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The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis, and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.
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Carcinoma Hepatocelular , Proteínas de Unión al ADN , Neoplasias Hepáticas , Proteínas Mitocondriales , Factores de Transcripción , Actinas/metabolismo , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Núcleo Celular/metabolismo , Coenzima A/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Metástasis de la Neoplasia , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND AND AIMS: To investigate the persistence of Lugol-unstained lesions (LULs) in the esophagus detected by chromoendoscopy and explore its association with progression to malignancy. METHODS: We enrolled 647 participants from a population-based screening trial who had biopsied LULs at the baseline chromoendoscopy and underwent a chromoendoscopy reexamination after a median of 4.39 years. Cases of persistent LUL were defined as those in whom a visible LUL was observed during reexamination at the documented location (±2cm) where a LUL was detected at baseline chromoendoscopy. Logistic regression was applied to explore risk factors for the persistence of LULs. The primary outcome was clinical-stage esophageal squamous cell carcinoma (ESCC) identified over 6.78 years of follow-up and the secondary outcome was reexamination-detected severe dysplasia and above lesions (SDA). The cumulative incidence was calculated to assess the progression risk associated with the persistence of LULs. RESULTS: The proportion of participants with persistent LULs was 81.92%. Dysplasia (adjusted OR=6.16, 95%CI: 2.70 to 17.80), large LULs (adjusted OR=1.90, 95%CI: 1.18 to 3.15), and irregularly shaped LULs (adjusted OR=1.63, 95%CI: 1.03 to 2.56) at baseline were associated with an increased risk of LUL persistence. Eleven clinical-stage ESCC cases and 31 SDAs detected during reexamination were identified, all of which originated from patients with persistent LULs (Pclinical-stageESCC =0.136, Preexamination-detected SDA =0.015). CONCLUSION: The persistence of LULs is associated with progression to malignancy in the esophagus, even in individuals without dysplastic lesions. Based on this, a more efficient post-screening surveillance strategy could be established.
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OBJECTIVE: To explore the robust relationship between insomnia and type 2 diabetes mellitus by two-sample Mendelian randomization analysis to overcome confounding factors and reverse causality in observational studies. METHODS: We identified strong, independent single nucleotide polymorphisms (SNPs) of insomnia from the most up to date genome wide association studies (GWAS) within European ancestors and applied them as instrumental variable to GWAS of type 2 diabetes mellitus. After excluding SNPs that were significantly associated with smoking, physical activity, alcohol consumption, educational attainment, obesity, or type 2 diabetes mellitus, we assessed the impact of insomnia on type 2 diabetes mellitus using inverse variance weighting (IVW) method. Weighted median and MR-Egger regression analysis were also conducted to test the robustness of the association. We calculated the F statistic of the selected SNPs to test the applicability of instrumental variable and F statistic over than ten indicated that there was little possibility of bias of weak instrumental variables. We further examined the existence of pleiotropy by testing whether the intercept term in MR-Egger regression was significantly different from zero. In addition, the leave-one-out method was used for sensitivity analysis to verify the stability and reliability of the results. RESULTS: We selected 248 SNPs independently associated with insomnia at the genome-wide level (P<5×10-8) as a preliminary candidate set of instrumental variables. After clumping based on the reference panel from 1000 Genome Project and removing the potential pleiotropic SNPs, a total of 167 SNPs associated with insomnia were included as final instrumental variables. The F statistic of this study was 39. 74, which was in line with the relevance assumption of Mendelian randomization. IVW method showed insomnia was associated with higher risk of type 2 diabetes mellitus that po-pulation with insomnia were 1. 14 times more likely to develop type 2 diabetes mellitus than those without insomnia (95% CI: 1.09-1.21, P<0.001). The weighted median estimator (WME) method and MR-Egger regression showed similar causal effect of insomnia on type 2 diabetes mellitus. And MR-Egger regression also showed that the effect was less likely to be triggered by pleiotropy. Sensitivity analyses produced directionally similar estimates. CONCLUSION: Insomnia is a risk factor of type 2 diabetes mellitus, which has positively effects on type 2 diabetes mellitus. Our study provides further rationale for indivi-duals at risk for diabetes to keep healthy lifestyle.
