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Objective: For elective cesarean section patients with gestational diabetes mellitus (GDM), there is a lack of evidence-based research on the use of enhanced recovery after surgery (ERAS). This study aims to compare the ERAS after-surgery protocol and traditional perioperative management. Research design and methods: In this retrospective cohort study, singleton pregnancies with good glucose control GDM, delivered by elective cesarean sections under intravertebral anesthesia at least 37 weeks from January 1 to December 31, 2022, were collected at the Third Affiliated Hospital of Sun Yat-sen University. We divided all enrolled pregnant women and newborns into an ERAS group and a control group (the traditional perioperative management group) based on their adherence to the ERAS protocol. The primary outcome was the preoperative blood glucose level, with an increase of more than 1 mmol/L indicating clinical significance when compared to the control group. The secondary outcome was centered around an adverse composite outcome that affected both mothers and newborns. Results: We collected a total of 161 cases, with 82 in the ERAS group and 79 in the control group. Although the mean preoperative blood glucose level in the ERAS group was significantly higher than in the control group (5.01 ± 1.06 mmol/L vs. 4.45 ± 0.90 mmol/L, p<0.001), the primary outcome revealed that the mean glycemic difference between the groups was 0.47 mmol/L (95% CI 0.15-0.80 mmol/L), which was below the clinically significant difference of 1 mmol/L. For the secondary outcomes, the ERAS group had an 86% lower risk of a composite adverse outcome compared to the control group. This included a 73% lower risk of perioperative maternal hypoglycemia and a 92% lower rate of neonatal hypoglycemia, all adjusted by age, hypertensive disorder of pregnancy, BMI, gestational weeks, primigravidae, primary pregnancy, GDM, surgery duration, and fasting glucose. Conclusion: Implementing a low-dose carbohydrate ERAS in pregnant women with GDM prior to elective cesarean section, compared to traditional perioperative management, does not lead to clinically significant maternal glucose increases and thus glucose-related maternal or neonatal perioperative complications.
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Glucemia , Cesárea , Diabetes Gestacional , Procedimientos Quirúrgicos Electivos , Recuperación Mejorada Después de la Cirugía , Humanos , Femenino , Embarazo , Cesárea/efectos adversos , Estudios Retrospectivos , Adulto , Recién Nacido , Procedimientos Quirúrgicos Electivos/efectos adversos , Glucemia/metabolismo , Glucemia/análisis , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/epidemiologíaRESUMEN
Chimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT04835519) with safety and efficacy as primary and secondary endpoints, respectively. Of the four patients treated, one has grade 4 (dose-limiting toxicity) and three have grade 1-2 cytokine release syndrome. Two patients have no detectable bone marrow blasts and one patient has blast reduction after treatment. Thus, overexpressing C-JUN endows CAR-T efficacy in AML.
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Inmunoterapia Adoptiva , Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-jun , Receptores Quiméricos de Antígenos , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Inmunoterapia Adoptiva/métodos , Persona de Mediana Edad , Masculino , Femenino , Proteínas Proto-Oncogénicas c-jun/metabolismo , Animales , Linfocitos T/inmunología , Linfocitos T/metabolismo , Anciano , Adulto , Línea Celular Tumoral , RatonesRESUMEN
BACKGROUND: Although pregnancy complicated by liver cirrhosis is rare, women with cirrhosis experience increased adverse pregnancy outcomes. This study aimed to evaluate pregnancy outcomes in women with liver cirrhosis and develop a predictive model using maternal factors for preterm birth in such pregnancies. METHODS: A retrospective analysis was conducted on pregnancy outcomes of a cirrhosis group (n = 43) and a non-cirrhosis group (n = 172) in a university hospital between 2010 and 2022. Logistic regression evaluated pregnancy outcomes, and a forward stepwise logistic regression model was designed to predict preterm birth in pregnant women with cirrhosis. The model's predictive performance was evaluated using the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC). RESULTS: The incidence of cirrhosis during pregnancy was 0.06% (50/81,554). Pregnant women with cirrhosis faced increased risks of cesarean section, preterm birth, intrahepatic cholestasis of pregnancy, thrombocytopenia, and postpartum hemorrhage. In pregnant women with cirrhosis, preterm birth risk significantly increased at an incidence rate of 46.51% (20/43). According to the prediction model, the key predictors of preterm birth in pregnant women with cirrhosis were intrahepatic cholestasis of pregnancy and total bilirubin. The model demonstrated accurate prediction, with an AUC of 0.847, yielding a model accuracy of 81.4%. CONCLUSIONS: Pregnant women with cirrhosis face a heightened risk of adverse obstetric outcomes, particularly an increased incidence of preterm birth. The preliminary evidence shows that the regression model established in our study can use the identified key predictors to predict preterm birth in pregnant women with cirrhosis, with high accuracy.
