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1.
Transl Psychiatry ; 10(1): 65, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32066697

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood, with a shift of symptoms including less hyperactivity/impulsivity and more co-morbidity of affective disorders in ADHDadult. Many studies have questioned the stability in diagnosing of ADHD from childhood to adulthood, and the shared and distinct aberrant functional connectivities (FCs) between ADHDchild and ADHDadult remain unidentified. We aim to explore shared and distinct FC patterns in ADHDchild and ADHDadult, and further investigated the cross-cohort predictability using the identified FCs. After investigating the ADHD-discriminative FCs from healthy controls (HCs) in both child (34 ADHDchild, 28 HCs) and adult (112 ADHDadult,77 HCs) cohorts, we identified both shared and distinct aberrant FC patterns between cohorts and their association with clinical symptoms. Moreover, the cross-cohort predictability using the identified FCs were tested. The ADHD-HC classification accuracies were 84.4% and 81.0% for children and male adults, respectively. The ADHD-discriminative FCs shared in children and adults lie in the intra-network within default mode network (DMN) and the inter-network between DMN and ventral attention network, positively correlated with total scores of ADHD symptoms. Particularly, inter-network FC between somatomotor network and dorsal attention network was uniquely impaired in ADHDchild, positively correlated with hyperactivity index; whereas the aberrant inter-network FC between DMN and limbic network exhibited more adult-specific ADHD dysfunction. And their cross-cohort predictions were 70.4% and 75.6% between each other. This work provided imaging evidence for symptomatic changes and pathophysiological continuity in ADHD from childhood to adulthood, suggesting that FCs may serve as potential biomarkers for ADHD diagnosis.

2.
Cytokine ; 127: 154998, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31972501

RESUMO

BACKGROUND: Graves' disease (GD) patients experience two major issues: one is the severe hyperthyroidism associated with newly diagnosed GD, and the other involves the disfiguring and dysfunctional features of active Graves' orbitopathy (GO). Therefore, the aim of our study was to identify potential markers involved in the initial phase of GD dysfunction and the development of active GO. METHODS: Seventy-eight subjects were recruited: 40 with newly diagnosed GD, 20 with inactive GO and 18 with active GO. GO activity was evaluated by the clinical activity score (CAS, active GO = CAS ≥ 3), and severity was assessed according to the NOSPECS classification. Plasma selenium concentrations were determined by dual channel hydride generation atomic fluorescence photometry. A liquid chip assay was used to measure plasma Th1 cytokines IFN-γ and TNF-α; Th2 cytokines IL4, IL5 and IL6; Th17 cytokine IL23; Treg cytokines IL10 and TGF-ß; and two chemokines, CCL2 (Th2 chemokine) and CXCL10 (Th1 chemokine). RESULTS: Among the three groups, newly diagnosed GD patients showed significantly elevated plasma levels of CXCL10 and IL-23 (all p < 0.05). Both CXCL10 and IL23 were significantly correlated with hyperthyroidism severity, specifically, increasing FT3 and FT4 and decreasing TSH. Notably, a very strong positive relationship between IL23 and CXCL10 was revealed (adjusted R square = 0.795; p < 0.001). Moreover, the selenium level was lower, while that of CCL2 was higher, in active GO than in inactive GO (p = 0.007, p < 0.001, respectively). Likewise, we also discovered that increasing CCL2 levels and decreasing selenium levels were associated with high CAS. Remarkably, after adjusting for potential confounding factors, selenium (OR, 0.919) and CCL2 (OR, 1.042) were still independent predictors for the diagnosis of active GO, and similar conclusions were drawn by receiver operating characteristic (ROC) curve analysis. CONCLUSION: Pro-inflammatory cytokines, especially Th17-associated cytokines (e.g., IL23) and Th1 chemokines (e.g., CXCL10), appear to be involved in the initial phase of GD dysfunction. Moreover, we revealed for the first time that decreased plasma selenium levels and increased concentrations of Th2 chemokines (e.g., CCL2) may reflect GO disease activity, shedding light on the diagnosis and evaluation of active GO.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31927110

RESUMO

BACKGROUND & AIMS: We investigated associations of intake of total fats, specific dietary fats, and fats from different food sources with risk of hepatocellular carcinoma (HCC) using data from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). METHODS: We analyzed data from a total of 138,483 women and men who participated in the NHS or HPFS. A validated semi-quantitative food frequency questionnaire was sent to NHS participants in 1980, 1984, 1986, and every 4 years thereafter; dietary information was collected from participants in the HPFS in 1986 and every 4 years thereafter. Multivariable hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression. RESULTS: After an average follow-up time of 26.6 years, 160 incident HCC cases were documented. Although there was a non-significant association between total fat intake and HCC, intake of vegetable fats reduced risk of HCC (HR for the highest vs lowest quartile, 0.61; 95% CI, 0.39-0.96; Ptrend=.02), but not animal or dairy fats. Replacing animal or dairy fats with an equivalent amount of vegetable fats was associated with a lower risk of HCC (HR per 1 standard deviation, 0.79; 95% CI, 0.65-0.97). Among fat subtypes, monounsaturated and polyunsaturated fatty acids, including n-3 (HR, 0.63; 95% CI, 0.41-0.96; Ptrend=.14) and n-6 polyunsaturated fatty acids (HR, 0.54; 95% CI, 0.34-0.86; Ptrend=.02), were inversely associated with risk of HCC. Higher ratios of monounsaturated or polyunsaturated fat to saturated fat were inversely associated with HCC risk (all Ptrend≤.02). In addition, when replacing saturated fats with monounsaturated or polyunsaturated fats, the HR per 1 standard deviation was 0.77 (95% CI, 0.64-0.92). CONCLUSIONS: In an analysis of data from 2 large cohort studies, we found higher intake of vegetable fats and polyunsaturated fats to be associated with lower risk of HCC. Replacing animal or dairy fats with vegetable fats, or replacing saturated fats with monounsaturated or polyunsaturated fats, was associated with reduced risk of HCC.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31944934

RESUMO

OBJECTIVE: Multimodal measurements of the same phenomena provide complementary information and highlight different perspectives, albeit each with their own limitations. A focus on a single modality may lead to incorrect inferences, which is especially important when a studied phenomenon is a disease. In this paper, we introduce a method that takes advantage of multimodal data in addressing the hypotheses of disconnectivity and dysfunction within schizophrenia (SZ). METHODS: We start with estimating and visualizing links within and among extracted multimodal data features using a Gaussian graphical model (GGM). We then propose a modularity-based method that can be applied to the GGM to identify links that are associated with mental illness across a multimodal data set. Through simulation and real data, we show our approach reveals important information about disease-related network disruptions that are missed with a focus on a single modality. We use functional MRI (fMRI), diffusion MRI (dMRI), and structural MRI (sMRI) to compute the fractional amplitude of low frequency fluctuations (fALFF), fractional anisotropy (FA), and gray matter (GM) concentration maps. These three modalities are analyzed using our modularity method. RESULTS: Our results show missing links that are only captured by the cross-modal information that may play an important role in disconnectivity between the components. CONCLUSION: we identified multimodal (fALFF, FA and GM) disconnectivity in the default mode network area in patients with SZ, which would not have been detectable in a single modality. SIGNIFICANCE: The proposed approach provides an important new tool for capturing information that is distributed among multiple imaging modalities.

