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1.
Mol Biol Evol ; 41(7)2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38842255

RESUMEN

The origins and extreme morphological evolution of the modern dog breeds are poorly studied because the founder populations are extinct. Here, we analyse eight 100 to 200 years old dog fur samples obtained from traditional North Swedish clothing, to explore the origin and artificial selection of the modern Nordic Lapphund and Elkhound dog breeds. Population genomic analysis confirmed the Lapphund and Elkhound breeds to originate from the local dog population, and showed a distinct decrease in genetic diversity in agreement with intense breeding. We identified eleven genes under positive selection during the breed development. In particular, the MSRB3 gene, associated with breed-related ear morphology, was selected in all Lapphund and Elkhound breeds, and functional assays showed that a SNP mutation in the 3'UTR region suppresses its expression through miRNA regulation. Our findings demonstrate analysis of near-modern dog artifacts as an effective tool for interpreting the origin and artificial selection of the modern dog breeds.


Asunto(s)
Pelaje de Animal , Selección Genética , Animales , Perros/genética , Polimorfismo de Nucleótido Simple , Cruzamiento , Suecia , Variación Genética , MicroARNs/genética
2.
Nutr Cancer ; 76(5): 432-441, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38439655

RESUMEN

BACKGROUND: Observational studies suggests that diets and medications affect bladder cancer (BC) development, which are subject to confounding and difficult to make causal inference. Here we aimed to investigate whether those observational associations are causal and determining the potential directions and pathways. METHODS: We used 2-sample Mendelian randomization (MR) analysis to assess associations of dietary intakes, medication uses and molecules with BC risk. Genetic summary data were derived from participants of predominantly European ancestry with rigorous instruments selection, where univariable MR, mediation MR and multivariable MR were performed. RESULTS: The results of univariable MR showed 4 dietary intakes and 4 medication uses having a protective effect on BC, while 4 circulating metabolites, 440 circulating proteins and 2 gut microbes were observed to be causally associated with BC risk. Through mediation MR, we found 572 analytes showing consistent mediating effects between dietary intakes or medication uses and BC risk. Furthermore, 9 out of 16 diet-medication pairs showed significant interactions and alterations on BC when consumed jointly. CONCLUSION: In summary, the findings obtained from the current study have important implications for informing prevention strategies that point to potential lifestyle interventions or medication prescriptions to reduce the risk of developing BC.HighlightsThe current study extends observational literature in showing the importance of diets and medications on bladder cancer prevention.The associations of diets and medications on bladder cancer prevention might be through circulating metabolites, circulating proteins and gut microbiotaOur results provide a new understanding of interactions in certain diet-medication pairs which should be taken into account by both physicians and patients during the development of a treatment strategy.


Asunto(s)
Ascomicetos , Neoplasias de la Vejiga Urinaria , Humanos , Análisis de la Aleatorización Mendeliana , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/prevención & control , Estilo de Vida , Ingestión de Alimentos
3.
Arch Toxicol ; 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38992170

RESUMEN

Genetic variants can affect gene expression by altering the level of N6-methyladenosine (m6A) modifications. A better understanding of the association of these genetic variants with susceptibility to cervical cancer (CC) can promote advances in disease screening and treatment. Genome-wide identification of m6A-associated functional SNPs for CC was performed using the TCGA and JENGER databases, incorporating the data from RNA-seq and MeRIP-seq. The screened risk-associated SNP rs1059288 (A>G), which is located in the 3' UTR of TAPBP, was further validated in a case-control study involving 921 cases and 1077 controls. The results revealed a significant association between rs1059288 and the risk of CC (OR 1.48, 95% CI 1.13-1.92). Mechanistically, the presence of the risk G allele of rs1059288 was associated with increased m6A modification of TAPBP compared with the A allele. This modification was facilitated by the m6A methyltransferase METTL14 and the reading protein YTHDF2. Immunohistochemical staining of tissue microarrays containing 61 CC and 45 normal tissues showed an overexpression of TAPBP in CC. Furthermore, the upregulation of TAPBP promoted the growth and migration of CC cells as well as tumor-forming ability, inhibited apoptosis, and conferred increased resistance to commonly used chemotherapeutic drugs such as bleomycin, cisplatin, and doxorubicin. Knockdown of TAPBP inhibited the JAK/STAT/MICB signaling pathway in CC cells and upregulated certain immune genes including ISG15, IRF3, PTPN6, and HLA-A. These findings offer insights into the involvement of genetic variations in TAPBP in the development and progression of CC.

