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Pegmolesatide, a synthetic, polyethylene-glycolylated, peptide-based erythropoiesis-stimulating agent (ESA), has been recently approved in China. Pegmolesatide is derived from the structure of endogenous erythropoietin (EPO), a natural product in mammals. This study compared the in vitro effects and selectivity of pegmolesatide to those of recombinant EPO and carbamylated EPO (CEPO) through computer-aided analyses and biological tests. The findings indicate that pegmolesatide exhibited the same stimulating effect on erythropoiesis as EPO with fewer side effects than EPO and CEPO.
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Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.
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Conducta Alimentaria , Hipotálamo , Neuronas , Neuropéptido Y , Ratas Sprague-Dawley , Animales , Femenino , Masculino , Ratas , Desoxiglucosa/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Conducta Alimentaria/efectos de los fármacos , Glucosa/metabolismo , Área Hipotalámica Lateral/metabolismo , Área Hipotalámica Lateral/efectos de los fármacos , Hormonas Hipotalámicas/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Melaninas/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Neuropéptidos/metabolismo , Orexinas/metabolismo , Hormonas Hipofisarias/metabolismo , Receptores de Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/genética , Proteínas Inactivadoras de Ribosomas Tipo 1/farmacología , Saporinas/farmacologíaRESUMEN
BACKGROUND: In a previous study, autologous bone marrow infusion (ABMI) was performed in patients with decompensated liver cirrhosis (DLC) and acquired immunodeficiency syndrome and achieved good results, but whether splenectomy affected outcome was unclear. AIM: To investigate the efficacy of ABMI combined with splenectomy for treatment of DLC. METHODS: Eighty-three patients with DLC were divided into an intervention group (43 cases) and control group (40 cases) according to whether splenectomy was performed. The control group was treated with ABMI through the right omental vein, and the intervention group was additionally treated with splenectomy. RESULTS: After ABMI, the prothrombin time, serum total bilirubin levels, ascites volume and model for end-stage liver disease score in both groups were significantly lower, while the albumin levels were significantly higher than before ABMI (P < 0.01), but there were no significant differences between the groups (P > 0.05). After ABMI, the white blood cell and platelets counts in both groups were significantly higher than before ABMI (P < 0.01), and the counts in the intervention group were significantly higher than in the control group (P < 0.01). After ABMI the CD4+ and CD8+ T cell counts in both groups were significantly higher than before ABMI (P < 0.01). The CD8+ T cell counts in the intervention group increased continuously and the increase had a shorter duration compared with control group. CONCLUSION: ABMI through the portal vein in patients with DLC can significantly improve liver synthetic and secretory functions, and splenectomy promotes improvement of bone marrow hematopoietic and cellular immune functions.
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BACKGROUND: Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock. METHODS: This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis. RESULTS: Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups. CONCLUSION: Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.
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Sepsis , Choque Séptico , Humanos , Choque Séptico/tratamiento farmacológico , Enfermedad Crítica , Estudios ProspectivosRESUMEN
BACKGROUND: The purpose of this study is to compare the prognosis and effective rate of interventional embolization and surgical clipping in the treatment of middle cerebral artery aneurysms, to provide evidence-based basis for the selection of clinical treatment. METHODS: By searching PubMed, Cochrane library, Medline, Embase and other databases, we collected the related studies interventional embolization and surgical clipping in the treatment of middle cerebral artery aneurysms, whether it was a randomized controlled trial or not. According to the relevant inclusion and exclusion criteria, 2 researchers independently screened and extracted the relevant data. Quality of life, residual neck and recurrence rate, incidence of ischemic cerebral infarction, intracranial infection rate, incidence of vasospasm and rebleeding rate were measured. Revman5.4 software was used for Meta-analysis. RESULTS: There were 3658 patients included in 30 literatures, including 1478 patients treated with interventional embolization and 2180 patients treated with surgical clipping. The rate of low quality of life (odds ratio [OR] = 1.68, 95% confidence interval [CI]: 1.36-2.07, P < .00001) and intracranial infection rate (OR = 8.79,95% CI: 4.47-17.27, P < .00001) in the interventional embolization group were lower than those in the surgical clipping group. The postoperative rebleeding rate (OR = 0.46, 95% CI: 0.29-0.73, P = .0009), residual neck and recurrence rate (OR = 0.32, 95% CI: 0.24-0.43, P < .00001) in the interventional embolization group were higher than those in the surgical clipping group. The heterogeneity of residual neck and recurrence rate were high, so subgroup analysis was performed. We divide them into short-term group (OR = 0.68, 95% CI: 0.40-1.13, P = .13) and long-term group (OR = 0.23, 95% CI: 0.16-0.33, P < .00001). The results showed that the residual neck and recurrence rate in the interventional embolization group were higher than those in the surgical clipping group. There was no significant difference in the incidence of cerebral vasospasm (OR = 1.09, 95% CI: 0.64-1.86, P = .74) and ischemic stroke (OR = 0.87, 95% CI: 0.63-1.19, P = .37) between the 2 treatments. CONCLUSION: According to the current clinical research evidence, compared with interventional embolization in the treatment of middle cerebral artery aneurysms, the quality of life of patients after clipping is lower, the incidence of intracranial infection is higher, but the residual neck, and recurrence rate are reduced. The risk of rebleeding is also reduced. There was no significant difference in the incidence of vasospasm and ischemic stroke between the 2 groups.
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Embolización Terapéutica , Aneurisma Intracraneal , Accidente Cerebrovascular Isquémico , Humanos , Aneurisma Intracraneal/cirugía , Calidad de Vida , Embolización Terapéutica/efectos adversos , Bases de Datos Factuales , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
To investigate the role of glial cells in the regulation of glucoprivic responses in rats, a chemogenetic approach was used to activate astrocytes neighboring catecholamine (CA) neurons in the ventromedial medulla (VLM) where A1 and C1 CA cell groups overlap (A1/C1). Previous results indicate that activation of CA neurons in this region is necessary and sufficient for feeding and corticosterone release in response to glucoprivation. However, it is not known whether astrocyte neighbors of CA neurons contribute to glucoregulatory responses. Hence, we made nanoinjections of AAV5-GFAP-hM3D(Gq)-mCherry to selectively transfect astrocytes in the A1/C1 region with the excitatory designer receptor exclusively activated by designer drugs (DREADDs), hM3D(Gq). After allowing time for DREADD expression, we evaluated the rats for increased food intake and corticosterone release in response to low systemic doses of the antiglycolytic agent, 2-deoxy-d-glucose (2DG), alone and in combination with the hM3D(Gq) activator clozapine-n-oxide (CNO). We found that DREADD-transfected rats ate significantly more food when 2DG and CNO were coadministered than when either 2DG or CNO was injected alone. We also found that CNO significantly enhanced 2DG-induced FOS expression in the A1/C1 CA neurons, and that corticosterone release also was enhanced when CNO and 2DG were administered together. Importantly, CNO-induced activation of astrocytes in the absence of 2DG did not trigger food intake or corticosterone release. Our results indicate that during glucoprivation, activation of VLM astrocytes cells markedly increases the sensitivity or responsiveness of neighboring A1/C1 CA neurons to glucose deficit, suggesting a potentially important role for VLM astrocytes in glucoregulation.
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Astrocitos , Corticosterona , Ratas , Animales , Astrocitos/metabolismo , Desoxiglucosa/farmacología , Ratas Sprague-Dawley , Bulbo Raquídeo/metabolismo , Glucosa/metabolismo , Catecolaminas/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: G protein-coupled receptor 40 (GPR40) is a receptor for medium- and long-chain free fatty acids (FFAs). GPR40 activation improves type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), and the complications of T2DM and MetS. Periodontitis, a common oral inflammatory disease initiated by periodontal pathogens, is another complication of T2DM and MetS. Since FFAs play a key role in the pathogenesis of MetS which exacerbates periodontal inflammation and GPR40 is a FFA receptor with anti-inflammatory properties, it is important to define the role of GPR40 in MetS-associated periodontitis. MATERIALS AND METHODS: We induced MetS and periodontitis by high-fat diet and periodontal injection of lipopolysaccharide (LPS), respectively, in wild-type and GPR40-deficient mice and determined alveolar bone loss and periodontal inflammation using micro-computed tomography, histology, and osteoclast staining. We also performed in vitro study to determine the role of GPR40 in the expression of proinflammatory genes. RESULTS: The primary outcome of the study is that GPR40 deficiency increased alveolar bone loss and enhanced osteoclastogenesis in control mice and the mice with both MetS and periodontitis. GPR40 deficiency also augmented periodontal inflammation in control mice and the mice with both MetS and periodontitis. Furthermore, GPR40 deficiency led to increased plasma lipids and insulin resistance in control mice but had no effect on the metabolic parameters in mice with MetS alone. For mice with both MetS and periodontitis, GPR40 deficiency increased insulin resistance. Finally, in vitro studies with macrophages showed that deficiency or inhibition of GPR40 upregulated proinflammatory genes while activation of GPR40 downregulated proinflammatory gene expression stimulated synergistically by LPS and palmitic acid. CONCLUSION: GPR40 deficiency worsens alveolar bone loss and periodontal inflammation in mice with both periodontitis and MetS, suggesting that GPR40 plays a favorable role in MetS-associated periodontitis. Furthermore, GPR40 deficiency or inhibition in macrophages further upregulated proinflammatory and pro-osteoclastogenic genes induced by LPS and palmitic acid, suggesting that GPR40 has anti-inflammatory and anti-osteoclastogenic properties.
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Pérdida de Hueso Alveolar , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Síndrome Metabólico , Periodontitis , Ratones , Animales , Síndrome Metabólico/complicaciones , Síndrome Metabólico/metabolismo , Pérdida de Hueso Alveolar/patología , Diabetes Mellitus Tipo 2/complicaciones , Lipopolisacáridos/efectos adversos , Microtomografía por Rayos X , Periodontitis/metabolismo , Inflamación , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Antiinflamatorios , Ácidos Grasos no Esterificados , Ácidos Palmíticos/efectos adversosRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of Cidan Capsule combined with adjuvant transarterial chemoembolization (TACE) in patients with a high risk of early recurrence after curative resection of hepatocellular carcinoma (HCC). METHODS: A multicenter, randomized controlled trial was conducted in patients with high-risk recurrence factors after curative resection of HCC from 9 medical centers between July 2014 and July 2018. Totally 249 patients were randomly assigned to TACE with or without Cidan Capsule administration groups by stratified block in a 1:1 ratio. Postoperative adjuvant TACE was given 4-5 weeks after hepatic resection in both groups. Additionally, 125 patients in the TACE plus Cidan group were administrated Cidan Capsule (0.27 g/capsule, 5 capsules every time, 4 times a day) for 6 months with a 24-month follow-up. Primary endpoints included disease-free survival (DFS) and tumor recurrence rate (TRR). Secondary endpoint was overall survival (OS). Any drug-related adverse events (AEs) were observed and recorded. RESULTS: As the data cutoff in July 9th, 2018, the median DFS was not reached in the TACE plus Cidan group and 234.0 days in the TACE group (hazard ratio, 0.420, 95% confidence interval, 0.290-0.608; P<0.01). The 1- and 2-year TRR in the TACE plus Cidan and TACE groups were 31.5%, 37.1%, and 60.8%, 63.4%, respectively (P<0.01). Median OS was not reached in both groups. The 1- and 2-year OS rates in TACE plus Cidan and TACE groups were 98.4%, 98.4%, and 89.5%, 87.9%, respectively (P<0.05). The most common grade 3-4 AEs included fatigue, abdominal pain, lumbar pain, and nausea. One serious AE was reported in 1 patient in the TACE plus Cidan group, the death was due to retroperitoneal mass hemorrhage and hemorrhagic shock, and was not related to study drug. CONCLUSIONS: Cidan Capsule in combination with TACE can reduce the incidence of early recurrence in HCC patients at high-risk of recurrence after radical hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment. (Registration No. NCT02253511).
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Quimioembolización Terapéutica/efectos adversos , Hepatectomía , Supervivencia sin Enfermedad , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
GPR40, a G protein-coupled receptor for free fatty acids (FFAs), is considered as a therapeutic target for type 2 diabetes mellitus (T2DM) since GPR40 activation in pancreatic beta cells enhances glucose-stimulated insulin secretion. Nonalcoholic fatty liver disease (NAFLD) is a common complication of T2DM or metabolic syndrome (MetS). However, the role of GPR40 in NAFLD associated with T2DM or MetS has not been well established. Given that it is known that cholesterol and FFAs are critically involved in the pathogenesis of nonalcoholic steatohepatitis (NASH) and LDL receptor (LDLR)-deficient mice are a good animal model for human hyperlipidemia including high cholesterol and FFAs, we generated GPR40 and LDLR double knockout (KO) mice in this study to determine the effect of GPR40 KO on hyperlipidemia-promoted NASH. We showed that GPR40 KO increased plasma levels of cholesterol and FFAs in high-fat diet (HFD)-fed LDLR-deficient mice. We also showed that GPR40 KO exacerbated HFD-induced hepatic steatosis, inflammation and fibrosis. Further study demonstrated that GPR40 KO led to upregulation of hepatic CD36 and genes involved in lipogenesis, fatty acid oxidation, fibrosis and inflammation. Finally, our in vitro mechanistic studies showed that while CD36 was involved in upregulation of proinflammatory molecules in macrophages by palmitic acid (PA) and lipopolysaccharide (LPS), GPR40 activation in macrophages exerts anti-inflammatory effects. Taken together, this study demonstrated for the first time that loss of GPR40 in LDLR-deficient mice exacerbated HFD-induced hyperlipidemia, hepatic steatosis, inflammation and fibrosis potentially through a CD36-dependent mechanism, suggesting that GPR40 may play a beneficial role in hyperlipidemia-associated NASH in LDLR-deficient mice.
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Diabetes Mellitus Tipo 2 , Hiperlipidemias , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Antígenos CD36/genética , Antígenos CD36/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Ácidos Grasos no Esterificados/metabolismo , Fibrosis , Hiperlipidemias/complicaciones , Hiperlipidemias/genética , Inflamación/patología , Hígado/metabolismo , Síndrome Metabólico/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores de LDL/metabolismoRESUMEN
Background and aim: The molecular signatures of lung adenocarcinoma (LUAD) are not well understood. Centromere protein F (CENPF) has been shown to promote oncogenesis in many cancers; however, its role in LUAD has not been illustrated. We explored the role of CENPF in LUAD. Methods: CENPF expression level was investigated in public online database firstly, the prognosis of CENPF in LUAD were also assessed by Kaplan-Meier analysis. Then quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed using 13 matched pairs of clinical LUAD tissue samples. Subsequently, the impact of CENPF expression on cell proliferation, cell cycle, apoptosis, colony formation was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), flow cytometric analysis and colony formation assay, respectively. Finally, experimental xenograft lung cancer model of nude mice armpit of right forelimb to determine the effect of CENPF on LUAD tumorigenesis. Results: CENPF mRNA expression was significantly elevated in LUAD tissues compared with adjacent non-tumor lung tissues in Gene Expression Profiling Interactive Analysis (GEPIA) (P < 0.001). Up-regulated CENPF was remarkably positively associated with pathological stage, relapse free survival (RFS) as well as overall survival (OS) of LUAD patients. Besides, CENPF knockdown greatly suppressed A549 cell proliferation, induced S phase arrest, promoted apoptosis and decreased colony numbers of LUAD cells. Furthermore, knockdown of CENPF significantly inhibited the tumor growth of the LUAD cells in an experimental xenograft lung cancer model of nude mice armpit of right forelimb. Conclusion: Taken together, these results demonstrated that CENPF may serve as a potential biomarker of prognostic relevance and a potential therapeutic target for LUAD.
