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BACKGROUND: CD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear. METHODS: The expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells. Flow cytometry analyses were employed to evaluate the rate of phagocytosis. Humanized patient-derived xenografts (Hu-PDXs) models were established to assess the efficacy of anti-CD47 immunotherapy or the combination of anti-CD47 and anti-VEGF therapy in treating gastric cancer. The infiltrated immune cells in the xenograft were analyzed by immunohistochemistry. RESULTS: In this study, we have substantiated the high expression of CD47 in gastric cancer tissues, establishing a strong association with unfavorable prognosis. Through the utilization of SIRPα-Fc to target CD47, we have effectively enhanced macrophage phagocytosis of PDCs in vitro and impeded the growth of Hu-PDXs. It is noteworthy that anti-CD47 immunotherapy has been observed to sustain tumor angiogenic vasculature, with a positive correlation between the expression of VEGF and CD47 in gastric cancer. Furthermore, the successful implementation of anti-angiogenic treatment has further augmented the anti-tumor efficacy of anti-CD47 therapy. In addition, the potent suppression of tumor growth, prevention of cancer recurrence after surgery, and significant prolongation of overall survival in Hu-PDX models can be achieved through the simultaneous targeting of CD47 and VEGF using the bispecific fusion protein SIRPα-VEGFR1 or by combining the two single-targeted agents. CONCLUSIONS: Our preclinical studies collectively offer substantiation that CD47 holds promise as a prospective target for gastric cancer, while also highlighting the potential of anti-angiogenic therapy to enhance tumor responsiveness to anti-CD47 immunotherapy.
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Neoplasias , Neoplasias Gástricas , Animales , Humanos , Antígeno CD47 , Modelos Animales de Enfermedad , Inmunoterapia , Leucocitos Mononucleares/metabolismo , Recurrencia Local de Neoplasia , Fagocitosis , Factor A de Crecimiento Endotelial VascularRESUMEN
BACKGROUND: Gastric cancer (GC) is a leading cause of cancer deaths, and an increased number of GC patients adopt to next-generation sequencing (NGS) to identify tumor genomic alterations for precision medicine. METHODS: In this study, we established a hybridization capture-based NGS panel including 612 cancer-associated genes, and collected sequencing data of tumors and matched bloods from 153 gastric cancer patients. We performed comprehensive analysis of these sequencing and clinical data. RESULTS: 35 significantly mutated genes were identified such as TP53, AKAP9, DRD2, PTEN, CDH1, LRP2 et al. Among them, 29 genes were novel significantly mutated genes compared with TCGA study. TP53 is the top frequently mutated gene, and tends to mutate in male (p = 0.025) patients and patients whose tumor located in cardia (p = 0.011). High tumor mutation burden (TMB) gathered in TP53 wild-type tumors (p = 0.045). TMB was also significantly associated with DNA damage repair (DDR) genes genotype (p = 0.047), Lauren classification (p = 1.5e-5), differentiation (1.9e-7), and HER2 status (p = 0.023). 38.31% of gastric cancer patients harbored at least one actionable alteration according to OncoKB database. CONCLUSIONS: We drew a comprehensive mutational landscape of 153 gastric tumors and demonstrated utility of target next-generation sequencing to guide clinical management.