5.
Hum Brain Mapp ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31904902

RESUMO

Electroconvulsive therapy is regarded as the most effective antidepressant treatment for severe and treatment-resistant depressive episodes. Despite the efficacy of electroconvulsive therapy, the neurobiological underpinnings and mechanisms underlying electroconvulsive therapy induced antidepressant effects remain unclear. The objective of this investigation was to identify electroconvulsive therapy treatment responsive multimodal biomarkers with the 17-item Hamilton Depression Rating Scale guided brain structure-function fusion in 118 patients with depressive episodes and 60 healthy controls. Results show that reduced fractional amplitude of low frequency fluctuations in the prefrontal cortex, insula and hippocampus, linked with increased gray matter volume in anterior cingulate, medial temporal cortex, insula, thalamus, caudate and hippocampus represent electroconvulsive therapy responsive covarying functional and structural brain networks. In addition, relative to nonresponders, responder-specific electroconvulsive therapy related brain networks occur in frontal-limbic network and are associated with successful therapeutic outcomes. Finally, electroconvulsive therapy responsive brain networks were unrelated to verbal declarative memory. Using a data-driven, supervised-learning method, we demonstrated that electroconvulsive therapy produces a remodeling of brain functional and structural covariance that was unique to antidepressant symptom response, but not linked to memory impairment.

6.
Neuroimage ; 207: 116370, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31751666

RESUMO

Although both resting and task-induced functional connectivity (FC) have been used to characterize the human brain and cognitive abilities, the potential of task-induced FCs in individualized prediction for out-of-scanner cognitive traits remains largely unexplored. A recent study Greene et al. (2018) predicted the fluid intelligence scores using FCs derived from rest and multiple task conditions, suggesting that task-induced brain state manipulation improved prediction of individual traits. Here, using a large dataset incorporating fMRI data from rest and 7 distinct task conditions, we replicated the original study by employing a different machine learning approach, and applying the method to predict two reading comprehension-related cognitive measures. Consistent with their findings, we found that task-based machine learning models often outperformed rest-based models. We also observed that combining multi-task fMRI improved prediction performance, yet, integrating the more fMRI conditions can not necessarily ensure better predictions. Compared with rest, the predictive FCs derived from language and working memory tasks were highlighted with more predictive power in predominantly default mode and frontoparietal networks. Moreover, prediction models demonstrated high stability to be generalizable across distinct cognitive states. Together, this replication study highlights the benefit of using task-based FCs to reveal brain-behavior relationships, which may confer more predictive power and promote the detection of individual differences of connectivity patterns underlying relevant cognitive traits, providing strong evidence for the validity and robustness of the original findings.

7.
Cancer Epidemiol Biomarkers Prev ; 29(1): 133-140, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31666286

RESUMO

BACKGROUND: We hypothesized that the risk of colorectal cancer in night-shift workers might be different according to insulin receptor substrate status. METHODS: Among 77,470 eligible women having night work assessed in the Nurses' Health Study, we documented a total of 1,397 colorectal cancer cases, of which 304 or 308 had available data on IRS1 and IRS2, respectively. We used duplication-method Cox proportional hazards regression analysis for competing risks to calculate HRs and 95% confidence intervals (CI) for each colorectal cancer subtype. We measured tumor IRS1 or IRS2 expression by immunohistochemistry (IHC). RESULTS: Compared with women who never worked night shifts, those working ≥15 years night shifts had a marginal trend of increased overall risk of colorectal cancer (P trend = 0.06; multivariable HR = 1.20; 95% CI, 0.99-1.45). Longer duration of night-shift work was associated with a higher risk of IRS2-positive tumors (multivariable HR = 2.69; 95% CI, 1.48-4.89; P trend = 0.001, ≥15 years night shifts vs. never) but not with IRS2-negative tumors (multivariable HR = 0.90; 95% CI, 0.54-1.51; P trend = 0.72; P heterogeneity for IRS2 = 0.008). Similarly, the corresponding multivariable HRs were 1.81 for IRS1-positive tumors (95% CI, 0.94-3.48; P trend = 0.06) and 1.13 for IRS1-negative tumors (95% CI, 0.71-1.80; P trend = 0.56; P heterogeneity for IRS1 = 0.02). CONCLUSIONS: Our molecular pathologic epidemiology data suggest a potential role of IRS in mediating carcinogenesis induced by night-shift work. IMPACT: Although these findings need validation, rotating night shift might increase colorectal cancer risk in women with abnormal insulin receptor pathways.

8.
Int J Cancer ; 146(5): 1241-1249, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31116416

RESUMO

Although increasing dairy product intake has been associated with risk of several cancers, epidemiological studies on hepatocellular carcinoma are sparse and have yielded inconsistent results. We prospectively assessed the associations of dairy products (total, milk, butter, cheese and yogurt) and their major components (calcium, vitamin D, fats and protein) with the risk of hepatocellular carcinoma development among 51,418 men and 93,427 women in the Health Professionals Follow-Up Study and the Nurses' Health Study. Diets were collected at baseline and updated every 4 years using validated food frequency questionnaires. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression model. During up to 32 years of follow-up, a total of 164 hepatocellular carcinoma cases were documented. After adjustment for most known hepatocellular carcinoma risk factors, higher total dairy product intake was associated with an increased risk of hepatocellular carcinoma (highest vs. lowest tertile, HR = 1.85, 95% CI: 1.19-2.88; ptrend = 0.009). For the same comparison, we observed significant positive associations of high-fat dairy (HR = 1.81, 95% CI: 1.19-2.76; ptrend = 0.008) and butter (HR = 1.58, 95% CI: 1.06-2.36; ptrend = 0.04) with hepatocellular carcinoma risk. There was a nonsignificant inverse association between yogurt intake and hepatocellular carcinoma risk (HR = 0.72, 95% CI: 0.49-1.05; ptrend = 0.26). Our data suggest that higher intake of high-fat dairy foods was associated with higher, whereas higher yogurt consumption might be associated with lower risk of developing hepatocellular carcinoma among U.S. men and women.

9.
J Affect Disord ; 260: 281-286, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31521864

RESUMO

BACKGROUND: White matter abnormalities have been implicated in mental disorders including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ); however, the shared and distinct white matter integrity across mental disorders is still unclear. METHODS: A total of 290 participants (MDD = 85, BD = 42, SZ = 68, and healthy controls = 95) were included in the present study. Tract-based spatial statistics were performed to measure fractional anisotropy (FA) and characterize shared and distinguishing white matter changes across mental disorders. RESULTS: We found that decreased FA converged across MDD, BD and SZ in the body and genu of the corpus callosum, bilateral anterior and posterior corona radiata, and right superior corona radiata. By contrast, diagnosis-specific effect was only found in MDD in the anterior portion of anterior corona radiata. LIMITATIONS: The small and imbalanced sample size, and possible confounding effects of medication. CONCLUSIONS: Our findings suggest that abnormally reduced white matter integrity in the interhemispheric and thalamocortical circuit could be consistently involved in the pathogenesis of MDD, BD and SZ.

10.
J Cell Physiol ; 235(2): 1025-1035, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31240705

RESUMO

Cutaneous malignant melanoma (hereafter called melanoma) is one of the most aggressive cancers with increasing incidence and mortality rates worldwide. In this study, we performed a systematic investigation of the tumor microenvironmental and genetic factors associated with melanoma to identify prognostic biomarkers for melanoma. We calculated the immune and stromal scores of melanoma patients from the Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm and found that they were closely associated with patients' prognosis. Then the differentially expressed genes were obtained based on the immune and stromal scores, and prognostic immune-related genes further identified. Functional analysis and the protein-protein interaction network further revealed that these genes enriched in many immune-related biological processes. In addition, the abundance of six infiltrating immune cells was analyzed using prognostic immune-related genes by TIMER algorithm. The unsupervised clustering analysis using immune-cell proportions revealed eight clusters with distinct survival patterns, suggesting that dendritic cells were most abundant in the microenvironment and CD8+ T cells and neutrophils were significantly related to patients' prognosis. Finally, we validated these genes in three independent cohorts from the Gene Expression Omnibus database. In conclusion, this study comprehensively analyzed the tumor microenvironment and identified prognostic immune-related biomarkers for melanoma.