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Diabetes Mellitus Tipo 2 , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Trastornos del Inicio y del Mantenimiento del Sueño/genética , Estudio de Asociación del Genoma Completo , Reproducibilidad de los Resultados , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Análisis de la Aleatorización MendelianaRESUMEN
Haplogroups and single-nucleotide polymorphisms (SNP) of mitochondrial DNA (mtDNA) were associated with the prognosis of many types of cancer patients. However, whether mtDNA haplogroups contribute to clinical outcomes of colorectal cancer (CRC) in Chinese population remains to be determined. In this study, mtDNA of tissue samples from 445 CRC patients from Northwestern China was sequenced to evaluate the association between haplogroup and prognosis. The mtDNA sequencing data of 1015 CRC patients from Southern China were collected for validation. We found patients with mtDNA haplogroup M7 had a significantly higher death risk when compared with patients with other haplogroups in both Northwestern (Hazard ratio [HR] = 3.093, 95% CI = 1.768-5.411, p < 0.001) and Southern (HR = 1.607, 95% CI = 1.050-2.459, p = 0.029) China. Then, a haplogroup M7-based mtSNP classifier was selected by using LASSO Cox regression analysis. A nomogram comprising the mtSNP classifier and clinicopathological variables was developed to predict the prognosis of CRC patients (area under the curve [AUC] 0.735, 95% CI = 0.679-0.791). Furthermore, patients with high- and low-risk scores calculated by the haplogroup M7-based mtSNP classifier exhibited significantly different overall survival (OS) and recurrence-free survival (RFS) (all p < 0.001). Finally, RNA-seq and immunohistochemical analyses indicated the poor prognosis of patients with haplogroup M7 may be related to mitochondrial dysfunction and immune abnormalities in CRC tissues. In conclusion, the haplogroup M7 and haplogroup M7-based mtSNP classifier seems to be a practical and reliable prognostic predictor for CRC patients, which provides a potential tool of clinical decision-making for patients with haplogroup M7 in Chinese population.
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Neoplasias Colorrectales , ADN Mitocondrial , Humanos , ADN Mitocondrial/genética , Pueblos del Este de Asia , Mitocondrias/genética , Pronóstico , HaplotiposRESUMEN
Hepatoblastoma is the most common liver cancer in children, and the aggressive subtype often has a poor prognosis and lacks effective targeted therapy. Although aggressive hepatoblastoma (HB) is often accompanied by abnormally high expression of the transcription factor c-Myc, the underlying mechanism remains unclear. In this study, we found that mitochondrial fragmentation was enhanced by c-Myc overexpression in human aggressive HB tissues and was associated with poor prognosis. Then, a mouse model resembling human HB was established via hydrodynamic injection of c-Myc plasmids. We observed that liver-specific knockout of the mitochondrial fusion molecule MFN1 or overexpression of mitochondrial fission molecule DRP1 promoted the occurrence of c-Myc-driven liver cancer. In contrast, when MFN1 was overexpressed in the liver, tumor formation was delayed. In vitro experiments showed that c-Myc transcriptionally upregulated the expression of DRP1 and decreased MFN1 expression through upregulation of miR-373-3p. Moreover, enhanced mitochondrial fragmentation significantly promoted aerobic glycolysis and the proliferation of HB cells by significantly increasing reactive oxygen species (ROS) production and activating the RAC-alpha serine/threonine-protein kinase (AKT)/mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathways. Taken together, our results indicate that c-Myc-mediated mitochondrial fragmentation promotes the malignant transformation and progression of HB by activating ROS-mediated multi-oncogenic signaling.