4.
Biochem Genet ; 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38349439

RESUMEN

SUMOylation, an important post-translational protein modification, plays a critical role in cancer development and immune processes. This study aimed to construct diagnostic and prognostic models for cervical cancer (CC) using SUMOylation-related genes (SRGs) and explore their implications for novel clinical therapies. We analyzed the expression profiles of SRGs in CC patients and identified 15 SRGs associated with CC occurrence. After the subsequent qPCR verification of 20 cases of cancer and adjacent tissues, 13 of the 15 SRGs were differentially expressed in cancer tissues. Additionally, we identified molecular markers associated with the prognosis and recurrence of CC patients, based on SRGs. Next, a SUMOScore, based on SRG expression patterns, was generated to stratify patients into different subgroups. The SUMOScore showed significant associations with the tumor microenvironment, immune function features, immune checkpoint expression, and immune evasion score in CC patients, highlighting the strong connection between SUMOylation factors and immune processes. In terms of immune therapy, our analysis identified specific chemotherapy drugs with higher sensitivity in the subgroups characterized by high and low SUMOScore, indicating potential treatment options. Furthermore, we conducted drug sensitivity analysis to evaluate the response of different patient subgroups to conventional chemotherapy drugs. Our findings revealed enrichment of immune-related pathways in the low-risk subgroup identified by the prognostic model. In conclusion, this study presents diagnostic and prognostic models based on SRGs, accompanied by a comprehensive index derived from SRGs expression patterns. These findings offer valuable insights for CC diagnosis, prognosis, treatment, and immune-related analysis.

5.
Int Immunol ; 34(7): 379-394, 2022 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-35561666

RESUMEN

Emerging evidence indicates that hypoxia and immunity play important roles in tumorigenesis and development. However, the hypoxia-immune-related prognostic risk model has not been established in cervical cancer (CC). We aimed to construct a hypoxia-immune-related prognostic risk model, which has potential application in predicting the prognosis of CC patients and the response to targeted therapy. The RNA-seq data and corresponding clinical information were retrieved from The Cancer Genome Atlas (TCGA) database. The hypoxia status and immune status of CC patients were evaluated using the Consensus Clustering method and single-sample gene set enrichment analysis (ssGSEA), respectively. The univariate Cox regression, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression were applied to establish the prognostic risk model of CC. The chemotherapy response for six chemotherapeutic agents of each CC patient was calculated according to the Genomics of Drug Sensitivity in Cancer (GDSC). And the Connectivity Map (CMap) database was performed to screen candidate small-molecule drugs. In this study, we identified seven gene signatures (P4HA2, MSMO1, EGLN1, ZNF316, IKZF3, ISCU and MYO1B) with prognostic values. And the survival time of patients with low risk was significantly longer than those with high risk. Meanwhile, CC patients in the high-risk group yielded higher sensitivity to five chemotherapeutic agents. And we listed 10 candidate small-molecule drugs that exhibited a high correlation with the prognosis of CC. Thus, the prognostic model can accurately predict the prognosis of patients with CC and may be helpful for the development of new hypoxia-immune prognostic markers and therapeutic strategies for CC.


Asunto(s)
Neoplasias del Cuello Uterino , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hipoxia/genética , Pronóstico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética
6.
BJU Int ; 131(4): 443-451, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36053730