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Adenocarcinoma del Pulmón/genética , Biomarcadores de Tumor/genética , Proteínas Cromosómicas no Histona/genética , Neoplasias Pulmonares/genética , Proteínas de Microfilamentos/genética , Recurrencia Local de Neoplasia/epidemiología , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Animales , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas Cromosómicas no Histona/análisis , Proteínas Cromosómicas no Histona/metabolismo , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Pulmón/patología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Ratones , Proteínas de Microfilamentos/análisis , Proteínas de Microfilamentos/metabolismo , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Pronóstico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
G-protein-coupled receptor 40 (GPR40) is highly expressed in pancreatic islets, and its activation increases glucose-stimulated insulin secretion from pancreas. Therefore, GPR40 is considered as a target for type 2 diabetes mellitus (T2DM). Since nonalcoholic fatty liver disease (NAFLD) is associated with T2DM and GPR40 is also expressed by hepatocytes and macrophages, it is important to understand the role of GPR40 in NAFLD. However, the role of GPR40 in NAFLD in animal models has not been well defined. In this study, we fed wild-type or GPR40 knockout C57BL/6 mice a high-fat diet (HFD) for 20 wk and then assessed the effect of GPR40 deficiency on HFD-induced NAFLD. Assays on metabolic parameters showed that an HFD increased body weight, glucose, insulin, insulin resistance, cholesterol, and alanine aminotransferase (ALT), and GPR40 deficiency did not mitigate the HFD-induced metabolic abnormalities. In contrast, we found that GPR40 deficiency was associated with increased body weight, insulin, insulin resistance, cholesterol, and ALT in control mice fed a low-fat diet (LFD). Surprisingly, histology and Oil Red O staining showed that GPR40 deficiency in LFD-fed mice was associated with steatosis. Immunohistochemical analysis showed that GPR40 deficiency also increased F4/80, a macrophage biomarker, in LFD-fed mice. Furthermore, results showed that GPR40 deficiency led to a robust upregulation of hepatic fatty acid translocase (FAT)/CD36 expression. Finally, our in vitro studies showed that GPR40 knockdown by siRNA or a GPR40 antagonist increased palmitic acid-induced FAT/CD36 mRNA in hepatocytes. Taken together, this study indicates that GPR40 plays an important role in homeostasis of hepatic metabolism and inflammation and inhibits nonalcoholic steatohepatitis by possible modulation of FAT/CD36 expression.
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Antígenos CD36/biosíntesis , Hígado Graso/metabolismo , Hígado/metabolismo , Receptores Acoplados a Proteínas G/deficiencia , Animales , Peso Corporal , Antígenos CD36/genética , Dieta Alta en Grasa , Dislipidemias/genética , Hígado Graso/patología , Hepatitis/metabolismo , Hepatitis/patología , Resistencia a la Insulina/genética , Hígado/patología , Pruebas de Función Hepática , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores Acoplados a Proteínas G/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common tumor in primary liver cancer, but the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined. This study aimed to develop a novel prognostic classifier for patients with ICC after surgery. METHODS: Using a proteomics approach, we screened tumor markers that up-regulated in ICC tissues, and narrowed down by bioinformatics analysis, western blot and immunohistochemistry. Prognostic markers were identified using Cox regression analyses in primary training cohort and the predictive models for time to recurrence (TTR) were established. The predictive accuracy of predictive model was validated in external validation cohort and prospective validation cohort. MTT assay, clonal formation assay and trans-well assays were used to verify the effect on the proliferation and migration in ICC cell line. RESULTS: Triosephosphate isomerise (TPI1) was significantly up-regulated in ICC tissues and Kaplan-Meier analysis reveals that higher TPI1 expression was strongly correlated with higher recurrence rate of ICC patients. In the primary training cohort, mean TTR was significantly longer (p < 0.0001) than in the low-risk group (26.9 months for TTR, 95% CI 22.4-31.5) than in the high-risk group (14.5 months for TTR, 95% CI 10.6-18.4). Similar results were observed in two validation cohorts. In addition, a nomogram to predict recurrence was developed. Moreover, Knockdown of TPI1 by shRNA inhibited ICC cell growth, colony information, migration, invasion in vitro. CONCLUSIONS: Current prognostic models were accurate in predicting recurrence for ICC patients after surgical resection.
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Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Proteómica/métodos , Triosa-Fosfato Isomerasa/genética , Neoplasias de los Conductos Biliares/genética , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Colangiocarcinoma/genética , Estudios de Cohortes , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Nomogramas , Pronóstico , Estudios Prospectivos , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Hindbrain catecholamine (CA) neurons are essential for elicitation of protective counterregulatory responses (CRRs) to glucose deficit, including increased feeding and elevation of circulating corticosterone, epinephrine, and glucose. Severe or repeated antecedent glucoprivation results in attenuation of these CRRs and failure to correct glucose deficit, constituting a potentially lethal condition known as hypoglycemia-associated autonomic failure (HAAF) that may occur in patients with diabetes on insulin therapy. Recently, we demonstrated that selective pharmacogenetic activation of CA neuron subpopulations in the ventrolateral medulla during normoglycemia elicits these CRRs in a site-specific manner. In the present experiment, we examined the effect of repeated pharmacogenetic activation of CA neurons in the A1/C1 cell group on subsequent elicitation of feeding, corticosterone secretion, and respiratory quotient. We found that this prior treatment attenuated these responses to subsequent pharmacogenetic stimulation, similar to attenuation of these CRRs following repeated antecedent glucoprivation. This suggests that functional impairment of A1/C1 CA neurons resulting from antecedent glucoprivation may account, at least in part, for impairment of specific CRRs critical for restoration of normoglycemia in response to glucose deficit. Thus, a pharmacogenetic approach to selective activation of key neural circuits could provide a means of identifying neuropathogenic mechanisms contributing to HAAF.
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Catecolaminas/metabolismo , Corticosterona/metabolismo , Neuronas/metabolismo , Animales , Animales Modificados Genéticamente , Catecolaminas/genética , Clozapina/análogos & derivados , Clozapina/farmacología , Desoxiglucosa/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Genotipo , Glucosa/genética , Glucosa/metabolismo , Integrasas/genética , Integrasas/metabolismo , Masculino , Ratas , Ratas Long-EvansRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) is a public health emergency of international concern. The global population lacks immunity to COVID-19 and is generally susceptible. Underlying conditions, especially chronic respiratory diseases, may affect progression, treatment and prognosis of COVID-19. CASE SUMMARY: We report a patient with confirmed COVID-19 combined with asthma. It took 41 d from disease onset to discharge to obtain two negative tests for this coronavirus. CONCLUSION: This case indicates the dynamic clinical characteristics, laboratory and computed tomography findings and adjustment of treatment, and the possible relationship between glucocorticoid therapy and coronavirus clearance.
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BACKGROUND: Tumor mutation burden (TMB) has an important association with immunotherapy responses. TMB in the Chinese population has not been well established. Finding differences between the Chinese and Caucasian populations and elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. METHODS: Chinese cancer patients fresh tissue (n=2,177), formalin-fixed, paraffin-embed (FFPE) specimens (n=3,294), and pleural fluid (n=189) were profiled using a 295- or 520-gene next-generation sequencing (NGS) panel. The association of the TMB status with a series of molecular features and biological pathways was determined using bootstrapping. RESULTS: TMB, measured by 295- or 520-cancer-related gene panels, was correlated with whole-exome sequencing (WES) TMB based on the in silico simulation in The Cancer Genome Atlas cohort. The median TMB of our data was slightly higher than that from the Foundation Medicine Inc. (FMI) dataset. TMB was also slightly different within the same cancer type between the Chinese and Caucasian population. We discovered that the underlying pathways of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 23-gene and a 16-gene signature to predict TMB prediction for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively, indicating a histology-specific mechanism for driving high-TMB in lung cancer. CONCLUSIONS: TMB varies among different ethnic populations. Our findings extend the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types.
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Nitrogen metabolism plays an important role in the nitrogen cycle and transformation in Dianchi Lake. Not only do eukaryotes participate in nitrogen transformation but prokaryotes, as the main drivers of the nitrogen cycle, also play an extremely important role in the nitrogen cycle. Based on 16S rDNA high-throughput sequencing technology, 13 sites in Caohai and Waihai of Dianchi Lake were monitored, and PICRUSt function analysis method was adopted to analyze the microbial community diversity and key genes of nitrogen metabolism in Dianchi Lake. Bacteria belonging to 35 phyla and 427 genera were found in Dianchi Lake water and mainly included Proteobacteria and Bacteroidetes. Archaea had 14 phyla and 61 genera and mainly belonged to Euryarchaeota. The overall bacterial richness index of Dianchi Lake was higher than that of archaea, and the bacterial diversity index of Caohai was higher than that of Waihai. Functional prediction showed functional richness of bacteria and archaea. There were 35 KO pathways involved in nitrogen metabolism in bacteria, including key genes such as nitrogenous nitrate-reducing gene nirB, nitric oxide reductase gene norB in denitrification, and nitroreductase gene nasK. There were 23 KO pathways involved in nitrogen metabolism in archaea, involving nifH, nifK, and nifD nitrogenase genes in nitrogen fixation. The copy number of nitrogenase genes was significantly higher than that of other nitrogenase genes. The copy number of nitrogen-fixing genes of archaea was higher than that of bacteria, the nitrogen metabolism capacity of archaea in Caohai was higher than that in Waihai, and the potential of nitrogen-fixation of archaea in Dianchi Lake water was higher than that of bacteria. From the perspective of community structure and function prediction of bacteria and archaea, this study discussed the differences of nitrogen cycle in bacteria and archaea in different areas of Dianchi Lake and provided a decision basis for water environment management in Dianchi Lake.
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Archaea , Bacterias , Genes Bacterianos , Lagos , Ciclo del Nitrógeno , Bacterias/genética , Biodiversidad , Nitrógeno , FilogeniaRESUMEN
Leptin administration into the hindbrain, and specifically the nucleus of the solitary tract, increases phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin receptor activation, in hypothalamic nuclei known to express leptin receptors. The ventromedial nucleus of the hypothalamus (VMH) shows the greatest response, with a threefold increase in pSTAT3. This experiment tested the importance of VMH leptin receptor-expressing neurons in mediating weight loss caused by fourth ventricle (4V) leptin infusion. Male Sprague-Dawley rats received bilateral VMH 75-nL injections of 260 ng/µL of leptin-conjugated saporin (Lep-Sap) or blank-saporin (Blk-Sap). After 23 days they were fitted with 4V infusion cannulas and 1 wk later adapted to housing in a calorimeter before they were infused with 0.9 µg leptin/day for 14 days. There was no effect of VMH Lep-Sap on weight gain or glucose clearance before leptin infusion. Leptin inhibited food intake and respiratory exchange ratio in Blk-Sap but not Lep-Sap rats. Leptin had no effect on energy expenditure or brown adipose tissue temperature of either group. Inguinal and epididymal fat were significantly reduced in leptin-treated Blk-Sap rats, but the response was greatly attenuated in Lep-Sap rats. VMH pSTAT3 was increased in leptin-treated Blk-Sap but not Lep-Sap rats. These results support the concept that leptin-induced weight loss results from an integrated response across different brain areas. They also support previous reports that VMH leptin receptors do not play a significant role in maintaining energy balance in basal conditions but limit weight gain during positive energy balance.
