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Background: Although genetic factors are known to play a role in the pathogenesis of bladder cancer, population-level familial risk estimates are scarce. We aimed to quantify the familial risk of bladder cancer and analyze interactions between family history and smoking or alcohol consumption. Methods: Using the National Health Insurance database, we constructed a cohort of 5,524,403 study subjects with first-degree relatives (FDRs) and their lifestyle risk factors from 2002 to 2019. Familial risk was calculated using hazard ratios (HRs) with 95% confidence intervals (CIs) that compare the risk of individuals with and without affected FDRs. Interactions between family history and smoking or alcohol intake were assessed on an additive scale using the relative excess risk due to interaction (RERI). Results: Offspring with an affected parent had a 2.09-fold (95% CI: 1.41 - 3.08) increased risk of disease compared to those with unaffected parents. Familial risks of those with affected father and mother were 2.26 (95% CI: 1.51 - 3.39) and 1.10 (95% CI: 0.27 - 4.41), respectively. When adjusted for lifestyle factors, HR reduced slightly to 2.04 (95% CI: 1.38 - 3.01), suggesting that a genetic predisposition is the main driver in the familial aggregation. Smokers with a positive family history had a markedly increased risk of disease (HR: 3.60, 95% CI: 2.27 - 5.71), which exceeded the sum of their individual risks, with statistically significant interaction (RERI: 0.72, 95% CI: 0.31 - 1.13). For alcohol consumption, drinkers with a positive family history also had an increased risk of disease, although the interaction was not statistically significant (RERI: 0.05, 95% CI: -3.39 - 3.48). Conclusion: Smokers and alcohol consumers with a positive family history of bladder cancer should be considered a high-risk group and be advised to undergo genetic counseling.
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CONTEXT: Population-based studies on the familial aggregation of Graves disease (GD) are scarce and gene-environment interactions are not well-studied. OBJECTIVE: We evaluated the familial aggregation of GD and assessed interactions between family history and smoking. METHODS: Using the National Health Insurance database, which includes information on familial relationships and lifestyle risk factors, we identified 5 524 403 individuals with first-degree relatives (FDRs). Familial risk was calculated using hazard ratios (HRs), comparing the risk of individuals with and without affected FDRs. Interactions between smoking and family history were assessed on an additive scale using relative excess risk due to interaction (RERI). RESULTS: The HR among individuals with affected FDRs was 3.39 (95% CI, 3.30-3.48) compared with those without affected FDR, and among individuals with affected twin, brother, sister, father, and mother, the HRs were 36.53 (23.85-53.54), 5.26 (4.89-5.66), 4.12 (3.88-4.38), 3.34 (3.16-3.54), and 2.63 (2.53-2.74), respectively. Individuals with both a positive family history and smoking had an increased risk of disease (HR 4.68) with statistically significant interaction (RERI 0.94; 95% CI, 0.74-1.19). Heavy smokers with a positive family history showed a nearly 6-fold increased risk, which was higher than moderate smoking, suggesting a dose-response interaction pattern. Current smoking also showed a statistically significant interaction with family history (RERI 0.52; 95% CI, 0.22-0.82), while this was not observed for former smoking. CONCLUSION: A gene-environment interaction can be suggested between smoking and GD-associated genetic factors, which diminishes after smoking cessation. Smokers with a positive family history should be considered a high-risk group and smoking cessation should be advised.
