ABSTRACT
1-Nitropyrene (1-NP) is a neurodevelopmental toxicant. This study was to evaluate the impact of exposure to 1-NP after weaning on anxiety-like behavior. Five-week-old mice were administered with 1-NP (0.1 or 1 mg/kg) daily for 4 weeks. Anxiety-like behaviour was measured using elevated-plus maze (EPM) and open field test (OFT). In EPM test, time spending in open arm and times entering open arm were reduced in 1-NP-treated mice. In OFT test, time spent in the center region and times entering the center region were diminished in 1-NP-treated mice. Prefrontal dendritic length and number of dendrite branches were decreased in 1-NP-treated mice. Prefrontal PSD95, an excitatory postsynaptic membrane protein, and gephyrin, an inhibitory postsynaptic membrane protein, were downregulated in 1-NP-treated mice. Further analysis showed that peripheral steroid hormones, including serum testosterone (T) and estradiol (E2), testicular T, and ovarian E2, were decreased in 1-NP-treated mice. Interestingly, T and E2 were diminished in 1-NP-treated prefrontal cortex. Prefrontal T and E2 synthases were diminished in 1-NP-treated mice. Mechanistically, GCN2-eIF2α, a critical pathway that regulates ribosomal protein translation, was activated in 1-NP-treated prefrontal cortex. These results indicate that exposure to 1-NP after weaning induces anxiety-like behaviour partially by inhibiting steroid hormone synthesis in prefrontal cortex.
Subject(s)
Anxiety , Prefrontal Cortex , Pyrenes , Weaning , Animals , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Anxiety/chemically induced , Male , Pyrenes/toxicity , Female , Mice , Behavior, Animal/drug effects , Testosterone/blood , EstradiolABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure to 1-nitropyrene (1-NP), a key component of motor vehicle exhaust, on autism-like behaviors in a mouse model. Three-chamber test finds that prenatal 1-NP exposure causes autism-like behaviors during the weaning period. Patch clamp shows that inhibitory synaptic transmission is reduced in medial prefrontal cortex of 1-NP-exposed weaning pups. Immunofluorescence finds that prenatal 1-NP exposure reduces the number of prefrontal glutamate decarboxylase 67 (GAD67) positive interneurons in fetuses and weaning pups. Moreover, prenatal 1-NP exposure retards tangential migration of GAD67-positive interneurons and downregulates interneuron migration-related genes, such as Nrg1, Erbb4, and Sema3F, in fetal forebrain. Mechanistically, prenatal 1-NP exposure reduces hydroxymethylation of interneuron migration-related genes through inhibiting ten-eleven translocation (TET) activity in fetal forebrain. Supplement with alpha-ketoglutarate (α-KG), a cofactor of TET enzyme, reverses 1-NP-induced hypohydroxymethylation at specific sites of interneuron migration-related genes. Moreover, α-KG supplement alleviates 1-NP-induced migration retardation of interneurons in fetal forebrain. Finally, maternal α-KG supplement improves 1-NP-induced autism-like behaviors in weaning offspring. In conclusion, prenatal 1-NP exposure causes autism-like behavior partially by altering DNA hydroxymethylation of interneuron migration-related genes in developing brain.
Subject(s)
Brain , Disease Models, Animal , Prenatal Exposure Delayed Effects , Animals , Mice , Prenatal Exposure Delayed Effects/metabolism , Prenatal Exposure Delayed Effects/genetics , Female , Pregnancy , Brain/drug effects , Brain/metabolism , Autistic Disorder/genetics , Autistic Disorder/chemically induced , Autistic Disorder/metabolism , DNA Methylation/drug effects , DNA Methylation/genetics , Behavior, Animal/drug effects , Male , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/chemically induced , Autism Spectrum Disorder/metabolism , Pyrenes/toxicity , Mice, Inbred C57BLABSTRACT
Background: Pulmonary arterial hypertension (PAH) leads to myocardial remodeling, manifesting as mechanical dyssynchrony (M-dys) and electrical dyssynchrony (E-dys), in both right (RV) and left ventricles (LV). However, the impacts of layer-specific intraventricular M-dys on biventricular functions and its association with E-dys in PAH remain unclear. Methods: Seventy-nine newly diagnosed patients with PAH undergoing cardiac magnetic resonance scanning were consecutively recruited between January 2011 and December 2017. The biventricular volumetric and layer-specific intraventricular M-dys were analyzed. The QRS duration z-scores were calculated after adjusting for age and sex. Results: 77.22 % of patients were female (mean age 30.30 ± 9.79 years; median follow-up 5.53 years). Further, 29 (36.71 %) patients succumbed to all-cause mortality by the end of the study. At the baseline, LV layer-specific intraventricular M-dys had apparent transmural gradients compared with RV in the radial and circumferential directions. However, deceased patients lost the transmural gradients. The LV longitudinal strain rate time to late diastolic peak in the myocardial region (LVmyoLSRTTLDPintra) predicted long-term survival. The Kaplan-Meier curve revealed that patients with PAH with LVmyoLSRTTLDPintra <20.01 milliseconds had a worse prognosis. Larger right ventricle (RV) intraventricular M-dys resulted in worse RV ejection fraction. However, larger LV intraventricular M-dys in the late diastolic phase indicated remarkable exercise capacity and higher LV stroke volume index. E-dys and intraventricular M-dys had no direct correlations. Conclusions: The layer-specific intraventricular M-dys had varying impacts on biventricular functions in PAH. PAH patients with LVmyoLSRTTLDPintra <20.01 milliseconds had a worse prognosis. LV intraventricular M-dys in the late diastolic phase needs more attention to precisely evaluate LV function.