11.
J Cell Physiol ; 235(1): 548-562, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31232471

RESUMO

Accumulating evidence implies that N6-methyladenosine (m6A) methylation participated in the tumorigenesis of gastric cancer (GC). Here we synthetically analyzing the prognostic value and expression profile of seven m6A methylation-relevant genes through silico analysis of sequencing data downloaded from The Cancer Genome Atlas, Kaplan-Meier plotter, and Gene Expression Omnibus database. We explored the methyltransferase-like 3 (METTL3) expression in GC cell line and tumor tissues by reverse transcription quantitative polymerase chain reaction and western blot analysis. The m6A methylation status of total RNA was measured by m6A RNA methylation quantification kit. Small interfering RNA was used to establish METTL3 knockdown cell lines. We also measure the proliferation and migration capability GC cell. Furthermore, we detect the epithelial cell mesenchymal transition marker and m6A methylation level after METTL3 knock down. Our result revealed that METTL3 was significantly increased in GC tissues compared with control in big crowd data sets. Survival analysis showed that METTL3 serve as a poor prognostic factor for GC patients. The expression level of METTL3 gradually increased with the progress of tumor stage and grade. GFI1 is an important transcription factor associated with METTL3. We verified the up-trend of METTL3 in messenger RNA and protein expression and observed a significant increase in the m6A methylation status of total RNA in the GC cells and tissues. METTL3 knockdown inhibited total RNA m6A methylation level, as well as cell proliferation and migration capacity. Moreover, METTL3 knockdown decreased α-smooth muscle actin. Taken together, our finding revealed that m6A methylation writer METTL3 serve as an oncogene in tumorigenesis of GC.

12.
Hum Brain Mapp ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31876339

RESUMO

Exploring brain changes across the human lifespan is becoming an important topic in neuroscience. Though there are multiple studies which investigated the relationship between age and brain imaging, the results are heterogeneous due to small sample sizes and relatively narrow age ranges. Here, based on year-wise estimation of 5,967 subjects from 13 to 72 years old, we aimed to provide a more precise description of adult lifespan variation trajectories of gray matter volume (GMV), structural network correlation (SNC), and functional network connectivity (FNC) using independent component analysis and multivariate linear regression model. Our results revealed the following relationships: (a) GMV linearly declined with age in most regions, while parahippocampus showed an inverted U-shape quadratic relationship with age; SNC presented a U-shape quadratic relationship with age within cerebellum, and inverted U-shape relationship primarily in the default mode network (DMN) and frontoparietal (FP) related correlation. (b) FNC tended to linearly decrease within resting-state networks (RSNs), especially in the visual network and DMN. Early increase was revealed between RSNs, primarily in FP and DMN, which experienced a decrease at older ages. U-shape relationship was also revealed to compensate for the cognition deficit in attention and subcortical related connectivity at late years. (c) The link between middle occipital gyrus and insula, as well as precuneus and cerebellum, exhibited similar changing trends between SNC and FNC across the adult lifespan. Collectively, these results highlight the benefit of lifespan study and provide a precise description of age-related regional variation and SNC/FNC changes based on a large dataset.

13.
Am J Gastroenterol ; 114(12): 1870-1877, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31688024

RESUMO

OBJECTIVES: Adherence to a healthy diet has been associated with a reduced risk of type 2 diabetes (T2D). Hepatocellular carcinoma (HCC) may have overlapping mechanisms with T2D, such as inflammation and insulin resistance. Thus, we examined the association between a previously developed T2D prevention dietary pattern and HCC risk. METHODS: We followed 87,943 women in the Nurses' Health Study and 49,665 men in the Health Professionals Follow-up Study for up to 32 years. The dietary diabetes risk reduction score, which includes dietary glycemic index, cereal fiber, ratio of polyunsaturated to saturated fats, trans fat, sugar-sweetened beverages, nuts, coffee, and red and processed meats, was obtained using validated food frequency questionnaires and updated every 4 years. The Cox proportional hazards regression model was used to calculate multivariable hazard ratios and confidence intervals (95% CIs). RESULTS: During over 1.9 million person-years, a total of 160 incident HCC cases were identified. The dietary diabetes risk reduction score was associated with a lower risk of HCC (top vs bottom quartile; hazard ratio: 0.57, 95% CI: 0.34-0.95; Ptrend = 0.03). All the individual food and beverage items were associated with the risk of HCC in the expected direction, although the association was weaker than the overall dietary pattern. DISCUSSION: Greater adherence to the T2D prevention diet was associated with a lower risk of developing HCC among US men and women. Further studies are needed to confirm and extend our findings.