RESUMEN

OBJECTIVES: To investigate the association of polygenic risk score (PRS) and bladder cancer (BC) risk and whether this PRS can be offset by a healthy lifestyle. METHODS: Individuals with BC (n = 563) and non-BC controls (n = 483 957) were identified in the UK Biobank, and adjusted Cox regression models were used. A PRS was constructed based on 34 genetic variants associated with BC development, while a healthy lifestyle score (HLS) was constructed based on three lifestyle factors (i.e., smoking, physical activity, and diet). RESULTS: Overall, a negative interaction was observed between the PRS and the HLS (P = 0.02). A 7% higher and 28% lower BC risk per 1-standard deviation (SD) increment in PRS and HLS were observed, respectively. A simultaneous increment of 1 SD in both HLS and PRS was associated with a 6% lower BC risk. In addition, individuals with a high genetic risk and an unfavourable lifestyle showed an increased BC risk compared to individuals with low genetic risk and a favourable lifestyle (hazard ratio 1.55, 95% confidence interval 1.16-1.91; P for trend <0.001). Furthermore, population-attributable fraction (PAF) analysis showed that 12%-15% of the BC cases might have been prevented if individuals had adhered to a healthy lifestyle. CONCLUSION: This large-scale cohort study shows that a genetic predisposition combined with unhealthy behaviours have a joint negative effect on the risk of developing BC. Behavioural lifestyle changes should be encouraged for people through comprehensive, multifactorial approaches, although high-risk individuals may be selected based on genetic risk.


Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias de la Vejiga Urinaria , Humanos , Predisposición Genética a la Enfermedad/genética , Estudios de Cohortes , Factores de Riesgo , Estilo de Vida , Neoplasias de la Vejiga Urinaria/genética
7.
Cancer Control ; 30: 10732748231168756, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37078136

RESUMEN

OBJECTIVES: The abnormal expression of immune-related genes (IRGs) plays an important role in the occurrence and progression of ovarian cancer (OC), which is the main cause of mortality among gynecological cancer patients. This study aims to establish a prognostic risk model and comprehensively analyze the relationship between OC risk score and prognosis, immune cell infiltration (ICI) and therapeutic sensitivity in OC. METHODS: We retrospectively evaluated the clinicopathological characteristics of consecutive OC patients in the Cancer Genome Atlas (TCGA) database. First, the prognostic risk model was constructed by bioinformatics methods. And then, we systematically assessed model robustness, and correlations between risk score and prognosis, and immune cell infiltration. The ICGC cohort was used to verify the prognostic risk model. Finally, we evaluated their value in the treatment of OC immunotherapy and chemotherapy. RESULTS: A total of 10 IRGs were identified to construct the prognostic risk model. Survival analysis revealed that patients in the low-risk group had a better prognosis (P < .01), and the risk score might be considered an independent predictor for predicting the prognosis. In addition, risk scores and patient clinical information were used to construct clinical nomograms, improving the prediction's precision. We also explored the relationship between the risk score and ICI, immunotherapy and drug sensitivity. CONCLUSIONS: Collectively, we identified a novel ten IRGs signature that may be applied as a prognostic predictor of OC, thereby benefiting clinical decision-making and personalized treatment of patients.


Asunto(s)
Neoplasias Ováricas , Humanos , Femenino , Pronóstico , Estudios Retrospectivos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Inmunoterapia , Biomarcadores
8.
Arch Toxicol ; 97(1): 177-188, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36220961

RESUMEN

Tobacco smoking is one of the most important environmental risk factors involving bladder tumorigenesis. However, smoking-related genes in bladder carcinogenesis and corresponding genetic effects on bladder cancer risk remain unclear. Weighted correlation network analysis (WGCNA) underlying transcriptome of bladder cancer tissues was applied to identify smoking-related genes. The logistic regression model was utilized to estimate genetic effects of single nucleotide polymorphisms (SNPs) in smoking-related genes on bladder cancer risk in the Chinese and European populations with a total of 6510 cases and 6569 controls, as well as the interaction with smoking status. Transcriptome of cells and tissues was used to profile the expression pattern of candidate genes and their genetic variants. Our results demonstrated that a total of 24 SNPs in 14 smoking-related genes were associated with the risk of bladder cancer, of which rs9348451 in CDKAL1 exhibited an interaction with smoking status (ORinteraction = 1.38, Pinteraction = 1.08 × 10-2) and tobacco smoking might combine with CDKAL1 rs9348451 to increase the risk of bladder cancer (Ptrend = 4.27 × 10-4). Moreover, rs9348451 was associated with CDKAL1 expression in bladder cancer, especially in smokers (P < 0.001). Besides, CDKAL1 was upregulated in bladder cancer compared to normal adjacent tissues, as well as upregulated via treatment of cigarette smoke extracts. This study highlights the important role of nurture and nature, as well as their interaction on tumorigenesis, which provides a new way to decipher the etiology of bladder cancer with smoking status.


Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias de la Vejiga Urinaria , Humanos , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Neoplasias de la Vejiga Urinaria/genética , Carcinogénesis , Fumar/efectos adversos , Fumar/genética , Estudios de Casos y Controles
9.
RNA Biol ; 19(1): 1007-1018, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-35980273

RESUMEN

Ovarian cancer (OV) is characterized by high incidence and poor prognosis. Increasing evidence indicates that aberrant alternative splicing (AS) events are associated with the pathogenesis of cancer. We examined prognosis-related alternative splicing events and constructed a clinically applicable model to predict patients' outcomes. Public database including The Cancer Genome Atlas (TCGA), TCGA SpliceSeq, and the Genomics of Drug Sensitivity in Cancer databases were used to detect the AS expression, immune cell infiltration and IC50. The prognosis-related AS model was constructed and validated by using Cox regression, LASSO regression, C-index, calibration plots, and ROC curves. A total of eight AS events (including FLT3LG|50942|AP) were selected to establish the prognosis-related AS model. Compared with high-risk group, low-risk group had a better outcome (P = 1.794e-06), was more sensitive to paclitaxel (P = 0.022), and higher proportions of plasma cells. We explored the upstream regulatory mechanisms of prognosis-related AS and found that two splicing factor and 156 tag single nucleotide polymorphisms may be involved in the regulation of prognosis-related AS. In order to assess patient prognosis more comprehensively, we constructed a clinically applicable model combining risk score and clinicopathological features, and the 1 -, and 3-year AUCs of the clinically applicable model were 0.812, and 0.726, which were 7.5% and 3.3% higher than that of the risk score. We constructed a prognostic signature for OV patients and comprehensively analysed the regulatory characteristics of the prognostic AS events in OV.


Asunto(s)
Empalme Alternativo , Neoplasias Ováricas , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Neoplasias Ováricas/genética
10.
Environ Res ; 204(Pt B): 111997, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34506781

RESUMEN

Nitrosamines, a group of emerging nitrogenous pollutants, are ubiquitously found in the drinking water system. However, less is known about how systemic biological responses resist or tolerate nitrosamines, especially long-term co-exposure at low concentrations. In this study, untargeted metabolomics was used to investigate the metabolic perturbations in human esophageal epithelial Het-1A cells induced by a mixture of nine common nitrosamines in drinking water at environmentally relevant, human-internal-exposure, and genotoxic concentrations. Generally, the disrupted metabolic spectrum became complicated with nitrosamines dose increasing. Notably, two inflammation-associated pathways, namely, cysteine (Cys) and methionine (MET) metabolism, and nicotinate and nicotinamide metabolism, changed significantly under the action of nitrosamines, even at the environmentally relevant level. Furthermore, targeted metabolomics and molecular biology indicators in cells were identified in mice synchronously. For one thing, the up-regulated Cys and MET metabolism provided methyl donors for histone methylation in the context of pro-inflammatory response. For another, the down-regulated NAD+/NADH ratio inhibited the deacetylation of NF-кB p65 and eventually activated the NF-кB signaling pathway. Taken collectively, the metabolomics molecular signatures were important indicative markers for nitrosamines-induced inflammation. The potential crosstalk between the inflammatory cascade and metabolic regulation also requires further studies. These findings suggest that more attention should be paid to long-term co-exposure at low concentrations in the control of nitrosamines pollution in drinking water. Additionally, this study also highlights a good prospect of the combined metabolomic-molecular biology approach in environmental toxicology.