ABSTRACT
PURPOSE: To investigate the imaging characteristics and prognostic factors for the long-term survival of Behcet's disease (BD) with arterial involvement. METHODS: In this retrospective study, BD patients with arterial involvement were identified from January 2003 to January 2020. Arterial lesions were detected by ultrasonography, traditional arteriography, and/or computed tomography angiography (CTA). Cox proportional hazards regression analyses were performed to identify the prognostic factors. RESULTS: Totally, 84 BD patients with arterial involvement were identified (73.8 % males). The mean age at BD diagnosis was 39.1 ± 13.1 years. Arterial involvement was the initial manifestation in 33.3 % of the patients, and the median time from BD diagnosis to arterial involvement was 6 (IQR 1-15.5) years for the rest of patients. Systemic artery involvement and pulmonary artery involvement (PAI) were found in 64 and 27 patients, respectively. Approximately 94.0 % (79/84) of the patients had more than one artery involved concurrently or successively during the course of BD. Aneurysm/dilation was the most prevalent lesion in the aorta (76.0 %), while stenosis/occlusion was the main lesion of the coronary artery (90.9 %) and other aortic branches (74.5 %). Pulmonary hypertension was found in 70.4 % (19/27) of patients with PAI. The 5- and 10-year survival rates of BD patients with arterial involvement were 87.4 % and 84.1 %, respectively. Cardiac involvement (HR: 4.34) and pulmonary artery aneurysm/dilation (HR: 4.89) were independently associated with mortality. CONCLUSIONS: Arterial lesions associated with BD usually involve multiple arteries and manifest differently in different types of arteries. Cardiac involvement and pulmonary artery aneurysm/dilation are independent prognostic factors of BD patients with arterial involvement.
Subject(s)
Aneurysm , Behcet Syndrome , Male , Humans , Adult , Middle Aged , Female , Behcet Syndrome/diagnostic imaging , Follow-Up Studies , Retrospective Studies , Prognosis , Pulmonary Artery/diagnostic imagingABSTRACT
Right heart thrombus (RHT) is a rare but life-threatening condition in acute pulmonary embolism (APE) without clear management guidelines. This study aimed to address the clinical characteristics and outcomes of RHT-APE in Chinese patients. In this study, 17 RHT-APE and 329 non-RHT-APE patients, who were diagnosed between September 2015 and August 2019, were retrospectively recruited with the median follow-up was 360 days. The overall prevalence of RHT was 4.91% in APE. Its prevalence increased along the increase of APE risk stratifications. Comparisons showed that with higher proportion of male gender and younger age, RHT-APE patients also had worse hemodynamic instability and heart function, and higher risk stratification levels than non-RHT-APE patients. After adjusting by age and gender, multivariate logistic regression analysis found high/intermediate-high risk stratification, decreased right ventricular (RV) motion, NT-proBNP >600 pg/mL, and RV dysfunction were risk factors for RHT. Kaplan-Meier analysis showed non-RHT had better prognosis than RHT patients (30-day survival: log-rank: p < 0.001; 90-day survival: log-rank: p = 0.002). The multivariate logistic regression analysis showed RHT was an independent risk factor for 30-day mortality in APE. The subgroup analysis showed RHT would result in worse outcomes in patients who already had higher APE early mortality risk. RHT would increase the risk of 30- and 90-day mortality in APE. More attention should be paid to young male APE patients with decreased RV motion, NT-proBNP >600 pg/mL, RV dysfunction, or high level of risk stratification, to exclude the coexistence of RHT.
