RESUMO
BACKGROUND: Metformin has been shown to have potent analgesic effects; however, the underlying mechanism of synaptic plasticity mediating analgesia remained ambiguous. METHODS: In this study, animal behavioral tests, whole-cell patchclamp recording, immunofluorescence staining, and network pharmacology techniques were applied to elucidate the mechanisms and potential targets of metformin-induced analgesia. RESULTS: Single or consecutive injections of metformin significantly inhibited spinal nerve ligation (SNL)-induced neuropathic pain, and formalin-induced acute inflammatory pain. Network pharmacology analysis of metformin action targets in pain database-related targets revealed 25 targets, including five hub targets (nitric oxide synthase 1 (NOS1), NOS2, NOS3, epidermal growth factor receptor (EGFR), and plasminogen (PLG)). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that metformin-induced analgesia was markedly correlated with calcium signaling and synaptic transmission. Intrathecal injection of metformin significantly reversed nerve injury-induced c-Fos (neural activity biomarker) mRNA and protein expression in neuropathic rats by regulating NOS2 expression. In addition, whole-cell recordings of isolated spinal neurons demonstrated that metformin dose-dependently inhibited the enhanced frequency and amplitude of miniature excitatory synaptic currents (mEPSCs) but did not affect those of miniature inhibitory synaptic currents (mIPSCs) in neuropathic pain. CONCLUSIONS: This study further demonstrated that metformin might inhibit spinal glutamatergic transmission and abnormal nociceptive circuit transduction by monitoring synaptic transmission in pain. Results of this work provide an in-depth understanding of metformin analgesia via synaptic plasticity.
Assuntos
Neuralgia , Transmissão Sináptica , Ratos , Animais , Ratos Sprague-Dawley , Transmissão Sináptica/fisiologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Nervos Espinhais/metabolismo , Neurônios/metabolismoRESUMO
BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common types in the world with a high mortality rate. Despite advances in treatment strategies, the overall survival (OS) remains short. Our study aims to establish a reliable prognostic signature closely related to the survival of LUAD patients that can better predict prognosis and possibly help with individual monitoring of LUAD patients. METHODS: Raw RNA-sequencing data were obtained from Fudan University and used as a training group. Differentially expressed genes (DEGs) for the training group were screened. The univariate, least absolute shrinkage and selection operator (LASSO), and multivariate cox regression analysis were conducted to identify the candidate prognostic genes and construct the risk score model. Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic power and performance of the signature. Moreover, The Cancer Genome Atlas (TCGA-LUAD) dataset was further used to validate the predictive ability of prognostic signature. RESULTS: A prognostic signature consisting of seven prognostic-related genes was constructed using the training group. The 7-gene prognostic signature significantly grouped patients in high and low-risk groups in terms of overall survival in the training cohort [hazard ratio, HR = 8.94, 95% confidence interval (95% CI)] [2.041-39.2]; P = 0.0004), and in the validation cohort (HR = 2.41, 95% CI [1.779-3.276]; P < 0.0001). Cox regression analysis (univariate and multivariate) demonstrated that the seven-gene signature is an independent prognostic biomarker for predicting the survival of LUAD patients. ROC curves revealed that the 7-gene prognostic signature achieved a good performance in training and validation groups (AUC = 0.91, AUC = 0.7 respectively) in predicting OS for LUAD patients. Furthermore, the stratified analysis of the signature showed another classification to predict the prognosis. CONCLUSION: Our study suggested a new and reliable prognostic signature that has a significant implication in predicting overall survival for LUAD patients and may help with early diagnosis and making effective clinical decisions regarding potential individual treatment.
