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Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.
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Neoplasias da Mama , Proteínas de Ciclo Celular , Humanos , Feminino , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Prognóstico , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismoRESUMO
Infusing CRISPR/donor-loaded adeno-associated viral vectors (AAV/CRISPR) could enable in vivo hepatic gene editing to remedy hemophilia B (HB) with inherited deficiency of clotting factor IX (FIX). Yet, current regimens focus on correcting HB with simple mutations in the coding region of the F9, overlooking those carrying complicated mutations involving the regulatory region. Moreover, a possible adverse effect of treatment-related inflammation remains unaddressed. Here we report that a single DNA cutting-mediated long-range replacement restored the FIX-encoding function of a mutant F9 (mF9) carrying both regulatory and coding defects in a severe mouse HB model, wherein incorporation of a synthetic Alb enhancer/promoter-mimic (P2) ensured FIX elevation to clinically meaningful levels. Through single-cell RNA sequencing (scRNA-seq) of liver tissues, we revealed that a subclinical hepatic inflammation post-AAV/CRISPR administration regulated the vulnerability of the edited mF9-harboring host cells to cytotoxic T lymphocytes (CTLs) and the P2 activity in a hepatocytic subset-dependent manner via modulating specific sets of liver-enriched transcription factors (LETFs). Collectively, our study establishes an AAV/CRISPR-mediated gene-editing protocol applicable to complicated monogenetic disorders, underscoring the potentiality of improving therapeutic benefits through managing inflammation.
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Alelos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Dependovirus/genética , Fator IX/genética , Hepatócitos/metabolismo , Elementos Facilitadores Genéticos , Edição de Genes/métodos , Hemofilia B/genética , Mutação , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismoRESUMO
Starting in the 1970s, individuals, businesses and the public have increasingly benefited from policies prohibiting smoking indoors, saving thousands of lives and billions of dollars in healthcare expenditures. Smokefree policies to protect against secondhand smoke exposure, however, do not fully protect the public from the persistent and toxic chemical residues from tobacco smoke (also known as thirdhand smoke) that linger in indoor environments for years after smoking stops. Nor do these policies address the economic costs that individuals, businesses and the public bear in their attempts to remediate this toxic residue. We discuss policy-relevant differences between secondhand smoke and thirdhand smoke exposure: persistent pollutant reservoirs, pollutant transport, routes of exposure, the time gap between initial cause and effect, and remediation and disposal. We examine four policy considerations to better protect the public from involuntary exposure to tobacco smoke pollutants from all sources. We call for (a) redefining smokefree as free of tobacco smoke pollutants from secondhand and thirdhand smoke; (b) eliminating exemptions to comprehensive smoking bans; (c) identifying indoor environments with significant thirdhand smoke reservoirs; and (d) remediating thirdhand smoke. We use the case of California as an example of how secondhand smoke-protective laws may be strengthened to encompass thirdhand smoke protections. The health risks and economic costs of thirdhand smoke require that smokefree policies, environmental protections, real estate and rental disclosure policies, tenant protections, and consumer protection laws be strengthened to ensure that the public is fully protected from and informed about the risks of thirdhand smoke exposure.
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INTRODUCTION: Risk stratification of cutaneous squamous cell carcinoma (CSCC) is essential for managing patients. Artificial intelligence and machine learning might help stratify patients with CSCC by risk using more than solely clinical and histopathological factors. METHODS: A retrospective cohort of 104 CSCCs excised with clear margins was retrieved. Clinical and histopathological risk factors were evaluated. Hematoxylin and eosin-stained slides were scanned and analyzed by an algorithm based on the stacked predictive sparse decomposition technique. Cellular morphometric biomarkers (CMBs) were identified via machine learning and used to derive a cellular morphometric risk score (CMRS) that classified CSCC into clusters of differential prognosis. Concordance analysis, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated and compared with results obtained with the Brigham and Women's Hospital (BWH) staging system. The performance of the combination of the BWH staging system and the CMBs was also analyzed. RESULTS: There were no differences among CMRS groups in terms of clinical and histopathological risk factors and T-stage assignment, but there were significant differences in prognosis. Combining the CMRS with BWH staging systems increased distinctiveness and improved prognostic performance. C-indices were 0.92 for local recurrence and 0.91 for nodal metastasis when combining the two approaches. The NPV was 94.41% and 96.00%, the PPV was 36.36% and 41.67%, and accuracy reached 86.75% and 89.16% with the combined approach. CONCLUSION: CMRS is helpful for CSCC risk stratification beyond classic clinical and histopathological risk features. Combining the information from the CMRS and the BWH staging system offers outstanding prognostic performance for high-risk CSCC patients.