ABSTRACT
1-Nitropyrene (1-NP), a typical nitro-polycyclic aromatic hydrocarbon, is a developmental toxicant. This study was to evaluate gestational 1-NP-induced anxiety-like behavior in male adult offspring. Pregnant mice were orally administered to 1-NP daily throughout pregnancy. Anxiety-like behaviors, as determined by Elevated Plus-Maze (EPM) and Open-Field Test (OFT), were showed in male adult offspring whose mothers were exposed to 1-NP. Gestational 1-NP exposure reduced dendritic arborization, dendritic length and dendritic spine density in ventral hippocampus of male adult offspring. Additional experiments showed that gephyrin, an inhibitory synaptic marker, was reduced in fetal forebrain and hippocampus in male adult offspring. Nrg1 and Erbb4, two gephyrin-related genes, were reduced in 1-NP-exposed fetuses. Accordingly, 5hmC contents in two CpG sites (32008909 and 32009239) of Nrg1 gene and three CpG sites (69107743, 69107866 and 69107899) of Erbb4 gene were decreased in 1-NP-exposed fetuses. Mechanistically, ten-eleven translocation (TET) activity and alpha-ketoglutarate (α-KG) content were decreased in 1-NP-exposed fetal forebrain. Supplementation with α-KG alleviated 1-NP-induced downregulation of gephyrin-related genes, prevented hippocampal synaptic damage, and improved anxiety-like behavior in male adult offspring. These results indicate that early-life 1-NP exposure causes anxiety-like behavior in male adulthood partially by altering hippocampal epigenetic reprogramming of synaptic plasticity.
Subject(s)
Prenatal Exposure Delayed Effects , Pregnancy , Humans , Female , Mice , Male , Animals , Prenatal Exposure Delayed Effects/chemically induced , Hippocampus , Anxiety/chemically induced , Neuronal Plasticity , Epigenesis, GeneticABSTRACT
AIMS: This study aimed to identify mechanisms of drug resistance to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAFV600E metastatic colorectal cancer (mCRC). METHODS: Forty-one patients with BRAFV600E mCRC from July 2018 and June 2020 were evaluated, with tissue and/or plasma samples collected. We profiled tissue and plasma samples using whole-exome sequencing and targeted sequencing of 425 cancer-relevant genes. Clinical cohort analysis from published studies was performed to consolidate our findings. RESULTS: BRAF mutant in baseline plasma and its dynamics are significantly associated with VIC-related response, and concurrent RNF43 mutation significantly sensitises tumour to VIC treatment. VIC resistance frequently involves genes in PI3K, MAPK pathway, and several novel resistance mechanisms such as TGFBR2 and SMAD4 mutations, and copy-number gains in PTK2, MYC, and GATA6 have been identified. We also firstly describe acquired altered genes in DNA damaging repair pathway, occurring in 33 % of patients after VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumour mutation burden both at baseline and progression plasma. CONCLUSION: Analysis of ctDNA can provide novel insights into molecular resistance mechanisms to VIC in BRAFV600E mCRC patients, allowing accurate guidance for clinicians in personalised treatment strategies.
Subject(s)
Circulating Tumor DNA , Colorectal Neoplasms , Drug Resistance, Neoplasm , Humans , Cetuximab/pharmacology , Cetuximab/therapeutic use , Circulating Tumor DNA/genetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Irinotecan/pharmacology , Irinotecan/therapeutic use , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Vemurafenib/therapeutic useABSTRACT
AIMS: Orchestrating the transition from reversible medial hypertrophy to irreversible plexiform lesions is crucial for pulmonary arterial hypertension related to congenital heart disease (CHD-PAH). Transgelin is an actin-binding protein that modulates pulmonary arterial smooth muscle cell (PASMC) dysfunction. In this study, we aimed to probe the molecular mechanism and biological function of transgelin in the pathogenesis of CHD-PAH. METHODS AND RESULTS: Transgelin expression was detected in lung tissues from both CHD-PAH patients and monocrotaline (MCT)-plus aortocaval (AV)-induced PAH rats by immunohistochemistry. In vitro, the effects of transgelin on the proliferation, migration, and apoptosis of human PASMCs (HPASMCs) were evaluated by the cell count and EdU assays, transwell migration assay, and TUNEL assay, respectively. And the effect of transgelin on the expression of HPASMC phenotype markers was assessed by the immunoblotting assay. (i) Compared with the normal control group (n = 12), transgelin expression was significantly overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group: 18.2 ± 5.1 vs. 13.6 ± 2.6%, P < 0.05; irreversible group vs. control group: 29.9 ± 4.7 vs. 13.6 ± 2.6%, P < 0.001; irreversible group vs. reversible group: 29.9 ± 4.7 vs. 18.2 ± 5.1, P < 0.001). This result was further confirmed in MCT-AV-induced PAH rats. Besides, the transgelin expression level was positively correlated with the pathological grading of pulmonary arteries in CHD-PAH patients (r = 0.48, P = 0.03, n = 19). (ii) Compared with the normal control group (n = 12), TGF-ß1 expression was notably overexpressed in the pulmonary arterioles of the reversible (n = 15) and irreversible CHD-PAH group (n = 4) (reversible group vs. control group: 14.8 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. control group: 20.1 ± 4.4 vs. 6.0 ± 2.5%, P < 0.001; irreversible group vs. reversible group: 20.1 ± 4.4 vs. 14.8 ± 4.4, P < 0.01). The progression-dependent correlation between TGF-ß1 and transgelin was demonstrated in CHD-PAH patients (r = 0.48, P = 0.04, n = 19) and MCT-AV-induced PAH rats, which was further confirmed at sub-cellular levels. (iii) Knockdown of transgelin diminished proliferation, migration, apoptosis resistance, and phenotypic transformation of HPASMCs through repressing the TGF-ß1 signalling pathway. On the contrary, transgelin overexpression resulted in the opposite effects. CONCLUSIONS: These results indicate that transgelin may be an indicator of CHD-PAH development via boosting HPASMC dysfunction through positive regulation of the TGF-ß1 signalling pathway, as well as a potential therapeutic target for the treatment of CHD-PAH.