14.
Anal Chem ; 91(24): 15804-15810, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31718146

RESUMO

Because of the extremely low solubility of gas pollution, elucidating the pathogenetic mechanism between air pollution and the lung inflammatory response has remained a significant challenge. Here, we develop a bioinspired nanoporous membrane (BNM) with a three-phase interface as a gas exposure model that mimicks the airway mechanism, gas molecules contacting with alveolar cells directly, enabling high cell viability and sensitive inflammatory response analysis. Specifically, the top side of the porous anodic alumina (PAA) membrane was in contact with the medium for cell culture, and the bottom side contacted the gas phase directly for gas exposure. Compared with the two-phase interface, the viability of cells on the BNM was enhanced up to 3-fold. Additionally, results demonstrated that the inflammatory responses of cells stimulated by gas pollution (formaldehyde and benzene as models) from the gas phase were more obvious than those induced by gas pollution from solution, especially the increment of interleukin-2 (IL-2), IL-6, and tumor necrosis factor α (TNF-α), which was almost 2 times greater than that induced by gas pollution from solution. Furthermore, an enzyme inhibitor was introduced to evaluate potential applications of the BNM.

15.
J Cell Biochem ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31692042

RESUMO

Lung cancer is one of the deadliest cancers worldwide. To increase the survival rate of lung cancer, it is necessary to explore specific prognosis markers. More and more evidence finds that noncoding RNA is closely associated with the survival of lung cancer, and cancer stem cells (CSCs) also play a significant role in the progress of lung cancer. The objective of this study is to find CSLCs genes that affect the prognosis of lung cancer. The differential expression of long noncoding RNAs (lncRNAs), microRNAs (miRNAs), messenger RNAs (mRNAs) in the Cancer Genome Atlas (TCGA) database and differential expression data from microarray of CD326+ and CD326- A549 cell are intersected to identify stable and consistent expression genes (2 lncRNAs, 15 miRNAs, and 134 mRNAs). The intersection of lncRNAs and miRNAs is analyzed by univariate and multivariate Cox regression to obtained prognostic genes. Two miRNAs (miR-30b-5p and miR-29c-3p) are significantly correlated with the overall survival rate. Then using these two miRNAs to construct a risk score model as a prognosis signature of lung cancer. Subsequently, we analyzed the association between two miRNAs and clinical information of lung cancer patients, of which T stage, Neoplasm cancer and risk score (P < .05) can be used as independent prognostic indicators of lung cancer. Finally, target genes of 2 miRNAs and 134 mRNAs were annotated with Gene Ontology and analyzed with Kyoto Encyclopedia of Genes and Genomes pathway, and verified with the GEO database. In summary, this study illustrates the role of miRNAs in the promotion of lung cancer by CSCs, which is important to find molecular biomarkers of lung cancer.

16.
Neuroimage Clin ; : 102080, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31735637

RESUMO

Electroconvulsive therapy (ECT) works rapidly and has been widely used to treat depressive disorders (DEP). However, identifying biomarkers predictive of response to ECT remains a priority to individually tailor treatment and understand treatment mechanisms. This study used a connectome-based predictive modeling (CPM) approach in 122 patients with DEP to determine if pre-ECT whole-brain functional connectivity (FC) predicts depressive rating changes and remission status after ECT (47 of 122 total subjects or 38.5% of sample), and whether pre-ECT and longitudinal changes (pre/post-ECT) in regional brain network biomarkers are associated with treatment-related changes in depression ratings. Results show the networks with the best predictive performance of ECT response were negative (anti-correlated) FC networks, which predict the post-ECT depression severity (continuous measure) with a 76.23% accuracy for remission prediction. FC networks with the greatest predictive power were concentrated in the prefrontal and temporal cortices and subcortical nuclei, and include the inferior frontal (IFG), superior frontal (SFG), superior temporal (STG), inferior temporal gyri (ITG), basal ganglia (BG), and thalamus (Tha). Several of these brain regions were also identified as nodes in the FC networks that show significant change pre-/post-ECT, but these networks were not related to treatment response. This study design has limitations regarding the longitudinal design and the absence of a control group that limit the causal inference regarding mechanism of post-treatment status. Though predictive biomarkers remained below the threshold of those recommended for potential translation, the analysis methods and results demonstrate the promise and generalizability of biomarkers for advancing personalized treatment strategies.

17.
Respir Res ; 20(1): 219, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615518

RESUMO

BACKGROUND: Plasma metabolomics profile (PMP) in COPD has been associated with clinical characteristics, but PMP's relationship to survival has not been reported. We determined PMP differences between patients with COPD who died an average of 2 years after enrollment (Non-survivors, NS) compared to those who survived (S) and also with age matched controls (C). METHODS: We studied prospectively 90 patients with severe COPD and 30 controls. NS were divided in discovery and validation cohorts (30 patients each) and the results compared to the PMP of 30 S and C. All participants completed lung function tests, dyspnea scores, quality of life, exercise capacity, BODE index, and plasma metabolomics by liquid and gas chromatography / mass spectometry (LC/MS, LC/MS2, GC/MS). Statistically, we used Random Forest Analysis (RFA) and Support Vector Machine (SVM) to determine metabolites that differentiated the 3 groups and compared the ability of metabolites vs. clinical characteristics to classify patients into survivors and non-survivors. RESULTS: There were 79 metabolites statistically different between S and NS [p < 0.05 and false discovery rate (q value) < 0.1]. RFA and SVM classification of COPD survivors and non-survivors had a predicted accuracy of 74 and 85% respectively. Elevation of tricyclic acid cycle intermediates branched amino acids depletion and increase in lactate, fructose and xylonate showed the most relevant differences between S vs. NS suggesting alteration in mitochondrial oxidative energy generation. PMP had similar predictive power for risk of death as information provided by clinical characteristics. CONCLUSIONS: A plasma metabolomic profile characterized by an oxidative energy production difference between survivors and non-survivors was observed in COPD patients 2 years before death.

18.
Exp Ther Med ; 18(5): 3415-3424, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31602216

RESUMO

Sphingosine-1-phosphate (S1P) has been reported to enhance the function of islet ß-cells, providing a potential therapeutic target for diabetes mellitus. In the present study, the effects of S1P on the proliferation and apoptosis of ß-cells in type 2 diabetic mice were investigated. The mice were administered intraperitoneal S1P solution daily at a dose of 20 µg/kg for three weeks. The intraperitoneal glucose tolerance test (IPGTT) and homeostatic model assessment of insulin resistance (HOMA-IR) index determination were carried out. Immunohistochemical staining was used to detect the protein expression of insulin, antigen Ki-67 and S1P receptor isoforms (S1PR1/S1PR2/S1PR3) in pancreatic islets. Compared with the diabetic control (DC) group, the IPGTT results and HOMA-IR index in the S1P treatment group were decreased. The islets in the S1P group exhibited higher insulin immunostaining intensity than the DC group, as well as higher proliferation (P<0.05) and lower apoptosis rates (P<0.05). Positive staining for the S1P receptors S1PR1, S1PR2 and S1PR3 was observed in the cytoplasm and membrane of the islet cells. S1PR1 and S1PR2 proteins showed increased expression in the S1P and DC groups compared with the normal control group (P<0.01 and P<0.05, respectively), whereas no significant difference was observed in the expression of S1PR3 among these groups. In conclusion, extracellular S1P can induce islet ß-cell proliferation and decrease cell apoptosis in diabetic mice. S1P function may be mediated via S1PR1 and S1PR2; therefore, targeting S1P/S1PR signalling pathways may be a novel therapeutic strategy for diabetes mellitus.