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BACKGROUND: Congenital anomalies of the kidney and urinary tracts (CAKUT) are the leading cause of kidney failure in children with phenotypic and genotypic heterogeneity. Our objective was to describe the genetic spectrum and identify the risk factors for kidney failure in children with CAKUT. METHODS: Clinical and genetic data were derived from a multicenter network (Chinese Children Genetic Kidney Disease Database, CCGKDD) and the Chigene database. A total of 925 children with CAKUT who underwent genetic testing from 2014 to 2020 across China were studied. Data for a total of 584 children wereobtained from the CCGKDD, including longitudinal data regarding kidney function. The risk factors for kidney failure were determined by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: A genetic diagnosis was established in 96 out of 925 (10.3%) children, including 72 (8%) with monogenic variants, 20 (2%) with copy number variants (CNVs), and 4 (0.4%)with major chromosomal anomalies. Patients with skeletal abnormalities were more likely to have large CNVs or abnormal karyotypes than monogenic variants. Eighty-two patients from the CCGKDD progressed to kidney failure at a median age of 13.0 (95% confidence interval, 12.4-13.6) years, and twenty-four were genetically diagnosed with variants of PAX2, TNXB, EYA1, HNF1B and GATA3 or the 48, XXYY karyotype. The multivariate analysis indicated that solitary kidney, posterior urethral valves, bilateral hypodysplasia, the presence of certain variants and premature birth were independent prognostic factors. CONCLUSIONS: The genetic spectrum of CAKUT varies among different subphenotypes. The identified factors indicate areas that require special attention.
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Tobacco-specific nitrosamines (TSNAs) are emitted during smoking and form indoors by nitrosation of nicotine. Two of them, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are human carcinogens with No Significant Risk Levels (NSRLs) of 500 and 14 ng day-1, respectively. Another TSNA, 4-(methylnitrosamino)-4-(3-pyridyl) butanal (NNA), shows genotoxic and mutagenic activity in vitro. Here, we present additional evidence of genotoxicity of NNA, an assessment of TSNA dermal uptake, and predicted exposure risks through different pathways. Dermal uptake was investigated by evaluating the penetration of NNK and nicotine through mice skin. Comparable mouse urine metabolite profiles suggested that both compounds were absorbed and metabolized via similar mechanisms. We then investigated the effects of skin constituents on the reaction of adsorbed nicotine with nitrous acid (epidermal chemistry). Higher TSNA concentrations were formed on cellulose and cotton substrates that were precoated with human skin oils and sweat compared to clean substrates. These results were combined with reported air, dust, and surface concentrations to assess NNK intake. Five different exposure pathways exceeded the NSRL under realistic scenarios, including inhalation, dust ingestion, direct dermal contact, gas-to-skin deposition, and epidermal nitrosation of nicotine. These results illustrate potential long-term health risks for nonsmokers in homes contaminated with thirdhand tobacco smoke.