Subject(s)
Hypertension, Pulmonary , Pulmonary Arterial Hypertension , Animals , Humans , Rats , Cell Proliferation/genetics , Hypertension, Pulmonary/etiology , Microfilament Proteins/metabolism , Monocrotaline/metabolism , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Pulmonary Arterial Hypertension/etiology , Pulmonary Artery , Transforming Growth Factor beta1/metabolismABSTRACT
A boy, aged 5 years, attended the hospital due to progressive psychomotor regression for 2.5 years. Motor function regression was the main manifestation in the early stage, and brain MRI and whole-exome sequencing (WES) of the family showed no abnormalities. After the age of 4 years and 9 months, the boy developed cognitive function regression, and brain MRI showed cerebellar atrophy. The reanalysis of WES results revealed a compound heterozygous mutation, [NM_000520, c.784C>T(p.His262Tyr]), c.1412C>T(p.Pro471Leu)], in the HEXA gene. The enzyme activity detection showed a significant reduction in the level of ß-hexosaminidase encoded by this gene. The boy was diagnosed with juvenile Tay-Sachs disease (TSD). TSD has strong clinical heterogeneity, and cerebellar atrophy may be an important clue for the diagnosis of juvenile TSD. The reanalysis of genetic data when appropriate based on disease evolution may improve the positive rate of WES.
Subject(s)
Tay-Sachs Disease , Atrophy , Humans , Magnetic Resonance Imaging , Male , Mutation , Tay-Sachs Disease/diagnosis , Tay-Sachs Disease/geneticsABSTRACT
BACKGROUND: Methylene blue (MB) alone or combined with 99mtechnetium-labeled sulphur colloid (Tc99m) or indocyanine green (ICG) is widely used for sentinel lymph node biopsy (SLNB) of early-stage breast cancer in developing countries and regions. However, studies investigating the effectiveness of MB combined with another tracer have produced heterogeneous results. The purpose of this network meta-analysis (NMA) was to evaluate the detection rate of MB alone, MB + Tc99m, and MB + ICG, and to examine the differences between the 3 methods. METHODS: We conducted a comprehensive electronic literature search on the PubMed, Embase, Web of Science, CNKI, and Wanfang Data databases from inception to October 2021. The meta-analysis included 7,498 patients in 49 studies. The risk of bias for each study was independently assessed as low, moderate, or high using criteria adapted from the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Fixed- and random-effects models were used to calculate pooled estimates. Mixed-comparison analysis using random-effects models. We assessed statistical heterogeneity by I2 statistics and evaluated publication bias using Begg's test. RESULTS: The identification rate (IR), false-negative rate (FNR), sensitivity (SEN), and accuracy rate (AR) using MB + Tc99m were 96%, 7%, 93%, and 96%, respectively; the IR, FNR, SEN, and AR using MB + ICG were 97%, 7%, 93%, and 97%, respectively. The NMA found that IR and AR between MB + ICG and MB + Tc99m was OR =1.37 (95% CI: 0.41-4.20) and OR =1.33 (95% CI: 0.56-3.32), respectively. DISCUSSION: Our results are similar to those of most previous studies, and meta-analysis showed that the MB + Tc99m or MB + ICG mapping methods can be used to obtain higher IR and lower FNR than MB alone. Our NMA showed no statistical significance between MB + Tc99m and MB + ICG with IR and AR. Both MB + Tc99m and MB + ICG can be used as effective mapping methods in SLNB of early-stage breast cancer to improve the detection rate.