RESUMO
The liquid biopsy is being integrated into cancer diagnostics and surveillance. However, critical questions still remain, such as how to precisely evaluate cancer mutation burden and interpret the corresponding clinical implications. Herein, we evaluated the role of peripheral blood cell-free DNA (cfDNA) in characterizing the dynamic mutation alterations of 48 cancer driver genes from cervical cancer patients. We performed targeted deep sequencing on 93 plasma cfDNA from 57 cervical cancer patients and from this developed an algorithm, allele fraction deviation (AFD), to monitor in an unbiased manner the dynamic changes of genomic aberrations. Differing treatments, including chemotherapy (n = 22), radiotherapy (n = 14) and surgery (n = 15), led to a significant decrease in AFD values (Wilcoxon, p = 0.029). The decrease of cfDNA AFD values was accompanied by shrinkage in the size of the tumor in most patients. However, in a subgroup of patients where cfDNA AFD values did not reflect a reduction in tumor size, there was a detection of progressive disease (metastasis). Furthermore, a low AFD value at diagnosis followed a later increase of AFD value also successfully predicted relapse. These results show that plasma cfDNA, together with targeted deep sequencing, may help predict treatment response and disease development in cervical cancer.
Assuntos
Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Alelos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Quimiorradioterapia/métodos , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Genoma/genética , Genômica/métodos , Humanos , Pessoa de Meia-Idade , Mutação/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapiaRESUMO
This study reports the development of a novel dummy template molecularly imprinted polymer (MIP)-coated barbell-shaped stir bar. The MIP stir bar coatings were prepared by using 2,2-bis(4-hydroxyphenyl)butane (BPB), 4,4'-dihydroxydiphenylmethane (BPF), 4-tert-butylphenol (PTBP), and tetrabromobisphenol A (TBBA) as dummy templates using a capillary in situ polymerization method. Uniform coatings can be prepared controllably. The method is simple, easy, and reproducible. The barbell-shaped stir bar was developed by using medical silicone tubes as wheels. The wheels could be removed and reinstalled when necessary; therefore, the barbell-shaped stir bar was easy to disassemble and reassemble. The novel MIP-coated stir bar showed good selectivity for the target analyte, bisphenol A (BPA). The established method is selective and sensitive with a lower detection limit for BPA of 0.003 µg/L. The dummy template MIP-coated stir bar is suitable for trace BPA analysis in real environmental water samples without template leakage. The novel stir bar can be used at least 100 times.
RESUMO
Accurate indel calling plays an important role in precision medicine. A benchmarking indel set is essential for thoroughly evaluating the indel calling performance of bioinformatics pipelines. A reference sample with a set of known-positive variants was developed in the FDA-led Sequencing Quality Control Phase 2 (SEQC2) project, but the known indels in the known-positive set were limited. This project sought to provide an enriched set of known indels that would be more translationally relevant by focusing on additional cancer related regions. A thorough manual review process completed by 42 reviewers, two advisors, and a judging panel of three researchers significantly enriched the known indel set by an additional 516 indels. The extended benchmarking indel set has a large range of variant allele frequencies (VAFs), with 87% of them having a VAF below 20% in reference Sample A. The reference Sample A and the indel set can be used for comprehensive benchmarking of indel calling across a wider range of VAF values in the lower range. Indel length was also variable, but the majority were under 10 base pairs (bps). Most of the indels were within coding regions, with the remainder in the gene regulatory regions. Although high confidence can be derived from the robust study design and meticulous human review, this extensive indel set has not undergone orthogonal validation. The extended benchmarking indel set, along with the indels in the previously published known-positive set, was the truth set used to benchmark indel calling pipelines in a community challenge hosted on the precisionFDA platform. This benchmarking indel set and reference samples can be utilized for a comprehensive evaluation of indel calling pipelines. Additionally, the insights and solutions obtained during the manual review process can aid in improving the performance of these pipelines.