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Nicotiana , Nitrosaminas , Animais , Carcinógenos/toxicidade , Poeira , Ingestão de Alimentos , Humanos , Camundongos , Nicotina/química , Nitrosaminas/química , Nicotiana/química , Nicotiana/metabolismoRESUMO
BACKGROUND: Infertility affects approximately 15% of couples worldwide with male infertility being responsible for approximately 50% of cases. Although accumulating evidence demonstrates the critical role of the X chromosome in spermatogenesis during the last few decades, the expression patterns and potential impact of the X chromosome, together with X linked genes, on male infertility are less well understood. METHODS: We performed X chromosome exome sequencing followed by a two-stage independent population validation in 1333 non-obstructive azoospermia cases and 1141 healthy controls to identify variant classes with high likelihood of pathogenicity. To explore the functions of these candidate genes in spermatogenesis, we first knocked down these candidate genes individually in mouse spermatogonial stem cells (SSCs) using short interfering RNA oligonucleotides and then generated candidate genes knockout mice by CRISPR-Cas9 system. RESULTS: Four low-frequency variants were identified in four genes (BCORL1, MAP7D3, ARMCX4 and H2BFWT) associated with male infertility. Functional studies of the mouse SSCs revealed that knocking down Bcorl1 or Mtap7d3 could inhibit SSCs self-renewal and knocking down Armcx4 could repress SSCs differentiation in vitro. Using CRISPR-Cas9 system, Bcorl1 and Mtap7d3 knockout mice were generated. Excitingly, Bcorl1 knockout mice were infertile with impaired spermatogenesis. Moreover, Bcorl1 knockout mice exhibited impaired sperm motility and sperm cells displayed abnormal mitochondrial structure. CONCLUSION: Our data indicate that the X-linked genes are associated with male infertility and involved in regulating SSCs, which provides a new insight into the role of X-linked genes in spermatogenesis.
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Cromossomos Humanos X/genética , Proteínas Repressoras/genética , Espermatogênese/genética , Testículo/crescimento & desenvolvimento , Animais , Sistemas CRISPR-Cas/genética , Exoma/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Motilidade dos Espermatozoides/genética , Espermatogônias/metabolismo , Espermatogônias/patologia , Testículo/patologia , Sequenciamento do ExomaRESUMO
BACKGROUND: The effect of chemical exposure on obesity has raised great concerns. Real-world chemical exposure always imposes mixture impacts, however their exposure patterns and the corresponding associations with obesity have not been fully evaluated. OBJECTIVES: To discover obesity-related mixed chemical exposure patterns in the general U.S. METHODS: Sparse Decompositional Regression (SDR), a model adapted from sparse representation learning technique, was developed to identify exposure patterns of chemical mixtures with exclusion (non-targeted model) and inclusion (targeted model) of health outcomes. We assessed the relationships between the identified chemical mixture patterns and obesity-related indexes. We also conducted a comprehensive evaluation of this SDR model by comparing to the existing models, including generalized linear regression model (GLM), principal component analysis (PCA), and Bayesian kernel machine regression (BKMR). RESULTS: Eight core exposure patterns were identified using the non-targeted SDR model. Patterns of high levels of MEP, high levels of naphthalene metabolites (ΣOH-Nap), and a pattern of high exposure levels of MCOP, MCNP, and MCPP were positively associated with obesity. Patterns of high levels of BP3, and a pattern of higher mixed levels of MPB, PPB, and MEP were found to have negative associations. Associations were strengthened using the targeted SDR model. In the single chemical analysis by GLM, BP3, MBP, PPB, MCOP, and MCNP showed significant associations with obesity or body indexes. The SDR model exceeded the performance of PCA in pattern identification. Both SDR and BKMR identified a positive contribution of ΣOH-Nap and MCOP, as well as a negative contribution of BP3 and PPB to obesity. CONCLUSION: Our study identified five core exposure patterns of chemical mixtures significantly associated with obesity using the newly developed SDR model. The SDR model could open a new avenue for assessing health effects of environmental mixture contaminants.