ABSTRACT
OBJECTIVES: Right ventricular (RV) function is considered the major determinant of prognosis in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this meta-analysis was to evaluate RV remodelling and function following balloon pulmonary angioplasty (BPA) in patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). METHODS: We reviewed all studies evaluating RV function by cardiac magnetic resonance (CMR) and/or echocardiography pre- and post-BPA from PubMed/Medline prior to 15 December 2019. Ten (299 patients) of the 29 studies retrieved met the inclusion criteria: 5 CMR and 5 echocardiography studies. The systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines. RESULTS: Pooled data from CMR studies revealed BPA resulted in a significantly decreased RV end-diastolic volume index (weighted mean difference (WMD) - 28.33 ml/m2, p < 0.00001) and RV end-systolic volume index (WMD - 29.06 ml/m2, p < 0.00001) accompanied by an increased RV ejection fraction (RVEF, WMD 8.97%, p < 0.00001). Data from the echocardiography studies showed BPA resulted in decreased RV basal diameter (WMD - 0.37 cm, p = 0.0009) and an increase of RV fractional area change (WMD 5.97 %, p = 0.003), but improvements of tricuspid annular plane systolic excursion (TAPSE) and S' were not significant. CONCLUSIONS: BPA improves RVEF and decreases RV volumes in patients with inoperable CTEPH or persistent/recurrent PH after PEA. KEY POINTS: ⢠Balloon pulmonary angioplasty improves RVEF and decreases RV volumes in patients with inoperable CTEPH or persistent/recurrent PH after PEA.
Subject(s)
Angioplasty, Balloon , Hypertension, Pulmonary , Pulmonary Embolism , Ventricular Dysfunction, Right , Humans , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/diagnostic imaging , Hypertension, Pulmonary/therapy , Pulmonary Embolism/complications , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/therapy , Ventricular Function, Right , Ventricular RemodelingABSTRACT
OBJECTIVE: Reportedly, nestin was re-expressed in proliferative synthetic-type pulmonary artery smooth muscle cells (PASMCs) and obligatory for PASMC proliferation in pulmonary arterial hypertension (PAH). Accordingly, nestin is increased in pulmonary vascular lesions of congenital heart disease (CHD)-associated PAH patients. We tested the hypothesis whether nestin was re-expressed in proliferative synthetic-type PASMCs and associated with pulmonary vascular remodeling in CHD-PAH. MATERIALS AND METHODS: Nestin expression was tested using lung tissues from CHD-PAH patients and monocrotaline (MCT) plus aortocaval (AV) shunt-induced PAH rats, human PASMCs (HPASMCs), and pulmonary artery endothelial cells (PAECs) and PASMCs from MCT-AV-induced PAH rats. The role and possible mechanism of nestin on HPASMC proliferation, apoptosis, cell cycle and migration were investigated by assays of CCK-8, EdU, TUNEL, flow cytometry, transwell chamber and immunoblotting assays. RESULTS: Nestin was solely expressed in proliferative synthetic-type PASMCs, but rarely detected in PAECs. Nestin was barely detected in normal pulmonary arterioles and occlusive pulmonary vascular lesions. Its expression was robustly increased in developing pulmonary vasculature, but returned to normal levels at the late stage of pulmonary vascular remodeling in lung tissues from CHD-PAH patients and MCT-AV-induced PAH rats. Besides, nestin peaks were consistent with the histological features in lung tissues of MCT-AV-induced PAH rats. Moreover, nestin overexpression effectively promoted HPASMC phenotypic transformation, proliferation, apoptosis resistance and migration via enhancing Wnt/ß-catenin activation. CONCLUSIONS: These data indicated that nestin was re-expressed in proliferative synthetic-type PASMCs and might represent a potential marker of pulmonary vascular remodeling in CHD-PAH.
Subject(s)
Heart Defects, Congenital/metabolism , Heart Defects, Congenital/physiopathology , Lung/physiopathology , Nestin/metabolism , Pulmonary Arterial Hypertension/metabolism , Pulmonary Arterial Hypertension/physiopathology , Vascular Remodeling , Adolescent , Adult , Aged , Animals , Biomarkers/metabolism , Child , Child, Preschool , Endothelial Cells/metabolism , Female , Heart Defects, Congenital/complications , Humans , Male , Middle Aged , Monocrotaline , Myocytes, Smooth Muscle/metabolism , Phenotype , Proliferating Cell Nuclear Antigen/metabolism , Pulmonary Arterial Hypertension/complications , Pulmonary Artery/pathology , Rats, Sprague-Dawley , Time Factors , Wnt Signaling Pathway , Young AdultABSTRACT
OBJECTIVE: The inhaled sevoflurane (sevo) is known to protect against myocardial ischemia/reperfusion (I/R) injury (MIRI), in which the functions of microRNAs (miRNAs) have been uncovered. However, the effect of sevo regulating miR-204 on this disease remains unknown. This research aims to explore the roles of sevo and miR-204 in the progression of MIRI. METHODS: The MIRI mice models induced by coronary artery ligation were treated by sevo, miR-204 mimics or silenced coactosin-like protein-1 (Cotl1). The pathology of mice myocardial tissues, apoptosis and ultrastructure of cardiomyocytes were observed. The expression of miR-204, Cotl1, Bax and Bcl-2 was determined. The contents of oxidative stress-related factors and inflammatory factors in mouse myocardial tissues were assessed, and the serum levels of indicators that correlated with myocardial infarction were determined as well. The target relation between miR-204 and Cotl1 was confirmed. RESULTS: MiR-204 was down-regulated, and Cotl1 was up-regulated in myocardial tissues of MIRI mice, and Cotl1 was targeted by miR-204. Sevo, elevated miR-204 and inhibited Cotl1 could promote cardiac function of MIRI mice, and protect myocardial tissue against MIRI by repressing the cardiomyocyte apoptosis, oxidative stress and inflammation reaction in MIRI mice. CONCLUSION: We found that sevo could up-regulate miR-204 to ameliorate MIRI in mice by inhibiting Cotl1 expression, which may provide candidates for the MIRI treatment.