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Colestasis Intrahepática , Complicaciones del Embarazo , Nacimiento Prematuro , Embarazo , Recién Nacido , Femenino , Humanos , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/etiología , Estudios Retrospectivos , Cesárea/efectos adversos , Resultado del Embarazo/epidemiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiologíaRESUMEN
BACKGROUND: The association between excessive serum total bile acid (TBA) and adverse perinatal outcomes in individuals with non-intrahepatic cholestasis of pregnancy (non-ICP) hypercholanemia has not been determined, and it is unclear if this link is similar to that observed in patients with ICP. OBJECTIVE: To examine the adverse perinatal outcomes in two specific subcategories: those with ICP and those with non-ICP, including individuals with liver disease and asymptomatic hypercholanemia of pregnancy (AHP), at different levels of TBA. Investigate the correlation between TBA levels and adverse perinatal outcomes of ICP, liver disease, and AHP. METHODS: From 2013 to 2021, pregnant women with excessive TBA levels were taken from the electronic medical record database of our hospital and categorized into three groups: ICP (n = 160), liver disease (n = 164), and AHP (n = 650). This was done as part of a retrospective cohort research project. Multivariable regression and subgroup analyses were performed to examine the association between TBA levels and adverse perinatal outcomes in each group. RESULTS: The study found no significant differences in adverse perinatal outcomes between the ICP and liver disease groups at different TBA levels. However, at moderate TBA levels, both groups had a higher risk of adverse perinatal outcomes than the AHP group (p < 0.017). Among liver disease cases with TBA ≥ 100µmol/L, three cases of perinatal deaths (6.67%) associated with moderate-to-severe acute hepatitis occurred between 27 and 33 weeks of gestation. A 59% higher chance of perinatal death was found for every 10 µmol/L rise in TBA, even after significant variables and confounders were taken into account (adjusted odds ratio (aOR) = 1.59; 95% confidence interval (CI): 1.06-2.40; p = 0.03). CONCLUSIONS: If a pregnant woman has moderate-to-severe liver disease and TBA ≥ 100µmol/L, preterm termination of pregnancy (before 34 weeks) may be considered.
If someone doesn't have ICP but does have moderate-to-severe hepatitis and TBA levels of 100 µmol/L or more, they should be treated more aggressively, and their pregnancies should be terminated earlier (before 34 weeks) than what is usually done for ICP.
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Colestasis Intrahepática , Muerte Perinatal , Complicaciones del Embarazo , Recién Nacido , Embarazo , Femenino , Humanos , Mujeres Embarazadas , Ácidos y Sales Biliares , Estudios Retrospectivos , Complicaciones del Embarazo/epidemiología , Colestasis Intrahepática/complicaciones , Colestasis Intrahepática/epidemiologíaRESUMEN
We present a panel of central nervous system (CNS) complications associated with coronavirus disease 2019 (COVID-19) and their clinical characteristics. We aim to investigate associations between neurological autoantibodies and COVID-19 patients with predominant CNS complications. In this retrospective multi-center study, we analyze neurologic complications associated with COVID-19 patients from Dec. 2022 to Feb. 2023 at four tertiary hospitals in China. CSF and/or serum in the enrolled patients were tested for autoantibodies using tissue-based assays (TBAs) and cell-based assays (CBAs). A total of 34 consecutive patients (median age was 40.5 years [range 15-83], 50% were female) were enrolled. CNS syndromes included encephalitis (n=15), encephalopathies (n=6), meningoencephalitis (n=3), ADEM (n=2), depression (n = 2), Alzheimer's disease (n=2), Parkinson disease (n=1), and central nervous system vasculitis (n=1). Twenty-eight specimens (of 44 tested; 11/27 [40.7%] CSF, 13/17 [76.5%] serums) were confirmed by TBAs to be autoantibodies positive. However, only a few autoantibodies (1 with MOG and 1 with NMDAR) were detected by CBAs assays. Twenty-four patients received immunotherapy. After a mean time of 7.26 months of follow-up, 75.8% (25/33) of patients had good outcome (mRS score ≤2). Although no significant difference was observed between the two groups, the proportion of positive CSF autoantibodies in the poor outcomes group was higher than that in the good outcomes group (57.1% vs 31.5%, P = 0.369). Autoantibodies were frequently observed in COVID-19-associated CNS complications. The identification of these autoantibody-positive COVID-19 cases is important as they respond favorably to immunotherapy.
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BACKGROUND: Chimeric antigen receptor (CAR) T cells have shown significant activity in B-lineage malignancies. However, their efficacy in myeloid leukemia has not been successful due to unclear molecular mechanisms. METHODS: We conducted in vitro and in vivo experiments to investigate whether myeloid leukemia cells directly induce CAR down-regulation. Furthermore, we designed a CD33 CARKR in which all lysines in the cytoplasmic domain of CAR were mutated to arginine and verified through in vitro experiments that it could reduce the down-regulation of surface CARs and enhance the killing ability. Transcriptome sequencing was performed on various AML and ALL cell lines and primary samples, and the galectin-1-specific inhibitory peptide (anginex) successfully rescued the killing defect and T-cell activation in in vitro assays. RESULTS: CAR down-regulation induced by myeloid leukemia cells under conditions of low effector-to-tumor ratio, which in turn impairs the cytotoxicity of CAR T cells. In contrast, lysosomal degradation or actin polymerization inhibitors can effectively alleviate CAR down-regulation and restore CAR T cell-mediated anti-tumor functions. In addition, this study identified galectin-1 as a critical factor used by myeloid leukemia cells to induce CAR down-regulation, resulting in impaired T-cell activation. CONCLUSION: The discovery of the role of galectin-1 in cell surface CAR down-regulation provides important insights for developing strategies to restore anti-tumor functions.
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Galectina 1 , Leucemia Mieloide , Humanos , Galectina 1/genética , Galectinas , Línea Celular , Linfocitos TRESUMEN
Background: With the application of the new labor management model in China, the normal length of the second stage of labor is significantly longer than that of the old model. It is unclear whether a longer stage of labor worsens umbilical artery blood gas analysis (UABGA) in newborns. The aim of this study was to investigate the correlation between the second stage of labor length, UABGA results, and neonatal intensive care unit (NICU) transfer rates under the new labor management model. Methods: This is a retrospective cohort study including full-term, cephalic, vaginal deliveries. Exclusion criteria were preterm deliveries or deliveries by cesarean section during labor. The pH, base excess (BE), and lactate results of UABGA in newborns clearly reflect neonatal metabolic acidosis and intrauterine oxygenation of the fetus. The correlation between the length of the second stage of labor and the results of UABGA and NICU transfer rate was analyzed using linear or logistic regression and curve fitting. Results: Of the total 2,140 cases, after adjusting for maternal age, gestational week, high-risk pregnancy factors, body mass index (BMI) before pregnancy, induced delivery, oxytocin during labor stage, labor analgesia, abnormal fetal position in labor stage, vaginal device delivery, length of first labor stage, and weight of the newborn, every 1 hour increase in the length of the second stage of labor decreased the UABGA pH by 0.01 [95% confidence interval (CI): -0.02 to -0.01, P<0.001], decreased the UABGA BE by 0.66 mmol/L (95% CI: -0.84 to -0.48, P<0.001), increased the UABGA lactate level by 0.39 mmol/L (95% CI: 0.29 to 0.50, P<0.001), and increased the NICU transfer rate by 26% (95% CI: 1.07 to 1.48, P=0.005). In the stratified analysis, when the length of the second stage of labor increased from 3 to 4 or more hours, there was no significant change in UABGA pH, BE, lactate, or NICU transfer rates. Conclusions: Under the new criteria for the management of labor stage, the length of the second stage increasing from 3 to 4 or more hours did not negatively impact newborns. Therefore, clinician should not be too worried about the longer second stage of labor worsening adverse outcomes in newborns.