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Predisposição Genética para Doença , Doença de Graves , Masculino , Feminino , Humanos , Fumar/efeitos adversos , Fumar/epidemiologia , Fatores de Risco , Irmãos , Doença de Graves/etiologia , Doença de Graves/genética , FamíliaRESUMO
OBJECTIVES: We evaluated the familial risk of seropositive rheumatoid arthritis (RA) and examined interactions between family history and smoking. METHODS: Using the National Health Insurance and Health Screening Program databases, which include information on familial relationships and lifestyle factors, we identified 5 524 403 individuals with first-degree relatives (FDRs) from 2002-2018. We calculated familial risk using hazard ratios (HRs) with 95% CIs which compare the risk of individuals with and without affected FDRs. Interactions between smoking and family history were assessed on an additive scale using the relative excess risk due to interaction (RERI). RESULTS: Individuals with affected FDR had 4.52-fold (95% CI 3.98, 5.12) increased risk of disease compared with those with unaffected FDR. Familial risk adjusted for lifestyle factors decreased slightly (HR 4.49), suggesting that a genetic contribution is the predominant driver in the familial aggregation of RA. Smoking was associated with an increased risk of disease that was more pronounced among heavy (HR 1.92 95% CI 1.70, 2.18) compared with moderate (HR 1.15 95% CI 1.04, 1.28) smoking. In the interaction analysis, the risk associated with the combined effect of smoking and family history was higher than the sum of their individual effects, though statistically non-significant (RERI 1.30 95% CI â0.92, 3.51). Heavy smokers with a positive family history showed a prominent interaction (RERI 4.13 95% CI â0.88, 9.13) which exceeded moderate smokers (RERI 0.61 95% CI â1.90, 3.13), suggesting a dose-response interaction pattern. CONCLUSION: Our findings indicate the possibility of an interaction between RA-associated genes and smoking.
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Artrite Reumatoide , Fumar , Humanos , Fumar/efeitos adversos , Fumar/epidemiologia , Fatores de Risco , Predisposição Genética para Doença , Estudos de Coortes , Artrite Reumatoide/etiologia , Artrite Reumatoide/genéticaRESUMO
PURPOSE: We quantified the familial risk of renal cell cancer (RCC) among first-degree relatives (FDRs) on a population level, and examined interactions between family history and body mass index or blood glucose. MATERIALS AND METHODS: Using the National Health Insurance database, which covers the entire Korean population, and the National Health Screening Program, we constructed a cohort of 5,524,403 individuals with blood-related FDRs and their lifestyle factors from 2002 to 2018. We calculated familial risk using incidence risk ratios (IRRs) with 95% confidence intervals, which compares the risk of individuals with and without FDR. The combined effect and interaction of a given risk factor and family history of RCC were measured by the relative excess risk due to interaction. RESULTS: Individuals with affected FDRs showed a 2.29-fold (95% CI 1.68-3.13) increased risk of disease. Familial risk adjusted for lifestyle factors showed minimal attenuation (IRR 2.25; 95% CI: 1.65-3.08), suggesting that genetic predisposition is the main contributor in the familial aggregation of RCC. Individuals with both a positive family history and overweight/obesity (IRR 3.71, 95% CI 2.50-4.92) or hyperglycemia (IRR 4.52, 95% CI 2.59-6.45) had a significantly higher risk that exceeded the sum of their individual risks, suggesting an interaction that was statistically significant (relative excess risk due to interaction 95% CI: 0.91, -0.21-2.12; 2.21, 0.28-4.14). CONCLUSIONS: Our findings suggest an interaction between genetic and environmental factors, namely obesity and hyperglycemia. Individuals with both factors should be considered a high-risk group and advised to undergo genetic counseling.
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Carcinoma de Células Renais , Hiperglicemia , Neoplasias Renais , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/genética , Família , Predisposição Genética para Doença , Humanos , Hiperglicemia/epidemiologia , Neoplasias Renais/etiologia , Neoplasias Renais/genética , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/genética , Fatores de RiscoRESUMO
OBJECTIVES: Higher prevalence of suicidality has been reported in individuals with ASD. This study aimed to (1) Estimate the prevalence of suicidal ideation (SI) in epidemiologically-ascertained, population-based, samples of children with ASD or Autism Spectrum Screening Questionnaire (ASSQ) Screen Positivity (ASP); (2) Determine whether ASD/ASP is an independent risk factor for SI, controlling for known SI risk factors; and, (3) Develop an explanatory model for SI in children with ASD/ASP. METHODS: Participants came from three epidemiologically-ascertained samples of school-aged Korean children (n = 14,423; 3,702; 4,837). ASSQ ≥ 14 was the cutoff for ASP. A subsample (n = 86) was confirmed to have ASD. SI was based on parents' endorsement of items on the Behavioral Assessment System for Children-2-Parent Report Scale-Children. Logistic regressions were used to assess associations between SI and ASD/ASP, controlling for demographics, peer victimization, behavior problems, and depression. To develop an explanatory model for SI within ASD/ASP, the associations between SI and child characteristics (comorbid conditions, ASD symptoms, IQ, adaptive function) were tested. RESULTS: SI was higher in children with ASD (14%) and ASP (16.6-27.4%) than ASSQ Screen Negative (ASN) peers (3.4-6.9%). ASD/ASP was strongly predictive of SI (ORs: 2.87-5.67), after controlling for known SI risk factors compared to ASN. Within the ASD and ASP groups, anxiety was the strongest predictor of SI. CONCLUSIONS: SI prevalence was higher in non-clinical samples of children with ASD and ASP, relative to ASN peers. These results underscore the need for routine screening for SI in children with ASD and social difficulties, particularly those with high anxiety. HighlightsPopulation-based, epidemiologically-ascertained, school-aged childrenASD and ASP are independent risk factors for SI in school-aged childrenAnxiety is an independent risk factor for SI in children with ASD or ASP.