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Obesidade , Adulto , Humanos , Inquéritos Nutricionais , Teorema de Bayes , Obesidade/induzido quimicamente , Obesidade/epidemiologia , Análise de Componente Principal , Cromatografia GasosaRESUMO
Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. These changes are not specific to tumors but also take place during the physiological growth of tissues. Indeed, the cellular and tissue mechanisms present in the tumor have their physiological counterpart in the repair of tissue lesions and wound healing. These molecular mechanisms have been acquired during metazoan evolution, first to eliminate the infection of the tissue injury, then to enter an effective regenerative phase. Cancer itself could be considered a phenomenon of antagonistic pleiotropy of the genes involved in effective tissue repair. Cancer and tissue repair are complex traits that share many intermediate phenotypes at the molecular, cellular, and tissue levels, and all of these are integrated within a Systems Biology structure. Complex traits are influenced by a multitude of common genes, each with a weak effect. This polygenic component of complex traits is mainly unknown and so makes up part of the missing heritability. Here, we try to integrate these different perspectives from the point of view of the metabolic changes observed in cancer.
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Neoplasias , Animais , Neoplasias/genética , Fenótipo , Biologia de SistemasRESUMO
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow (BM) was collected from control and THS-exposed mice and transplanted into BM-ablated recipient mice, which were followed for tumor development for 1 year. We found that in utero and early-life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen (SP) and BM B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in BM transplantation recipient mice, potentially caused by THS-induced B-cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS-exposed BM stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early-life developmental periods represent vulnerable windows of susceptibility for these effects.
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Sistema Imunitário/efeitos dos fármacos , Leucemia/etiologia , Linfoma/etiologia , Nicotiana/efeitos adversos , Fumaça/efeitos adversos , Animais , Leucemia/imunologia , Linfoma/imunologia , Camundongos Transgênicos , Poluição por Fumaça de Tabaco/efeitos adversos , Poluição por Fumaça de Tabaco/análiseRESUMO
Azoxymethane (AOM) is a widely used carcinogen to study chemical-induced colorectal carcinogenesis and is an agent for studying fulminant hepatic failure. The inter-strain susceptibility to acute toxicity by AOM has been reported, but its association with host genetics or gut microbiota remains largely unexplored. Here a cohort of genetically diverse Collaborative Cross (CC) mice was used to assess the contribution of host genetics and the gut microbiome to AOM-induced acute toxicity. We observed variation in AOM-induced acute liver failure across CC strains. Quantitative trait loci (QTL) analysis revealed three chromosome regions significantly associated with AOM toxicity. Genes located within these QTL, including peroxisome proliferator-activated receptor alpha (Ppara), were enriched for enzyme activator and nucleoside-triphosphatase regulator activity. We further demonstrated that the protein level of PPARα in liver tissues from sensitive strains was remarkably lower compared to levels in resistant strains, consistent with protective role of PPAR family in liver injury. We discovered that the abundance levels of gut microbial families Anaeroplasmataceae, Ruminococcaceae, Lactobacillaceae, Akkermansiaceae and Clostridiaceae were significantly higher in the sensitive strains compared to the resistant strains. Using a random forest classifier method, we determined that the relative abundance levels of these microbial families predicted AOM toxicity with the area under the receiver-operating curve (AUC) of 0.75. Combining the three genetic loci and five microbial families increased the predictive accuracy of AOM toxicity (AUC of 0.99). Moreover, we found that Ruminococcaceae and Lactobacillaceae acted as mediators between host genetics and AOM toxicity. In conclusion, this study shows that host genetics and specific microbiome members play a critical role in AOM-induced acute toxicity, which provides a framework for analysis of the health effects from environmental toxicants.