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Biomarcadores de Tumor/genética , Análisis Mutacional de ADN/métodos , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Gástricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Medicina de Precisión , Análisis de Secuencia de ADN/métodos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Adulto JovenRESUMEN
Evidence indicates that central galanin is involved in regulation of insulin resistance in animals. This study investigates whether type 1 galanin receptor (GAL1) in the brain mediates the ameliorative effect of galanin on insulin resistance in skeletal muscles of type 2 diabetic rats. Rats were intracerebroventricularly (i.c.v.) injected with galanin(1-13)-bradykinin(2-9) amide (M617), a GAL1 agonist, and/or Akti-1/2, an Akt inhibitor, via caudal veins once per day for 10 days. Insulin resistance in muscle tissues was evaluated by glucose tolerance and 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) tests, peroxisome proliferator-activated receptor-γ (PPARγ), glucose transporter 4 (GLUT4) mRNA expression levels, Akt phosphorylation, and GLUT4 and vesicle-associated membrane protein 2 (VAMP2) concentration at plasma membranes in muscle cells. The results show that i.c.v. treatment with M617 increased glucose tolerance, 2-NBDG uptake, PPARγ levels, Akt phosphorylation, GLUT4 protein, and GLUT4 mRNA expression levels as well as GLUT4 and VAMP2 concentration at plasma membranes. All increases may be blocked by pretreatment with Akti-1/2. These results suggest that activated central GAL1 may trigger the Akt signaling pathway to alleviate insulin resistance in muscle cells. Therefore, the impact of galanin on insulin resistance is mediated mainly by GAL1 in the brain, and the GAL1 agonist may be taken as a potential antidiabetic agent for treatment of type 2 diabetes mellitus. © 2016 Wiley Periodicals, Inc.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Resistencia a la Insulina/fisiología , Receptor de Galanina Tipo 1/metabolismo , 4-Cloro-7-nitrobenzofurazano/análogos & derivados , 4-Cloro-7-nitrobenzofurazano/metabolismo , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Bradiquinina/administración & dosificación , Bradiquinina/análogos & derivados , Desoxiglucosa/análogos & derivados , Desoxiglucosa/metabolismo , Diabetes Mellitus Experimental/patología , Modelos Animales de Enfermedad , Galanina/administración & dosificación , Galanina/análogos & derivados , Galanina/uso terapéutico , Prueba de Tolerancia a la Glucosa , Transportador de Glucosa de Tipo 4/metabolismo , Insulina/metabolismo , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , PPAR gamma/metabolismo , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Wistar , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/metabolismo , Proteína 2 de Membrana Asociada a Vesículas/metabolismoRESUMEN
The ectonucleotidase CD73 degrades adenosine triphosphate (ATP) to adenosine which potently inhibits host immune responses against cancer. This study investigated the expression level and prognostic significance of CD73 in human rectal adenocarcinoma. Our data demonstrated that CD73 staining strongly marked both malignant epithelial cells and stromal components where the protein and messenger RNA (mRNA) expression levels of CD73 were significantly increased compared with paracancerous controls. High CD73 expression in tumor cells can be used as an independent factor for predicting poor patients' prognosis; however, patients with higher density of stromal CD73 were more likely to have favorable characteristics (early T and tumor-node-metastasis (TNM) stages) and overall survival. Notably, combined CD73 expression analysis in both tumoral and stromal compartments was more efficient to foretell patient's outcome where patients with increased CD73 in tumor cells but decreased CD73 in stroma displayed a worst prognosis. Taken together, the current study revealed CD73 expression was increased in both tumoral and stromal compartments. Although upregulated CD73 expression in tumor cells correlates with a poor prognosis in patients with rectal adenocarcinoma, the combination of CD73 expression in malignant epithelial cells and tumor stroma may have a better prognostic value.
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5'-Nucleotidasa/biosíntesis , Adenocarcinoma/genética , Inmunidad Celular/genética , Neoplasias del Recto/genética , 5'-Nucleotidasa/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Femenino , Proteínas Ligadas a GPI/biosíntesis , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Neoplasias del Recto/metabolismo , Neoplasias del Recto/patología , Células del Estroma/metabolismo , Células del Estroma/patologíaAsunto(s)
Anastomosis Quirúrgica/efectos adversos , Endoscopía/métodos , Esófago/cirugía , Fístula , Yeyuno/cirugía , Neoplasias Gástricas/cirugía , Técnicas de Sutura , Anciano , Anastomosis Quirúrgica/métodos , Esofagectomía/métodos , Fístula/diagnóstico , Fístula/etiología , Fístula/fisiopatología , Fístula/cirugía , Gastrectomía/métodos , Humanos , Masculino , Reoperación/métodos , Cavidad Torácica/diagnóstico por imagen , Cavidad Torácica/patología , Resultado del TratamientoRESUMEN
Claudin18.2 (CLDN18.2) is overexpressed in cancers of the digestive system, rendering it an ideal drug target for antibody-drug conjugates (ADCs). Despite many CLDN18.2-directed ADCs undergoing clinical trials, the inconclusive underlying mechanisms pose a hurdle to extending the utility of these agents. In our study, αCLDN18.2-MMAE, an ADC composed of an anti-CLDN18.2 monoclonal antibody and the tubulin inhibitor MMAE, induced a dose-dependent apoptosis via the cleavage of caspase-9/PARP proteins in CLDN18.2-positive gastric cancer cells. It was worth noting that autophagy was remarkably activated during the αCLDN18.2-MMAE treatment, which was characterized by the accumulation of autophagosomes, the conversion of autophagy marker LC3 from its form I to II, and the complete autophagic flux. Inhibiting autophagy by autophagy inhibitor LY294002 remarkably enhanced αCLDN18.2-MMAE-induced cytotoxicity and caspase-mediated apoptosis, indicating the cytoprotective role of autophagy in CLDN18.2-directed ADC-treated gastric cancer cells. Combination with an autophagy inhibitor significantly potentiated the in vivo antitumoral efficacy of αCLDN18.2-MMAE. Besides, the Akt/mTOR pathway inactivation was demonstrated to be implicated in the autophagy initiation in αCLDN18.2-MMAE-treated gastric cancer cells. In conclusion, our study highlighted a groundbreaking investigation into the mechanism of the CLDN18.2-directed ADC, focusing on the crucial role of autophagy, providing a novel insight to treat gastric cancer by the combination of CLDN18.2-directed ADC and autophagy inhibitor.
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Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid-derived suppressor cells in the tumor microenvironment, contributing to tumor immunological escapes. Many studies have demonstrated that multiple factors could induce myeloid precursor cells into myeloid-derived suppressor cells, not dendritic cells. In our study, we found that tumor supernatants could induce the generation of myeloid-derived suppressor cells by disturbing the development of dendritic cells. Twist and miR-34a may regulate the effect of tumor cells inducing myeloid-derived suppressor cells via TGF-ß and/or IL-10.
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MicroARNs/genética , MicroARNs/metabolismo , Células Mieloides/patología , Neoplasias/patología , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo , Animales , Diferenciación Celular/genética , Células Dendríticas/metabolismo , Células Dendríticas/patología , Femenino , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Células Mieloides/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVES: To investigate the impacts of laparoscopic bariatric surgery on fasting glucagon-like peptide-1 (GLP-1) and Ghrelin level in patients with type 2 diabetes mellitus (T2DM), and the mechanism in surgical treatment of T2DM. METHODS: From March 2010 to August 2011, 44 patients with T2DM underwent laparoscopic bariatric, including laparoscopic Roux-en-Y gastric bypass (LRYGB, n = 14), laparoscopic mini-gastric bypass (LMGB, n = 11), laparoscopic sleeve gastrectomy (LSG, n = 9) and laparoscopic adjustable gastric banding (LAGB, n = 10). The curative effects, changes of metabolism and gastrointestinal hormones were analyzed respectively. RESULTS: Within 6 months after surgery, the clinical complete remission of T2DM was 11, 8, 6, 3 cases in LRYGB, LMGB, LSG, LAGB group respectively; the clinical partial remission was 3, 3, 2, 4 cases respectively. The inefficacy was 1, 3 patients in LSG and LAGB group respectively. The effects of surgery within 6 months postoperative among 4 groups were different (χ(2) = 8.162, P < 0.05). The levels of body mass index (F = 275.29) and homeostasis model assessment of insulin resistance (F = 40.09) of 4 groups were declined in 6 months postoperatively (P < 0.01). The extents of decrease were no significance among 4 groups. Compared to preoperative level, GLP-1 in LRYGB ((116 ± 33) vs. (66 ± 20) ng/L and LMGB group ((103 ± 22) vs. (65 ± 16) ng/L) was higher in the first month after surgery (F = 21.76 and 139.21, P < 0.05). The changes in LSG and LAGB group were no significance (P > 0.05). The level of Ghrelin in LRYGB, LMGB, LSG group at the first week after surgery were (208 ± 79), (275 ± 102) and (258 ± 91) ng/L respectively, and they were lower than preoperative (there were (398 ± 114), (439 ± 96) and (446 ± 105) ng/L, F = 55.08, 49.96 and 46.47, all P < 0.01). But the level of Ghrelin in LRYGB and LMGB groups rebounded in the first postoperative month. The postoperative level of Ghrelin was higher in LAGB group (F = 29.24, P = 0.001). CONCLUSIONS: There are difference efficacies and impacts on gastrointestinal hormones among different modes of bariatric surgery. The change of gastrointestinal hormones is plausible mechanism of T2DM remission after surgery.
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Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Endoscopía Gastrointestinal/métodos , Ghrelina/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Obesidad Mórbida/cirugía , Adulto , Femenino , Gastrectomía , Humanos , Laparoscopía/métodos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Patients with gastric cancer liver metastasis (GCLM) are often treated with palliative care, and they show a poor prognosis. In gastric cancer, high CD47 expression has been shown to indicate a poor prognosis. CD47, expressed on the cell surface, prevents the cells from being phagocytosed by macrophages. Anti-CD47 antibodies have been shown to be effective in the treatment of metastatic leiomyosarcoma. Nonetheless, the role of CD47 in GCLM has not yet been elucidated. Here, we showed that CD47 expression in GCLM tissues was higher than that in situ. Moreover, we demonstrated that high CD47 expression correlated with an adverse prognosis. Accordingly, we investigated the role of CD47 in the development of GCLM in mouse liver. Knockdown of CD47 inhibited GCLM development. Furthermore, in vitro engulfment assays showed that decreased CD47 expression led to an increased phagocytic activity of Kupffer cells (KCs). Using enzyme-linked immunosorbent assay, we determined that CD47 knockdown promoted cytokine secretion by macrophages. Furthermore, we found that tumor-derived exosomes decreased KC-mediated phagocytosis of gastric cancer cells. Finally, in a heterotopic xenograft model, the administration of anti-CD47 antibodies inhibited tumor growth. In addition, as 5-fluorouracil (5-Fu)-based chemotherapy is the cornerstone in GCLM treatment, we administered a combination of anti-CD47 antibodies and 5-Fu, which acted synergistically to suppress the tumor. Overall, we demonstrated that tumor-derived exosomes are involved in GCLM progression, targeting CD47 inhibits gastric cancer tumorigenesis, and a combination of anti-CD47 antibodies and 5-Fu shows potential for treating GCLM.
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As one of the most common forms of solid tumours, gastric carcinoma has been revealed as the third leading cause of death worldwide. The symptom of gastric cancer is usually not obvious and thus difficult to detect at earlier stages. Therefore, gastric cancer is already in the advanced stage once detected in patients, which has a poor prognosis due to ineffective therapies and multiple resistance. Recent advance in understanding the microenvironment of cancer has significantly promoted the development of immunotherapy for advanced gastric cancer. Immunotherapy can induce immune responses in gastric cancer patients thus leads to the destruction of cancer cells. In comparison of traditional therapy, immunotherapy has demonstrated robust efficacy and tolerable toxicity. Therefore, this novel strategy for treatment of advanced gastric cancer has gain increasingly popularity. In this review, we summarize recent progress of immunotherapy in advanced gastric cancer, such as immune check point inhibitors, adoptive cell therapy, VEGF inhibitors, cancer vaccines and CAR-T cell therapy. We highlight immunotherapies involved in clinical applications and discuss the existing challenges of current immunotherapies and promising strategies to overcome these limitations.
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Vacunas contra el Cáncer , Neoplasias Gástricas , Vacunas contra el Cáncer/uso terapéutico , Humanos , Factores Inmunológicos , Inmunoterapia , Inmunoterapia Adoptiva , Microambiente TumoralRESUMEN
BACKGROUND: A whole-exome or targeted cancer genes panel by next-generation sequencing has been used widely in assisting individualized treatment decisions. Currently, multiple algorithms are developed to estimate DNA copy numbers based on sequencing data, which makes a comprehensive global glance at chromosomal integrity possible. We aim to classify gastric cancers based on chromosomal integrity to guide personalized therapy. METHODS: We investigated copy number variations (CNV) across the entire genome of 124 gastric carcinomas via exome or targeted sequencing. Chromosomal integrity was classified as chromosomal stability (CS), chromosomal instability (CIN) and intermediate state (CIN/CS) based on CNV results. Chromosomal integrity was correlated to molecular features and clinical characteristics. RESULTS: According the states of chromosomal integrity, gastric carcinomas can be stratified into two cohorts: CS and CIN. Our results showed a significant relationship between CIN status and TP53 mutation, but not RB1, phosphatase and tensin homolog (PTEN), or other reported DNA damage repair genes. The mutation frequency of the TP53 gene had great relevance. Our study initially revealed clinical significance of chromosomal integrity that CIN patients were prone to HER2-positive and mucinous adenocarcinoma, while CS patients were a diffuse subtype and poorly differentiated but had longer overall survival. CONCLUSIONS: We classified gastric carcinomas into two states of chromosomal integrity with clinical implications. The dichotomy is applicable to clinical transformation. We proposed that classifying gastric cancers based on chromosomal integrity would enable us to achieve personalized therapy for patients and may be beneficial to patient stratification in future clinical trials.
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Adenocarcinoma Mucinoso , Neoplasias Gástricas , Inestabilidad Cromosómica/genética , Variaciones en el Número de Copia de ADN/genética , Humanos , Mutación , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
Trastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently.
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Ado-Trastuzumab Emtansina/uso terapéutico , Autofagia/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Ado-Trastuzumab Emtansina/farmacología , Femenino , Humanos , Masculino , Neoplasias Gástricas/patologíaRESUMEN
Obesity and diabetes mellitus are becoming 2 of the most leading risk factors that threaten public health worldwide. Obesity is a very strong but preventable risk factor for getting type 2 diabetes. Laparoscopic sleeve gastrectomy (LSG) has been a main approach to the surgical management of morbid obesity and type 2 diabetes but its role remains undefined. Here, we overviewed the clinical outcomes and regulatory mechanisms of LSG, aiming at providing thorough theoretical supports and effective technical guidance to the pathogenesis, prognosis, treatment and prevention of type 2 diabetes with obesity. Futher more, the prospectives and main drawbacks (such as considerable heterogeneity and unicity, little comparability and relevance) of LSG are also discussed.
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Diabetes Mellitus Tipo 2/complicaciones , Gastrectomía , Laparoscopía , Obesidad/cirugía , Humanos , Obesidad/complicacionesRESUMEN
BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is becoming a stand-alone bariatric surgery for obesity, but its effectiveness for Mainland Chinese patients remains unclear. OBJECTIVES: To evaluate the effectiveness and safety of LSG for Mainland Chinese patients SETTING: A tertiary hospital METHODS: Retrospective analysis of patients admitted for LSG between January 2011 and February 2012 was performed. Medium-term outcome measures were: total weight loss (%TWL), excess weight loss (%EWL), co-morbidities, improvement, and complications. RESULTS: Seventy patients (body mass index [BMI] 40.8±5.9 kg/m2) underwent LSG, comprising 40 women and 30 men. The most common co-morbidity was diabetes (n = 29, 41.4%). Lost to follow-up rate for weight loss was 15.7%, 31.4%, and 41% at 1, 2, and 3 years. The %TWL was 34.4±6.1, 34.7±6.2 and 33.7±7.1 at 1, 2, and 3 years. The %EWL increased to 77.1±13.0, 77.9±12.2 and 77.2±13.1 at 1, 2, and 3years. The proportions of patients having successful weight loss were 100% or 85% at 3 years according the definition of %TWL>10% or %EWL>50%. Approximately 79.3%, 51.7%, and 44.8% of patients completed follow-up for glycemic control at each time point, respectively. The proportions of patients with optimal glycemic control (fasting blood glucose [FBG]<5.6 mmol/L; hemoglobin A1C [HbA1C]<6.5%) were 47.9%, 60.0%, and 69.2% at 1, 2, and 3years. The weight loss and glycemic control effect may be greater in the high BMI group (≥40 kg/m2). Early and late complications occurred in 8.6% and 7.1% of patients during follow-up. CONCLUSIONS: LSG is effective in weight loss and glycemic control and is safe for Mainland Chinese obese patients, especially for patients with a BMI≥40 kg/m2.
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Cirugía Bariátrica/métodos , Gastrectomía/métodos , Laparoscopía/métodos , Obesidad Mórbida/cirugía , Adolescente , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , China/etnología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/etnología , Femenino , Gastrectomía/efectos adversos , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/complicaciones , Obesidad Mórbida/etnología , Complicaciones Posoperatorias/etnología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Resultado del Tratamiento , Pérdida de Peso/etnología , Pérdida de Peso/fisiología , Adulto JovenRESUMEN
The recombination efficiency and cell specificity of Cre driver lines are critical for exploring pancreatic ß cell biology with the Cre/LoxP approach. Some commonly used Cre lines are based on the short Ins2 promoter fragment and show recombination activity in hypothalamic neurons; however, whether this stems from endogenous Ins2 promoter activity remains controversial. In this study, we generated Ins2-Cre knockin mice with a targeted insertion of IRES-Cre at the Ins2 locus and demonstrated with a cell lineage tracing study that the Ins2 gene is not transcriptionally active in the hypothalamus. The Ins2-Cre driver line displayed robust Cre expression and activity in pancreatic ß cells without significant alterations in insulin expression. In the brain, Cre activity was mainly restricted to the choroid plexus, without significant recombination detected in the hippocampus or hypothalamus by the LacZ or fluorescent tdTomato reporters. Furthermore, Ins2-Cre mice exhibited normal glucose tolerance and insulin secretion upon glucose stimulation in vivo. In conclusion, this Ins2-Cre driver line allowed high-fidelity detection of endogenous Ins2 promoter activity in vivo, and the negative activity in the hypothalamus demonstrated that this system is a promising alternative tool for studying ß cell biology.
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Técnicas de Sustitución del Gen , Sitios Genéticos , Hipotálamo/citología , Hipotálamo/metabolismo , Insulina/genética , Integrasas/genética , Integrasas/metabolismo , Neuronas/metabolismo , Animales , Activación Enzimática , Orden Génico , Marcación de Gen , Vectores Genéticos/genética , Glucosa/metabolismo , Recombinación Homóloga , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Ratones , Ratones Transgénicos , FenotipoRESUMEN
OBJECTIVE: To investigate the efficacy and safety of laparoscopic sleeve gastrectomy(LSG) for the treatment of obesity with type 2 diabetes mellitus(T2DM). METHODS: Clinical data of 32 obesity patients with T2DM patients undergoing LSG from May 2010 to February 2012 in our department were retrospectively analyzed. Their body weight indexes (body weight, waist circumference, BMI, EWL), blood glucose indexes [glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), insulin resistance index (HOMA-IR)], and blood lipid indexes [total cholesterol, triglyceride, low density lipoprotein cholesterol(LDL-C), high density lipoprotein cholesterol(HDL-C)] were measured 1, 3, 6, 12 months after operation and compared with preoperative levels. Improvement in complications was observed. RESULTS: All the patients completed operation under laparoscopy except 1 case because of abdominal cavity adhesion. The average operative time was (115.0±19.6) min, and the average blood loss (69.0±29.7) ml. No operative death, anastomotic leakage, or surgical site infection were found. The body weight, waist circumference and BMI at 1, 3, 6, and 12 months after surgery were significantly lower(all P<0.05) showing a decreasing trend over time. EWL showed significant increasing trend (P<0.05). During 12 months of follow-up, no over-low weight was observed. From 1 month after surgery, HbA1c, FPG and HOMA-IR decreased significantly (P<0.05). HbA1c and FPG maintained stable level at 12 and 6 months after operation respectively. FPG of 28 patients returned to normal 3 months after operation. Clinical complete remission rate of T2DM was 87.5%(28/32), and clinical partial remission rate was 12.5%(4/32) at the 12-month follow-up. Serum total cholesterol, triglyceride and LDL-C decreased obviously after surgery(P<0.05). CONCLUSION: LSG procedure is a safe and effective surgical method in treatment of obesity with T2DM.
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Diabetes Mellitus Tipo 2/complicaciones , Gastrectomía , Laparoscopía , Obesidad/cirugía , Glucemia , Hemoglobina Glucada , Humanos , Insulina , Resistencia a la Insulina , Lípidos , Obesidad/complicaciones , Inducción de Remisión , Estudios RetrospectivosRESUMEN
OBJECTIVE: To evaluate the surgical outcomes and complications after laparoscopic adjustable gastric banding (LAGB) in obese patients. METHODS: This retrospective study included 228 patients (73 males and 155 females, mean age, 32.5 ± 10.3 years) who underwent LAGB at the Changhai Hospital of the Second Military Medical University from June 2003 to June 2011. The body weight and postoperative complications were followed up. RESULTS: The pre-operative mean body mass index (BMI) was 39.5 ± 6.3 kg/m(2). Except in one case of inadequate exposure of the stomach, all laparoscopic procedures were successfully accomplished, with no conversion to open surgery. The mean operation time was 65.0 ± 20.3 min. The mean hospital stay was 2.7 ± 0.9 days. Early postoperative complications (<30 days) occurred in five cases (2.2%) and late complications (>30 days) occurred in 75 cases (32.9%), including 56 cases (24.6%) with band-associated complications. The percentage of excess weight loss (EWL%) at 1, 3 and 5 years was 40.5 ± 30.5%, 59.5 ± 41.5% and 58.9 ± 46.4%, respectively. The percentages of patients with EWL% >25%, >50% and >75% were, respectively, 60%, 33% and 0% at 1 year follow-up, 43%, 39%, and 16% at 3 years follow-up and 40%, 34% and 16% at 5 years follow-up. CONCLUSION Although LAGB has low peri-operative mortality and morbidity rates, it is associated with a high late complication rate and unsatisfactory weight loss. It may be optional, but not the first choice, for the treatment of obesity.
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OBJECTIVE: To summarize the surgical technique and perioperative management of laparoscopic sleeve gastrectomy (LSG). METHODS: A total of 57 morbid obesity patients undergoing LSG surgery from May 2010 to December 2012 were enrolled in the study, whose clinical data in perioperative period were analyzed retrospectively. These patients had more than 1 year of follow-up. All the patients received preoperative preparation and postoperative management, and postoperative excess weight loss(EWL%) and improvement of preoperative complications was evaluated. RESULTS: All the cases completed the operation under laparoscopy, except 1 case because of the abdominal extensive adhesion. The average operation time was(102.0±15.2) min and the mean intraoperative blood loss (132.3±45.6) ml. Of 2 postoperative hemorrhage patients, 1 case received conservative treatment, and another one underwent laparoscopic exploration. The EWL% at 3 months, 6 months and 1 year after procedure was (54.9±13.8)%, (79.0±23.6)% and (106.9±25.1)% respectively. The preoperative complications were improved in some degree. There were no operative death, and anastomotic leak, anastomotic stenosis, or surgical site infection occurred. CONCLUSION: LSG is a safe and effective surgical technique, whose safety and efficacy may be increased by improving the perioperative management.
Asunto(s)
Gastrectomía/métodos , Laparoscopía , Humanos , Obesidad Mórbida , Estudios Retrospectivos , Pérdida de PesoRESUMEN
OBJECTIVE: To investigate the outcomes after 2 methods of laparoscopic gastric bypass surgery for patients with type 2 diabetes mellitus(T2DM). METHODS: From December 2009 to June 2011, 21 patients with T2DM underwent laparoscopic gastric bypass surgery, including laparoscopic Roux-en-Y gastric bypass (LRYGB, n=11), and laparoscopic mini-gastric bypass (LMGB, n=10). Clinical data were analyzed retrospectively. RESULTS: The clinical complete remission rate of T2DM was 64%(7/11) in LRYGB group, and 60%(6/10) in LMGB group. The clinical partial remission rate of T2DM was 36%(4/11) in LRYGB group, and 40%(4/10) in the LMGB group. There was no significant difference between the two groups(both P>0.05). The levels of BMI, waist circumference, HOMA-IR and HbA1c within the postoperative 6 months were improved in each group (all P<0.05), but there was no significant difference between the two groups(all P>0.05). There were no conversion or perioperative deaths in both groups. Compared to LMGB, the LRYGB group had longer operative time[(147.0±35.9) min vs. (110.5±39.7) min, P=0.038] and postoperative hospital stay [(8.9±2.3) d vs. (7.1±1.4) d, P=0.046). One patient suffered from ileus in LRYGB group, one patient suffered from reflux esophagitis and one suffered chronic diarrhea in LMGB group. The incidence of postoperative complication was similar between the two groups(P>0.05). CONCLUSION: LRYGB and LMGB may result in satisfactory and safe effects for the treatment of T2DM, while the LMGB is simpler and associates with quicker recovery.