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Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/epidemiologia , Criança , Humanos , Programas de Rastreamento , República da Coreia/epidemiologia , Ideação SuicidaRESUMO
RATIONALE: Chronic ulcerative colitis is an autoimmune disease in which epithelial injury continuously occurs in the colonic mucosa. While mesalazine (5-aminosalicylic acid) is used to treat ulcerative colitis, it can also cause liver failure, headaches, and abdominal pain; therefore, an alternative treatment is required. The purpose of this study was to evaluate the effectiveness of 80 stellate ganglion blocks in reducing pain and other symptoms in a patient with chronic ulcerative colitis. PATIENT CONCERNS: A 54-year-old female patient with a history of ulcerative colitis was concerned with worsening symptoms, such as abdominal discomfort and bloody-mucous stools, over the past 3âyears. DIAGNOSES: Oozing mucosal bleeding and a small amount of exudate were observed on colonoscopy; a diagnosis of ulcerative colitis was made upon histologic examination. INTERVENTIONS AND OUTCOMES: A total of 80 stellate ganglion blocks were administered, after which the patient's symptom and pain level was decreased from 6 to 4 points on the numeric rating scale (11-point, 0â=âno pain, 10â=âworst pain imaginable). Improved clinical signs were observed on colonoscopy at a follow-up assessment. LESSONS: The stellate ganglion block may be effective for the reduction of pain and other symptoms in patients with chronic ulcerative colitis.
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Bloqueio Nervoso Autônomo , Colite Ulcerativa , Dor Intratável/prevenção & controle , Gânglio Estrelado , Feminino , Humanos , Pessoa de Meia-Idade , Medição da DorRESUMO
LAY ABSTRACT: What is Already Known about This Subject: Genetics, (including de novo mutations), environmental factors (including toxic exposures), and their interactions impact autism spectrum disorder etiology. Paternal smoking is a candidate risk for autism spectrum disorder due to biological plausibility, high prevalence, and potential intervention.What This Study Adds: This original study and its replication confirms that paternal factors can substantially contribute to autism spectrum disorder risk for their offspring. It specifically indicates that paternal smoking both before and during pregnancy contributes significantly to autism spectrum disorder risk.Implications for practice, research, or policy: Smoking prevention, especially in pregnancy planning, may decrease autism spectrum disorder risk in offspring.