Asunto(s)
Agua Potable , Nitrosaminas , Contaminantes Químicos del Agua , Animales , Agua Potable/análisis , Contaminación Ambiental , Metabolómica , Ratones , Nitrosaminas/análisis , Nitrosaminas/toxicidad , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad
11.
J Appl Toxicol ; 42(10): 1651-1661, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35437791

RESUMEN

Nitrosamines were a class of important environmental carcinogens associated with digestive tract neoplasms. As the early toxic effect of nitrosamines, inflammatory response participated in the malignant transformation of cells and promoted the occurrence and development of tumors. However, the role of NLRP3 inflammasome in the nitrosamines-induced inflammatory response was unclear. In this study, the human esophageal epithelial cells (Het-1A) were used to explore potential mechanisms of the activation of NLRP3 inflammasome under co-exposure to nine nitrosamines commonly found in drinking water at the doses of 0, 4, 20, 100, 500, and 2500 ng/mL. The results showed that nitrosamines stimulated activation of the NLRP3 inflammasome and induced cellular oxidative damage in a dose-dependent manner. Pretreatment of reactive oxygen species scavenger N-acetyl-L-cysteine (NAC), particularly mitochondrial reactive oxygen species (mtROS) scavengers Mito-TEMPO, effectively inhibited the activation of NLRP3 inflammasome, suggesting that nitrosamines could mediate the activation of NLRP3 inflammasome via mtROS. Furthermore, we found that nitrosamines co-exposure also promoted cell pyroptosis through the NLRP3/caspase-1/GSDMD pathway, which was demonstrated by adding the caspase-1 inhibitor Z-YVAD-FMK and constructing NLRP3 downregulated Het-1A cell line. This study revealed the underlying mechanism of the activation of NLRP3 inflammasome initiated by nitrosamines co-exposure and provided new perspectives on the toxic effects of nitrosamines.


Asunto(s)
Inflamasomas , Nitrosaminas , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Nitrosaminas/toxicidad , Piroptosis/fisiología , Especies Reactivas de Oxígeno/metabolismo
12.
Ecotoxicol Environ Saf ; 244: 114071, 2022 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-36113270

RESUMEN

Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD+ in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC.


Asunto(s)
Carcinógenos Ambientales , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Niacina , Nitrosaminas , Animales , Carcinógenos/toxicidad , Transformación Celular Neoplásica , Dimetilnitrosamina/análogos & derivados , Neoplasias Esofágicas/inducido químicamente , Carcinoma de Células Escamosas de Esófago/inducido químicamente , Metaboloma , NAD , Niacina/toxicidad , Niacinamida/toxicidad , Nitrógeno/toxicidad , Nitrosaminas/toxicidad , Ratas , Esfingolípidos , Triptófano/toxicidad , Microambiente Tumoral
13.
Molecules ; 27(23)2022 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-36500247

RESUMEN

Proteomic profiling of extracellular vesicles (EVs) represents a promising approach for early detection and therapeutic monitoring of diseases such as cancer. The focus of this study was to apply robust EV isolation and subsequent data-independent acquisition mass spectrometry (DIA-MS) for urinary EV proteomics of prostate cancer and prostate inflammation patients. Urinary EVs were isolated by functionalized magnetic beads through chemical affinity on an automatic station, and EV proteins were analyzed by integrating three library-base analyses (Direct-DIA, GPF-DIA, and Fractionated DDA-base DIA) to improve the coverage and quantitation. We assessed the levels of urinary EV-associated proteins based on 40 samples consisting of 20 cases and 20 controls, where 18 EV proteins were identified to be differentiated in prostate cancer outcome, of which three (i.e., SERPINA3, LRG1, and SCGB3A1) were shown to be consistently upregulated. We also observed 6 out of the 18 (33%) EV proteins that had been developed as drug targets, while some of them showed protein-protein interactions. Moreover, the potential mechanistic pathways of 18 significantly different EV proteins were enriched in metabolic, immune, and inflammatory activities. These results showed consistency in an independent cohort with 20 participants. Using a random forest algorithm for classification assessment, including the identified EV proteins, we found that SERPINA3, LRG1, or SCGB3A1 add predictable value in addition to age, prostate size, body mass index (BMI), and prostate-specific antigen (PSA). In summary, the current study demonstrates a translational workflow to identify EV proteins as molecular markers to improve the clinical diagnosis of prostate cancer.


Asunto(s)
Vesículas Extracelulares , Neoplasias de la Próstata , Masculino , Humanos , Próstata , Proteómica/métodos , Espectrometría de Masas/métodos , Vesículas Extracelulares/metabolismo , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo
14.
BMC Genomics ; 22(1): 636, 2021 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-34474664

RESUMEN

BACKGROUND: Association mapping studies of quantitative trait loci (QTL) for canine hip dysplasia (CHD) can contribute to the understanding of the genetic background of this common and debilitating disease and might contribute to its genetic improvement. The power of association studies for CHD is limited by relatively small sample numbers for CHD records within countries, suggesting potential benefits of joining data across countries. However, this is complicated due to the use of different scoring systems across countries. In this study, we incorporated routinely assessed CHD records and genotype data of German Shepherd dogs from two countries (UK and Sweden) to perform genome-wide association studies (GWAS) within populations using different variations of CHD phenotypes. As phenotypes, dogs were either classified into cases and controls based on the Fédération Cynologique Internationale (FCI) five-level grading of the worst hip or the FCI grade was treated as an ordinal trait. In a subsequent meta-analysis, we added publicly available data from a Finnish population and performed the GWAS across all populations. Genetic associations for the CHD phenotypes were evaluated in a linear mixed model using 62,089 SNPs. RESULTS: Multiple SNPs with genome-wide significant and suggestive associations were detected in single-population GWAS and the meta-analysis. Few of these SNPs overlapped between populations or between single-population GWAS and the meta-analysis, suggesting that many CHD-related QTL are population-specific. More significant or suggestive SNPs were identified when FCI grades were used as phenotypes in comparison to the case-control approach. MED13 (Chr 9) and PLEKHA7 (Chr 21) emerged as novel positional candidate genes associated with hip dysplasia. CONCLUSIONS: Our findings confirm the complex genetic nature of hip dysplasia in dogs, with multiple loci associated with the trait, most of which are population-specific. Routinely assessed CHD information collected across countries provide an opportunity to increase sample sizes and statistical power for association studies. While the lack of standardisation of CHD assessment schemes across countries poses a challenge, we showed that conversion of traits can be utilised to overcome this obstacle.


Asunto(s)
Displasia Pélvica Canina , Animales , Perros , Estudio de Asociación del Genoma Completo , Genotipo , Displasia Pélvica Canina/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo
15.
Cancer Cell Int ; 21(1): 362, 2021 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-34238288

RESUMEN

BACKGROUND: To rummage autophagy-related prognostic, diagnostic, and therapeutic biomarkers in cervical cancer (CC). METHODS: The RNA-sequence and clinical information were from the TCGA and GTEx databases. We operated Cox regression to determine signatures related to overall survival (OS) and recurrence-free survival (RFS) respectively. The diagnostic and therapeutic effectiveness of prognostic biomarkers were further explored. RESULTS: We identified nine (VAMP7, MTMR14, ATG4D, KLHL24, TP73, NAMPT, CD46, HGS, ATG4C) and three risk signatures (SERPINA1, HSPB8, SUPT20H) with prognostic values for OS and RFS respectively. Six risk signatures (ATG4C, ATG4D, CD46, TP73, SERPINA1, HSPB8) were selected for qPCR. We screened five prognostic signatures(ATG4C, CD46, HSPB8, MTMR14, NAMPT) with diagnostic function through the GEO database. Correlation between our models and treatment targets certificated the prognostic score provided a reference for precision medicine. CONCLUSIONS: We constructed OS and RFS prognostic models in CC. Autophagy-related risk signatures might serve as diagnostic and therapeutic biomarkers.

16.
Chem Res Toxicol ; 34(8): 1866-1878, 2021 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-34296853

RESUMEN

The relationship between human papillomavirus (HPV) and esophageal cancer (EC) has been controversial, which may be caused by the difference in geographic regions of sample origin. Thus, we conducted a case-control study to find that HPV increased the risk of esophageal cancer, and the HPV18 detection rate is the highest (24.2%) among patients with EC, suggesting that HPV18 could be the most risk subtype of HPV infected. We then identified high-risk HPV18 and N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) to establish a model on the viral etiology cooperating with environmental carcinogens. Het-1A cells containing HPV18 were continuously exposed to MNNG or not; then the morphological phenotype and function assays were performed in 25th passage cells. MNNG promoted the proliferation and invasion abilities and inhibited apoptosis both in Het-1A-HPV18 and control group. However, the Het-1A-HPV18 had a stronger change in phenotypic features and formed more transformed foci in soft agar. Further, Western blot found p53 and p21 were down-regulated, and expression of c-Myc, MMP-2, and MMP-9 and Bcl-2/Bax ratio were up-regulated. Our results revealed that MNNG was easier to induce malignant transformation of Het-1A cells transfected with HPV18. It is good evidence for the close relationship between HPV and the etiology of EC, providing foundation for further study in molecular mechanism and specific intervention targets.


Asunto(s)
Alquilantes/efectos adversos , Transformación Celular Neoplásica/inducido químicamente , Neoplasias Esofágicas/etiología , Papillomavirus Humano 18/aislamiento & purificación , Infecciones por Papillomavirus/complicaciones , Anciano , Línea Celular , Neoplasias Esofágicas/inducido químicamente , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad
17.
Nutr Metab Cardiovasc Dis ; 31(11): 3076-3084, 2021 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-34518084

RESUMEN

BACKGROUND AND AIMS: The relationship between the body fat percentage (BFP) and hyperuricemia is still unknown in different gender subjects. The purpose of this study was to determine the magnitude of the association between the BFP and the presence of hyperuricemia in the sex-specific group among hypertensive patients. METHODS AND RESULTS: We conducted a cross-sectional study enrolling 14,234 hypertensive participates from the Chinese Hypertension Registry Study. Body fat percentage (BFP) was calculated by simple anthropometric parameters. Hyperuricemia was defined as serum uric acid (SUA) level 420 umol/L in men and 360 umol/L in women. The mean BFP was 24.5% in men and 37.1% in women. Multiple logistic analyses showed that the relationship between BFP with the risk of hyperuricemia in a dose-dependent manner among both men (odds ratio [OR] 1.07, 95% CI 1.06, 1.09) and women (OR 1.08, 95% CI 1.06, 1.09) in the fully adjusted model. Subgroup analyses showed the positive association between BFP and the risk of hyperuricemia was consistent in all stratification subgroups (all P for interaction >0.05). CONCLUSION: For patients with hypertension, BFP was positively associated with an increased risk of hyperuricemia among both men and women.


Asunto(s)
Adiposidad , Presión Sanguínea , Hipertensión/epidemiología , Hiperuricemia/epidemiología , Obesidad/epidemiología , Ácido Úrico/sangre , Biomarcadores/sangre , China/epidemiología , Estudios Transversales , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Hiperuricemia/sangre , Hiperuricemia/diagnóstico , Masculino , Obesidad/diagnóstico , Obesidad/fisiopatología , Pronóstico , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Factores Sexuales
18.
Ecotoxicol Environ Saf ; 222: 112494, 2021 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-34265532

RESUMEN

Copper (Cu) pollution in water and agricultural soil has always been a worldwide concern. This research aims to investigate the health effects of copper exposure on Caenorhabditis elegans (C. elegans) under the existing environmental quality standards (1 mg/L and 2 mg/L) via lifespan, reproduction, biological markers and transcriptome analysis. The results showed that copper of these two environmental standards shorten the lifespan of nematodes, reduced the brood size, reduced the frequency of pharyngeal pumps and prolonged defecation time as aging-related behaviors, and increased the levels of aging-related markers ROS, MDA and H2O2. There was a certain effect trend for the two exposure concentrations. Further, the possible molecular mechanism of copper-induced aging and reproductive effects on C. elegans was explored. Differential gene expression analysis was performed, and 2332 genes (567 up- and 1765 down-regulated genes) in the 1 mg/L group, 2449 DEGs (724 up- and 1725 down-regulated genes) in the 2 mg/L group in response to copper treatment. The top 20 regulated genes were vit (vit-1, vit-3, vit-4) genes, col genes (col-35, col-72, col-114, col-123, col-164, col-183, col-185), eea-1, him-18 and grl-20, which suggested that cuticle collagen synthesis and yolk expression were disrupted by copper. Analysis of KEGG pathway showed copper exposure widely affects longevity regulation pathways, thereby promoting aging. In summary, the sequencing results extensively and deeply reveal the health hazards of environmentally relevant doses of copper exposure to C. elegans, and behavioral testing verified that copper promoted aging of C. elegans.


Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animales , Escala de Evaluación de la Conducta , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Cobre/toxicidad , Peróxido de Hidrógeno , Longevidad , Masculino , Transcriptoma
19.
Reprod Domest Anim ; 56(6): 936-941, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33720451

RESUMEN

The aim of this study was to analyse the association between single-nucleotide polymorphisms within INHA and ACVR2B and litter size in Dazu black goats. In total, twenty-two SNPs were genotyped in 190 individuals by SNaPshot and resequencing. The results showed that three SNPs (SNP_1, SNP_12 and SNP_13 in this study) were detected to have significant additive genetic effect on the recorded goat litter size (p < .05). The SNP_1 (NC_030809.1), a non-synonymous substitution of G for T at chr2-g. 28314990 in the exon 2 of INHA gene (NM_001285606.1), resulted in homozygote 2 (HOM2) contributed 0.25 and heterozygote (HET) contributed 0.12 larger litter than homozygote 1 (HOM1). Meanwhile, SNP_12 (Chr22-g. 11721225 A > T) and SNP_13 (Chr22-g. 11721227 A > C) (NC_030829.1) simultaneously mutated at the first and third position of a triplet AAA (lysine, K) in the exon 4 of ACVR2B gene (XM_018066623.1) had estimated genetic effects of HOM1 (0.00) and HOM2 (0.03) larger than HET (-0.12). In conclusion, one SNPs (chr2-g. 28314990 T > G) within the exon 2 of INHA and two SNPs (Chr22-g. 11721225 A > T and Chr22-g. 11721227 A > C) in the exon 4 of ACVR2B gene were highly recommended as candidate markers of litter size in Dazu black goats. A large-scale association study to assess the impact of these variants on litter size is still necessary.


Asunto(s)
Cabras/genética , Tamaño de la Camada/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Activinas Tipo II/genética , Animales , Femenino , Cabras/fisiología , Inhibinas/genética , Embarazo , Análisis de Secuencia de ADN
20.
Mutagenesis ; 34(2): 127-133, 2019 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-30852614

RESUMEN

Because genetic variants in microRNAs (miRNAs) or their surrounding regions can alter miRNA processing, expression and final biological function, we investigated whether miRNA single-nucleotide polymorphisms (SNPs) are associated with cervical cancer (CC) susceptibility. Common miRNA SNPs (i.e. miR-146a rs2910164, miR-149 rs2292832, miR-196a2 rs11614913, miR-499 rs3746444, miR-605 rs2043556 and miR-618 rs2682818) were genotyped in the 954 patients and 1339 controls. The results showed that the miR-149 rs2292832 TC/CC genotypes were associated with a 21% increased risk of CC compared with the TT genotype [odds ratio (OR) = 1.21, 95% confidence interval (CI) = 1.00-1.47]. The association was more prominent among the subjects with age ≤ 48 years (OR = 1.55, 95% CI = 1.16-2.06), having history of abortion (OR = 1.44, 95% CI = 1.12-1.86), premenopausal status (OR = 1.41, 95% CI = 1.08-1.85) and patients with clinical stage II of CC (OR = 1.43, 95% CI = 1.08-1.90). The expression plasmids containing the pre-miR-149 sequence with C allele of rs2292832 transcribed higher amount of mature miR-149-5p/3p than these with T allele in the HeLa and SiHa cells. Therefore, the rs2292832 polymorphism might influence CC susceptibility through modulation of the procession of pre-miR-149 to mature miRNAs.


Asunto(s)
MicroARNs/genética , Neoplasias del Cuello Uterino/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Alelos , Pueblo Asiatico/genética , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/metabolismo , Carcinoma Adenoescamoso/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Femenino , Predisposición Genética a la Enfermedad , Células HeLa , Humanos , MicroARNs/metabolismo , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología
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