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1.
BMC Infect Dis ; 21(1): 987, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548016

RESUMO

BACKGROUND: We conducted a distributed lag non-linear time series analysis to quantify the association between air pollution and scarlet fever in Qingdao city during 2014-2018. METHODS: A distributed lag non-linear model (DLNM) combined with a generalized additive mixed model (GAMM) was applied to quantify the distributed lag effects of air pollutions on scarlet fever, with daily incidence of scarlet fever as the dependent variable and air pollutions as the independent variable adjusted for potential confounders. RESULTS: A total of 6316 cases of scarlet fever were notified, and there were 376 days occurring air pollution during the study period. Scarlet fever was significantly associated with air pollutions at a lag of 7 days with different relative risk (RR) of air pollution degrees [1.172, 95% confidence interval (CI): 1.038-1.323 in mild air pollution; 1.374, 95% CI 1.078-1.749 in moderate air pollution; 1.610, 95% CI 1.163-2.314 in severe air pollution; 1.887, 95% CI 1.163-3.061 in most severe air pollution]. CONCLUSIONS: Our findings show that air pollution is positively associated with scarlet fever in Qingdao, and the risk of scarlet fever could be increased along with the degrees of air pollution. It contributes to developing strategies to prevent and reduce health impact from scarlet fever and other non-vaccine-preventable respiratory infectious diseases in air polluted areas.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Escarlatina , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , China/epidemiologia , Cidades , Humanos , Escarlatina/epidemiologia
2.
Commun Biol ; 4(1): 1034, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465887

RESUMO

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10-10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10-9, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10-8, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19.


Assuntos
COVID-19/etnologia , COVID-19/genética , Grupos Étnicos/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença/genética , Humanos , Íntrons/genética , Polimorfismo de Nucleotídeo Único
3.
Tissue Cell ; 73: 101635, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34482185

RESUMO

Schwann cells can promote the survival of damaged neurons and axon regeneration by secreting or releasing some proteins and factors which may provide effective strategies to the remedy for ischemic stroke. The models of middle cerebral artery occlusion and oxygen-glucose deprivation (OGD) were established. Peroxiredoxin 6 (PRDX6) was found in Schwann-like cell conditioned medium (SCLC-CM) by mass spectrometry. The rehabilitative performance of SCLC-CM on focal cerebral ischemia of rats and on OGD-induced PC12 cells were assessed. SCLC-CM significantly improved neurological recovery, reducing the infarct volume of rats after stroke. PRDX6 could significantly inhibit neuron apoptosis in the OGD injury by mediating oxidative stress and activating the PTEN/PI3K/AKT pathway. In conclusion, PRDX6 secreted by Schwann-like cell protects neuron against focal cerebral ischemia, SCLC-CM might be a new effective early intervention for ischemic stroke.

4.
Pathol Res Pract ; 227: 153615, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34562827

RESUMO

BACKGROUND: CircRNAs are a new subset of noncoding RNAs formed by covalent closed loops and play crucial roles in the regulation of cancer gene expression. However, the roles and underlying mechanisms of circRNAs in gastric cancer (GC) remain indistinct. This study aimed to explore the role and mechanism of hsa_circ_0006421 (circPTK2) in GC. METHODS: The differential expression of circRNAs between GC tissues and adjacent normal tissues were identified by a circRNA expression profiling. Associations of circPTK2 or miR-134-5p expression with clinicopathological characteristics and prognosis of GC patients were analyzed by chi-square of Fisher's exact tests and Kaplan-Meier analysis. CCK8, colony formation, EdU assays and animal models were performed to assess the effects of circPTK2 on proliferation and invasion of GC cells. CircPTK2-specific probes were used to purify the RNA pulled down from the circPTK2, and enrichment of circPTK2 and miR-134-5p was detected by qRT-PCR. The effects of circPTK2 on miR-134-5p expression and CELF2/PTEN signaling were examined by qRT-PCR and Western blotting analysis. RESULTS: Low expression of circPTK2 and high expression of miR-134-5p were related to the poor survival, and high expression of miR-134-5p was related to the tumor recurrence in GC patients. Overexpressing circPTK2 suppressed the proliferation, colony formation, DNA synthesis and cell invasion as well as xenograft tumor growth and lung metastasis in vitro and in vivo, whereas silencing circPTK2 had the opposite effects. Moreover, circPTK2 was negatively correlated and co-localized with miR-134-5p in the cytoplasm of GC tissue cells. circPTK2 bound to and sponged miR-134-5p in GC cells, and miR-134-5p facilitated cell growth and invasion but attenuated circPTK2 induced tumor suppressive effects and CELF2/PTEN signaling activation in GC cells. CONCLUSIONS: circPTK2 functions as a tumor suppressor in GC by sponging miR-134-5p and activating the CELF2/PTEN axis.

5.
J Neurosurg ; : 1-10, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34450582

RESUMO

OBJECTIVE: Moyamoya disease (MMD) is a chronic, progressive steno-occlusive condition of the distal internal carotid arteries of unknown etiology. Collateral arterial networks typically develop in MMD, bypassing the steno-occlusion. Aneurysms arising on the collateral networks are a known source of hemorrhage. The choroidal collateral system is the most common location for collateral pathway aneurysms in MMD and associated hemorrhage. The authors performed data collection and analysis to further elucidate the best treatment approaches for ruptured aneurysms of the choroidal collateral system in MMD, which as yet remain unclear. METHODS: A comprehensive data collection and analysis of case reports and case series with ruptured choroidal collateral artery aneurysms (CCAAs) was performed. PRISMA guidelines for systematic reviews were followed and the Medline, Embase, and Scopus databases were searched for relevant studies. A database was created including patients with ruptured CCAA in MMD. Original data from case series were included whenever possible. A previously unreported case of a ruptured choroidal artery aneurysm in MMD treated by the authors was also included. RESULTS: The database comprised 72 patients with ruptured CCAA in MMD. The most common clinical symptoms were headache, nausea, and vomiting (39%). Initially, a conservative treatment approach was chosen in 29% of cases but led to rehemorrhage in 40% of cases; 63% of these rehemorrhages occurred during the first 35 days. Endovascular treatment seemed a safe option for aneurysm exclusion, mainly through parent vessel sacrifice, but had a treatment failure rate of 21%, due to inadequate access. Aneurysm treatment with revascularization as the initial treatment strategy led to aneurysm regression in 82% with no reported rehemorrhage. Aneurysm exclusion through open surgery was effective but was associated with a relatively high complication rate (25%). Outcome after rupture of CCAA was poor, with 41% of patients deceased or permanently disabled. Overall, patient outcomes were better in the endovascular and revascularization treatment group than in the conservative treatment group. CONCLUSIONS: Rupture of CCAA in MMD is associated with high morbidity and rerupture rate requiring urgent treatment.

6.
Diabetes ; 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376476

RESUMO

Foot process effacement is an important feature of early diabetic nephropathy (DN) which is closely related to the development of albuminuria. Under certain nephrotic conditions, the integrity and function of the glomerular slit diaphragm (SD) structure were impaired and replaced by the tight junction (TJ) structure, resulting in so-called SD-TJ transition, which could partially explain the effacement of foot processes at the molecular level. However, the mechanism underlying the SD-TJ transition has not been described in DN. Here, we demonstrated that impaired autophagic flux blocked p62 mediated degradation of ZO-1 (TJ protein) and promoted podocytes injury via activation of caspase 3 and caspase 8. Interestingly, the expression of VDR in podocytes was decreased under diabetic condition which impaired autophagic flux through down-regulating Atg3. Of note, we also found that VDR abundance was negatively associated with impaired autophagic flux and SD-TJ transition in the glomeruli from human renal biopsy samples with DN. Furthermore, VDR activation improved autophagic flux and attenuated SD-TJ transition in the glomeruli of diabetic animal models. In conclusion, our data provided the novel insight that VDR/Atg3 axis deficiency resulted in SD-TJ transition and foot processes effacement via blocking p62-mediated autophagy pathway in DN.

7.
BMC Med ; 19(1): 175, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34344359

RESUMO

BACKGROUND: The differential effect of pre-pregnancy low BMI on macrosomia has not been fully addressed. Herein, we conducted a city-wide population-based cohort study to illuminate the association between pre-pregnancy low BMI and macrosomia, stratifying by maternal age, parity, and GDM status. METHODS: All pregnant women who paid their first prenatal visit to the hospital in Qingdao during August 1, 2018, to June 30, 2020, were recruited to this study. The interactive effect of maternal age and pre-pregnancy low BMI on macrosomia was evaluated using logistic regression models, followed by strata-specific analyses. RESULTS: A total of 105,768 mother-child pairs were included, and the proportion of fetal macrosomia was 11.66%. The interactive effect of maternal pre-pregnancy BMI and age was statistically significant on macrosomia irrespective of parity (nullipara: Padjusted=0.0265; multipara: Padjusted=0.0356). The protective effect of low BMI on macrosomia was most prominent among nullipara aged 35 years and above (aOR=0.16, 95% CI 0.05-0.49) and multipara aged 25 years and below (aOR=0.17, 95% CI 0.05-0.55). In nullipara without GDM, the risk estimates gradually declined with increasing conception age (20-to-24 years: aOR=0.64, 95% CI 0.51-0.80; 25-to-29 years: aOR=0.43 95% CI 0.36-0.52; 30-to-34 years: aOR=0.40 95% CI 0.29-0.53; and ≥35 years: aOR=0.19, 95% CI 0.06-0.60). A similar pattern could also be observed in nullipara with GDM, where the aOR for low BMI on macrosomia decreased from 0.54 (95% CI 0.32-0.93) in pregnant women aged 25-29 years to 0.30 (95% CI 0.12-0.75) among those aged 30-34 years. However, younger multiparous mothers, especially those aged 25 years and below without GDM (aOR=0.21, 95% CI 0.06-0.68), were more benefited from a lower BMI against the development of macrosomia. CONCLUSIONS: Maternal low BMI is inversely associated with macrosomia irrespective of maternal age and parity. The impact of pre-pregnancy low BMI on macrosomia varied by maternal age and parity. The protective effect of a lower maternal BMI against fetal macrosomia was more prominent in nulliparous mothers aged 35 years and above, whereas multiparous mothers younger than 25 years of age were more benefited.

8.
Biol Open ; 10(9)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34369554

RESUMO

Arf GTPase-Activating proteins (ArfGAPs) mediate the hydrolysis of GTP bound to ADP-ribosylation factors (Arfs), which are critical to form transport intermediates. ArfGAPs have been thought to be negative regulators of Arfs; however, accumulating evidence indicates that ArfGAPs are important for cargo sorting and promote membrane traffic. Weibel-Palade bodies (WPBs) are cigar-shaped secretory granules in endothelial cells that contain von Willebrand factor (vWF) as their main cargo. WPB biogenesis at the Golgi was reported to be regulated by Arf and their regulators, but the role of ArfGAPs has been unknown. In this study, we performed siRNA screening of ArfGAPs to investigate the role of ArfGAPs in the biogenesis of WPBs. We found two ArfGAPs, SMAP1 and AGFG2, to be involved in WPB size and vWF exocytosis, respectively. SMAP1 depletion resulted in small-sized WPBs, and the lysosomal inhibitor leupeptin recovered the size of WPBs. The results indicate that SMAP1 functions in preventing the degradation of cigar-shaped WPBs. On the other hand, AGFG2 downregulation resulted in the inhibition of vWF secretion upon Phorbol 12-myristate 13-acetate (PMA) or histamine stimulation, suggesting that AGFG2 plays a role in vWF exocytosis. Our study revealed unexpected roles of ArfGAPs in vWF transport.

9.
Dig Liver Dis ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34305014

RESUMO

BACKGROUND: Persistent organ failure (POF) increases the risk of death in patients with acute biliary pancreatitis (ABP). Currently, there is no early risk assessment tool for POF in patients with ABP. AIMS: To establish and validate a dynamic nomogram for predicting the risk of POF in ABP. METHODS: This was a retrospective study of 792 patients with ABP, with 595 cases in the development group and 197 cases in the validation group. Least absolute shrinkage and selection operator regression screened the predictors of POF, and logistic regression established the model (P < 0.05). A dynamic nomogram showed the model. We evaluated the model's discrimination, calibration, and clinical effectiveness; used the bootstrap method for internal validation; and conducted external validation in the validation group. RESULTS: Neutrophils, haematocrit, serum calcium, and blood urea nitrogen were predictors of POF in ABP. In the development group and validation group, the areas under the receiver operating characteristic curves (AUROCs) were 0.875 and 0.854, respectively, and the Hosmer-Lemeshow test (P > 0.05) and calibration curve showed good consistency between the actual and prediction probability. Decision curve analysis showed that the dynamic nomogram has excellent clinical value. CONCLUSION: This dynamic nomogram helps with the early identification and screening of high-risk patients with POF in ABP.

10.
Curr Neuropharmacol ; 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34279201

RESUMO

Moyamoya disease (MMD) is a chronic cerebrovascular disease characterized by progressive stenosis of the arteries of the circle of Willis, with the formation of the collateral vascular network at the base of the brain. Its clinical manifestations are complicated. Numerous studies have attempted to clarify the clinical features of MMD, including its epidemiology, genetic characteristics, and pathophysiology. With the development of neuroimaging techniques, various neuroimaging modalities with different advantages have deepened the understanding of MMD in structural, functional, spatial, and temporal dimensions. At present, the main treatment for MMD focuses on neurological protection, cerebral blood flow reconstruction, and neurological rehabilitation, such as pharmacological treatment, surgical revascularization, and cognitive rehabilitation. In this review, we discuss recent progress in understanding the clinical features, neuroimaging evaluation, and treatment of MMD.

11.
Am J Physiol Renal Physiol ; 321(2): F225-F235, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34229478

RESUMO

Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from posttranslational hydroxylation, the mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia-reperfusion-, unilateral ureteral obstruction-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB, which plays a central role in the inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only under hypoxic conditions but also under normoxic conditions. Moreover, the induced HIF-1α by inflammation protected against tubular injury in AKI. Thus, our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.NEW & NOTEWORTHY Here, the mechanism of hypoxia-inducible factor-α (HIF-α) regulation in acute kidney injury (AKI) was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB was involved in the increasing expression of HIF-1α in AKI. Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription. Our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.


Assuntos
Injúria Renal Aguda/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/metabolismo , NF-kappa B/metabolismo , Injúria Renal Aguda/genética , Animais , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Inflamação/genética , Inflamação/metabolismo , Rim/efeitos dos fármacos , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Nitrilas/farmacologia , Sulfonas/farmacologia
12.
Can J Cardiol ; 37(9): 1438-1449, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34256087

RESUMO

BACKGROUND: Actigraphy-based measurements of physiologic parameters may enable design of patient-centric heart failure (HF) clinical trials. Recently, the Heart Failure Collaboratory focused on recommendations for meaningful change and use of actigraphy as an end point in HF clinical trials. We aimed to evaluate randomized controlled trials (RCTs) that have quantified the impact of HF interventions using actigraphy. METHODS: Using a scoping review strategy, we evaluated the use of actigraphy in HF RCTs. Studies were identified through electronic searches of Embase, OVID Medline, PubMed, and Cochrane Review. Data on trial characteristics and results were collected. RESULTS: We identified 11 RCTs with a total of 1,455 participants. The risk of bias across the included trials was high overall. All trials had the primary outcomes reflecting measures of either physical activity (n = 8), sleep (n = 2), or both (n = 1). Five trials evaluated response to pharmacologic therapies compared with placebo, 3 evaluated physical activity interventions, 2 evaluated group or cognitive therapy, and 1 evaluated sleep-ventilation strategy. Sample sizes ranged from 30 to 619 participants. There was significant heterogeneity relating to device type, body placement site, and handling of missing actigraphy data. Duration of monitoring ranged from 48 hours to 12 weeks. None of the studies evaluating pharmacologic therapies (n = 5) demonstrated a significant improvement of actigraphy-based primary end point measurements. CONCLUSIONS: There is significant heterogeneity in the use, methodology, and results of actigraphy-based HF RCTs. Our results highlight the need to develop, standardize, and validate actigraphy-specific outcomes for use in HF clinical trials.

13.
Br J Cancer ; 125(4): 582-592, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34088988

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM. METHODS: KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways. RESULTS: Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth. CONCLUSIONS: The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.

14.
Elife ; 102021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34142658

RESUMO

Lung cancer with loss-of-function of the LKB1 tumor suppressor is a common aggressive subgroup with no effective therapies. LKB1-deficiency induces constitutive activation of cAMP/CREB-mediated transcription by a family of three CREB-regulated transcription coactivators (CRTC1-3). However, the significance and mechanism of CRTC activation in promoting the aggressive phenotype of LKB1-null cancer remain poorly characterized. Here, we observed overlapping CRTC expression patterns and mild growth phenotypes of individual CRTC-knockouts in lung cancer, suggesting functional redundancy of CRTC1-3. We consequently designed a dominant-negative mutant (dnCRTC) to block all three CRTCs to bind and co-activate CREB. Expression of dnCRTC efficiently inhibited the aberrantly activated cAMP/CREB-mediated oncogenic transcriptional program induced by LKB1-deficiency, and specifically blocked the growth of human and murine LKB1-inactivated lung cancer. Collectively, this study provides direct proof for an essential role of the CRTC-CREB activation in promoting the malignant phenotypes of LKB1-null lung cancer and proposes the CRTC-CREB interaction interface as a novel therapeutic target.

15.
Virol J ; 18(1): 119, 2021 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-34092256

RESUMO

BACKGROUND: Bovine viral diarrhea (BVD) which is caused by Bovine viral diarrhea virus (BVDV), is an acute, contagious disease. In spite of the use of vaccines and elimination projects, BVDV still causes severe economic losses to the cattle industry for the past few years. The current study presents a preliminary analysis of the pathogenic mechanisms from the perspective of protein expression levels in infected host cells at different points in time to elucidate the infection process associated with BVDV. METHODS: We used the isobaric tags for relative and absolute quantitation (iTRAQ) technology coupled with liquid chromatography-tandem mass spectrometric (LC-MS/MS) approach for a quantitative proteomics comparison of BVDV NADL-infected MDBK cells and non-infected cells. The functions of the proteins were deduced by functional annotation and their involvement in metabolic processes explored by KEGG pathway analysis to identify their interactions. RESULTS: There were 357 (47.6% downregulated, 52.4% upregulated infected vs. control), 101 (52.5% downregulated, 47.5% upregulated infected vs. control), and 66 (21.2% downregulated, 78.8% upregulated infected vs. control) proteins were differentially expressed (fold change > 1.5 or < 0.67) in the BVDV NADL-infected MDBK cells at 12, 24, and 48 h after infection. GO analysis showed that the differentially expressed proteins (DEPs) are mainly involved in metabolic processes, biological regulation and localization. KEGG enrichment analysis showed that some signaling pathways that involved in the regulation of BVDV NADL-infection and host resistance are significantly (P < 0.05) enriched at different stages of the BVDV NADL-infection, such as Endocytosis signaling pathway, FoxO signaling pathway, Homologous recombination signaling pathway and Lysosome pathway. CONCLUSIONS: These results revealed that the DEPs in BVDV NADL-infected MDBK cells have a wide range of regulatory effects; in addition, they provide a lot of resources for the study of host cell proteomics after BVDV infection.

16.
BMC Public Health ; 21(1): 1044, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078335

RESUMO

BACKGROUND: Many studies have been conducted to assess the incidence of congenital heart disease (CHD). However, results were greatly inconsistent among these studies with a broad range of findings. METHODS: A prospective census-based cohort study was conducted in Qingdao, China, from August 1, 2018 to April 30, 2019. All of the local registered pregnant women were continuously investigated and followed from 15 to 20 weeks of gestation to delivery, tracking the CHD cases in both the fetal and neonatal stages. A logistic regression model was applied to assess the association between CHD and possible risk factors. RESULTS: The positive rate of prenatal CHD screening was 14.36 per 1000 fetuses and the incidence of CHD was 9.38 per 1000 live births. Results from logistic regression indicated that, living in the countryside (odds ratio, (OR): 0.771; 95% confidence interval, (CI): 0.628-0.946) and having a childbearing history (OR: 0.802; 95%CI: 0.676-0.951) were negatively associated with CHD. However, twin pregnancy (OR: 1.957, 95% CI: 1.245-3.076), illness in the first trimester (OR: 1.306; 95% CI: 1.048-1.628), a family history of CHD (OR: 7.156; 95% CI: 3.293-15.552), and having a child with a birth defect (OR: 2.086; 95% CI: 1.167-3.731) were positively associated with CHD. CONCLUSION: CHD is a serious health problem in Qingdao. The CHD incidence found in this study was similar to existing research. The positive rate of prenatal CHD screening was higher than the incidence of neonatal CHD. Moreover, CHD risk factors were identified in our study, and our findings may have great implications for formation CHD intervention strategies.


Assuntos
Cardiopatias Congênitas , Criança , China/epidemiologia , Estudos de Coortes , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Incidência , Recém-Nascido , Gravidez , Estudos Prospectivos , Fatores de Risco
17.
Nucleic Acids Res ; 49(10): 5779-5797, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34048572

RESUMO

Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and apoptosis during reactive oxygen species (ROS)-induced stress. We find that ROS significantly induces global mRNA N6-methyladenosine (m6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m6A levels that protect genomic integrity of cells in response to ROS.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Dano ao DNA , Reparo do DNA , Espécies Reativas de Oxigênio/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Desmetilação/efeitos dos fármacos , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metilação/efeitos dos fármacos , Camundongos , Fosforilação , Processamento de Proteína Pós-Traducional , RNA Interferente Pequeno , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , RNA-Seq , Sumoilação/efeitos dos fármacos , Espectrometria de Massas em Tandem , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo
18.
Int J Neurosci ; : 1-14, 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34042552

RESUMO

Background: Moyamoya disease (MMD) is a serious intracranial cerebrovascular disease. Cerebral hemorrhage caused by MMD will bring life risk to patients. Therefore, MMD detection is of great significance in the prevention of cerebral hemorrhage. In order to improve the accuracy of digital subtraction angiography (DSA) in the diagnosis of MMD, in this paper, a deep network architecture combined with 3 D convolutional neural network (3 D CNN) and bidirectional convolutional gated recurrent unit (BiConvGRU) is proposed to learn the spatiotemporal features for MMD detection.Methods: Firstly, 2 D convolutional neural network (2 D CNN) is utilized to extract spatial features for each frame of DSA. Secondly, the long-term spatiotemporal features of DSA sequence are extracted by BiConvGRU. Thirdly, the short-term spatiotemporal features of DSA are further extracted by 3 D convolutional neural network (3 D CNN). In addition, different features are extracted when gray images and optical flow images pass through the network, and multiple features are extracted by features fusion. Finally, the fused features are utilized to classify.Results: The proposed method was quantitatively evaluated on a data sets of 630 cases. The experimental results showed a detection accuracy of 0.9788, sensitivity and specificity were 0.9780 and 0.9796, respectively, and area under curve (AUC) was 0.9856. Compared with other methods, we can get the highest accuracy and AUC.Conclusions: The experimental results show that the proposed method is stable and reliable for MMD detection, which provides an option for doctors to accurately diagnose MMD.

19.
Pathol Res Pract ; 223: 153319, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33991848

RESUMO

BACKGROUND: Nuclear Receptor Subfamily 5 Group A Member 2 (NR5A2, LRH-1) is an oncogene in a wide range of cancer types. Bioinformatics analysis on glioblastoma multiforme (GBM) tumors has revealed that the miR-139-5p-NR5A2 axis may be putatively regulated by the long non-coding RNA (lncRNA) RP3-439F8.1. This led us to hypothesize the existence of a RP3-439F8.1-miR-139-5p-NR5A2 regulatory axis in GBM cells. METHODS: Gene expression analysis was performed in GBM tumor samples and normal controls from our hospital, the Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) cohort, and the Gene Expression Omnibus (GEO) database (GSE7696). Cell proliferation, apoptosis, Matrigel Transwell, colony formation, and cell cycle assays were performed in T98 G and U251 cells in vitro. An orthotopic U251 xenograft murine model was employed to test the effects of RP3-439F8.1 knockdown in vivo. RESULTS: NR5A2 was upregulated in the three independent GBM tumor cohorts. In vitro, NR5A2 overexpression enhanced GBM cell proliferation, colony formation, invasiveness, and G0-G1 cell cycle phase shift via co-activating ß-catenin/TCF4 signaling, with no apparent effect upon apoptosis. In contrast, RP3-439F8.1 knockdown produced the opposite effects. RP3-439F8.1 knockdown reduced tumor progression in vivo, increasing overall survival in model mice. Further in vitro experiments revealed that RP3-439F8.1 acts as a competing endogenous RNA (ceRNA) to regulate NR5A2 by sponging the microRNA miR-139-5p. These findings were clinically validated by a positive correlation between RP3-439F8.1 and NR5A2 and a negative correlation between RP3-439F8.1 and miR-139-5p in GBM tumors. CONCLUSIONS: Our study supports a tumorigenic role for RP3-439F8.1 in GBM through the RP3-439F8.1/miR-139-5p/NR5A2 axis.

20.
JCI Insight ; 6(7)2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830080

RESUMO

No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2-induced tumorigenesis. Cotargeting of aberrant p16-CDK4/6-RB signaling and CRTC1-MAML2 fusion-activated AREG/EGFR signaling with the respective CDK4/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4/6 inhibitors as a potential viable strategy for patients with MEC.

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