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Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/etiologia , Causalidade , Família , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Fatores de Risco , Fumar/efeitos adversosRESUMO
BACKGROUND: Existing reviews of screening tools for Autism Spectrum Disorder (ASD) focus on young children, and not all screening tools have been examined against validated diagnostic procedures. AIMS: To examine the validity of screening tools for ASD in non-young children and adults to provide clinical recommendations about the use of these tools in a variety of clinical settings. METHODS AND PROCEDURES: Electronic databases, including MEDLINE, EMBASE, PsychINFO, Cochrane Library and CINAHL, were searched through March 2017. Studies examining the validity of ASD screening tools against the Autism Diagnostic Observation Schedule and/or the Autism Diagnostic Interview - Revised in non-young children (age 4 or above) and adults were included. Three authors independently reviewed each article for data extraction and quality assessment. OUTCOMES AND RESULTS: 14 studies met the inclusion criteria, of which 11 studies were with children (4-18 years of age) and 3 studies included adults only (19 years of age and above). Included studies were conducted in a general population/low-risk sample (Nâ¯=â¯3) and a clinically referred/high-risk sample (Nâ¯=â¯11). In total 11 tools were included. CONCLUSIONS AND IMPLICATIONS: Only three screening tools (the Autism-Spectrum Quotient, the Social Communication Questionnaire, and the Social Responsiveness Scale) were examined in more than 2 studies. These tools may assist in differentiating ASD from other neurodevelopmental and psychiatric disorders or typically developed children. In young adult populations, the paucity of the existing research in this group limits definitive conclusion and recommendations.
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Transtorno do Espectro Autista/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Programas de Rastreamento , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Thermoresponsive and biodegradable linear-dendritic nanoparticles containing poly( N-isopropylacrylamide), poly(l-lactic acid), and poly(l-lysine) dendrons were investigated for sustained release of nerve growth factor (NGF) in response to temperature change. The nanoparticles and their degradants were not cytotoxic to neuron-like PC12 cells for at least one month. The nanoparticles were preferentially taken up by PC12 cells 6-13-times more at temperatures above (37 °C) than below (25 °C) the lower critical solution temperature of the nanoparticles. NGF could be loaded into the nanoparticles in aqueous solution and slowly released from the nanoparticles for 12 and 33 days at 25 and 37 °C, respectively. The released NGF was biologically active by promoting neurite outgrowth of PC12 cells. This work demonstrates a new concept of using thermoresponsive and biodegradable linear-dendritic nanoparticles for thermally targeted and sustained release of NGF and other protein drugs for the treatment of Alzheimer's disease and other neurological disorders.
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Preparações de Ação Retardada/química , Nanopartículas/química , Fator de Crescimento Neural/química , Crescimento Neuronal/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Neurônios/efeitos dos fármacos , Células PC12 , Poliésteres/química , Polilisina/química , RatosRESUMO
OBJECTIVES: To describe the first case of Descemet membrane endothelial keratoplasty (DMEK) combined with argon laser photocoagulation and intracameral 5-fluorouracil (5-FU) injection in a patient with epithelial downgrowth after cataract surgery. METHODS: Case report and review of the literature. RESULTS: A 77-year-old female underwent uneventful cataract surgery using a clear corneal incision in her left eye. Six months after surgery, an epithelial cell sheet began to cover the posterior cornea and then spread to the anterior chamber structures, leading to anterior synechia and corectopia at 2 years. Argon laser photocoagulation was used to remove epithelial downgrowth on the iris surface. However, retrocorneal epithelial downgrowth gradually progressed, resulting in bullous keratopathy. DMEK with intracameral 5-FU injection was performed to remove epithelial tissue and replace the diseased endothelium with healthy endothelium. One year after surgery, her vision improved to 20/50 and the endothelial cell count was 1,643 cells/mm in her left eye. There were no further complications or recurrence of epithelial downgrowth. CONCLUSIONS: DMEK with preoperative argon laser and intraoperative 5-FU is a useful option for the treatment of diffuse epithelial downgrowths.
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Extração de Catarata/efeitos adversos , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/métodos , Endotélio Corneano/patologia , Distrofia Endotelial de Fuchs/cirurgia , Complicações Pós-Operatórias , Idoso , Feminino , Seguimentos , Distrofia Endotelial de Fuchs/diagnóstico , Distrofia Endotelial de Fuchs/etiologia , Humanos , Tomografia de Coerência Óptica , Acuidade VisualRESUMO
PURPOSE: To report a case of iris-fixated phakic intraocular lens (pIOL) implantation in a patient with an extremely steep cornea, shallow anterior chamber, and small corneal diameter caused by retinopathy of prematurity (ROP) and scleral encircling. METHODS: Case report. RESULTS: Iris-fixated pIOLs were implanted in a 19-year-old patient with refraction of -18.5 -0.75 × 180 in the right eye and -15.5 -1.25 × 180 in the left eye. The keratometric values were 53.50 and 51.25 diopters (D) in the right eye and 54.75 and 51.75 D in the left eye. The white-to-white diameter and anterior chamber depth were 10.6 and 3.37 mm, respectively, in the right eye and 10.5 and 3.33 mm, respectively, in the left eye. CONCLUSION: A small pIOL was used to guarantee a safety distance and resulted in a one-line gain in uncorrected distant visual acuity and stable endothelial cell density 1 year after surgery. An iris-fixated pIOL Vis therefore an effective option for myopic patients with ROP.