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Hepatoblastoma , Neoplasias Hepáticas , MicroARNs , Animales , Hepatoblastoma/genética , Hepatoblastoma/metabolismo , Hepatoblastoma/patología , Neoplasias Hepáticas/metabolismo , Mamíferos , Ratones , Especies Reactivas de Oxígeno , Transducción de SeñalRESUMEN
The interplay between virus and host has been one of the hot spot in virology, and it is also the important aspect of revealing the mechanism of virus infection. Increasing studies revealed that several key molecules took part in the process of virus-host interaction. White spot syndrome virus (WSSV) has been proved to affect several physiological processes of the host cells, especially apoptosis. While the relationship between them still remains unclear. In this study, a IFI27 gene (LvIFI27) of Litopenaeus vannamei was cloned. It is indicated that LvIFI27 was induced upon endoplasmic reticulum (ER)-stress and unfolded protein response activator Thapsigargin. Unlike human IFI27 locating to mitochondria, LvIFI27 lied to ER, and was involved in cell apoptosis process. Moreover, results of cumulative mortality analysis showed that LvIFI27 might contributed to WSSV proliferation by promoting apoptosis during the process of viral infection. Findings in this study enriched our understanding of the relationship between WSSV infection and ER-stress mediated apoptosis.
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Proteínas de Artrópodos , Infecciones por Virus ADN/veterinaria , Estrés del Retículo Endoplásmico , Proteínas de la Membrana/genética , Penaeidae , Animales , Apoptosis , Proteínas de Artrópodos/genética , Penaeidae/genética , Penaeidae/virología , Respuesta de Proteína Desplegada , Virus del Síndrome de la Mancha Blanca 1RESUMEN
Numerous studies have proved that endoplasmic reticulum (ER)-stress is an important cause of aquatic animal diseases. Therefore, for effectively preventing and controlling aquatic animal diseases, a systematic and in-depth understanding of the environmental stress response in aquatic animals is necessary. In present study, the influence of ER-stress in Litopenaeus vannamei was investigated using Illumina HiSeq based RNA-Seq. Comparing to the cDNA library of hemocytes treated with DMSO in L. vannamei, 286 unigenes were significantly upregulated and 473 unigenes were significantly down-regulated in the Thapsigargin treated group. KEGG analysis indicated that the differentially expressed genes (DEGs) are mainly related to ER-stress, immune as well as metabolism. Besides the classical ER-stress response pathways, the regulation of cell cycle and DNA replication are also important measures of ER-stress response. It has been suggested that the influence of ER-stress on immune genes might be an important factor in environmental stress inducing shrimp disease. Our investigation exhibited that immune-related DEG Prophenoloxidase activating enzyme 2 (LvPPAE2) roled in anti-pathogen immunity of shrimp. This study provides a solid foundation for uncovering the environmental adaptation response and especially its relationship with L. vannamei immune system.
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Enfermedades de los Animales , Penaeidae , Enfermedades de los Animales/metabolismo , Animales , Retículo Endoplásmico , Perfilación de la Expresión Génica/veterinaria , Hemocitos , TranscriptomaRESUMEN
In shrimp, several glutathione peroxidase (GPX) genes have been cloned and functionally studied. Increasing evidence suggests the genes' involvement in white spot syndrome virus (WSSV)- or Vibrio alginolyticus-infection resistance. In the present study, a novel GXP gene (LvGPX3) was cloned in Litopenaeus vannamei. Promoter of LvGPX3 was activated by NF-E2-related factor 2. Further study showed that LvGPX3 expression was evidently accelerated by oxidative stress or WSSV or V. alginolyticus infection. Consistently, downregulated expression of LvGPX3 increased the cumulative mortality of WSSV- or V. alginolyticus-infected shrimp. Similar results occurred in shrimp suffering from oxidative stress. Moreover, LvGPX3 was important for enhancing Antimicrobial peptide (AMP) gene expression in S2 cells with lipopolysaccharide treatment. Further, knockdown of LvGPX3 expression significantly suppressed expression of AMPs, such as Penaeidins 2a, Penaeidins 3a and anti-lipopolysaccharide factor 1 in shrimp. AMPs have been proven to be engaged in shrimp WSSV- or V. alginolyticus-infection resistance; it was inferred that LvGPX3 might enhance shrimp immune response under immune challenges, such as increasing expression of AMPs. The regulation mechanism remains to be further studied.