Assuntos
Benchmarking , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biologia Computacional , Controle de Qualidade , Mutação INDEL , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Neuropathic pain (NP), resulting from nerve injury, alters neural plasticity in spinal cord and brain via the release of inflammatory mediators. The remodeling of store-operated calcium entry (SOCE) involves the refilling of calcium in the endoplasmic reticulum via STIM1 and Orai1 proteins and is crucial for maintaining neural plasticity and neurotransmitter release. The mechanism underlying SOCE-mediated NP remains largely unknown. In this study, we found SOCE-mediated calcium refilling was significantly higher during neuropathic pain, and the major component Orai1 was specifically co-localized with neuronal markers. Intrathecal injection of SOCE antagonist SKF96365 remarkably alleviated nerve injury- and formalin-induced pain and suppressed c-Fos expression in response to innocuous mechanical stimulation. RNA sequencing revealed that SKF96365 altered the expression of spinal transcription factors, including Fos, Junb, and Socs3, during neuropathic pain. In order to identify the genes critical for SKF96365-induced effects, we performed weighted gene co-expression network analysis (WGCNA) to identify the genes most correlated with paw withdrawal latency phenotypes. Of the 16 modules, MEsalmon module was the most highly correlated with SKF96365 induced effects. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the enriched genes of MEsalmon module were significantly related to Toll-like receptor signaling, steroid biosynthesis, and chemokine signaling, which may mediate the analgesic effect caused by SKF9636 treatment. Additionally, the SOCE antagonist YM-58483 produced similar analgesic effects in nerve injury- and formalin-induced pain. Our results suggest that manipulation of spinal SOCE signaling might be a promising target for pain relief by regulating neurotransmitter production and spinal transcription factor expression.
Assuntos
Canais de Cálcio , Neuralgia , Humanos , Canais de Cálcio/genética , Cálcio/metabolismo , Células Cultivadas , Neuralgia/tratamento farmacológico , Fatores de Transcrição/metabolismo , Formaldeído , Neurotransmissores , AnalgésicosRESUMO
Certified RNA reference materials are indispensable for assessing the reliability of RNA sequencing to detect intrinsically small biological differences in clinical settings, such as molecular subtyping of diseases. As part of the Quartet Project for quality control and data integration of multi-omics profiling, we established four RNA reference materials derived from immortalized B-lymphoblastoid cell lines from four members of a monozygotic twin family. Additionally, we constructed ratio-based transcriptome-wide reference datasets between two samples, providing cross-platform and cross-laboratory 'ground truth'. Investigation of the intrinsically subtle biological differences among the Quartet samples enables sensitive assessment of cross-batch integration of transcriptomic measurements at the ratio level. The Quartet RNA reference materials, combined with the ratio-based reference datasets, can serve as unique resources for assessing and improving the quality of transcriptomic data in clinical and biological settings.
RESUMO
Characterization and integration of the genome, epigenome, transcriptome, proteome and metabolome of different datasets is difficult owing to a lack of ground truth. Here we develop and characterize suites of publicly available multi-omics reference materials of matched DNA, RNA, protein and metabolites derived from immortalized cell lines from a family quartet of parents and monozygotic twin daughters. These references provide built-in truth defined by relationships among the family members and the information flow from DNA to RNA to protein. We demonstrate how using a ratio-based profiling approach that scales the absolute feature values of a study sample relative to those of a concurrently measured common reference sample produces reproducible and comparable data suitable for integration across batches, labs, platforms and omics types. Our study identifies reference-free 'absolute' feature quantification as the root cause of irreproducibility in multi-omics measurement and data integration and establishes the advantages of ratio-based multi-omics profiling with common reference materials.