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Cirurgia da Córnea a Laser/métodos , Iris/cirurgia , Miopia/cirurgia , Lentes Intraoculares Fácicas , Retinopatia da Prematuridade/complicações , Acuidade Visual , Córnea/patologia , Córnea/cirurgia , Topografia da Córnea , Feminino , Seguimentos , Humanos , Miopia/complicações , Miopia/fisiopatologia , Retinopatia da Prematuridade/diagnóstico , Fatores de Tempo , Adulto JovemRESUMO
A colonic arteriovenous malformation (AVM) is a significant vascular lesion of the gastrointestinal tract and a common cause of lower gastrointestinal bleeding. AVMs are usually identified endoscopically as bright red, flat lesions. AVMs with a polypoid appearance are extremely rare in the large intestine. We present two cases of colonic polypoid AVM, which were detected incidentally during screening colonoscopy. Both the patients had no history of gastrointestinal bleeding such as melena or hematochezia. Colonoscopy revealed pedunculated polyps overlaid by hyperemic mucosa in the ascending colon and proximal sigmoid colon. Microscopic examination showed aberrant vessels with thickened, hypertrophic walls in the mucosa and the submucosa, and arteries were directly connected to veins without capillary beds. These features were compatible with a diagnosis of AVM with a polypoid appearance. No immediate or delayed bleeding was noted after polypectomy.
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Malformações Arteriovenosas/cirurgia , Pólipos do Colo/cirurgia , Endoscopia/métodos , Idoso , Malformações Arteriovenosas/diagnóstico , Pólipos do Colo/diagnóstico , Colonoscopia/métodos , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
The Social Responsiveness Scale (SRS) is an autism rating scales in widespread use, with over 20 official foreign language translations. It has proven highly feasible for quantitative ascertainment of autistic social impairment in public health settings, however, little is known about the validity of the reinforcement in Asia populations or in references to DSM5. The current study aims to evaluate psychometric properties and cross-cultural aspects of the SRS-Korean version (K-SRS).The study subjects were ascertained from three samples: a general sample from 3 regular education elementary schools (n=790), a clinical sample (n=154) of 6-12-year-olds from four psychiatric clinics, and an epidemiological sample of children with ASD, diagnosed using both DSM IV PDD, DSM5 ASD and SCD criteria (n=151). Their parents completed the K-SRS and the Autism Spectrum Screening Questionnaire(ASSQ). Descriptive statistics, correlation analyses and principal components analysis (PCA) were performed on the total population. Mean total scores on the K-SRS differed significantly between the three samples. ASSQ scores were significantly correlated with the K-SRS T-scores. PCA suggested a one-factor solution for the total population.Our results indicate that the K-SRS exhibits adequate reliability and validity for measuring ASD symptoms in Korean children with DSM IV PDD and DSM5 ASD. Our findings further suggest that it is difficult to distinguish SCD from other child psychiatric conditions using the K-SRS.This is the first study to examine the relationship between the SRS subscales and DSM5-based clinical diagnoses. This study provides cross-cultural confirmation of the factor structure for ASD symptoms and traits measured by the SRS. Autism Res 2016, 9: 970-980. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/etnologia , Comparação Transcultural , Manual Diagnóstico e Estatístico de Transtornos Mentais , Transtorno de Comunicação Social/diagnóstico , Transtorno de Comunicação Social/etnologia , Transtorno do Espectro Autista/classificação , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Programas de Rastreamento/estatística & dados numéricos , Psicometria/estatística & dados numéricos , Reprodutibilidade dos Testes , República da Coreia , Transtorno de Comunicação Social/classificaçãoRESUMO