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Resistencia a la Enfermedad/genética , Glutatión Peroxidasa/genética , Estrés Oxidativo/genética , Penaeidae/genética , Penaeidae/metabolismo , Animales , Péptidos Antimicrobianos/genética , Clonación Molecular , Expresión Génica , Técnicas de Silenciamiento del Gen , Predisposición Genética a la Enfermedad , Penaeidae/microbiología , Penaeidae/virología , Filogenia , Análisis de SecuenciaRESUMEN
We aim to compare the relative heritability contributed by variants of behavior-related environmental phenotypes and elucidate the role of these factors in the conundrum of "missing heritability" of type 2 diabetes. Methods: We used Linkage-Disequilibrium Adjusted Kinships (LDAK) and LDAK-Thin models to calculate the relative heritability of each variant and compare the relative heritability for each phenotype. Biological analysis was carried out for the phenotype whose variants made a significant contribution. Potential hub genes were prioritized based on topological parameters of the protein-protein interaction network. We included 16 behavior-related phenotypes and 2607 valid variants. In the LDAK model, we found the variants of alcohol consumption and caffeine intake were identified as contributing higher relative heritability than that of the random variants. Compared with the relative expected heritability contributed by the variants associated with type 2 diabetes, the relative expected heritability contributed by the variants associated with these two phenotypes was higher. In the LDAK-Thin model, the relative heritability of variants of 11 phenotypes was statistically higher than random variants. Biological function analysis showed the same distributions among type 2 diabetes and alcohol consumption. We eventually screened out 31 hub genes interacting intensively, four of which were validated and showed the upregulated expression pattern in blood samples seen in type 2 diabetes cases. Conclusion: We found that alcohol consumption contributed higher relative heritability. Hub genes may influence the onset of type 2 diabetes by a mediating effect or a pleiotropic effect. Our results provide new insight to reveal the role of behavior-related factors in the conundrum of "missing heritability" of type 2 diabetes.
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Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Comorbilidad , Diabetes Mellitus Tipo 2/sangre , Estudio de Asociación del Genoma Completo , Humanos , Modelos Genéticos , Fenotipo , Polimorfismo de Nucleótido Simple , Mapas de Interacción de Proteínas/genéticaRESUMEN
Ferroptosis and endoplasmic reticulum stress (ERS) are common events in the process of myocardial ischemia/reperfusion injury (IRI). The suppression of chromobox7 (CBX7) has been reported to protect against ischemia/reperfusion injury, This research is purposed to expose the impacts and mechanism of CBX7 in myocardial IRI. CBX7 expression was detected using RT-qPCR and western blotting analysis. CCK-8 assay detected cell viability. Inflammatory response and oxidative stress were detected by ELISA, DCFH-DA probe and related assay kits. Flow cytometry analysis and caspase3 activity assay were used to detect cell apoptosis. C11-BODIPY 581/591 staining and ferro-orange staining were used to detect lipid reactive oxygen species (ROS) and Fe2+ level, respectively. Western blotting was used to detect the expression of proteins associated with apoptosis, ferroptosis and ERS. In the hypoxia/reoxygenation (H/R) model of rat cardiomyocytes H9c2, CBX7 was highly expressed. CBX7 interference significantly protected against inflammatory response, oxidative stress, apoptosis, ferroptosis and ERS induced by H/R in H9c2 cells. Moreover, after the pretreatment with ferroptosis activator erastin or ERS agonist Tunicamycin (TM), the protective effects of CBX7 knockdown on the inflammation, oxidative stress and apoptosis in H/R-induced H9c2 cells was partially abolished. To summarize, CBX7 down-regulation may exert anti-ferroptosis and anti-ERS activities to alleviate H/R-stimulated myocardial injury.
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BACKGROUND: Mitochondrial DNA's (mtDNA) haplogroups and SNPs were associated with the risk of different cancer. However, there is no evidence that the same haplogroup or mitochondrial SNP (mtSNP) exhibits the pleiotropic effect on multiple cancers. METHODS: We recruited 2,489 participants, including patients with colorectal, hepatocellular, lung, ovarian, bladder, breast, pancreatic, and renal cell carcinoma. In addition, 715 healthy individuals from Northern China served as controls. Next, cross-tumor analysis was performed to determine whether mtDNA variation is associated with multiple cancers. RESULTS: Our results revealed a significant decrease in the occurrence risk of multiple cancers among individuals belonging to haplogroup A [OR = 0.553, 95% confidence interval (CI) = 0.375-0.815, P = 0.003]. Furthermore, we identified 11 mtSNPs associated with multiple cancers and divided the population into high-risk and low-risk groups. Low-risk groups showed a significantly reduced risk of occurrence compared with high-risk groups (OR = 0.614, 95% CI = 0.507-0.744, P < 0.001). Furthermore, using interaction analysis, we identified a special group of individuals belonging to haplogroup A/M7 and the low-risk population, who exhibit a lower risk of multiple cancers compared with other populations (OR = 0.195, 95% CI = 0.106-0.359, P < 0.001). Finally, gene set enrichment analysis confirmed that haplogroup A/M7 patients had lower expression levels of cancer-related pathway genes compared with haplogroup D patients. CONCLUSIONS: We found that specific mtDNA haplogroups and mtSNPs may play a role in predicting multiple cancer predisposition in Chinese populations. IMPACT: This may provide a potential tool for early screening in clinical settings for individuals in the Chinese population.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , ADN Mitocondrial/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , China/epidemiología , Neoplasias Renales/epidemiología , Neoplasias Renales/genéticaRESUMEN
Recently, much progress has been made in unsupervised denoising learning. However, existing methods more or less rely on some assumptions on the signal and/or degradation model, which limits their practical performance. How to construct an optimal criterion for unsupervised denoising learning without any prior knowledge on the degradation model is still an open question. Toward answering this question, this work proposes a criterion for unsupervised denoising learning based on the optimal transport theory. This criterion has favorable properties, e.g., approximately maximal preservation of the information of the signal, whilst achieving perceptual reconstruction. Furthermore, though a relaxed unconstrained formulation is used in practical implementation, we prove that the relaxed formulation in theory has the same solution as the original constrained formulation. Experiments on synthetic and real-world data, including realistic photographic, microscopy, depth, and raw depth images, demonstrate that the proposed method even compares favorably with supervised methods, e.g., approaching the PSNR of supervised methods while having better perceptual quality. Particularly, for spatially correlated noise and realistic microscopy images, the proposed method not only achieves better perceptual quality but also has higher PSNR than supervised methods. Besides, it shows remarkable superiority in harsh practical conditions with complex noise, e.g., raw depth images. Code is available at https://github.com/wangweiSJTU/OTUR.
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Litopenaeus vannamei Smad5 (LvSmad5) in cytoplasm has been proved to be involved in environmental stress response. As LvSmad5 could also locate in nucleus under specific stress, it was conjectured that LvSmad5 might participate in environmental stress response. While, the experimental evidence is still lacking. In this study, cytosolic LvSmad5 mutant or nuclear LvSmad5 mutant was expressed in Drosophila S2 cells, and then transcriptomic analysis of mentioned cells was performed using Illumina HiSeq based RNA-Seq, to reveal the function of LvSmad5 in nucleus. By comparing the two groups of cDNA libraries from S2 cells with cytosolic or nucleus LvSmad5 mutant, 86 differentially expressed genes as well as 765 differentially expressed transcripts were found. It was revealed that genes in the ER-stress response pathway, such as unfolded protein response and ER-associated degradation (ERAD) were enriched. Additionally, some kinds of metabolic reprogramming occurred in S2 cells with over-expressing nuclear LvSmad5, for significant changes in the expression of some metabolism-related genes. To test our infer that nuclear LvSmad5 was engaged in environmental stress response, homologous gene of Drosophila translocation in renal carcinoma on chromosome 8 in L.vannamei (LvTRC8) was chosen for further investigation. And studies about LvTRC8, a member of ERAD showed that it was induced by ER-stress or heat shock treatment. Suppressed the expression of LvTRC8 increased the cumulative mortality of shrimp upon stress. In some degree, these results support our speculation that nuclear LvSmad5 are involved in the environmental stress response of L. vannamei in fact.