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Acetazolamide (AZA) is a carbonic anhydrase inhibitor (CAI) with neuroprotective effects. Hyperhomocysteinemia is associated with blood-brain-barrier (BBB) disruption in brain disorders. A previous study indicated that AZA might have a new role in brain disorders. However, its function in hyperhomocysteinemia-related BBB disruption has not been reported. Here, we aim to clarify the role of AZA in homocysteine (Hcy)-mediated BBB dysfunction using both in vivo and in vitro assays. We found that AZA improved memory and cognitive function, and reduced brain edema in Hcy-stimulated hyperhomocysteinemia model rats. This protective effect of AZA on hyperhomocysteinemia rats was accompanied by improved BBB permeability and increased expression levels of the tight junction proteins, occludin, and claudin-5. The in vitro assay results show that AZA prevented Hcy-induced cell injury and attenuated the increased permeability in Hcy-treated bEnd.3 brain endothelial cells. The Hcy-induced decrease in occludin and claudin-5, and increase in MMP-2 and MMP-9 expression levels were attenuated by AZA in bEnd.3 cells. Moreover, the Hcy-induced downregulation of the Wnt/ß-catenin signaling pathway in bEnd.3 cells was abolished by AZA. Inhibition of Wnt/ß-catenin by ICG-001 reversed the protective effects of AZA in Hcy-treated bEnd.3 cells. We also prove that this process is mediated by WTAP. These findings suggest that acetazolamide mitigated the Hcy-induced compromised brain vascular endothelial integrity by regulating the activation of the Wnt/ß-catenin signaling pathway.
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Encefalopatías , Hiperhomocisteinemia , Fármacos Neuroprotectores , Acetazolamida/metabolismo , Acetazolamida/farmacología , Animales , Barrera Hematoencefálica , Encefalopatías/metabolismo , Inhibidores de Anhidrasa Carbónica/metabolismo , Inhibidores de Anhidrasa Carbónica/farmacología , Claudina-5/metabolismo , Claudina-5/farmacología , Células Endoteliales/metabolismo , Homocisteína/metabolismo , Hiperhomocisteinemia/inducido químicamente , Hiperhomocisteinemia/tratamiento farmacológico , Hiperhomocisteinemia/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Ocludina/metabolismo , Ocludina/farmacología , Ratas , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismo , beta Catenina/farmacologíaRESUMEN
@#Abstract: Objective To investigate the impacts of vaccination with inactivated SARS-COV-2 vaccine on the clinical manifestations and serological responses of COVID-19 patients infected by Delta and Alpha variants. Methods Clinical and experimental data of 341 confirmed SARS-COV-2 patients were collected from The Eighth Affiliated Hospital of Guangzhou Medical University May 1- September 30, 2021. The subjects were divided into Delta and Alpha variant group according to virus variants, and were divided into vaccinated group and unvaccinated group according to whether they had received inactivated COVID-19 vaccine or not. The clinical manifestations and serological responses of patients with Delta and Alpha variant, and vaccinated and unvaccinated patients with Delta and Alpha variants were compared. Results Totally 253 patients were infected with Delta variant (103 vaccinated and 150 unvaccinated patients), and 88 patients were infected with Alpha variant (21 vaccinated and 67 unvaccinated patients). The proportion of asymptomatic infection in Delta variants group was significantly lower than that in Alpha variants group (P<0.01). Delta variant group of vaccination rates and vaccine breakthrough infection rate was 40.7% (103/253) and 22.9% (58/253), were higher than Alpha variant group was 23.9% (21/88) and 8.0% (7/88), difference was statistically significant (χ2= 8.009, 9.484, P<0.01). The proportion of cough and fever in Delta variant group was higher than that in Alpha variant group (both P<0.01), the peak viral load was higher than that of Alpha variant group (P<0.01), the virus duration was longer than that of Alpha variant group (P<0.01), the levels of SAA, CRP and IFN were higher than those