19.
Exp Ther Med ; 18(5): 3603-3614, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31602237

RESUMO

Sphingolipid metabolism is dysregulated in type 2 diabetes mellitus (T2DM); however, the focus of previous studies was mostly limited to ceramide (Cer), and only few studies have investigated other metabolites, including sphingosine-1 phosphate (So1P). The present study aimed to examine the involvement of 8 major sphingolipid metabolites, including Cer, glucosyl ceramide (GluCer), lactosyl ceramide (LacCer), sphingomyelin (SM), sphinganine (Sa), So1P, sphingosine (So) and sphinganine-1-phosphate (Sa1P), during the progression of T2DM, and to evaluate the ability of serum sphingolipids to predict cases of diabetes with an elevated risk of cardiovascular complications. Blood samples were obtained from 245 participants who were divided into 3 groups: Healthy controls, pre-diabetes (pre-DM) and diagnosed diabetes. The 8 major sphingolipid metabolites were measured by high-performance liquid chromatography-tandem mass spectrometry and blood parameters were determined by routine laboratory assays for all subjects. Among the sphingolipid metabolites, So1P was associated with sex and lean mass index, but not with the body mass index. So1P was highest in healthy controls and gradually decreased when the disease proceeded to pre-DM and T2DM. GluCer, SM, Sa and So decreased in pre-DM and rose again in T2DM, graphically exhibiting a 'U' shape change during the progression of diabetes. So1P and Sa were identified to be significantly associated with cardiovascular complications by multivariate logistic regression analysis. Receiver operating characteristic curve analysis also suggested that So1P and Sa were able to indicate cardiovascular complications in diabetic patients. Pre-DM and diabetes were significantly associated with decreased So1P, SM, Sa and So, compared with the healthy controls. So1P was correlated with the progression of T2DM, and was a predictor of an elevated risk of cardiovascular complications among T2DM patients, along with Sa. The present study was registered with ClinicalTrials.gov (no. NCT02826759; April 2016).

20.
Pharmacol Res ; 148: 104461, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31542404

RESUMO

Intestinal epithelial barrier dysfunction is a key pathology of colitis. Autophagy of epithelial cells maintains homeostasis of the intestinal barrier by inhibiting apoptosis and stimulating degradation of the tight junction protein claudin-2. This study investigated the effects and mechanism of activity of sinensetin, a polymethylated flavonoid isolated from tangerine peel and citrus, on intestinal barrier dysfunction in colitis. Animal model of colitis were established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid and oral treatment with dextran sulfate sodium. Epithelial barrier function was evaluated by measuring the serum recovery of fluorescein isothiocyanate-4 kD dextran in vivo and transepithelial electrical resistance in Caco-2 cells, respectively. Epithelial cell autophagy assayed by autophagosome formation and expression of autophagy-related protein. Sinensetin reversed colitis-associated increase in intestinal permeability, significantly promoted epithelial cell autophagy, and further decreased epithelial cell apoptosis, and reduced mucosal claudin-2. Sinenstetin alleviated colitis symptoms rats and mice with colitis. Knockdown of 5' adenosine monophosphate-activated protein kinase (AMPK) reversed the promotion of epithelial autophagy by sinensetin. In conclusion, sinensetin significantly alleviated intestinal barrier dysfunction in colitis by promoting epithelial cell autophagy, and further inhibiting apoptosis and promoting claudin-2 degradation. The results highlighted novel potential benefits of sinensetin in colitis.

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