PURPOSE: To investigate the characteristics of retinal pigment epithelium (RPE) and retinal damage induced by selective retina therapy (SRT) in mice, and to elucidate longitudinal changes in RPE cells. METHODS: C57BL/6J mice received SRT and continuous-wave laser photocoagulation (cwPC). The cell death pattern was evaluated using TUNEL assay, and proliferative potential of the RPE cells was evaluated using 5-ethynyl-2'-dexoyuridine (EdU) assay. To investigate the cell-cell integrity of RPE cells, ß-catenin staining was performed. The number and hexagonality of RPE cells in the SRT-treated area were estimated using a Voronoi diagram with time periods of 3 hours to 14 days. Antibodies to microphthalmia-associated transcription factor (MiTF) and orthodenticle homeobox 2 (Otx2) were used to confirm the specific characteristics of RPE cells in the SRT-treated area. RESULTS: The number of TUNEL-positive cells located in the neural retina was significantly lower in lesions treated with SRT compared to those treated with cwPC. EdU-positive RPE cells were first detected 3 to 12 hours after SRT, and increased until 3 to 7 days after SRT. ß-catenin staining showed that hexagonality was compromised and subsequently, RPE cells expanded in size within the targeted location. The number of RPE cells in SRT lesions decreased gradually until 12 hours after SRT and recovered by 14 days. Upregulated expression of MiTF and Otx2 was observed for 2 weeks in the SRT lesions. CONCLUSIONS: Selective retina therapy seems to induce selective RPE damage without collateral thermal injury in the neural retina. Furthermore, SRT-treated lesions recovered by proliferation of RPE cells that were present in the treated lesions and by expansion of adjacent RPE cells.
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Fotocoagulação a Laser/efeitos adversos , Lasers de Estado Sólido/efeitos adversos , Doenças Retinianas/cirurgia , Epitélio Pigmentado da Retina/patologia , Animais , Western Blotting , Contagem de Células , Morte Celular , Proliferação de Células , Modelos Animais de Doenças , Células Epiteliais/patologia , Imuno-Histoquímica , Fotocoagulação a Laser/métodos , Lasers de Estado Sólido/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversosRESUMO
PURPOSE: To investigate leptin expression and distribution in the tissue of lacrimal gland epithelial tumours, and leptin concentration in the tears secreted by these tumours. METHODS: Clinical records and microscopic slides of six pleomorphic adenoma (PA), three adenoid cystic carcinoma (ACC), and one chronic sclerosing dacryoadenitis (CSD) cases were reviewed. Normal-appearing gland tissue adjacent to tumours from patients with PA served as controls. Tissue leptin expression and distribution were assessed using leptin immunohistochemistry staining. Preoperative and postoperative leptin concentrations in tears were measured in the tumour-affected eye in two patients with PA, two with ACC and one with CSD, and in the contralateral eye in one patient with ACC and one with CSD. RESULTS: Moderate cytoplasmic staining was observed in all tumour-adjacent morphologically normal tissue, PA, ACC and CSD tissues. ACC tissues revealed moderate nuclear staining in tumour cells, whereas other tissues did not reveal leptin nuclear staining (p=0.012). Leptin in tears was not detected in the eyes of patients with PA preoperatively and postoperatively. However, leptin was detected in tears of patients with ACC and CSD preoperatively, and its concentration markedly decreased at 1â month postoperatively. Leptin was not detected in any sample from the contralateral eyes of patients for which such samples were available. CONCLUSIONS: The leptin concentration in tears was greater in patients with ACC than in those with PA. Leptin nuclear staining was only observed in the ACC tissue. Further investigations should be conducted to identify the cause and significance of these findings.
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Adenoma Pleomorfo/metabolismo , Carcinoma Adenoide Cístico/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Neoplasias Oculares/metabolismo , Doenças do Aparelho Lacrimal/metabolismo , Leptina/metabolismo , Adulto , Idoso , Dacriocistite/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Lágrimas/metabolismo , Adulto JovemRESUMO
We delineated the mechanism regulating the inhibition of centrosome amplification by metformin in Drosophila intestinal stem cells (ISCs). Age-related changes in tissue-resident stem cells may be closely associated with tissue aging and age-related diseases, such as cancer. Centrosome amplification is a hallmark of cancers. Our recent work showed that Drosophila ISCs are an excellent model for stem cell studies evaluating age-related increase in centrosome amplification. Here, we showed that metformin, a recognized anti-cancer drug, inhibits age- and oxidative stress-induced centrosome amplification in ISCs. Furthermore, we revealed that this effect is mediated via down-regulation of AKT/target of rapamycin (TOR) activity, suggesting that metformin prevents centrosome amplification by inhibiting the TOR signaling pathway. Additionally, AKT/TOR signaling hyperactivation and metformin treatment indicated a strong correlation between DNA damage accumulation and centrosome amplification in ISCs, suggesting that DNA damage might mediate centrosome amplification. Our study reveals the beneficial and protective effects of metformin on centrosome amplification via AKT/TOR signaling modulation. We identified a new target for the inhibition of age- and oxidative stress-induced centrosome amplification. We propose that the Drosophila ISCs may be an excellent model system for in vivo studies evaluating the effects of anti-cancer drugs on tissue-resident stem cell aging.
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Senescência Celular , Centrossomo/metabolismo , Drosophila/metabolismo , Metformina/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/química , Centrossomo/ultraestrutura , Dano ao DNA , Regulação para Baixo , Feminino , Proteínas de Fluorescência Verde/metabolismo , Hipoglicemiantes/uso terapêutico , Intestinos/efeitos dos fármacos , Masculino , Estresse Oxidativo , Paraquat/química , Transdução de SinaisRESUMO
Age-related changes in long-lived tissue-resident stem cells may be tightly linked to aging and age-related diseases such as cancer. Centrosomes play key roles in cell proliferation, differentiation and migration. Supernumerary centrosomes are known to be an early event in tumorigenesis and senescence. However, the age-related changes of centrosome duplication in tissue-resident stem cells in vivo remain unknown. Here, using anti-γ-tubulin and anti-PH3, we analyzed mitotic intestinal stem cells with supernumerary centrosomes in the adult Drosophila midgut, which may be a versatile model system for stem cell biology. The results showed increased centrosome amplification in intestinal stem cells of aged and oxidatively stressed Drosophila midguts. Increased centrosome amplification was detected by overexpression of PVR, EGFR, and AKT in intestinal stem cells/enteroblasts, known to mimic age-related changes including hyperproliferation of intestinal stem cells and hyperplasia in the midgut. Our data show the first direct evidence for the age-related increase of centrosome amplification in intestinal stem cells and suggest that the Drosophila midgut is an excellent model for studying molecular mechanisms underlying centrosome amplification in aging adult stem cells in vivo.
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Centrossomo/ultraestrutura , Drosophila/citologia , Células-Tronco/ultraestrutura , Animais , Senescência Celular , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Receptores ErbB/metabolismo , Intestinos/citologia , Mitose , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Peptídeos de Invertebrados/metabolismoRESUMO
Although the diverse effects of ionizing radiation on biological and pathological processes at various levels ranging from molecular to whole body are well studied, the effects on adult stem cells by ionizing radiation remain largely unknown. In this study, we characterized the functional modifications of adult Drosophila midgut intestinal stem cells after ionizing radiation treatment. A dose of 10 Gy of radiation decreased the proliferative capacity of intestinal stem cells. Interestingly, after irradiation at 2 Gy, the intestinal stem cells exhibited increased proliferative activity, misdifferentiation and γH2AvD and 8-oxo-dG levels. In addition, the guts irradiated with 2 Gy showed increased JNK and AKT activities. Furthermore, we showed that 2 Gy of ionizing radiation induced centrosome amplification in intestinal stem cells of adult midguts. Our data gives molecular insights into the effects of ionizing radiation on functional modifications of stem cells. The adult Drosophila midgut intestinal stem cells offer a potentially rich new system for the exploration of the biological effects of ionizing radiation.