RESUMO
Cognitive impairments are core aspects of schizophrenia and are highly related to poor outcomes. However, the effect of therapy on cognitive impairments remains unsatisfactory as its biological mechanisms are not fully understood. The purpose of this study was to investigate the disrupted intrinsic neural activity of the frontal areas and to further examine the functional connectivity of frontal areas related to cognitive impairments in schizophrenia. We collected brain imaging data using a 3T Siemens Prisma MRI system in 32 patients with schizophrenia and 34 age- and sex-matched healthy controls. The mean fractional amplitude of low-frequency fluctuation (mfALFF) in the frontal regions was calculated and analyzed to evaluate regional neural activity alterations in schizophrenia. Seed regions were generated from clusters showing significant changes in mfALFF in schizophrenia, and its resting-state functional connectivity (rs-FC) with other brain regions were estimated to detect possible aberrant rs-FC indicating cognitive impairments in schizophrenia. We found that mfALFF in the bilateral frontal cortices was increased in schizophrenia. mfALFF-based rs-FC revealed that decreased rs-FC between left middle frontal gyrus (MFG) and left medial superior frontal gyrus (MFSG) was associated with poor delayed memory (r = 0.566, Bonferroni-corrected p = 0.012). These findings demonstrate increased neural activity in the frontal cortices in schizophrenia. FC analysis revealed a diminished rs-FC pattern between the left MFG and left MSFG that was associated with cognitive impairments. These findings have provided deeper insight into the alterations in brain function related to specific domains of cognitive impairment and may provide evidence for precise interventions for cognitive deficits in schizophrenia.
Assuntos
Disfunção Cognitiva , Esquizofrenia , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Lobo Frontal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Esquizofrenia/diagnóstico por imagemRESUMO
Deficit schizophrenia (DS) patient is a homogenous subtype of schizophrenia that includes primary and enduring negative symptoms. This study aimed to compare the differences in cognitive functioning and plasma levels of C-reactive protein (CRP) and inflammatory cytokines among DS patients, nondeficit schizophrenia (NDS) patients, and healthy controls (HCs). A total of 141 schizophrenia patients and 67 HCs were included in this study. The schizophrenia patients were divided into DS (N= 51) and NDS (N=90) groups based on the Proxy for the Deficit Syndrome Scale (PDS). The Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were used to evaluate the clinical symptoms and cognitive performances, respectively. The plasma level of CRP, IL-1ß, Il-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNF-α, and IFN-γ were measured using enzyme-linked immunosorbent assays (ELISAs). Our results showed that DS patients had the worst cognitive performance, especially in the immediate memory, attention, and language dimensions, compared to the NDS and HC groups. Compared to the HCs group, DS patients had higher levels of CRP, IL-1ß, IL-6, IL-8, IFN-γ, and total proinflammatory cytokines, and NDS patients had higher levels of IL-1ß, IFN-γ, and proinflammatory cytokines. We also found that CRP levels were significantly increased in DS patients compared to NDS patients. Moreover, stepwise logistic regression analysis revealed that CRP is an independent risk factor for DS. Sex stratification analysis showed significant differences in almost all cytokines in female samples but not in male samples. The significant differences in cognitive performance and inflammatory components among groups suggest that deficit syndrome is an independent endophenotype of schizophrenia patients with unique immune-inflammatory features, but may have sex characteristics.
Assuntos
Esquizofrenia , Feminino , Humanos , Masculino , Biomarcadores , Cognição , Interleucina-6 , Interleucina-8 , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismoRESUMO
BACKGROUND: The anterior cingulate cortex (ACC) is a crucial region in the pathophysiology of major depressive disorder (MDD). However, the relationship between functional alterations of the ACC subregions, anhedonia and sleep quality remains unclear in MDD patients. METHODS: The resting-state functional connectivity (rsFC) of ACC subregions was measured in 41 first-episode medication-naïve MDD patients and 63 healthy controls who underwent functional magnetic resonance imaging. Between-group differences were examined using two-sample t-test. Furthermore, correlation and mediation analyses were carried out to investigate the relationships between the aberrant rsFC of ACC subregions, anhedonia and sleep quality in the patients and controls. RESULTS: Compared to healthy controls, the MDD patients exhibited increased rsFC of ACC subregions to areas of the anterior default mode network (DMN) and showed decreased rsFC of the right subgenual ACC to left precuneus (PCUN), which belongs to the posterior DMN. In MDD group, the sleep quality and consummatory anhedonia are correlated with some rsFC, which involves the angular gyrus (ANG) and superior frontal gyrus (SFG). More importantly, the rsFC between the right perigenual ACC and left SPG mediates the association between anhedonia and sleep quality in MDD. LIMITATIONS: The cross-sectional design and the subjective questionaries for assessment. CONCLUSION: These findings confirm the functional alterations of the ACC subregions and reveal the mediating role of ACC subregions in sleep and reward dysfunction in MDD.
Assuntos
Transtorno Depressivo Maior , Anedonia , Estudos Transversais , Transtorno Depressivo Maior/diagnóstico por imagem , Giro do Cíngulo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Qualidade do SonoRESUMO
Orexin-A and brain-derived neurotrophic factor (BDNF) are implicated in regulating metabolic syndrome (MetS) and cognitive impairment of schizophrenia. However, the associations among them remains unclear. Here, we aimed to investigate the relationship between Orexin-A levels, BDNF, MetS, clinical symptom profile, and cognitive function in schizophrenia patients following long-term clozapine treatment. We measured Orexin-A and BDNF levels in 140 schizophrenia patients with and without MetS. We assessed clinical symptoms on the Positive and Negative Syndrome Scale and cognitive function by the assessment of Neuropsychological Status (RBANS), and examined their associations with Orexin-A. Patients with MetS had significantly lower Orexin-A levels and higher coding test, attention span and delayed retention in RBANS (P < 0.05). Correlation analysis showed that Orexin-A was associated with BDNF, TG, HDLC, PANSS active social avoidance and emotional withdrawal significantly. Besides, Orexin-A significantly interacted with BDNF for metabolic and cognitive profiles including waist circumference, delayed retention and list recognition. Logistic regression analysis showed that Orexin-A level (odds ratio [OR] = 0.380, 95% confidence interval [CI]: 0.151-0.952, P = 0.039) and total illness duration (OR = 0.932, 95% CI: 0.875-0.991, P = 0.025) were predictive variables of MetS. However, there was no significant relationship between Orexin-A and cognitive function after adjustment for age, sex and educational levels. Totally, a lower plasma Orexin-A level seems to be related to metabolic parameters more than cognitive profiles. The interaction of Orexin-A with BDNF may be partly responsible for worse MetS and better cognition of elderly schizophrenia, but the causal relationship needs further clarification.
Assuntos
Clozapina , Disfunção Cognitiva , Síndrome Metabólica , Esquizofrenia , Idoso , Fator Neurotrófico Derivado do Encéfalo , Clozapina/uso terapêutico , Disfunção Cognitiva/complicações , Humanos , Síndrome Metabólica/complicações , Orexinas , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológicoRESUMO
BACKGROUND: Malaria significantly rebounded in 2018 in the Comoros; this created an urgent need to conduct clinical trials to investigate the effectiveness of artemisinin and its derivatives. METHODS: An open-label, non-randomised controlled trial of artemisinin-piperaquine (AP) and artemether-lumefantrine (AL) was conducted in Grande Comore island from June 2019 to January 2020. A total of 238 uncomplicated falciparum malaria cases were enrolled and divided 1:1 into two treatments. The primary endpoint was the 42-day adequate clinical and parasitological responses (ACPR). Secondary endpoints were parasitaemia and fever clearance at day 3, gametocytes and tolerability. RESULTS: The 42-day ACPR before and after PCR correction were 91.43% (95% CI 83.93-95.76%) and 98.06% (95% CI 92.48-99.66%) for AP treatment, respectively, and 96.00% (95% CI 88.17-98.14%) and 98.97% (95% CI 93.58-99.95%) for AL treatment, respectively. Complete clearance of the parasitaemia and fever for both groups was detected on day 3. Gametocytes disappeared on day 21 in the AP group and on day 2 in AL group. Specifically, the adverse reactions were mild in both groups. CONCLUSIONS: It was found that AP and AL maintained their high efficacy and tolerance in the Comoros. Nonetheless, asymptomatic malaria infections bring new challenges to malaria control.
Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Malária , Quinolinas , Antimaláricos/efeitos adversos , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/efeitos adversos , Combinação de Medicamentos , Etanolaminas/efeitos adversos , Fluorenos/efeitos adversos , Humanos , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Piperazinas , Plasmodium falciparum , Quinolinas/efeitos adversosRESUMO
It has been proposed that immune abnormalities may be implicated with pathophysiology of schizophrenia. The nod-like receptor pyrin domain-contraining protein 3 (NLRP3) can trigger immune-inflammatory cascade reactions. In this study, we intended to identify the role of gene encoding NLRP3 (NLRP3) in susceptibility to schizophrenia and its clinical features. For the NLRP3 mRNA expression analysis, 53 drug-naïve patients with first-episode schizophrenia and 56 healthy controls were enrolled. For the genetic study, a total of 823 schizophrenia patients and 859 controls were recruited. Among them, 239 drug-naïve patients with first-episode schizophrenia were enrolled for clinical evaluation. There is no significant difference in NLRP3 mRNA levels between patients with schizophrenia and healthy controls (p = 0.07). We did not observe any significant differences in allele and genotype frequencies of rs10754558 polymorphism between the schizophrenia and control groups. We noticed significant differences in the scores of RBANS attention and total scores between the patients with different genotypes of rs10754558 polymorphism (p = 0.001 and p < 0.01, respectively). Further eQTL analysis presented a significant association between the rs10754558 polymorphism and NLRP3 in frontal cortex (p = 0.0028, p = 0.028 after Bonferroni correction). Although our findings did not support NLRP3 confer susceptibility to schizophrenia, NLRP3 may be a risk factor for cognitive impairment, especially attention deficit in this disorder.
RESUMO
Objectives: To investigate the differences in psychotic symptoms and cognitive function in schizophrenics with and without depression and to compare gender differences in the correlation between depressive symptoms and clinical characteristics in those patients. Methods: A total of 190 schizophrenia patients and 200 healthy controls were recruited in the study. We used the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to evaluate the psychiatric symptoms, depressive symptoms and cognitive function, respectively. Patients with CDSS score ≥7 were divided into depression group, and CDSS < 7 was viewed as without depression. Results: Patients with schizophrenia had lower total scores of RBANS and five subscale (immediate memory, visual span, verbal function, attention, and delayed memory) scores compared to healthy controls. In the case group, patients who concomitant with depression had higher PANSS scores (Ps < 0.001) and lower RBANS (Ps < 0.05) scores than those without depression. After gender stratification, PANSS total scores and subscale scores were significantly different between schizophrenics with and without depressive symptoms in both male and female groups (Ps < 0.001). For cognitive function, there were significant differences in RBANS total score and subscale scores except attention between female patients with and without schizophrenia but not in male schizophrenia patients. Furthermore, the correlation analysis showed that the total CDSS score was positively correlated with PANSS score (P < 0.001) and RBANS score in male and female groups (male: P = 0.010, female: P = 0.001). Conclusion: Our findings provided evidence supporting the gender differences in psychiatric symptoms and cognitive function between schizophrenia patients with and without depressive symptoms.
RESUMO
OBJECTIVES: Previous studies and meta-analysis indicated that rs1344706 was associated with schizophrenia in European population, whereas the conclusions in other populations were disputed. To further explore whether the allele A of rs1344706 would increase the risk of schizophrenia in different populations and update the original meta-analysis, we conducted a systematic review and meta-analysis worldwide. METHODS: A literature search was performed in PubMed, Embase, Cochrane Library, PsycINFO and Web of Science (up to 10 July 2019) according to the inclusion criteria. RESULTS: A total of 27 articles were included. Our meta-analysis showed an association between rs1344706 and schizophrenia in total populations [P = 0.000; odds ratio (OR) = 1.105; 95% confidence interval (CI), 1.048-1.165], Europe population (P = 0.025; OR = 1.108; 95% CI, 1.013-1.222) and Asian population(P = 0.005; OR = 1.094; 95% CI, 1.027-1.164). CONCLUSIONS: Our findings suggested that the risk of single nucleotide polymorphism rs1344706 A-allele may increase the risk of schizophrenia worldwide. Also, this ethnicity-dependent effects of ZNF804A variant on schizophrenia may be related to the opposite allele direction. But to elucidate the underlying biological mechanism, further studies with large participant populations are needed.