of Alpha variant group (all P<0.05), CD4+T cell count was lower than that of Alpha variant group (P<0.05), IgG and IgM levels were lower than those of Alpha variant group (both P<0.01). The proportion of moderate COVID-19 in the vaccinated group was lower than that in the unvaccinated group (P<0.01). In these two variants, the peak viral load of vaccinated group was lower than that of the unvaccinated group (both P<0.01), the duration of virus was shorter than that of unvaccinated group (both P<0.01). The levels of SAA, CRP and IL-6 in the vaccinated group were lower than those in the unvaccinated group (all P<0.05), CD4+T cell level was higher than that of unvaccinated group (both P<0.05), IgG and IgM level were higher than those in unvaccinated group (both P<0.05). Conclusions Delta variant can lead to higher viral load and more severe disease course, which is associated with vaccine breakthrough infection. Inactivated vaccines for COVID-19 can reduce severe illness and death by reducing viral load, disease duration and inflammatory response through humoral and cellular immune mechanisms.
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[This corrects the article DOI: 10.3389/fonc.2021.640166.].
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CD19 chimeric antigen receptor (CAR)-T cells have been used to treat patients with refractory chronic lymphocytic leukemia (CLL). However, approximately 50% of patients do not respond to this therapy. To improve the clinical outcome of these patients, it is necessary to develop strategies with other optimal targets to enable secondary or combinational CAR-T cell therapy. By screening a panel of surface antigens, we found that CD32b (FcγRIIb) was homogeneously expressed at high site density on tumor cells from CLL patients. We then developed a second-generation CAR construct targeting CD32b, and T cells transduced with the CD32 CAR efficiently eliminated the CD32b+ Raji leukemic cell line in vitro and in a mouse xenograft model. Furthermore, CD32b CAR-T cells showed cytotoxicity against primary human CLL cells that were cultured in vitro or transplanted into immunodeficient mice. The efficacy of CD32b CAR T cells correlated with the CD32b density on CLL cells. CD32b is not significantly expressed by non-B hematopoietic cells. Our study thus identifies CD32b as a potential target of CAR-T cell therapy for CLL, although further modification of the CAR construct with a safety mechanism may be required to minimize off-target toxicity.
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Inmunoterapia Adoptiva , Leucemia Linfocítica Crónica de Células B/terapia , Receptores de IgG/genética , Animales , Línea Celular Tumoral , Expresión Génica , Humanos , Inmunoterapia Adoptiva/métodos , Leucemia Linfocítica Crónica de Células B/genética , RatonesRESUMEN
Parkinson's disease (PD) is a common neurodegenerative disease with global health and economic impact. 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and oxidative stress are reported to participate in the pathological mechanism of PD. Ramelteon is a novel oral hypnotic agent that has recently been reported to display neuronal protective effects. However, it is unknown whether Ramelteon possesses a beneficial effect in PD. In this study, we aimed to examine the potential function of Ramelteon in MPP+-challenged neurons. We found that Ramelteon rescued the cell viability reduced by MPP+-stimulation. Further, oxidative stress in MPP+-challenged SH-SY5Y cells was mitigated by Ramelteon as verified by the upregulated levels of mitochondrial reactive oxygen species (ROS) and protein carboxyl, and the upregulation of NADPH oxidase 4 (NOX-4). Furthermore, the declined mitochondrial membrane potential (ΔΨm) caused by MPP+ was reversed by Ramelteon. Importantly, Ramelteon attenuated MPP+-induced apoptosis, accompanied by a decreased ratio of Bax/Bcl-2, inhibition of cytochrome C release, and downregulation of cleaved caspase-3. For the first time, we conclude that Ramelteon might ameliorate MPP+-induced neurotoxicity in neuronal cells in a mitochondrial-dependent pathway.
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1-Metil-4-fenilpiridinio/toxicidad , Indenos/farmacología , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Mitocondrias/metabolismo , Neuronas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Enfermedad de ParkinsonRESUMEN
Chimeric antigen receptor (CAR)-T cell therapy emerges as a new treatment for refractory or relapsed (r/r) B-cell non-Hodgkin lymphoma (B-NHL); however, the overall response rate (ORR) of which in the B-NHL patients is much lower compared to the patients with r/r B acute lymphoblastic leukemia (B-ALL). We previously confirmed that sequential infusions of CD20 and CD22 CAR-T cells significantly improved the prognosis of the B-NHL patients, while some advanced patients still progressed to death during these CAR-T cell treatments. In this study, we showed that timely sequential administration of the second CAR-T cells could enhance expansion of prior CAR-T cells with stronger tumor-killing capacity in vitro and in vivo. We further conducted compassionate treatments on two advanced B-NHL patients with short-interval sequential infusions of CD19/22/20 CAR-T cells. Disease progression was observed in both patients after primary CAR-T cell infusion but robust re-expansion of prior CAR-T cells and anti-tumor effects was induced by infusion of a secondary CAR-T cells. These results indicate sequential infusions of CAR-T cells with a short interval may improve therapeutic efficacy in the B-NHL patients by promoting expansion of prior CAR-T cells.
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Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores Quiméricos de Antígenos/uso terapéutico , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Adolescente , Animales , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Niño , Preescolar , Humanos , Inmunoterapia Adoptiva/efectos adversos , Células Jurkat , Células K562 , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: Cerebral ischemia-reperfusion injury is commonly induced during the treatment of ischemic stroke and is reported to be related to the blood-brain barrier destruction and brain vascular endothelial cell dysfunction. Anagliptin is a novel antidiabetic agent recently reported to protect neurons from oxidative stress. In the present study, we aim to investigate the protective property of anagliptin against oxygen-glucose deprivation and reperfusion (OGD/R)-induced injury on endothelial cells and clarify the potential underlying mechanism. METHODS: OGD/R modeling was established on bEnd.3 brain endothelial cells. Cell viability was detected using the MTT assay, and the mitochondrial reactive oxygen species (ROS) level was measured using the mitoses red staining assay. The endothelial monolayer permeability was determined using an FITC-dextran permeation assay. The expression levels of NOX-4 and ZO-1 were evaluated using qRT-PCR and Western blot assays. The expressions of MLC-2, p-MLC-2, and myosin light chain kinase (MLCK) were determined using Western blot. RESULTS: First, the decreased cell viability, upregulated NOX-4, and elevated mitochondrial ROS level in the endothelial cells induced by OGD/R were reversed by treatment with anagliptin. Second, the enlarged endothelial permeability and the decreased expression level of ZO-1 in the endothelial cells induced by OGD/R were alleviated by anagliptin. Third, the downregulation of ZO-1 and enlarged brain endothelial monolayer permeability induced by OGD/R were ameliorated by an MLCK inhibitor, ML-7. Lastly, the elevated expressions of MLCK and p-MLC-2 induced by OGD/R were suppressed by anagliptin. CONCLUSION: Anagliptin protected against hypoxia/reperfusion-induced brain vascular endothelial permeability by increasing the expression ZO-1, mediated by inhibition of the MLCK/MLC-2 signaling pathway.
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Antígenos CD19/metabolismo , Inmunoterapia Adoptiva , Leucemia Prolinfocítica Tipo Células B/inmunología , Leucemia Prolinfocítica Tipo Células B/terapia , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/terapia , Receptores Quiméricos de Antígenos/inmunología , Adolescente , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Inducción de Remisión , Resultado del TratamientoRESUMEN
This study examined the association between physical accessibility to organic and local food, and sociodemographic factors in New Orleans, Louisiana. Spatial regression models were used to investigate how sociodemographic variables such as income, race/ethnicity, education, and age correlate with driving, bicycling, and walking distances to stores that sell organic or local food. The distances were calculated from GIS and real-time speed information from Google Maps. The results indicated that physical access to such stores is positively associated with population density, median housing value, education, non-Hispanic Blacks, and Hispanics, and is negatively associated with median housing age. We found no disparities in access to organic and local food on the basis of income and race.
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This study examines the perceived neighbourhood characteristics and environmental barriers in association with two different types of walking - recreational and destination - in the context of a rural town in Mississippi. A cross-sectional survey was used to assess residents' walking behaviours, perceived neighbourhood characteristics, and perceived environmental barriers to walking in three types of neighbourhoods: traditional, early conventional suburban and late conventional suburban. Descriptive statistics, one-way analysis of variance (ANOVA) and regression analyses identified environmental factors correlated with walking. A total of 362 surveys were completed and returned by random adult members of the households contacted, for a 38.5% response rate. Perceived aesthetics are significantly associated with more frequent recreational and destination walking in this rural town. Higher perceived accessibility are associated with more frequent destination walking, and greater perceived social environment barriers to walking are associated with sedentary behaviour in the rural population studied. Of all factors related to a neighbourhood's built environment, the most important factor in promoting walking in rural towns is aesthetics. The relationships among accessibility, social environment and walking underscore the importance of community planning in incorporating mixed land uses, providing a connected pedestrian infrastructure and facilitating targeted social interventions to encourage more walking.
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BACKGROUND: Integrator complex subunit 6 (INTS6) was found to play a tumour suppressing role in certain types of solid tumours. In this study, we wanted to determine the expression level of INTS6 in hepatocellular carcinoma (HCC) and evaluate its clinical characteristics and mechanisms in HCC patients (Lui and Lu, European Journal of Cancer, 51:S94, 2015). METHODS: First, we used a microarray analysis to explore the mRNA expression levels in HCC and paired normal liver tissues; second, we used qRT-PCR to measure the INTS6 mRNA levels in a cohort of 50 HCC tissues and adjacent normal liver tissues; third, we used Western blot analyses to detect the INTS6 protein levels in 20 paired HCC and normal liver tissues; fourth, we used immunohistochemistry to determine the INTS6 expression levels in 70 archived paraffin-embedded HCC samples. Finally, we investigated the suppressive function of INTS6 in the Wnt pathway. RESULTS: Herein, according to the microarray data analysis, the expression levels of INTS6 were dramatically down-regulated in HCC tissues vs. those in normal liver tissues (p<0.05). qRT-PCR and Western blot analyses showed that the INTS6 mRNA and protein expression was significantly down-regulated in tumour tissues compared to the adjacent normal liver tissues (p<0.05). Immunohistochemical assays revealed that decreased INTS6 expression was present in 62.9% (44/70) of HCC patients. Correlation analyses showed that INTS6 expression was significantly correlated with serum alpha-fetoprotein levels (AFP, p =0.004), pathology grade (p =0.005), and tumour recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had shorter overall and disease-free survival rates than patients with high INTS6 expression levels (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor of overall survival and disease-free survival rates. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/ß-catenin signalling pathway. CONCLUSION: The results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients.
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Proteínas Adaptadoras Transductoras de Señales/genética , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas Represoras/genética , Proteínas Ribosómicas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Carcinoma Hepatocelular/patología , Proliferación Celular/genética , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas de Unión al ARN , Vía de Señalización WntRESUMEN
Intestinal obstruction due to congenital intestinal malrotation is usually diagnosed in neonates but may, in rare cases, occur during pregnancy. The absence of specific symptoms in combination with its low incidence makes timely detection of intestinal malrotation-related obstruction difficult in expectant mothers. We present a rare case of a 23-year-old woman with a twin pregnancy following in vitro fertilization-embryo transfer (IVF-ET) who presented with symptoms of intestinal obstruction at 22+4 weeks of gestation. This diagnosis was not confirmed by imaging and the patient was managed conservatively. Following caesarean section, she gave birth to two healthy full-term infants. During the operation, malposition of the bowel and the typical Ladd's band confirmed intestinal malrotation. This is the first report of a congential malrotation complicating a multiple pregnancy, and highlights that malrotation without volvulus can be managed conservatively.