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Cuarto Ventrículo , Leptina/administración & dosificación , Leptina/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Receptores de Leptina/efectos de los fármacos , Receptores de Leptina/metabolismo , Núcleo Hipotalámico Ventromedial/metabolismo , Pérdida de Peso/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/crecimiento & desarrollo , Animales , Temperatura Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Glucosa/metabolismo , Infusiones Intraventriculares , Masculino , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/biosíntesis , Factor de Transcripción STAT3/genética , Saporinas/farmacología , Núcleo Hipotalámico Ventromedial/efectos de los fármacosRESUMEN
Glucose is the required metabolic substrate for the brain. Yet the brain stores very little glucose. Therefore, the brain continuously monitors glucose availability to detect hypoglycemia and to mobilize system-wide responses to protect and restore euglycemia. Catecholamine (CA) neurons in the hindbrain are critical elements of the brain's glucoregulatory mechanisms. They project widely throughout the brain and spinal cord, innervating sites controlling behavioral, endocrine and visceral responses. Hence, CA neurons are capable of triggering a rapid, coordinated and multifaceted response to glucose challenge. This article reviews experimental data that has begun to elucidate the importance of CA neurons for glucoregulation, the functions of specific CA subpopulations in the ventrolateral medulla, and the extended circuitry through which they engage other levels of the nervous system to accomplish their essential glucoregulatory task. Hopefully, this review also suggests the vast amount of work yet to be done in this area and the justification for engaging in that effort.
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Glucosa/metabolismo , Bulbo Raquídeo/metabolismo , Neuronas/metabolismo , Rombencéfalo/metabolismo , Animales , Bulbo Raquídeo/fisiología , Neuronas/fisiología , Rombencéfalo/fisiologíaRESUMEN
The aim of this study was to gain insight into the knowledge of, attitude toward, and practical experience with listeriosis among medical staff. In two hospitals in Fangshan, Beijing, 410 medical staff members were randomly selected using a random sampling method. Each selected staff member was invited to participate in a standardized questionnaire interview. In total, 397 valid questionnaires were collected. With regard to the staff members' general knowledge of listeriosis, they answered 65.96% of the items correctly. The knowledge scores among obstetricians and gynecologists were higher than those of other clinical doctors (p < 0.05); however, obstetricians and gynecologists were less knowledgeable about which drugs are effective against listeriosis than the other doctors (p = 0.007). The percentage of participants with a positive attitude about preventing listeriosis was 96.47%, the percentage with practice formation was 52.39%. The medical staff's mean score for knowledge of listeriosis was 4.61 ± 1.83. The mean score for attitude toward listeriosis was 9.71 ± 1.31. There was a significant association between attitude and knowledge of listeriosis (r = 0.221, p < 0.001). Medical staff obtained a mean score of 2.10 ± 1.07 for the practice formation. There was a significant association between practice formation and knowledge of listeriosis (r = 0.502, p < 0.001). The mean knowledge-attitude-practice (KAP) score for listeriosis among medical staff was 16.41 ± 3.19. The KAP scores were significantly correlated with age (r = 0.129, p = 0.011), occupation (r = -0.103, p = 0.041), department (r = -0.168, p = 0.001), and professional title (r = 0.166, p = 0.001). To improve medical outcomes and foodborne disease surveillance, medical staff should receive more training on listeriosis and the content of the training should be adjusted.
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Enfermedades Transmitidas por los Alimentos/prevención & control , Conocimientos, Actitudes y Práctica en Salud , Listeriosis/prevención & control , Cuerpo Médico , Adulto , Anciano , Beijing , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto JovenRESUMEN
This paper investigates the anti-unwinding finite-time attitude synchronization control problem for Spacecraft formation flying with external disturbances. Two finite-time controllers are designed based on rotation matrix and terminal sliding mode method. By designing a novel sliding mode surface, the first controller is developed when the upper bound of the external disturbances can be exactly known. However, this value is not always available in reality. In addition, the direct use of the upper bound of the external disturbances can result in the chattering problem. For the purpose of overcoming the disadvantage of the first controller, a modified control law is proposed, in which the adaptive law is applied to estimate the unknown value online. Theoretical analysis and numerical simulations are presented to demonstrate the validity of the proposed controllers.