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Azoximetano/toxicidade , Carcinógenos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Microbioma Gastrointestinal , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/microbiologia , Camundongos de Cruzamento Colaborativo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/genética , Falência Hepática Aguda/microbiologia , Masculino , Camundongos , Locos de Características Quantitativas , Especificidade da EspécieRESUMO
Allergy to house dust mites (HDMs) can cause allergic rhinitis, allergic asthma and allergic skin disorders, which is becoming an enormous worldwide health and economic burden. To explore the relationship between air pollution and HDMs sensitization in children, this study used immunoblotting to determine the concentration of HDM serum-specific IgE (sIgE) in children with allergic diseases in Hangzhou. HDM sIgE was used to reflect the sensitization of children with HDMs. Using the meteorological and atmospheric pollutant data for Hangzhou, a distributed lag nonlinear model was founded to evaluate the effect of atmospheric pollutants on HDMs sensitization. Particulate matter (PM) 2.5 and PM10 were the main air pollutants in Hangzhou. The positive rate of HDM sIgE in children's serum increased with increasing PM2.5 and PM10 concentrations, and this effect was most obvious on the seventh and tenth days after increased PM2.5 and PM10 concentrations, respectively. In addition, there was a significant positive correlation between the concentration of HDM sIgE and the total serum IgE concentration. The rate of sensitization to HDMs rose dramatically in the first 3 years after birth. In addition, the period between June and November had the largest number of HDM sIgE-positive patients. Studies have shown that PM2.5 and PM10 are important factors in HDM sensitization, which presented obvious dose effects and lag effects. Children under the age of 3 years were the most susceptible to HDMs, and the period from June to November had a high risk of dust mite exposure. Avoiding exposure to particulate matter may have benefits in preventing HDM sensitization in children.
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Poluentes Atmosféricos/efeitos adversos , Alérgenos/imunologia , Hipersensibilidade/etiologia , Pyroglyphidae/imunologia , Poluentes Atmosféricos/análise , Animais , Criança , Pré-Escolar , China , Feminino , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/imunologia , Imunoglobulina E/sangue , Lactente , Material Particulado/efeitos adversos , Material Particulado/análise , Fatores de RiscoRESUMO
OBJECTIVE: The Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum. DESIGN: We monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis. RESULTS: CC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκb1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS. CONCLUSIONS: CC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.
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Carcinogênese/patologia , Modelos Animais de Doenças , Predisposição Genética para Doença/etiologia , Neoplasias Gástricas/etiologia , Animais , Carcinogênese/genética , Camundongos de Cruzamento Colaborativo , Feminino , Masculino , Camundongos , Neoplasias Gástricas/patologiaRESUMO
In this cross-sectional study, we evaluated associations between cadmium, lead, and mercury levels and the presence of albuminuria in US adults who participated in the National Health and Nutrition Examination Survey during the period 2009-2012. A total of 2,926 adults aged ≥20 years were included, representing a population-based sample of 18,264,307 persons. Data on blood and urinary levels of cadmium, lead, and mercury and urinary albumin concentration (albuminuria, measured as albumin:creatinine ratio (ACR) ≥30 mg/g) were obtained. Multivariate linear regression was used to analyze associations between log-transformed cadmium, lead, and mercury levels and the presence of albuminuria. Urinary ACR was significantly higher among participants with a blood cadmium level of 0.349-0.692 µg/L (quartile 3) than in those with a blood cadmium level less than or equal to 0.243 µg/L (quartile 1) (crude ß = 0.15, 95% confidence interval (CI): 0.01, 0.28). Participants with a urinary cadmium level greater than or equal to 0.220 µg/L had a significantly higher ACR (0.220-0.403 µg/L (quartile 3): crude ß = 0.12 (95% CI: 0.03, 0.21); ≥0.404 µg/L (quartile 4): crude ß = 0.29 (95% CI: 0.18, 0.39)) than those with a urinary cadmium level less than or equal to 0.126 µg/L (quartile 1). In conclusion, only blood and urinary cadmium levels, not mercury or lead levels, were associated with albuminuria among adults in this population.
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Albuminúria/epidemiologia , Cádmio/sangue , Chumbo/sangue , Mercúrio/sangue , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Estados Unidos/epidemiologiaRESUMO
Variations in oral bacterial communities have been linked to oral cancer suggesting that the oral microbiome is an etiological factor that can influence oral cancer development. The 4-nitroquinoline 1-oxide (4-NQO)-induced murine oral and esophageal cancer model is frequently used to assess the effects of preventive and/or therapeutic agents. We used this model to assess the impact of the microbiome on tumorigenesis using axenic (germ-free) and conventionally housed mice. Increased toxicity was observed in germ-free mice, however, no difference in tumor incidence, multiplicity, and size was observed. Transcriptional profiling of liver tissue from germ-free and conventionally housed mice identified 254 differentially expressed genes including ten cytochrome p450 enzymes, the largest family of phase-1 drug metabolizing enzymes in the liver. Gene ontology revealed that differentially expressed genes were enriched for liver steatosis, inflammation, and oxidative stress in livers of germ-free mice. Our observations emphasize the importance of the microbiome in mediating chemical toxicity at least in part by altering host gene expression. Studies on the role of the microbiome in chemical-induced cancer using germ-free animal models should consider the potential difference in dose due to the microbiome-mediated changes in host metabolizing capacity, which might influence the ability to draw conclusions especially for tumor induction models that are dose dependent.
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4-Nitroquinolina-1-Óxido/toxicidade , Carcinogênese/patologia , Carcinógenos/toxicidade , Transformação Celular Neoplásica/patologia , Neoplasias Esofágicas/patologia , Microbiota , Neoplasias Bucais/patologia , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/genética , Neoplasias da Língua/induzido quimicamente , Neoplasias da Língua/genética , Neoplasias da Língua/patologiaRESUMO
Recently, potential health concerns have been raised about thirdhand smoke (THS), a much less well-understood type of smoke exposure defined as residual tobacco smoke sorbed onto indoor surfaces after active smoking has ceased. THS exposure is derived from the involuntary inhalation, ingestion, or dermal uptake of indoor pollutants. The timescale for exposure to THS pollution is generally much longer than secondhand smoke, and could stretch to days, months, or years (long-term, low-level exposure). Recent studies showed that exposure to THS at early age in mice can affect body weight, immunity, and lung cancer development. However, adverse health effects of THS in human populations remain poorly understood and many questions remain unanswered. One major question is how genetic factors influence susceptibility to THS-induced health effects, especially tumor development and whether there is an age-specific window of susceptibility for these effects. By addressing these questions, we will provide a better understanding of the effects of THS on human health and disease. This information would address critical knowledge gaps that are required for the formulation of policies related to indoor air quality. IMPLICATIONS: THS, the residual tobacco smoke remaining in the environment after tobacco has been smoked, represents an underestimated public health hazard. Evidence supports its widespread presence in indoor environments. Vulnerable populations are believed to include infants and children living in a smoking household exposed to THS and/or secondhand smoke, and exposure has been identified as a risk factor for lung cancer later in life. These and future studies will provide novel and important evidence of how early-life exposure to THS affects cancer development and other diseases, which should be useful for framing and enforcing new policies against passive smoking in the world.
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Predisposição Genética para Doença/genética , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Fumar/efeitos adversos , Fumar/genética , Poluição por Fumaça de Tabaco/efeitos adversos , Poluição do Ar em Ambientes Fechados/análise , Animais , Características da Família , Predisposição Genética para Doença/epidemiologia , Humanos , Neoplasias Pulmonares/epidemiologia , Fatores de Risco , Populações VulneráveisRESUMO
Cell cycle regulation in hematopoietic stem cells (HSCs) is tightly controlled during homeostasis and in response to extrinsic stress. p53, a well-known tumor suppressor and transducer of diverse stress signals, has been implicated in maintaining HSC quiescence and self-renewal. However, the mechanisms that control its activity in HSCs, and how p53 activity contributes to HSC cell cycle control, are poorly understood. Here, we use a genetically engineered mouse to show that p53 C-terminal modification is critical for controlling HSC abundance during homeostasis and HSC and progenitor proliferation after irradiation. Preventing p53 C-terminal modification renders mice exquisitely radiosensitive due to defects in HSC/progenitor proliferation, a critical determinant for restoring hematopoiesis after irradiation. We show that fine-tuning the expression levels of the cyclin-dependent kinase inhibitor p21, a p53 target gene, contributes significantly to p53-mediated effects on the hematopoietic system. These results have implications for understanding cell competition in response to stresses involved in stem cell transplantation, recovery from adverse hematologic effects of DNA-damaging cancer therapies, and development of radioprotection strategies.
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Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos da radiação , Homeostase/genética , Tolerância a Radiação/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/genética , Feminino , Raios gama , Dosagem de Genes , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Longevidade/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
Exposure to thirdhand smoke (THS) is a recently described health concern that arises in many indoor environments. However, the carcinogenic potential of THS, a critical consideration in risk assessment, remains untested. Here we investigated the effects of short-term early exposure to THS on lung carcinogenesis in A/J mice. Forty weeks after THS exposure from 4 to 7 weeks of age, the mice had increased incidence of lung adenocarcinoma, tumor size and, multiplicity, compared with controls. In vitro studies using cultured human lung cancer cells showed that THS exposure induced DNA double-strand breaks and increased cell proliferation and colony formation. RNA sequencing analysis revealed that THS exposure induced endoplasmic reticulum stress and activated p53 signaling. Activation of the p53 pathway was confirmed by an increase in its targets p21 and BAX. These data indicate that early exposure to THS is associated with increased lung cancer risk.
Assuntos
Neoplasias Pulmonares/induzido quimicamente , Fumar/efeitos adversos , Fatores de Tempo , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Proliferação de Células/fisiologia , Modelos Animais de Doenças , Incidência , Camundongos , Nicotiana/efeitos adversosRESUMO
BACKGROUND: Our previous study found that most Mycoplasma pneumoniae (MP) pneumonia (MPP)patients had elevated serum total immunoglobulin E (IgE) levels. OBJECTIVE: To determine components of MP that can cause an IgE increase in children, and to clarify its specific mechanism. METHODS: The components of MP cells were isolated by serum IgE from patients with MP pneumonia. These components obtained through the prokaryotic expression were used as allergens to detect the proportion of allergen-specific IgE produced in MPP patients, and the clinical characteristics and related immune parameters of these patients who produced this allergen-specific IgE were also analyzed. In addition, a cell experiment was used to verify the biological effect of these components in vitro. RESULTS: P1-specific IgE was detected in serum of MPP children. An approximately 24-kDa polypeptide of P1 protein was obtained through prokaryotic expression purified by nickel agarose affinity chromatography. Approximately 9.2% of MPP patients produced IgE against this polypeptide of P1 protein, which was more likely to be produced in MPP patients with no history of allergies or family history of allergy-related diseases. P1-specific IgE-positive MPP patients had more severe clinical symptoms, with excessive secretion of interleukin (IL)-4 and IL-5 and overdifferentiation of Th0 cells into Th2 cells. Tests also demonstrated that the P1 protein stimulated excessive secretion of IL-4 and IL-5 in peripheral blood mononuclear cells from the peripheral blood of healthy donors. CONCLUSION: Mycoplasma pneumoniae is not only an infectious agent but also an allergen for certain individuals. The P1 protein of MP can induce the production of P1-specific IgE.
Assuntos
Alérgenos/imunologia , Proteínas de Bactérias/imunologia , Imunoglobulina E/biossíntese , Mycoplasma pneumoniae/imunologia , Pneumonia por Mycoplasma/imunologia , Alérgenos/genética , Proteínas de Bactérias/genética , Criança , Pré-Escolar , Clonagem Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Imunoglobulina E/sangue , Lactente , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Masculino , Mycoplasma pneumoniae/química , Mycoplasma pneumoniae/patogenicidade , Pneumonia por Mycoplasma/microbiologia , Pneumonia por Mycoplasma/patologia , Estudos Prospectivos , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th1/microbiologia , Células Th2/imunologia , Células Th2/microbiologiaRESUMO
Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as "missing heritability." Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases.