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1.
Aging Cell ; : e13519, 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34825761

RESUMO

Ageing is characterized by degeneration and loss of function across multiple physiological systems. To study the mechanisms and consequences of ageing, several metrics have been proposed in a hierarchical model, including biological, phenotypic and functional ageing. In particular, phenotypic ageing and interconnected changes in multiple physiological systems occur in all ageing individuals over time. Recently, phenotypic age, a new ageing measure, was proposed to capture morbidity and mortality risk across diverse subpopulations in US cohort studies. Although phenotypic age has been widely used, it may overlook the complex relationships among phenotypic biomarkers. Considering the correlation structure of these phenotypic biomarkers, we proposed a composite phenotype analysis (CPA) strategy to analyse 71 biomarkers from 2074 individuals in the Rugao Longitudinal Ageing Study. CPA grouped these biomarkers into 18 composite phenotypes according to their internal correlation, and these composite phenotypes were mostly consistent with prior findings. In addition, compared with prior findings, this strategy exhibited some different yet important implications. For example, the indicators of kidney and cardiovascular functions were tightly connected, implying internal interactions. The composite phenotypes were further verified through associations with functional metrics of ageing, including disability, depression, cognitive function and frailty. Compared to age alone, these composite phenotypes had better predictive performances for functional metrics of ageing. In summary, CPA could reveal the hidden relationships of physiological systems and identify the links between physiological systems and functional ageing metrics, thereby providing novel insights into potential mechanisms underlying human ageing.

2.
Nat Commun ; 12(1): 6058, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663816

RESUMO

The tumor ecosystem of papillary thyroid carcinoma (PTC) is poorly characterized. Using single-cell RNA sequencing, we profile transcriptomes of 158,577 cells from 11 patients' paratumors, localized/advanced tumors, initially-treated/recurrent lymph nodes and radioactive iodine (RAI)-refractory distant metastases, covering comprehensive clinical courses of PTC. Our data identifies a "cancer-primed" premalignant thyrocyte population with normal morphology but altered transcriptomes. Along the developmental trajectory, we also discover three phenotypes of malignant thyrocytes (follicular-like, partial-epithelial-mesenchymal-transition-like, dedifferentiation-like), whose composition shapes bulk molecular subtypes, tumor characteristics and RAI responses. Furthermore, we uncover a distinct BRAF-like-B subtype with predominant dedifferentiation-like thyrocytes, enriched cancer-associated fibroblasts, worse prognosis and promising prospect of immunotherapy. Moreover, potential vascular-immune crosstalk in PTC provides theoretical basis for combined anti-angiogenic and immunotherapy. Together, our findings provide insight into the PTC ecosystem that suggests potential prognostic and therapeutic implications.


Assuntos
Ecossistema , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Transcriptoma , Adolescente , Carcinoma/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Radioisótopos do Iodo , Linfonodos/metabolismo , Masculino , Análise de Célula Única , Câncer Papilífero da Tireoide/patologia , Células Epiteliais da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
3.
Front Neurol ; 12: 712245, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34690913

RESUMO

Background: Neurofilaments in cerebrospinal fluid (CSF) and in blood are considered promising biomarkers of amyotrophic lateral sclerosis (ALS) because their levels can be significantly increased in patients with ALS. However, the roles of neurofilaments, especially blood neurofilaments, in the prognosis of ALS are inconsistent. We performed a meta-analysis to explore the prognostic roles of blood neurofilaments in ALS patients. Methods: We searched all relevant studies on the relationship between blood neurofilament levels and the prognosis of ALS patients in PubMed, Embase, Scopus, and Web of Science before February 2, 2021. The quality of the included articles was assessed using the Quality in Prognosis Studies (QUIPS) scale, and R (version 4.02) was used for statistical analysis. Results: Fourteen articles were selected, covering 1,619 ALS patients. The results showed that higher blood neurofilament light chain (NfL) levels in ALS patients were associated with a higher risk of death [medium vs. low NfL level: HR = 2.43, 95% CI (1.34-4.39), p < 0.01; high vs. low NfL level: HR = 4.51, 95% CI (2.45-8.32), p < 0.01]. There was a positive correlation between blood phosphorylated neurofilament heavy chain (pNfH) levels and risk of death in ALS patients [HR = 1.87, 95% CI (1.35-2.59), p < 0.01]. The levels of NfL and pNfH in blood positively correlated with disease progression rate (DPR) of ALS patients [NfL: summary r = 0.53, 95% CI (0.45-0.60), p < 0.01; pNfH: summary r = 0.51, 95% CI (0.24-0.71), p < 0.01]. Conclusion: The blood neurofilament levels can predict the prognosis of ALS patients; specifically, higher levels of blood neurofilaments are associated with a greater risk of death.

4.
Int J Biol Markers ; 36(3): 48-54, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34596453

RESUMO

BACKGROUND: This study explored the relevance between rs1695 and susceptibility to the lung cancer in the Chinese Han population. Stratification analysis was conducted on the basis of age, gender, smoking status, tumor-related family history, and pathological type to observe relations between rs1695 and susceptibility to lung cancer in the subgroups. METHODS: A case-control study was performed with 974 lung cancer patients who were pathologically diagnosed and 1005 healthy cases based on physical examination to analyze the association between rs1695 and the risk of lung cancer. RESULTS: The frequencies of the AA, GA, and GG genotypes of rs1695 were 68.4%, 28.7%, and 2.9% in cases and 64.8%, 30.8%, and 4.2% in controls, respectively. After adjustment for age, gender, smoking status, and family history, it appears that the rs1695 G allele decreases the risk of lung cancer (OR = 0.811, 95% CI 0.684-0.961, P = 0.016). Moreover, compared with the AA genotype, the GA + GG genotype decreased lung cancer susceptibility (OR = 0.808, 95% CI 0.663-0.985, P = 0.035) and the GG genotype (OR = 0.591, 95% CI 0.347-0.988, P = 0.048). In a stratified analysis, the risk of lung cancer in the G allele carriers decreased among the males, patients without a tumor-related family history, and patients with lung adenocarcinoma, especially in smokers. CONCLUSION: The polymorphism of locus rs1695 is related to the risk of lung cancer and is expected to be a target for the prediction of lung cancer.

5.
J Genet Genomics ; 48(10): 928-935, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34531147

RESUMO

High altitude is an extreme environment that imposes hypoxic pressure on physiological processes, and natives living at high altitudes are more adaptive in certain physiological processes. So far, epigenetic modifications under extreme changes in hypoxic pressures are relatively less understood. Here, we recruit 32 Tibetan elite alpinists (TEAs), who have successfully mounted Everest (8848 m) at least five times. Blood samples and physiological phenotypes of TEAs and 32 matched non-alpinist Tibetan volunteers (non-TEAs) are collected for analysis. Genome-wide DNA methylation analysis identifies 23,202 differentially methylated CpGs (Padj < 0.05, |ß| > 0.1) between the two groups. Some differentially methylated CpGs are in hypoxia-related genes such as PPP1R13L, MAP3K7CL, SEPTI-9, and CUL2. In addition, Gene ontology enrichment analysis reveals several inflammation-related pathways. Phenotypic analysis indicates that 12 phenotypes are significantly different between the two groups. In particular, TEAs exhibit higher blood oxygen saturation levels and lower neutrophil count, platelet count, and heart rate. For DNA methylation association analysis, we find that two CpGs (cg16687447, cg06947206) upstream of PTEN were associated with platelet count. In conclusion, extreme hypoxia exposure leads to epigenetic modifications and phenotypic alterations of TEA, providing us clues for exploring the molecular mechanism underlying changes under extreme hypoxia conditions.

8.
J Exp Med ; 218(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34259830

RESUMO

Transforming growth factor-ß (TGFß) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFß signaling in myofibroblast differentiation: TGFß induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFß. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.


Assuntos
Citoesqueleto/metabolismo , Proteínas de Homeodomínio/genética , Miofibroblastos/patologia , Escleroderma Sistêmico/patologia , Adulto , Idoso , Animais , Estudos de Casos e Controles , Diferenciação Celular/fisiologia , Citoesqueleto/genética , Feminino , Regulação da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Miofibroblastos/citologia , Miofibroblastos/fisiologia , Pele/patologia , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem , Quinases Associadas a rho/metabolismo
9.
Exp Gerontol ; 152: 111439, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34098010

RESUMO

BACKGROUND: Few studies have investigated the association of the neutrophil-to-lymphocyte ratio (NLR) with gait speed, but whether the NLR is predictive of slow gait speed in older adults remains unknown. The aim of this study is to examine the association of NLR levels with risk of slow gait speed development in older adults. METHODS: Overall, 1753 participants (53.11% male, aged 60-92 years, with a mean age of 77.01 ± 4.27 years) from the second wave of the Rugao Longitudinal Aging Study were included. The second wave was recognized as the baseline in this study. Gait speed was measured using a 5-m walk test at baseline and at the 3.5-year follow-up. A slow gait speed was considered a walking speed less than 0.8 m/s. The NLR was calculated based on absolute blood neutrophil and lymphocyte counts. Logistic regression models were used to investigate the association between NLR levels and slow gait speed. RESULTS: In the cross-sectional analysis, 394 individuals were identified as having slow gait speed. We found that increased NLR levels were associated with a higher risk of slow gait speed in older adults with and without comorbidities (P-value <0.05). During the 3.5-year follow-up period, 440 individuals had developed new-onset slowness. After confounding factors were controlled, increased NLR levels were significantly and independently associated with an increased risk of slow gait speed among older adults with (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.87-7.89) and without (OR 3.29, 95% CI: 1.54-7.10) comorbidities. CONCLUSION: The NLR is an inexpensive and easily obtainable inflammatory biomarker that robustly and independently predicts slow gait speed risk in older adults.


Assuntos
Neutrófilos , Velocidade de Caminhada , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Estudos Transversais , Feminino , Marcha , Humanos , Linfócitos , Masculino
10.
Cancer Sci ; 112(9): 3884-3894, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34077586

RESUMO

Gene alterations are recognized as important events in acute myeloid leukemia (AML) progression. Studies on hematopoiesis of altered genes contribute to a better understanding on their roles in AML progression. Our previous work reported a DEAH box helicase 15 (DHX15) R222G mutation in AML patients, and we showed DHX15 overexpression is associated with poor prognosis in AML patients. In this work, we further study the role of dhx15 in zebrafish developmental hematopoiesis by generating dhx15-/- zebrafish using transcription activator-like effector nuclease technology. Whole-mount in situ hybridization (WISH) analysis showed hematopoietic stem/progenitor cells were dramatically perturbed when dhx15 was deleted. Immunofluorescence staining indicated inhibited hematopoietic stem/progenitor cell (HSPC) proliferation instead of accelerated apoptosis were detected in dhx15-/- zebrafish. Furthermore, our data showed that HSPC defect is mediated through the unfolded protein response (UPR) pathway. DHX15 R222G mutation, a recurrent mutation identified in AML patients, displayed a compromised function in restoring HSPC failure in dhx15-/- ; Tg (hsp: DHX15 R222G) zebrafish. Collectively, this work revealed a vital role of dhx15 in the maintenance of definitive hematopoiesis in zebrafish through the unfolded protein respone pathway. The study of DHX15 and DHX15 R222G mutation could hold clinical significance for evaluating prognosis of AML patients with aberrant DHX15 expression.


Assuntos
RNA Helicases DEAD-box/metabolismo , Hematopoese/genética , Leucemia Mieloide Aguda/genética , Resposta a Proteínas não Dobradas/genética , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Apoptose/genética , Proliferação de Células/genética , RNA Helicases DEAD-box/genética , Técnicas de Inativação de Genes , Células-Tronco Hematopoéticas/metabolismo , Humanos , Hibridização In Situ , Leucemia Mieloide Aguda/metabolismo , Mutação , RNA Helicases/genética , RNA Helicases/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
11.
Gerontology ; 67(5): 572-580, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34000721

RESUMO

INTRODUCTION: The Healthy Ageing Index (HAI) has been shown not only to have wider applicability and predictive ability but also to adequately predict mortality in Western populations. There is still a lack of studies validating the applicability of the HAI in China. OBJECTIVE: To evaluate the applicability of the HAI and validate whether the HAI is suitable for monitoring ageing in the elderly population in China. METHODS: Data were obtained from the Rugao Longevity and Ageing Study. The modified HAI was constructed based on systolic blood pressure, chronic pulmonary diseases, cognitive function, fasting glucose, and kidney function. It was calculated in 1719 individuals aged 70-84 years at baseline. The adverse outcomes were mortality and disability. Demographic, physiologic, and clinical data were collected. Cox proportional hazards and logistic regression models were used to analyze the relationship between the modified HAI and adverse outcomes. RESULTS: A total of 1,719 older adults were analyzed in our study. A total of 793 (46.13%) males were recruited. The mean age was 75.69 ± 3.93 years. At the 5-year follow-up, there were 266 deaths and 275 individuals with disabilities. In the multivariable models, the modified HAI was associated with mortality (hazard ratio = 1.11, 95% confidence interval [CI]: 1.03-1.20) and disability (odds ratio = 1.11, 95% CI: 1.05-1.18). In the sensitivity analyses, similar associations remained after imputing missing data using multiple imputation and excluding participants with major cardiovascular disease at baseline. CONCLUSION: The modified HAI was a robust and independent predictor of adverse outcomes. It is a valid and feasible tool for monitoring ageing in older adults.


Assuntos
Pessoas com Deficiência , Envelhecimento Saudável , Idoso , Envelhecimento , China/epidemiologia , Humanos , Longevidade , Masculino , Fatores de Risco
12.
Eye (Lond) ; 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976397

RESUMO

OBJECTIVES: To determine the association of plasma homocysteine levels with retinal layer thickness in a large community cohort of older adults. METHODS: The Rugao Longevity and Ageing Study is an observational, prospective and community-based cohort study. A total of 989 older adults who underwent spectral-domain optical coherence tomography (SD-OCT) were included and analyzed. Foveal, macular retinal nerve fibre layer (mRNFL) and ganglion cell layer plus inner plexiform layer (GC-IPL) thicknesses were measured by SD-OCT. Plasma homocysteine levels were measured using chemiluminescence immunoassay. Linear regression analyses were performed to evaluate the relationship between plasma homocysteine and retinal layer thickness while controlling for confounding factors. RESULTS: Of the 989 participants, 500 (50.56%) were men. The mean age was 78.26 (4.58) years, and the mean plasma homocysteine level was 16.38 (8.05) µmol/L. In multivariable analyses, each unit increase in plasma homocysteine was associated with an 8.84 × 10-2 (95% CI: -16.54 × 10-2 to -1.15 × 10-2, p = 0.032) µm decrease in the average inner thickness of the GC-IPL after controlling for confounding factors. The association remained significant even in participants without major cardiovascular disease or diabetes (ß = -10.33 × 10-2, 95% CI: -18.49 × 10-2 to -2.18 × 10-2, p = 0.013). No significant associations of plasma homocysteine levels with macular thickness or mRNFL were found in primary and sensitivity analyses (p > 0.05). CONCLUSIONS: Increased plasma homocysteine levels are associated with a thinner GC-IPL. Plasma homocysteine may be a risk factor for thinner retinas in older adults.

13.
Br J Nutr ; : 1-7, 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34024293

RESUMO

Few studies have been conducted to investigate the association of kidney function decline with the trajectories of homocysteine (Hcy) over time, using repeated measurements. We aimed to investigate the association of kidney function with changes in plasma Hcy levels over time. Data were collected from the Rugao Longevity and Ageing Study. In detail, plasma Hcy and creatinine levels were measured in both waves (waves 2, 3 and 4) during the 3·5-year follow-up (n 1135). Wave 2 was regarded as the baseline survey. The estimated glomerular filtration rate (eGFR) was calculated based on creatinine. Subjects were categorised into four groups according to quartiles of eGFR at baseline. Linear mixed-effect models were used to investigate the association of eGFR with subsequent plasma Hcy levels. The mean eGFR at baseline was 90·84 (sd 11·42) ml/min per 1·73 m2. The mean plasma Hcy level was 14·09 (sd 6·82) at baseline and increased to 16·28 (sd 8·27) and 17·36 (sd 10·39) µmol/l during follow-ups. In the crude model, the interaction between time and eGFR at baseline was significant (ß = -0·02, 95 % CI -0·02, -0·01, P = 0·002). After adjusting for confounding factors, a significant relationship remained (ß = -0·02, 95 % CI -0·02, -0·01, P = 0·003), suggesting that kidney function decline at baseline was associated with a faster increase in Hcy levels. Kidney function decline is associated with a more pronounced increase in plasma Hcy levels. Further studies with longer follow-up periods and larger sample sizes are needed to validate our findings.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33769467

RESUMO

BACKGROUND: The altered microbiota, considered as quantitative traits, has also been identified to play pivotal roles in the host vascular physiology and might contribute to diseases. To understand the role of gut microbiota on vascular physiology in the sub-clinical elderly population and how lifestyles affect the composition of host gut microbiota to further impact the pathogenesis of vascular diseases. METHODS: Performed a population-based fecal metagenomic study over 569 elderly asymptomatic sub-clinical individuals in rural China. An association network was built based on clinical measurements and detailed epidemiologic questionnaires, including blood chemistry, arterial stiffness, carotid ultrasonography, and metagenomic datasets. RESULTS: Carotid arterial atherosclerosis indices, including intima-media thickness (IMT), were shown essentially in the network, and were significantly associated with living habits, socio-economic status, and diet. Using mediation analysis, we found that higher frequency of taking fresh fruits, fresh vegetables, and more exercise significantly reduces carotid arteries atherosclerosis in terms of IMT, PSV and EDV values the through the mediation of Alistepes, Oligella, and Prevotella. The gut microbes explained 16.5% of the mediation effect of lifestyles on the pathogenesis of carotid atherosclerosis. After adjusted, Faecalicatena (OR = 0.20∼0.30) was shown protective in the formation of carotid athersclerosis independently, while Libanicoccus (OR = 2.39∼2.43) were hazardous to carotid arterial IMTs. KEGG/KO analyses revealed a loss of anti-inflammation function in IMT subjects. CONCLUSIONS: Our study provided a Chinese population-wide phenotype-metagenomic network, revealing association and mediation effect of gut microbiota on carotid artery atherosclerosis, hinting at a therapeutic and preventive potential of microbiota in vascular diseases.

16.
Microbiome ; 9(1): 47, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597039

RESUMO

BACKGROUND: The human skin microbiota is considered to be essential for skin homeostasis and barrier function. Comprehensive analyses of its function would substantially benefit from a catalog of reference genes derived from metagenomic sequencing. The existing catalog for the human skin microbiome is based on samples from limited individuals from a single cohort on reference genomes, which limits the coverage of global skin microbiome diversity. RESULTS: In the present study, we have used shotgun metagenomics to newly sequence 822 skin samples from Han Chinese, which were subsequently combined with 538 previously sequenced North American samples to construct an integrated Human Skin Microbial Gene Catalog (iHSMGC). The iHSMGC comprised 10,930,638 genes with the detection of 4,879,024 new genes. Characterization of the human skin resistome based on iHSMGC confirmed that skin commensals, such as Staphylococcus spp, are an important reservoir of antibiotic resistance genes (ARGs). Further analyses of skin microbial ARGs detected microbe-specific and skin site-specific ARG signatures. Of note, the abundance of ARGs was significantly higher in Chinese than Americans, while multidrug-resistant bacteria ("superbugs") existed on the skin of both Americans and Chinese. A detailed analysis of microbial signatures identified Moraxella osloensis as a species specific for Chinese skin. Importantly, Moraxella osloensis proved to be a signature species for one of two robust patterns of microbial networks present on Chinese skin, with Cutibacterium acnes indicating the second one. Each of such "cutotypes" was associated with distinct patterns of data-driven marker genes, functional modules, and host skin properties. The two cutotypes markedly differed in functional modules related to their metabolic characteristics, indicating that host-dependent trophic chains might underlie their development. CONCLUSIONS: The development of the iHSMGC will facilitate further studies on the human skin microbiome. In the present study, it was used to further characterize the human skin resistome. It also allowed to discover the existence of two cutotypes on the human skin. The latter finding will contribute to a better understanding of the interpersonal complexity of the skin microbiome. Video abstract.


Assuntos
Microbiota , Moraxella/genética , Moraxella/isolamento & purificação , Propionibacteriaceae/genética , Propionibacteriaceae/isolamento & purificação , Pele/microbiologia , Adulto , Idoso , Antibacterianos/farmacologia , China/etnologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Resistência Microbiana a Medicamentos/genética , Grupos Étnicos , Feminino , Genes Bacterianos/efeitos dos fármacos , Humanos , Masculino , Metagenômica , Microbiota/efeitos dos fármacos , Microbiota/genética , Pessoa de Meia-Idade , Moraxella/efeitos dos fármacos , América do Norte/etnologia , Propionibacteriaceae/efeitos dos fármacos , Staphylococcus/efeitos dos fármacos , Staphylococcus/genética , Staphylococcus/isolamento & purificação , Simbiose , Adulto Jovem
17.
J Cancer ; 12(5): 1270-1283, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33531973

RESUMO

Objective: The expression and function of platinum transporters affect drug tissue concentration and therapeutic effects. We had previously characterized functional variant of platinum intake transporter SLC31A1 gene. We aimed to investigate the association of platinum efflux transporter gene ABCG2 polymorphism and combined ABCG2 and SLC31A1 polymorphisms with clinical outcomes of NSCLC patients receiving platinum-based chemotherapy. Methods: We genotyped thirteen tagging and functional SNPs of ABCG2 in 1004 patients, and assessed their association with response, toxicity and survival using unconditional logistic regression and Cox proportional hazards regression analyses respectively. Results: Nonsynonymous rs2231142 (odds ratio [OR] 2.07; 95 % confidence interval [CI] 1.26-3.63), rs1871744 (OR 0.60; 95 % CI 0.42-0.87) and their haplotype and diplotype were associated with objective response. Rs4148157 was associated with shorter overall survival (Log-rank P = 0.002; hazard ratio [HR] 1.22; 95 % CI 1.05-1.42). Furthermore, the combined SLC31A1 rs2233914 and ABCG2 rs1871744 genotype was significantly associated with poor response (OR 0.31; 95 % CI 0.17-0.56; P interaction = 0.003). And the combined genotypes of the functional rs10759637 of SLC31A1 and the nonsynonymous rs2231142 (Log-rank P = 5.20×10-5; HR 1.47; 95 % CI 1.19-1.81; P interaction = 0.007) or linked rs4148157 of ABCG2 were significantly associated with poor survival. Conclusion: This study reveals divergent association of ABCG2 polymorphism with response and survival of NSCLC patients receiving platinum-based chemotherapy, demonstrates the combined effects of functional variants of ABCG2 and SLC31A1 on clinical outcomes, and highlights pharmacogenetic relevance of platinum transporter genes interaction.

18.
Theranostics ; 11(1): 361-378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391480

RESUMO

Rationale: As the central hallmark of liver fibrosis, transdifferentiation of hepatic stellate cells (HSCs), the predominant contributor to fibrogenic hepatic myofibroblast responsible for extracellular matrix (ECM) deposition, is characterized with transcriptional and epigenetic remodeling. We aimed to characterize the roles of H3K27 methyltransferase EZH2 and demethylase JMJD3 and identify their effective pathways and novel target genes in HSCs activation and liver fibrosis. Methods: In primary HSCs, we analyzed effects of pharmacological inhibitions and genetic manipulations of EZH2 and JMJD3 on HSCs activation. In HSCs cell lines, we evaluated effects of EZH2 inhibition by DZNep on proliferation, cell cycling, senescence and apoptosis. In CCl4 and BDL murine models of liver fibrosis, we assessed in vivo effects of DZNep administration and Ezh2 silencing. We profiled rat primary HSCs transcriptomes with RNA-seq, screened the pathways and genes associated with DZNep treatment, analyzed EZH2 and JMJD3 regulation towards target genes by ChIP-qPCR. Results: EZH2 inhibition by DZNep resulted in retarded growth, lowered cell viability, cell cycle arrest in S and G2 phases, strengthened senescence, and enhanced apoptosis of HSCs, decreased hepatic collagen deposition and rescued the elevated serum ALT and AST activities of diseased mice, and downregulated cellular and hepatic expressions of H3K27me3, EZH2, α-SMA and COL1A. Ezh2 silencing by RNA interference in vitro and in vivo showed similar effects. JMJD3 inhibition by GSK-J4 and overexpression of wild-type but not mutant Jmjd3 enhanced or repressed HSCs activation respectively. EZH2 inhibition by DZNep transcriptionally inactivated TGF-ß1 pathway, cell cycle pathways and vast ECM components in primary HSCs. EZH2 inhibition decreased H3K27me3 recruitment at target genes encoding TGF-ß1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, and increased their expressions, while Jmjd3 overexpression manifested alike effects. Conclusions: EZH2 and JMJD3 antagonistically modulate HSCs activation. The therapeutic effects of DZNep as epigenetic drug in liver fibrosis are associated with the regulation of EZH2 towards direct target genes encoding TGF-ß1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, which are also regulated by JMJD3. Our present study provides new mechanistic insight into the epigenetic modulation of EZH2 and JMJD3 in HSCs biology and hepatic fibrogenesis.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Células Estreladas do Fígado/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Apoptose/genética , Benzazepinas/farmacologia , Ductos Biliares/cirurgia , Tetracloreto de Carbono/toxicidade , Ciclo Celular , Proteínas de Ciclo Celular/genética , Linhagem Celular , Proliferação de Células/genética , Senescência Celular/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Modelos Animais de Doenças , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Humanos , Indóis/farmacologia , Interleucina-10/genética , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Ligadura , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Camundongos , Piridonas/farmacologia , Pirimidinas/farmacologia , Interferência de RNA , Ratos
19.
J Invest Dermatol ; 141(5): 1254-1263.e6, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33069728

RESUMO

Genetic factors play a key role in the pathogenesis of autoimmune diseases, whereas the disease-causing variants remain largely unknown. Herein, we performed an exome-wide association study of systemic sclerosis in a Han Chinese population. In the discovery stage, 527 patients with systemic sclerosis and 5,024 controls were recruited and genotyped. In the validation study, an independent sample set of 479 patients and 1,096 controls were examined. In total, we found that four independent signals reached genome-wide significance. Among them, rs7574865 (Pcombined = 3.87 × 10-12) located within signal transducer and activator of transcription 4 gene was identified previously using samples of European ancestry. Additionally, another signal including three SNPs in linkage disequilibrium might be unreported susceptibility loci located in the epidermis differentiation complex region. Furthermore, two SNPs located within exon 3 of IGHM (rs45471499, Pcombined = 1.15 × 10-9) and upstream of LRP2BP (rs4317244, Pcombined = 4.17 × 10-8) were found. Moreover, rs4317244 was identified as an expression quantitative trait locus for LRP2BP that regulates tight junctions, cell cycle, and apoptosis in endothelial cell lines. Collectively, our results revealed three signals associated with systemic sclerosis in Han Chinese and suggested the importance of LRP2BP in systemic sclerosis pathogenesis. Given the limited sample size and discrepancies between previous results and our study, further studies in multiethnic populations are required for verification.

20.
Alzheimers Dement ; 17(1): 18-28, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32776666

RESUMO

China has the largest number of patients with dementia in the world. However, dementia in the Chinese population is still poorly understood and under-researched. Given the differences in genetic, demographic, sociocultural, lifestyle, and health profiles among Chinese and other ethnic/racial groups, it is crucial to build appropriate infrastructure for long-term longitudinal studies to advance Chinese cognitive aging and dementia research. We initiated a community-based prospective cohort-the Taizhou Imaging Study (TIS)-to accelerate the understanding of dementia and cerebrovascular diseases in Chinese. This article presents the rationale, aims, study design, and organization of TIS. In addition, we described some examples of the types of studies such a resource might support. The TIS provides a new framework for facilitating Chinese dementia research, encompassing invaluable resources including detailed epidemiological, sociocultural, neuroimaging, and omics data.

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