Subject(s)
Anesthetics, Inhalation/pharmacology , MicroRNAs/biosynthesis , Microfilament Proteins/antagonists & inhibitors , Myocardial Ischemia/drug therapy , Myocardial Reperfusion Injury/drug therapy , Sevoflurane/pharmacology , Animals , Disease Progression , Hemodynamics/drug effects , Male , Mice , Mice, Inbred C57BL , Myocardial Ischemia/pathology , Myocardial Reperfusion Injury/pathology , Myocardium/pathology , Myocytes, Cardiac/drug effects , Oxidative Stress/drug effects , Up-Regulation/drug effectsABSTRACT
Background: Inhibitory κB kinases (IKKs) play a key role in modulating proinflammatory and growth stimulating signals through their regulation of the nuclear factor κB (NF-κB) cascade. Therefore, the level of expression of IKKs represents a viable prognostic predictor with regard to various pathological processes. The prognostic value of IKKs expression in gastric cancer remains unclear. Methods: We used the 'Kaplan-Meier plotter' (KM plotter) online database, to explore the predictive prognostic value of individual IKKs members' mRNA expression to overall survival (OS) in different clinical data including pathological staging, histology, and therapies employed. Results: Our results revealed that a higher mRNA expression of inhibitor of NF-κB kinase subunit α (IKKα) was correlated to better OS, whereas higher mRNA expression of IKKß, inhibitor of NF-κB kinase subunit γ (IKKγ), inhibitor of NF-κB kinase subunit ε (IKKε), and suppressor of IKKε (SIKE) were generally correlated to unfavorable OS in gastric cancer. Increased mRNA expression of IKKε also showed better outcomes in stage IV gastric cancer. Further a correlation between elevated levels of mRNA expression of both IKKε and SIKE was found to have favorable OS in diffuse type gastric cancer. It was also revealed that high expression of SIKE had favorable OS when treated with other adjuvant therapies, while worse OS when treated only with 5FU therapy. Conclusion: Our results suggest that mRNA expression of individual IKKs and SIKE are associated with unique prognostic significance and may act as valuable prognostic biomarkers and potential targets for future therapeutic interventions in gastric cancer.
Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , I-kappa B Kinase/genetics , Intracellular Signaling Peptides and Proteins/genetics , Protein Serine-Threonine Kinases/genetics , RNA, Messenger/genetics , Stomach Neoplasms/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Databases, Factual , Disease Progression , Female , Humans , I-kappa B Kinase/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Isoenzymes/genetics , Isoenzymes/metabolism , Kaplan-Meier Estimate , Male , NF-kappa B/genetics , NF-kappa B/metabolism , Neoplasm Staging , Prognosis , Protein Serine-Threonine Kinases/metabolism , RNA, Messenger/metabolism , Signal Transduction , Stomach Neoplasms/diagnosis , Stomach Neoplasms/drug therapy , Stomach Neoplasms/mortality , NF-kappaB-Inducing KinaseABSTRACT
BACKGROUND: With the increased prevalence of obesity and sarcopenia, those patients with both visceral obesity and sarcopenia were at higher risk of adverse outcomes. AIM: The aim of this study was to ascertain the combined impact of visceral obesity and sarcopenia on short-term outcomes in patients undergoing colorectal cancer surgery. METHODS: We conducted a prospective study from July 2014 to February 2017. Patients' demographic, clinical characteristics, physical performance, and postoperative short-term outcomes were collected. Patients were classified into four groups according to the presence of sarcopenia or visceral obesity. Clinical variables were compared. Univariate and multivariate analyses evaluating the risk factors for postoperative complications were performed. RESULTS: A total of 376 patients were included; 50.8 and 24.5% of the patients were identified as having "visceral obesity" and "sarcopenia," respectively. Patients with sarcopenia and visceral obesity had the highest incidence of total, surgical, and medical complications. Patients with sarcopenia or/and visceral obesity all had longer hospital stays and higher hospitalization costs. Age ≥ 65 years, visceral obesity, and sarcopenia were independent risk factors for total complications. Rectal cancer and visceral obesity were independent risk factors for surgical complications. Age ≥ 65 years and sarcopenia were independent risk factors for medical complications. Laparoscopy-assisted operation was a protective factor for total and medical complications. CONCLUSION: Patients with both visceral obesity and sarcopenia had a higher complication rate after colorectal cancer surgery. Age ≥ 65 years, visceral obesity, and sarcopenia were independent risk factors for total complications. Laparoscopy-assisted operation was a protective factor.
Subject(s)
Colectomy , Colorectal Neoplasms/surgery , Laparoscopy , Obesity, Abdominal/epidemiology , Sarcopenia/epidemiology , Age Factors , Aged , Aged, 80 and over , Chi-Square Distribution , China/epidemiology , Colectomy/adverse effects , Colectomy/economics , Colectomy/methods , Colorectal Neoplasms/economics , Colorectal Neoplasms/epidemiology , Comorbidity , Female , Hospital Costs , Humans , Incidence , Laparoscopy/adverse effects , Laparoscopy/economics , Length of Stay , Logistic Models , Male , Middle Aged , Multivariate Analysis , Obesity, Abdominal/economics , Odds Ratio , Postoperative Complications/economics , Postoperative Complications/epidemiology , Prevalence , Proportional Hazards Models , Prospective Studies , Protective Factors , Risk Factors , Sarcopenia/economics , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: Nonmuscle-invasive bladder cancer (NMIBC, Stage T1 or lower) is treated with transurethral resection (TUR), while muscle-invasive bladder cancer (MIBC, Stage T2 or more) requires neoadjuvant chemotherapy before radical cystectomy. Hence, preoperative differentiation is vital. PURPOSE: To investigate whether intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) can differentiate NMIBC from MIBC and to assess whether there were correlations between IVIM parameters and the Ki-67 labeling index (LI). STUDY TYPE: Retrospective. SUBJECTS: Thirty-six patients diagnosed with bladder cancer confirmed by histopathological findings. FIELD STRENGTH/SEQUENCE: 3.0T magnetic resonance imaging (MRI) DWI with eight b-values ranging from 0 to 1000 s/mm2 . ASSESSMENT: Molecular diffusion coefficient (D), perfusion-related diffusion coefficient (D*), perfusion fraction (f), and apparent diffusion coefficient (ADC) were calculated by biexponential and monoexponential models fits, respectively. STATISTICAL TESTS: Comparisons were made between the MIBC and NMIBC group, and differences were analyzed by comparing the areas under the receiver-operating characteristic curves (AUCs). The correlations between these parameters and Ki-67 LI were assessed by Spearman's rank correlation analysis. RESULTS: The ADC and D value were significantly lower in patients with MIBC compared to those with NMIBC (P < 0.01). No significant (P > 0.05) differences were observed in D* and f. The AUC of D value (0.894) was significantly (P < 0.05) larger than the ADC value (0.786), with sensitivities and specificities of 95% and 87.5% (D) and 80% and 68.7% (ADC), respectively. In addition, the D and ADC values were significantly correlated with Ki-67 LI (r = -0.785, r = -0.643, respectively; both P < 0.01). DATA CONCLUSION: The D value obtained from IVIM exhibited better performance than conventional DWI for distinguishing NMIBC from MIBC and may serve as a potential imaging biomarker for bladder cancer invasion. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1054-1060.
Subject(s)
Cell Proliferation , Diffusion Magnetic Resonance Imaging/methods , Image Processing, Computer-Assisted/methods , Urinary Bladder Neoplasms/diagnostic imaging , Urinary Bladder Neoplasms/pathology , Adult , Aged , Female , Humans , Male , Middle Aged , Neoplasm Invasiveness/diagnostic imaging , Neoplasm Invasiveness/pathology , Phosphoproteins , Reproducibility of Results , Sensitivity and Specificity , Urinary Bladder/diagnostic imaging , Urinary Bladder/pathologyABSTRACT
BACKGROUND/AIM: The aim of this prospective double-center study was to explore the effect of nutritional risk on short-term outcomes in the patients who had gastric cancer and underwent a laparoscopic-assisted gastrectomy. PATIENTS AND METHODS: We conducted a study of patients who underwent laparoscopic-assisted gastrectomy in two large centers between June 2014 and April 2017. Patients' demographic and clinical characteristics and postoperative short-term outcomes were prospectively analyzed. Patients were divided into two groups depend on the preoperative presence of nutritional risk. Clinical variables were compared. Univariate analyses and multivariate logistic regression analyses evaluating the risk factors for postoperative complications were performed. RESULTS: A total of 256 patients, comprising 187 males and 69 females, met the inclusion criteria and were included in this study. The mean age was 61.81 years, the average BMI was 22.44 kg/m, and the average preoperative serum albumin was 39.42 g/l. Older age (P=0.001), higher tumor stage (P=0.047), lower BMI (P<0.001), lower preoperative serum albumin (P=0.005), and lower hemoglobin (P=0.013) were more common in the nutritional risk group. There were no significant differences in the short-term postoperative outcomes between nutritional risk and non-nutritional risk groups. Advanced age (P=0.024) and hypoalbuminemia (P=0.004) were independent risk factors for postoperative complications after laparoscopic-assisted gastrectomy. CONCLUSION: Nutritional risk may not be a clinical predictor of short-term outcomes after laparoscopic-assisted gastrectomy. Advanced age and preoperative hypoalbuminemia were independent risk factors for grade II or more postoperative complications.
Subject(s)
Gastrectomy/methods , Nutritional Status , Postoperative Complications/etiology , Stomach Neoplasms/pathology , Stomach Neoplasms/surgery , Age Factors , Aged , Body Mass Index , Female , Gastrectomy/adverse effects , Hemoglobins/metabolism , Humans , Hypoalbuminemia/blood , Hypoalbuminemia/complications , Laparoscopy , Male , Middle Aged , Neoplasm Staging , Nutrition Assessment , Preoperative Period , Prospective Studies , Risk Factors , Serum Albumin/metabolism , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: The bladder wall may thicken resulting from chronic inflammation after initial treatment (transurethral resection [TUR] or neoadjuvant chemotherapy), which may mimic the feature of recurrent or residual bladder tumors (RBT). Therefore, it is critical to discriminate RBT from benign lesions after initial treatment. PURPOSE: To investigate whether diffusion kurtosis imaging (DKI) could discriminate RBT from post-therapy bladder inflammatory lesions. STUDY TYPE: Retrospective. SUBJECTS: Fifty patients diagnosed with bladder cancer underwent TUR or received neoadjuvant chemotherapy. FIELD STRENGTH/SEQUENCE: 3.0T MRI/conventional T1 -weighted imaging (T1 WI), T2 WI, and diffusion-weighted imaging (DWI) with nine b-values ranging from 0-2000 s/mm2 . ASSESSMENT: Mean diffusion coefficients (MDa , MDb , and MDc ) and mean kurtosis values (MKa , MKb , and MKc ) were obtained from three different measurement methods. The region of interest (ROI) was placed 1) to encompass the entire portion of the thickening bladder wall or to portions that were the most restricted, with a b-value of 2) 2000 s/mm2 or 3) 1000 s/mm2 . STATISTICAL TESTS: The independent-samples t-test was used to compare the differences between RBT and the inflammatory group. Differences in DKI parameters were analyzed by comparing the areas under the receiver-operator characteristic curves (AUCs). RESULTS: In patients with RBT, the MD (MDa , MDb , MDc ) values were significantly lower and the MK (MKa , MKb , MKc ) values were significantly higher than those in patients in the inflammatory lesions group (all P < 0.01). The AUC of MKb (0.934) was significantly larger than those of MDb , MKa , and MKc (0.793, P < 0.05; 0.694, P < 0.01; 0.719, P < 0.01, respectively). DATA CONCLUSION: MK obtained from DKI provided better performance than conventional DWI in distinguishing RBT from inflammatory lesions after bladder cancer treatment. MK calculated with high b-values setting provided better performance in differentiation. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage 3 J. Magn. Reson. Imaging 2017.
Subject(s)
Diffusion Magnetic Resonance Imaging , Inflammation/diagnostic imaging , Urinary Bladder Neoplasms/diagnostic imaging , Aged , Area Under Curve , Chemotherapy, Adjuvant , Diffusion Tensor Imaging , Female , Humans , Image Interpretation, Computer-Assisted/methods , Imaging, Three-Dimensional/methods , Male , Middle Aged , Neoadjuvant Therapy , Normal Distribution , ROC Curve , Retrospective Studies , Sensitivity and SpecificityABSTRACT
BACKGROUND: A geriatric assessment is needed to identify high-risk elderly patients with gastric cancer. However, the current geriatric assessment has been considered to be either time-consuming or subjective. The present study aimed to investigate the predictive effect of sarcopenia on the postoperative complications for elderly patients who underwent radical gastrectomy. MATERIALS AND METHODS: We conducted a prospective study of patients who underwent radical gastrectomy from August 2014 to December 2015. Computed tomography-assessed lumbar skeletal muscle, handgrip strength, and gait speed were measured to define sarcopenia. RESULTS: Sarcopenia was present in 69 of 240 patients (28.8%) and was associated with lower body mass index, lower serum albumin, lower hemoglobin, and higher nutritional risk screening 2002 scores. Postoperative complications significantly increased in the sarcopenic patients (49.3% versus 24.6%, P < 0.001), compared with nonsarcopenic patients. The multivariate analysis demonstrated that sarcopenia (odds ratio: 2.959, 95% CI: 1.629-5.373, P < 0.001) and the Charlson comorbidity index ≥2 (odds ratio: 3.357, 95% CI: 1.144-9.848, P = 0.027) were independent risk factors for postoperative complications. CONCLUSIONS: Sarcopenia, presented as a new geriatric assessment factor, was a strong and independent risk factor for postoperative complications of elderly patients with gastric cancer.