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AnimalesRESUMEN
Variations in lipid levels are the result of combinations of genetic and environmental factors. We aim to investigate the indirect effect between siblings of the three polymorphisms of ADIPOQ on serum lipid levels in rural Chinese populations. A total of 2571 sibling pairs were enrolled as study participants. A generalized estimating equation was used to accommodate a family-based design. We used stratified analysis to detect sex combination differences in the indirect genetic effect. We found a significant association between the number of altered risk alleles of rs182052 and ego lipid levels of TG (ß = 0.177, P = 0.003), TC (ß = 0.140, P = 0.004) and LDL-C (ß = 0.098, P = 0.014). Ego and altered genotypes of rs182052 demonstrated a joint effect on ego lipid levels of TC (ß = 0.212, P = 0.019), HDL-C (ß = 0.099, P = 0.002) and LDL-C (ß = 0.177, P = 0.013) in recessive inheritance mode. In opposite-sex siblings, the altered GG genotype of rs182052 increased the ego lipid levels. Thus, our findings demonstrate that ADIPOQ has an indirect genetic effect on lipid levels in sibling pairs, and there are sex-combination differences in the indirect genetic effect in siblings.
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Adiponectina/genética , Pueblo Asiatico/genética , Accidente Cerebrovascular Isquémico/patología , Lípidos/sangre , Polimorfismo de Nucleótido Simple , Hermanos , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Humanos , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/genética , Masculino , Persona de Mediana EdadRESUMEN
Accumulating evidence suggests a relationship between type 2 diabetes mellitus and sleep problems. A comprehensive study is needed to decipher whether shared polygenic risk variants exist between diabetic traits and sleep traits. METHODS: We integrated summary statistics from different genome-wide association studies and investigated overlap in single-nucleotide polymorphisms (SNPs) associated with diabetes-related traits (type 2 diabetes, fasting glucose, fasting insulin, and glycated hemoglobin) and sleep traits (insomnia symptoms, sleep duration, and chronotype) using a conditional/conjunctional false discovery rate approach. Pleiotropic genes were further evaluated for differential expression analysis, and we assessed their expression pattern effects on type 2 diabetes by Mendelian randomization (MR) analysis. RESULTS: We observed extensive polygenic pleiotropy between diabetic traits and sleep traits. Fifty-eight independent genetic loci jointly influenced the risk of type 2 diabetes and the sleep traits of insomnia, sleep duration, and chronotype. The strongest shared locus between type 2 diabetes and sleep straits was FTO (lead SNP rs8047587). Type 2 diabetes (z score, 16.19; P = 6.29 × 10-59) and two sleep traits, sleep duration (z score, -6.66; P = 2.66 × 10-11) and chronotype (z score, 7.42; P = 1.19 × 10-13), were shared. Two of the pleiotropic genes, ENSA and PMPCA, were validated to be differentially expressed in type 2 diabetes, and PMPCA showed a slight protective effect on type 2 diabetes in MR analysis. CONCLUSIONS: Our study provided evidence for the polygenic overlap between diabetic traits and sleep traits, of which the expression of PMPCA may play a crucial role and provide support of the hazardous effect of being an "evening" person on diabetes risk.
