Scale (EQ-5D) was used to assess the quality of life. Multiple linear regression model was performed to analyze the associated factors. Results: The median age of the 1 075 responders was 60 (52, 67) years, and 797 (74.1%) were men. The EQ-5D and EQ-VAS indices were 0.7 (0.5, 0.8) and 60.0 (40.0, 80.0). Among the five dimensions in the quality of life scale, the frequency of anxiety/depression was the highest (59.8%), while problems in self-care was the lowest (35.8%). In the multiple linear regression model, female, increasing age, obesity, comorbidity(ies), anxiety/depression, social media channels, and receiving the CABG therapy were associated with the lower EQ-5D index (all P<0.05). In addition, increasing age, obesity, comorbidity (ies), depression, anxiety and depression, social media channels, and receiving the CABG therapy were associated with lower EQ-VAS index (all P<0.05). Conclusion: Over half of the patients with CHD in China have a low quality of life, which is related to gender, age, obesity, treatment pathway, the presence or absence of comorbidity (ies), and psychological state. In addition to managing the adverse effects of traditional socio-demographic factors on the quality of life, clinical practices should pay attention to the psychological state of patients. Moreover, establishing a WeChat group for doctor-patient communication could improve the quality of life of CHD patients.
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Masculino , Humanos , Femenino , Calidad de Vida/psicología , Autoinforme , Estudios Transversales , Enfermedad Coronaria , Encuestas y Cuestionarios , ObesidadRESUMEN
OBJECTIVE@#To assess the efficacy and safety of Guanxin Danshen Dripping Pills (GXDS) in the treatment of depression or anxiety in patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI).@*METHODS@#From September 2017 to June 2019, 200 CHD patients after PCI with depression and anxiety were included and randomly divided into GXDS (100 cases) and placebo control groups (100 cases) by block randomization and a random number table. Patients in the GXDS and control groups were given GXDS and placebo, respectively, 0.4 g each time, 3 times daily for 12 weeks. The primary outcomes were scores of Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Scale (GAD-7) and the Seattle Angina Pectoris Scale (SAQ). The secondary outcomes included 12 Health Survey Summary Form (SF-12) scores and the first onset time and incidence of major adverse cardiovascular events (MACEs). Other indices including blood pressure, blood lipids, microcirculation and inflammatory-related indices, etc. were monitored at baseline, week 4, and week 12.@*RESULTS@#In the full analysis set (200 cases), after treatment, the PHQ-9 and GAD-7 scores in the GXDS group were considerably lower than those in the control group (P<0.05). Compared with the baseline, the total PHQ-9 scores of the experimental and control groups decreased by 3.97 and 1.18, respectively. The corrected mean difference between the two groups was -2.78 (95% CI: -3.47, -2.10; P<0.001). The total GAD-7 score in the GXDS group decreased by 3.48% compared with the baseline level, while that of the placebo group decreased by 1.13%. The corrected mean difference between the two groups was -2.35 (95% CI: -2.95, -1.76; P<0.001). The degree of improvement in SAQ score, SF-12 score, endothelin and high-sensitive C-reactive protein levels in the GXDS group were substantially superior than those in the placebo group, and the differences between the two groups were statistically significant (P<0.05). Similar results were obtained in the per protocol population analysis of 177 patients. Three cases of MACES were reported in this study (1 in the GXDS group and 2 in the placebo group), and no serious adverse events occurred.@*CONCLUSIONS@#GXDS can significantly alleviate depression and anxiety, relieve symptoms of angina, and improve quality of life in patients with CHD after PCI. (Registration No. ChiCTR1800014291).
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Humanos , Intervención Coronaria Percutánea/efectos adversos , Calidad de Vida , Depresión , Enfermedad Coronaria/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Angina de Pecho/tratamiento farmacológico , Pronóstico , Ansiedad , Resultado del Tratamiento , Método Doble CiegoRESUMEN
Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex (TRiC) contains eight paralogous subunits (CCT1-8), and assists the folding of as many as 10% of cytosolic proteome. TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma, and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma. Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.
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Objective: To evaluate the anti-inflammatory activity of Crotalaria ferruginea extract (CFE) and its mechanism. Methods: An intratracheal lipopolysaccharide (LPS) instillation-induced acute lung injury (ALI) model was used to study the anti-inflammatory activity of CFE in vivo. The LPS-induced shock model was used to analyze the effect of CFE on survival. LPS-stimulated RAW264.7 cell model was used to investigate the anti-inflammatory activity of CFE in vitro and the effects on mitogen-Activated protein kinase (MAPK) or nuclear factor-κB (NF-κB) signaling pathways. Results: CFE administration decreased the number of inflammatory cells, reduced the levels of tumor necrosis factor-α (TNF-A), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and interferon-γ, and diminished protein content in the bronchoalveolar lavage fluid of mice. CFE also reduced lung wet-To-dry weight ratio, myeloperoxidase, and lung tissue pathological injury. CFE pre-Administration improved the survival rate of mice challenged with a lethal dose of LPS. CFE reduced LPS-Activated RAW264.7 cells to produce nitric oxide, TNF-α, MCP-1, and IL-6. Furthermore, CFE inhibited nuclear translocation and phosphorylation of NF-κB P65, extracellular signal-regulated kinase, c-Jun N-Terminal kinases, and P38 MAPKs. Conclusions: CFE exhibits potent anti-inflammatory activity in LPS-induced ALI mice, LPS-shock mice, and RAW264.7 cells, and its mechanism may be associated with the inhibition of NF-κB and MAPK signaling pathways. Crotalaria ferruginea may be a useful therapeutic drug for the treatment of ALI and other respiratory inflammations.
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Objective: To evaluate the anti-inflammatory activity of Crotalaria ferruginea extract (CFE) and its mechanism. Methods: An intratracheal lipopolysaccharide (LPS) instillation-induced acute lung injury (ALI) model was used to study the anti-inflammatory activity of CFE in vivo. The LPS-induced shock model was used to analyze the effect of CFE on survival. LPS-stimulated RAW264.7 cell model was used to investigate the anti-inflammatory activity of CFE in vitro and the effects on mitogen-Activated protein kinase (MAPK) or nuclear factor-κB (NF-κB) signaling pathways. Results: CFE administration decreased the number of inflammatory cells, reduced the levels of tumor necrosis factor-α (TNF-A), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and interferon-γ, and diminished protein content in the bronchoalveolar lavage fluid of mice. CFE also reduced lung wet-To-dry weight ratio, myeloperoxidase, and lung tissue pathological injury. CFE pre-Administration improved the survival rate of mice challenged with a lethal dose of LPS. CFE reduced LPS-Activated RAW264.7 cells to produce nitric oxide, TNF-α, MCP-1, and IL-6. Furthermore, CFE inhibited nuclear translocation and phosphorylation of NF-κB P65, extracellular signal-regulated kinase, c-Jun N-Terminal kinases, and P38 MAPKs. Conclusions: CFE exhibits potent anti-inflammatory activity in LPS-induced ALI mice, LPS-shock mice, and RAW264.7 cells, and its mechanism may be associated with the inhibition of NF-κB and MAPK signaling pathways. Crotalaria ferruginea may be a useful therapeutic drug for the treatment of ALI and other respiratory inflammations.
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Objective: To prepare berberine hydrochloride dry powder inhalation, and investigate its pharmacological effect on Staphylococcus aureus pneumonia after pulmonary administration. Methods: Berberine hydrochloride dry powder by spray drying and the experimental conditions was optimized by orthogonal experiment. The lung deposition, fluidity and appearance were characterized. The pharmacodynamic effects of the preparations on S. aureus pneumonia were performed with SD rats. Results: A berberine hydrochloride dry powder was prepared at an inlet temperature of 130 ℃ with a gas volume flow of 610 L/h and a feed volume flow of 3 mL/min. The berberine hydrochloride dry powder had a lung deposition rate (FPF) of 76.4% and an aerodynamic diameter of 4.61 μm. The stability index (SI) ≈ 1, the aeration energy ratio (AR) = 1.76 > 1, and the inflation energy (AE10) = 2.1 mJ < 10 mJ. Through the pharmacodynamic evaluation of S. aureus, we can know that the berberine hydrochloride dry powder inhalation effectively improved the pathological state of pneumonia rats, and significantly reduced (P < 0.05) the number of WBC, neutrophils, and the expression of inflammatory factors (TNF-α, IL-1β, and IL-6) in pneumonia rats. Conclusion: Berberine hydrochloride dry powder inhalation can directly reach the lesion site through pulmonary administration, so it has significant therapeutic effect on S. aureus pneumonia.
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Aim To study the protective effects of Mi-toQ against an altitude of 8 000 m plateau hypoxia in-jury on brain tissues of rats. Methods We studied the protective effects of MitoQ against hypoxia by the experiment of closed normobarie hypoxia to choose the best dose firstly. Then, an altitude of 8 000 m plateau hypoxia environment was stimulated using a large scale hypoharic and mionectic chamber, the histopathologi-cal slices were observed, and the level of oxidative stress and mitochondrial function as well as measurement apoptosis related proteins were determined to study the anti-hypobaric hypoxia effects of MitoQ on rats. Results MitoQ reduced the intercellular space, the degree of vacuolization of brain and oxidative stress level, prevented calcium overload, raised mitochondrial membrane potential and increased the activity of mi-tochondrial respiratory chain complexes II, IV. Furthermore, MitoQ decreased the expression level of Cyt C, caspase-3 and Bax, playing a protective role under the condition of hypobaric hypoxia on rats. Conclusions MitoQ prevents the damage and maintains the function of mitochondria of brain to protect rats under the condition of simulated altitude of 8 000 m plateau hypoxia environment.
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OBJECTIVE@#To study the clinical features of electrical status epilepticus during sleep (ESES) in children, as well as the clinical effect of methylprednisolone pulse therapy in children with ESES.@*METHODS@#A retrospective analysis was performed using the clinical data of 78 children with ESES. Among these children, 56 children who had had the failure of antiepileptic drugs were treated with methylprednisolone pulse therapy at a dose of 15-20 mg/(kg·d) for three courses. Each course of treatment was 3 days, followed by oral prednisone [1-2 mg/(kg·d)] for 3 days. The role of methylprednisolone pulse therapy in eliminating ESES, controlling clinical seizures, and improving intelligence and behaviors was analyzed.@*RESULTS@#The mean age of onset of epilepsy in 78 children was 6.8±2.4 years, and the mean age for the first occurrence of ESES was 7.6±2.5 years. Compared with normal children, children with ESES had delayed intelligence development and higher scores of some behavior problems. Methylprednisolone pulse therapy had an overall response rate of 73% (41/56) on clinical seizures, and the overall response rate on electroencephalography (EEG)/spike-wave index was 70% (39/56) after treatment. There were significant improvements in verbal intelligence quotient, performance intelligence quotient and full intelligence quotient, and significant reductions in the scores of learning problems, impulse-hyperactivity and hyperactivity index after treatment (P<0.05). The overall recurrence rate after 1-year follow-up was 29% (11/38).@*CONCLUSIONS@#ESES often presents around school age and impairs children's intelligence and behaviors. Methylprednisolone pulse therapy has a marked efficiency in reducing clinical seizures and EEG discharges in children with ESES and can improve intelligence and behavior development, but the recurrence rate remains high.
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Niño , Preescolar , Humanos , Anticonvulsivantes , Electroencefalografía , Estudios de Seguimiento , Metilprednisolona , Usos Terapéuticos , Estudios Retrospectivos , Sueño , Estado Epiléptico , QuimioterapiaRESUMEN
Curcumin( Cur) is a natural active substance extracted from the roots or tubers of traditional Chinese medicinal materials. It has anti-inflammatory and anti-tumor activities on brain diseases. Due to the poor stability,low solubility,poor absorption and low bioavailability of curcumin,N-acetyl-L-cysteine( NAC) was used as an absorption enhancer and mixed with curcumin to improve the absorption of curcumin in the body. In this paper,curcumin was smashed by airflow pulverization,and Cur-NAC mixtures were prepared by being grinded with liquid. Then,the raw material and the product were analyzed by differential scanning calorimetry( DSC),X-ray diffraction( XRD) for structural characterization. The dissolution was determined by high performance liquid chromatography( HPLC) analysis. The characteristic peaks of the samples prepared by grinding method were similar to those of the raw materials,while the melting temperature and the accumulated dissolution degree were not significantly changed. The crystal forms of the products were not changed,and no new crystal form was formed after grinding. After the administration of intranasal powder,blood samples were collected from the orbit,while the whole brain tissues were removed from the skull and dissected into 10 anatomical regions. The concentrations of curcumin in these samples were determined by UPLC-MS/MS. The concentrations of curcumin in plasma and brain were compared at different time points. After intranasal administration of two drugs,it was found that the concentration of curcumin after sniffing up the mixtures in plasma was high,and the concentration of the drug in the olfactory bulb,hippocampus,and pons was increased significantly. Within 0. 083-0. 5 h,the olfactory bulb,piriform lobe and hippocampus remained high concentrations,the endodermis,striatum,hypothalamus and midbrain reached high concentrations within 1-3 h; and the cerebellum,pons and brain extension maintained relatively high concentrations within 3-7 h. The experiment showed that nasal administration of Cur-NAC mixtures can significantly improve the bioavailability of curcumin,and lead to significant differences in brain tissue distribution.
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Animales , Ratas , Acetilcisteína , Farmacología , Administración Intranasal , Disponibilidad Biológica , Encéfalo , Química Encefálica , Cromatografía Liquida , Curcumina , Farmacocinética , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
Objective@#To explore the independent predictors for disease-specific survival (DSS) rate in patients with stage N1-3 testicular seminoma (TS), and establish a nomogram to predict individual 5-year DSS.@*Methods@#The data of N1-3 TS patients registered in the SEER database of National Cancer Institute (USA) from January 2004 to December 2015 were retrospectively analyzed. The 5-year overall survival (OS) rate and DSS rate were calculated using Kaplan-Meier method and the differences among different subgroups were assessed using log-rank test. Besides, the independent predictors of DSS were defined using multivariate Cox regression analysis, and nomogram was drawn using R software. Furthermore, the predictive performance of the nomogram was internally validated using the C-index and calibration plot.@*Results@#TNM stage ⅢA (HR=5.604, 95%CI: 1.252-25.083, P=0.024), ⅢB (HR=6.710, 95%CI: 1.923-23.410, P=0.003) and ⅢC (HR=13.189, 95%CI: 3.916-44.420, P<0.001), age at diagnosis ≥45 years old (HR=3.575, 95%CI: 2.014-6.344, P<0.001), and patients without spouse (HR=2.346, 95%CI: 1.406-3.914, P=0.001) were identified as independent risk factors for DSS. On internal validation, the predictive accuracy of our nomogram was 0.751 (C-index: 0.751, 95%CI: 0.694-0.808). Besides, the calibration plot showed that the predicted survival outcomes were highly consistent with the actual survival outcomes.@*Conclusion@#The study confirms that age at diagnosis ≥45 years old, TNM stage ≥ⅢA and patients without spouse are the independent risk factors for DSS in TS patients with stage N1-3, and the nomogram for predicting individual 5-year DSS is established.
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Objective To explore the independent predictors for disease-specific survival (DSS) rate in patients with stage N1-3 testicular seminoma (TS),and establish a nomogram to predict individual 5-year DSS.Methods The data of N1-3 TS patients registered in the SEER database of National Cancer Institute (USA) from January 2004 to December 2015 were retrospectively analyzed.The 5-year overall survival (OS) rate and DSS rate were calculated using Kaplan-Meier method and the differences among different subgroups were assessed using log-rank test.Besides,the independent predictors of DSS were defined using multivariate Cox regression analysis,and nomogram was drawn using R software.Furthermore,the predictive performance of the nomogram was internally validated using the C-index and calibration plot.Results TNM stage ⅢA (HR =5.604,95% CI:1.252-25.083,P =0.024),ⅢB (HR =6.710,95% CI:1.923-23.410,P =0.003) and ⅢC (HR =13.189,95% CI:3.916-44.420,P < 0.001),age at diagnosis ≥45 years old (HR =3.575,95% CI:2.014-6.344,P < 0.001),and patients without spouse (HR =2.346,95% CI:1.406-3.914,P =0.001) were identified as independent risk factors for DSS.On internal validation,the predictive accuracy of our nomogram was 0.751 (C-index:0.751,95% CI:0.694-0.808).Besides,the calibration plot showed that the predicted survival outcomes were highly consistent with the actual survival outcomes.Conclusion The study confirms that age at diagnosis ≥45 years old,TNM stage ≥ ⅢA and patients without spouse are the independent risk factors for DSS in TS patients with stage N1-3,and the nomogram for predicting individual 5-year DSS is established.
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OBJECTIVE@#To evaluate the safety and efficacy of allogeneic natural killer (NK) cells in the treatment of primary hepatocellular carcinoma (HCC), and to elucidate the mechanism of NK cells therapy.@*METHODS@#Twenty-one patients with primary HCC treated with allogeneic NK cells at the Fifth Medical Center of the PLA General Hospital were followed up for 1 year. Peripheral blood mononuclear cells (PBMCs) were isolated from patient-related donors and cultured in vitro for 15 days and infused to the patients in two consecutive days. Clinical data and laboratory data were collected and analyzed, including survival, clinical features, imaging changes, hematology, immunology, and biochemical indicators to evaluate the safety and efficacy of allogeneic NK cell therapy. The changes of peripheral blood lymphocyte subsets after treatment were also analyzed to explore the possible anti-tumor mechanisms.@*RESULTS@#(1) Of the 21 patients with primary HCC, 11 patients were treated once, 5 patients were treated twice, and 5 patients were treated 3 times. After allogeneic NK cells infusion, 10 patients had fever, 1 patient had slight hepatalgia and 1 patient had slight headache, no other adverse events occurred including acute and chronic graft-versus-host disease (GVHD). They resolved spontaneously within 8 hours without other treatment. (2) The total disease control rate was 76.2% during one-year follow-up. Among them, the patients with Barcelona clinic liver cancer (BCLC) stage A had a disease control rate of 100%, stable disease (SD) in 10 cases; BCLC stage B patients had a disease control rate of 60%, partial response (PR) in 1 case, and SD 2 in cases; BCLC stage C patients had a disease control rate of 50%, complete response (CR) in 1 case, and 2 cases of PR. (3) The frequencies of NK cells and CD8+ T cells in peripheral blood were significantly lower than that before at 24 hours after treatment, and the frequencies of CD4+ T cells and CD4/CD8 were significantly higher than the baseline.@*CONCLUSION@#Allogeneic NK cells have good safety and efficacy in the treatment of primary HCC. The anti-tumor effect of the allogeneic NK cells may play an important role in the activation of the patient's natural immune system and delay disease progression, suggesting that allogeneic NK cells combined with sorafenib may be a very effective treatment for advanced HCC, and further large-sample multicenter randomized controlled clinical trials are needed to validate this result.
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Humanos , Carcinoma Hepatocelular , Enfermedad Injerto contra Huésped , Células Asesinas Naturales , Leucocitos Mononucleares , Neoplasias HepáticasRESUMEN
OBJECTIVE@#To investigate the effect of rosuvastatin on homocysteine (Hcy) induced mousevascular smooth muscle cells(VSMCs) dedifferentiation and endoplasmic reticulum stress(ERS).@*METHODS@#VSMCs were co-cultured with Hcy and different concentration of rosuvastatin (0.1, 1.0 and 10 μmol/L). Cytoskeleton remodeling, VSMCs phenotype markers (smooth muscle actin-α, calponin and osteopontin) and ERS marker mRNAs (Herpud1, XBP1s and GRP78) were detected at predicted time. Tunicamycin was used to induce, respectively 4-phenylbutyrate(4-PBA) inhibition, ERS in VSMCs and cellular migration, proliferation and expression of phenotype proteins were analyzed. Mammalian target of rapamycin(mTOR)-P70S6 kinase (P70S6K) signaling agonist phosphatidic acid and inhibitor rapamycin were used in Rsv treated VSMCs. And then mTOR signaling and ERS associated mRNAs were detected.@*RESULTS@#Compared with Hcy group, Hcy+ Rsv group (1.0 and 10 μmol/L) showed enhanced α-SMA and calponin expression (<0.01), suppressed ERS mRNA levels (<0.01) and promoted polarity of cytoskeleton. Compared with Hcy group, Hcy+Rsv group and Hcy+4-PBA group showed suppressed proliferation, migration and enhanced contractile protein expression (<0.01); while tunicamycin could reverse the effect of Rsv on Hcy treated cells. Furthermore, alleviated mTOR-P70S6K phosphorylation and ERS (<0.01)were observed in Hcy+Rsv group and Hcy+rapamycin group, compared with Hcy group; while phosphatidic acid inhibited the effect of Rsv on mTOR signaling activation and ERS mRNA levels (<0.01).@*CONCLUSIONS@#Rosuvastatin could inhibit Hcy induced VSMCs dedifferentiation suppressing ERS, which might be regulated by mTOR-P70S6K signaling.
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Animales , Ratones , Actinas , Metabolismo , Proteínas de Unión al Calcio , Metabolismo , Desdiferenciación Celular , Células Cultivadas , Estrés del Retículo Endoplásmico , Proteínas de Choque Térmico , Metabolismo , Homocisteína , Proteínas de la Membrana , Metabolismo , Proteínas de Microfilamentos , Metabolismo , Músculo Liso Vascular , Biología Celular , Miocitos del Músculo Liso , Biología Celular , Proteínas Quinasas S6 Ribosómicas 70-kDa , Metabolismo , Rosuvastatina Cálcica , Farmacología , Serina-Treonina Quinasas TOR , Metabolismo , Proteína 1 de Unión a la X-Box , MetabolismoRESUMEN
Objective To investigate the clinical value and experience of transperitoneal and retroperitoneal robot-assisted partial nephrectomy for renal hi1 ar tumors.Methods We evaluated 48 patients who had partial nephrectomy for renal hilar tumor by robotic surgical syestem from January 2013 to March 2017.In those cases,35 were male and 13 were female,with an average age of 57.3 (range from 41 to 75 ),27 cases were ventral tumor and 21 cases were dorsal tumor.3 cases were totally confined to the renal parenchyma,the other 45 cases were partially confined to the renal parenchyma.18 cases were performed surgery by retroperitoneal route,the rest 30 cases were performed by peritoneal route.Results A total of 48 patients underwent successful robotic partial nephrectomy for renal hilar tumors.The mean warm ischemia time was 22 minutes (range from 16 to 33 minutes) and the mean estimated blood loss was 88 md (range from 50 to 350 ml).No bleeding-related complications were found.Histopathology confirmed 39 cases of ccRCC,7 cases of angioleiomyolipoma,2 cases of renal oncocytoma.There was one case in this review was positive surgical margin (2.1%) and found no sign of recurrence during the short term post-operation follow-up.All cases in this review are following up after surgery to date from 2 months to 4 years,no cases of tumor recurrence or metastasis were found.Conclusions The application of transperitoneal and retroperitoneal RAPN is the effective and safe way for renal hilar tumor resection,and it has a clear advantage of renal surgical incision stitching and tumor complete resection.The choice of surgical approaches depends on the size and location of tumor and the clinical experience of the surgeon.
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Objective To discuss the optimal operation mode and operation path in minimally invasive technique for living donor nephrectomy.Methods From September 2013 to August 2015, 68 living donor nephrectomy was retrospectively reviewed. Thirty-one patients were performed with robotic-assisted laparoscopic living donor nephrectomy(robotic group), twenty-nine patients underwent totally retroperitoneal laparoscopic living donor nephrectomy(non hand assisted group),and eight patients were performed with hand assisted retroperitoneal laparoscopic living donor nephrectomy(hand assisted group). Operation time, warm ischemia time, intraoperative hemorrhage volume, hospitalization time, complications and preoperative and postoperative serum creatinine value of the recipients between the two groups were compared.Results The operations of three groups were all performed successfully. Intraoperative hemorrhage volume in the three groups were(39±15)ml,(62±37)ml and(53±19)ml, and there were significant differences between these groups(P<0.05). But hospitalization time ,operation time, warm ischemia time and complications occurred rate in the three groups had no significant difference(P>0.05). In robotic group,2 donors occurred with splenic injury during operation and 1 donor was detected with hemorrhage after operation. In non-hand assisted group, 1 donor occurred with urinary tract infection, 1 donor occurred with external iliac vein thrombosis. In hand assisted group 1 donor was detected with wound fat liquefaction after operation. All the donors were followed up for more than 9 months, no hypertension, proteinuria and renal dysfunction complications were detected. The blood creatinine in three groups of recipients after operation of 5th day and 28th day were(118±26)μmol/L, (130±33)μmol/L,(128±41)μmol/L and(114±17)μmol/L,(116±34)μmol/L,(115±29)μmol/L, respectively, and there was no statistical difference(P>0.05).Conclusions Minimally invasive technique for living donor nephrectomy is beneficial to patients' recovery. Surgery doctors should combine personal experience and the hospital's hardware conditions and other factors. The principle is to ensure the donor's safety and to balance the interests of the donor and the recipient, to choose their own most skilled way of surgery.
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P2X7 receptors are closely associated with inflammation, and they have been found to be expressed on colonic cells broadly. In animal model of colonic inflammation, ATP/P2X7 signaling mainly promotes inflammation, and a variety of cells, including macrophages, dendritic cells, T cells, mast cells and enteric neurons are involved in this process. However, in the toxoplasmic ileitis, P2X7 signaling plays a role in inhibiting the inflammation. But, the underlying mechanisms are still not clear. This review outlined the research progresses of P2X7 receptors in inflammatory bowel disease (IBD) to provide some clues for the further studies on the relationship between P2X7 receptors and IBD.