Assuntos
Etnicidade/genética , Fatores de Transcrição Kruppel-Like/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Alelos , Povo Asiático/genética , Europa (Continente)/etnologia , Humanos , Íntrons/genética , Risco , Esquizofrenia/etnologia , População Branca/genéticaRESUMO
We use measured aerosol fine particulate matter (PM2.5) data, moderate resolution imaging spectroradiometer (MODIS) aerosol optical depth (AOD) data, and meteorological parameters (temperature, wind speed, wind direction, boundary layer height, and relative humidity) from the Chinese national control monitoring network, to consider seasonal and regional differences in the relationship between AOD and PM2.5. We propose a two-stage combined estimation model of PM2.5 concentrations based on the ε-support vector regression (ε-SVR/Epsilon-SVR) and the Mind Evolutionary Computation-BP neural network (MEC-BP) for analyzing spatiotemporal variations in PM2.5 concentrations in China between 2000 and 2017. The results showed that the two-stage combined estimation model provided a reliable estimation of the monthly ground-level PM2.5 concentrations at a spatial resolution of 1°×1° during 2000-2017 in China. This effectively offsets the time and space gaps in the current data sets of the ground monitoring network (R2=0.838, root mean square errors (RMSE)=11.512 µg·m-3, mean absolute percentage error (MAPE)=14.905%, mean squared percentage error (MSPE)=0.243%, mean absolute error (MAE)=6.476 µg·m-3, mean squared error (MSE)=132.519 µg·m-3). The preliminary spatiotemporal analysis results showed that:â Over the period 2000-2017, 2014 represented an important demarcation point for the annual PM2.5 concentration, as its trend changed from one of continuous increase to one of rapid decrease. The PM2.5 concentration decreases more rapidly in areas with high concentrations of PM2.5 in particular, including the northern coastal area, the eastern coastal area, and the middle reaches of the Changjiang River. â¡ During the studied period, the annual average PM2.5 concentration exceeded the second level criterion of the Chinese national air quality standard (35 µg·m-3) over more than 65% of China. Although the PM2.5 pollution situation in China improved to a certain extent in the latter years of the studied period, the air pollution situation remained poor.
RESUMO
Objective: Previous studies consistently showed the interaction between Sirtuin 1 (SIRT1) and immune inflammation is significantly related to metabolic abnormalities, but their role in the pathogenesis of metabolic syndrome caused by second-generation antipsychotics (SGAs) in schizophrenia patients largely remains unknown. Hence, the present study aimed to fill this gap. Methods: A total of 54 schizophrenia patients with olanzapine or clozapine monotherapy [metabolic syndrome (MetS)/non-MetS patients, 27/27] and 67 healthy subjects were recruited in the present study. The Positive and Negative Syndrome Scale was used, and the plasma levels of SIRT1, interleukin 6 (IL-6), IL-8, IL-10, and tumor necrosis factor α (TNF-α) were measured. Results: The results showed that schizophrenia patients treated with olanzapine or clozapine (both MetS and non-MetS groups) had significantly higher plasma levels of IL-6, IL-10, and TNF-α compared to normal controls (all P < 0.05). Moreover, the MetS patients exhibited markedly lower plasma levels of SIRT1 and higher plasma levels of IL-6 than non-MetS patients and normal controls (all P < 0.05). However, there were no significant differences in IL-8 levels between groups. Our correlation analysis showed that SIRT1 was significantly correlated with diastolic blood pressure, triglyceride, and high-density lipoprotein cholesterol in schizophrenia patients. The stepwise logistic regression analysis further identified the IL-6 × SIRT1 (ß = -0.463, t = 10.040, P = 0.002) as the influencing factor for the MetS in the patients. Conclusion: Our preliminary findings suggest that SIRT1 interacted with inflammatory cytokines associated with MetS in schizophrenia patients treated with SGA monotherapy.
RESUMO
PURPOSE: Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia and its progressive genomic basis over time remains unclear. We aimed to investigate the longitudinal genomic evolution of MPAL from diagnosis to relapse. METHODS: We performed whole genome sequencing (WGS) on bone marrow (BM) samples obtained at the four stages of this disease in a male patient with Philadelphia chromosome positive (Ph+) MPAL, including primary, complete cytogenetic remission (CCR), complete molecular remission (CMR), and relapse stage during the 3 year follow-up period. RESULTS: 156 single-nucleotide variants (SNVs) and indels were detected, which exhibited distinctive evolutionary behaviors. Seventeen mutations disappeared quickly upon DCTER treatment and never came back. Seven mutations, although disappeared initially, reoccurred with the withdrawal of TKI treatment. Notably, ten mutations emerged in spite of the active DCTER chemotherapy. Moreover, copy number loss played critical roles in monitoring MPAL progression, displaying 7, 0, 0, and 383 losses at the stages of primary, CCR, CMR, and relapse respectively. CONCLUSION: This longitudinal genomic investigation of the Ph+ MPAL patient established one MPAL evolution model in which the primary tumor acquired additional variations leading to tumor relapse. Moreover, the event of copy number loss remained a valuable hallmark in the progression of MPAL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Evolução Clonal , Variações do Número de Cópias de DNA , Leucemia Aguda Bifenotípica/genética , Recidiva Local de Neoplasia/genética , Adulto , Análise Mutacional de DNA , Progressão da Doença , Humanos , Leucemia Aguda Bifenotípica/tratamento farmacológico , Leucemia Aguda Bifenotípica/patologia , Estudos Longitudinais , Masculino , Recidiva Local de Neoplasia/patologia , Cromossomo Filadélfia , Sequenciamento Completo do GenomaRESUMO
INTRODUCTION: Targeted therapies are based on specific gene alterations. Various specimen types have been used to determine gene alterations, however, no systemic comparisons have yet been made. Herein, we assessed alterations in selected cancer-associated genes across varying sample sites in lung cancer patients. MATERIALS AND METHODS: Targeted deep sequencing for 48 tumor-related genes was applied to 153 samples from 55 lung cancer patients obtained from six sources: Formalin-fixed paraffin-embedded (FFPE) tumor tissues, pleural effusion supernatant (PES) and pleural effusion cell sediments (PEC), white blood cells (WBCs), oral epithelial cells (OECs), and plasma. RESULTS: Mutations were detected in 96% (53/55) of the patients and in 83% (40/48) of the selected genes. Each sample type exhibited a characteristic mutational pattern. As anticipated, TP53 was the most affected sequence (54.5% patients), however this was followed by NOTCH1 (36%, across all sample types). EGFR was altered in patient samples at a frequency of 32.7% and KRAS 10.9%. This high EGFR/ low KRAS frequency is in accordance with other TCGA cohorts of Asian origin but differs from the Caucasian population where KRAS is the more dominant mutation. Additionally, 66% (31/47) of PEC samples had copy number variants (CNVs) in at least one gene. Unlike the concurrent loss and gain in most genes, herein NOTCH1 loss was identified in 21% patients, with no gain observed. Based on the relative prevalence of mutations and CNVs, we divided lung cancer patients into SNV-dominated, CNV-dominated, and codominated groups. CONCLUSIONS: Our results confirm previous reports that EGFR mutations are more prevalent than KRAS in Chinese lung cancer patients. NOTCH1 gene alterations are more common than previously reported and reveals a role of NOTCH1 modifications in tumor metastasis. Furthermore, genetic material from malignant pleural effusion cell sediments may be a noninvasive manner to identify CNV and participate in treatment decisions.