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Background: Ovarian cancer (OC) is the most lethal gynecological malignancy worldwide. Increasing evidence indicates that TBC domain family is implicated in various cellular events contributing to initiation and development of different cancers, including OC. However, the role of TBC1D2, a crucial member of TBC domain family, remains unclear in OC. Methods: IHC and qRT-PCR were employed to determine TBC1D2 expression in OC tissues and cells. In vitro and in vivo assays involving proliferation, migration, invasion were performed to explore the role of TBC1D2 in OC development. The underlying mechanism by which TBC1D2 promotes OC metastasis were elucidated using bioinformatics analysis, western blotting and co-immunoprecipitation. Results: Upregulation of TBC1D2 was found in OC and was associated with a poor prognosis. Meanwhile, TBC1D2 promoted OC cell proliferation, migration, and invasion in vitro and facilitated tumor growth and metastasis in vivo. Moreover, TBC1D2 contributed to OC cell invasion by E-cadherin degradation via disassembling Rac1-IQGAP1 complex. In addition, miR-373-3p was screened out and identified to inhibit OVCAR3 invasion via negative regulation of TBC1D2. Conclusion: Our findings indicated that TBC1D2 is overexpressed in OC and contributes to tumor metastasis via E-cadherin degradation. This study suggests that TBC1D2 may be an underlying therapeutic target for OC.
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BACKGROUND: Post-vaccination safety is a major public health concern. The genetic predisposition on immune response has not been clearly identified. Clarifying whether individual genetic predisposition plays a role on adverse events (AEs) is critical for the prevention of AEs. METHODS: From July 2019 to June 2020, we performed a case-control study among children aged 3-24 months in seven Chinese provinces. Each child received a combination vaccination against diphtheria, tetanus, acellular pertussis, and Haemophilus influenzae type b (DTaP-Hib). Through daily telephone follow-up, we collected AEs within seven days. Oral swab samples were collected to investigate the effects of single nucleotide polymorphisms (SNPs) on the risk of AEs. RESULTS: 304 participants were included in the study. In univariate analysis, we discovered three protective SNPs (rs452204, OR = 0.67, P = 0.0352; rs9282763 and rs839, OR = 0.64, P = 0.0256) and one risk SNP (rs9610, OR = 2.20, P = 0.0397). In multivariate analysis, the effects of rs452204 and rs839 were found to be stable. The interaction between rs452204 and rs9610 was observed (OR = 7.25, 95% CI: 1.44-36.58, P = 0.0165). CONCLUSION: Genetic predisposition was associated with the risk of AEs after DTaP-Hib vaccination, emphasizing the potential application in the prevention of AEs.
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Vacunas contra Difteria, Tétanos y Tos Ferina Acelular , Predisposición Genética a la Enfermedad , Vacunas contra Haemophilus , Humanos , Lactante , Antígenos Bacterianos , Antígenos Virales , Estudios de Casos y Controles , China/epidemiología , Difteria/prevención & control , Vacunas contra Difteria, Tétanos y Tos Ferina Acelular/efectos adversos , Infecciones por Haemophilus/prevención & control , Haemophilus influenzae tipo b , Vacunas contra Haemophilus/efectos adversos , Tétanos/prevención & control , Vacunación/efectos adversos , Vacunas Combinadas/efectos adversos , Tos Ferina/prevención & control , PreescolarRESUMEN
BACKGROUND: Mitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis-associated cancer (CAC). METHODS: TFAM expression was examined in tissue samples of inflammatory bowel diseases (IBD) and CAC by immunohistochemistry. Intestinal epithelial cell (IEC)-specific TFAM-knockout mice (TFAMâ³IEC ) and colorectal cancer (CRC) cells with TFAM knockdown or overexpression were used to evaluate the role of TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial respiration function and biogenesis. RESULTS: The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity. The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3 (STAT3)/miR-23b-dependent manner. In addition, TFAM knockout impaired IEC turnover to promote dextran sulfate sodium (DSS)-induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS-induced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis. By contrast, TFAM expression was upregulated in CAC tissues and contributed to cell growth. Furthermore, it was demonstrated that ß-catenin induced the upregulation of TFAM through c-Myc in CRC cells. Mechanistically, TFAM promoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity. CONCLUSIONS: TFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis.