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Autosomal-recessive polycystic kidney disease (ARPKD; MIM #263200) is a severe, hereditary, hepato-renal fibrocystic disorder that causes early childhood morbidity and mortality. Mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, which encodes the protein fibrocystin/polyductin complex (FPC), cause all typical forms of ARPKD. Several mouse lines carrying diverse, genetically engineered disruptions in the orthologous Pkhd1 gene have been generated, but none expresses the classic ARPKD renal phenotype. In the current study, we characterized a spontaneous mouse Pkhd1 mutation that is transmitted as a recessive trait and causes cysticliver (cyli), similar to the hepato-biliary disease in ARPKD, but which is exacerbated by age, sex, and parity. We mapped the mutation to Chromosome 1 and determined that an insertion/deletion mutation causes a frameshift within Pkhd1 exon 48, which is predicted to result in a premature termination codon (UGA). Pkhd1cyli/cyli (cyli) mice exhibit a severe liver pathology but lack renal disease. Further analysis revealed that several alternatively spliced Pkhd1 mRNA, all containing exon 48, were expressed in cyli kidneys, but in lower abundance than in wild-type kidneys, suggesting that these transcripts escaped from nonsense-mediated decay (NMD). We identified an AAAAAT motif in exon 48 upstream of the cyli mutation which could enable ribosomal frameshifting, thus potentially allowing production of sufficient amounts of FPC for renoprotection. This mechanism, expressed in a species-specific fashion, may help explain the disparities in the renal phenotype observed between Pkhd1 mutant mice and patients with PKHD1-related disease. KEY MESSAGES: The Pkhd1cyli/cyli mouse expresses cystic liver disease, but no kidney phenotype. Pkhd1 mRNA expression is decreased in cyli liver and kidneys compared to wild-type. Ribosomal frameshifting may be responsible for Pkhd1 mRNA escape from NMD. Pkhd1 mRNA escape from NMD could contribute to the absent kidney phenotype.
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Hepatopatías , Riñón Poliquístico Autosómico Recesivo , Preescolar , Ratones , Humanos , Animales , Riñón Poliquístico Autosómico Recesivo/genética , Riñón Poliquístico Autosómico Recesivo/patología , Riñón/metabolismo , Mutación , Factores de Transcripción/genética , ARN Mensajero/genética , Receptores de Superficie Celular/genéticaRESUMEN
Aim: Accurate preoperative prediction of cervical lymph node metastasis (LNM) in patients with mPTMC provides a basis for surgical decision making and the extent of tumor resection. This study aimed to develop and validate an ultrasound radiomics nomogram for the preoperative assessment of LN status. Methods: A total of 450 patients pathologically diagnosed with mPTMC were enrolled, including 348 patients in the modeling group and 102 patients in the validation group. Univariate and multivariate logistic regression analyses were performed on the basic information, ultrasound characteristics, and American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) scores of the patients in the modeling group to identify independent risk factors for LNM in mPTMC and to construct a logistic regression equation and nomogram to predict the risk of LNM. The validation group data were used to evaluate the predictive performance of the nomogram. Results: Male sex, age <40 years, a single lesion with a maximum diameter >0.5 cm, capsular invasion, a maximum ACR score >9 points, and a total ACR score >19 points were independent risk factors for the development of cervical LNM in mPTMC. Both the area under the curve (AUC) and concordance index (C-index) of the prediction model constructed from the above six factors were 0.838. The calibration curve of the nomogram was close to the ideal diagonal line. Furthermore, decision curve analysis (DCA) demonstrated a significantly greater net benefit of the model. The external validation demonstrated the reliability of the prediction nomogram. Conclusions: The presented radiomics nomogram, which is based on ACR TI-RADS scores, shows favorable predictive value for the preoperative assessment of LNs in patients with mPTMC. These findings may provide a basis for surgical decision making and the extent of tumor resection.
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Nomogramas , Nódulo Tiroideo , Humanos , Masculino , Adulto , Metástasis Linfática , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Sleep problems are widespread among college students around the globe, especially in China. This study was designed to investigate the prevalence of poor sleep quality and identify associated factors among college students in Jilin Province, China. METHODS: A total of 6284 participants were completely collected by stratified cluster sampling in 2016. Information on basic demographics, lifestyles, social and family support, and subjective sleep quality was collected by questionnaire. The Pittsburgh Sleep Quality Index (PSQI) is a self-administered questionnaire used to assess sleep for one month. RESULTS: 1951 (31.0%) participants were classified into poor sleep quality group, as defined by a PSQI score > 5. Males scored significantly higher than females on sleep duration and use of sleep medication, while females scored significantly higher than males on PSQI total and sleep disturbances. The results of the multivariate logistic regression show the following factors to be significant predictors of poor sleep quality: freshman (OR = 1.523, 95% CI: 1.168-1.987), alcohol use (OR = 1.634, 1.425-1.874), gambling behaviors (OR = 1.167, 95% CI: 1.005-1.356), exercised for more than 30 min a week on less than one day (OR = 1.234, 95% CI: 1.016-1.498), the feelings of satisfied with parental love (OR = 1.849, 95% CI: 1.244-2.749), and harmonious/neutral relationship with classmates (OR = 2.206, 95% CI: 1.312-3.708; OR = 1.700, 95% CI: 1.414-2.045),. No study pressure of this academic year (OR = 0.210, 95% CI: 0.159-0.276), no truancy in the past month (OR = 0.510, 95% CI: 0.354-0.735), never had self-injurious behaviors (OR = 0.413, 95% CI: 0.245-0.698), very harmonious family relationship (OR = 0.377, 95% CI: 0.219-0.650), frequent communication with parents (OR = 0.524, 95% CI: 0.312-0.880), the feelings of satisfied with maternal love (OR = 0.432, 95% CI: 0.257-0.725), and frequent excursions to gymnasium (OR = 0.770, 95% CI: 0.659-0.899) were the protective factors. CONCLUSIONS: The implication of the present study may be that college students must be made aware of the consequences of inadequate sleep quality and risk factors could be improved if students tried to change their behavior and subjective consciousness.
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Calidad de Vida/psicología , Trastornos del Inicio y del Mantenimiento del Sueño/psicología , Trastornos del Sueño-Vigilia/psicología , Estudiantes/psicología , Estudiantes/estadística & datos numéricos , Adolescente , Adulto , China/epidemiología , Estudios Transversales , Femenino , Humanos , Modelos Logísticos , Masculino , Prevalencia , Factores de Riesgo , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Trastornos del Sueño-Vigilia/epidemiología , Encuestas y Cuestionarios , Universidades/estadística & datos numéricos , Adulto JovenRESUMEN
STUDY DESIGN: .: A meta-analysis. OBJECTIVE: .: The goal of this study was to accurately evaluate the risk ratio (RR) of recurrence in chordoma patients with wide margin after removing the tumors using surgery, compared with inadequate margin (intralesional or marginal). SUMMARY OF BACKGROUND DATA: .: As a rare malignant bone cancer, the more effective treatment for sacral chordoma is still surgical resection. However, there is no convincing evidence and risk ratio about sacral chordoma patients would be benefit from which kind of surgical margin. METHODS: .: We searched the PubMed, Cochrane Library, Web of Science, and EMBASE from inception to December 2018. The heterogeneity analysis and calculation of the pooled risk ratio were performed using RevMan 5.3 software. The assessment of publication bias and sensitivity analysis was conducted using StataSE 15.1 software. The protocol for this meta-analysis was registered on International prospective register of systematic reviews (PROSPERO, CRD42019127441). RESULTS: .: Twelve studies with a total of 436 patients who met the inclusion criteria were included. The pooled results indicated that patients in the wide group had lower recurrence rate than those in the inadequate group (RRâ=â0.42, 95% confidence interval [CI] 0.31-0.57; Pâ<â0.001). And patients in the wide group had lower mortality rate than those in the inadequate group (RRâ=â0.49, 95% CI 0.26-0.91; Pâ=â0.02). No significant differences in the risk of mortality were found between relapsed patients in the two groups (RRâ=â0.64, 95% CI 0.35-1.15; Pâ=â0.13). CONCLUSION: .: In sacral chordoma patients, wide margin is associated with low recurrence risk, when it is feasible, a wide excision should be considered appropriate for sacrum chordoma. LEVEL OF EVIDENCE: 2.
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Cordoma/cirugía , Márgenes de Escisión , Recurrencia Local de Neoplasia/cirugía , Sacro/cirugía , Neoplasias de la Columna Vertebral/cirugía , Humanos , Motivación , Recurrencia Local de Neoplasia/patología , Oportunidad Relativa , Osteosarcoma , Estudios Retrospectivos , Programas Informáticos , Resultado del TratamientoRESUMEN
OBJECTIVE: The benefits of accelerated hyperfractionated radiotherapy (HART) and conventional fractionation radiotherapy (CFRT) in the treatment of head and neck cancer (HNC) remain controversial. In this study, we analyzed the therapeutic effects of these two treatment regimens to explore whether HART can improve the overall survival (OS) rate and locoregional control (LRC) rate in patients with HNC. METHODS: The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for eligible studies. The OS rate and LRC rate were considered as the efficacy outcomes. I 2 was used to test the heterogeneity among studies with a cutoff value of 50%. Potential publication bias was assessed by funnel plots and Egger's test. We also performed a sensitivity analysis to assess the stability of the results. In this meta-analysis, all analyses were performed using R 3.5.3 software. RESULTS: Twelve qualified articles including a total of 2,935 patients were identified. HART had a significant beneficial effect on OS rate (HR = 0.80, 95% CI: 0.65-0.98). Compared with CFRT, HART demonstrated a significantly higher LRC rate (HR = 0.82, 95% CI: 0.71-0.96). CONCLUSION: Our meta-analysis showed that HART can significantly improve OS and LRC compared with CFRT in patients with HNC.
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BACKGROUND: Suicide is a major global mental health problem among college students. The aim of the current study was to explore the association between the psychological strains of the strain theory of suicide and suicidal behaviors among college students. METHODS: Participants comprised 1912 college students (16-28 years old, 47.2% female) from three universities in Jilin Province, China, who completed the self-report assessments of psychological strains (40 items Psychological Strains Scale) and suicidal behaviors (Suicidal Behaviors Questionnaire-Revised). The demographic characteristics included four variables: health status, psychological status, academic status and economic status. RESULTS: Approximately 15.0% (286/1912) of participants were classified as having suicide risk, based on the cut-off scores of the SBQ-R. The prevalence of suicidal behaviors among males and females was 11.9% (120/1009) and 18.4% (166/903), respectively. Value strain (ORâ¯=â¯1.075, 95%CI: 1.057-1.094), aspiration strain (ORâ¯=â¯1.082, 95%CI: 1.064-1.101), deprivation strain (ORâ¯=â¯1.073, 95%CI: 1.052-1.093), and coping strain (ORâ¯=â¯1.095, 95%CI: 1.075-1.116) were risk factors for suicidality in college students. Coping strain (ORâ¯=â¯1.050, 95%CI: 1.023-1.077) was still positively associated with suicide risk in multivariate logistic regression. Logistic regression analysis indicated that coping strain had the highest correlation with suicidal behaviors. LIMITATIONS: The directionality of the relationships cannot be deduced because this study is cross-sectional. CONCLUSION: This study confirms a strong association between psychological strains and suicidal behaviors in college students. Some measures can be taken to reduce psychological strains to mitigate suicide risk among college students. More studies investigating coping strain among college students are warranted.
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Adaptación Psicológica , Estudiantes/psicología , Ideación Suicida , Suicidio/psicología , Adolescente , Adulto , China/epidemiología , Estudios Transversales , Femenino , Encuestas Epidemiológicas , Humanos , Modelos Logísticos , Masculino , Prevalencia , Factores de Riesgo , Autoinforme , Autoevaluación (Psicología) , Estudiantes/estadística & datos numéricos , Suicidio/estadística & datos numéricos , Encuestas y Cuestionarios , Universidades/estadística & datos numéricos , Adulto JovenRESUMEN
OBJECTIVE: We performed a meta-analysis to evaluate the diagnostic value of positron emission tomography/computed tomography (PET/CT) in the detection of para-aortic lymph node metastasis in cervical cancer. METHODS: We searched the PubMed, Embase, Web of Science, Cochrane Library, Chinese Biological Medicine (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang and VIP databases in all languages from their inception to September 2018. Stat15.0 software was used to obtain pooled estimates of sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) as well as a summary receiver operating characteristic (SROC) curves. Deek's funnel plot was used to assess publication bias. QUADAS-2 was used to evaluate the quality of the studies. The protocol for this meta-analysis is registered in PROSPERO (CRD42019115330). RESULTS: We obtained 14 studies, and the pooled estimates for sensitivity and specificity of PET/CT were 0.71 (95% confidence interval (CI) = 0.54-0.83) and 0.97 (95% CI = 0.93-0.98), respectively. Pooled PLR and NLR were 21.53 and 0.30, respectively. The diagnostic odds ratio (DOR) was70.59, and the area under the curve (AUC) was 0.95. CONCLUSION: PET/CT is an effective and important imaging method for the diagnosis of para-aortic lymph node metastasis in early cervical cancer.
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Ganglios Linfáticos/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/patología , Femenino , Humanos , Metástasis Linfática , Oportunidad Relativa , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones , Sesgo de Publicación , Curva ROCRESUMEN
We aimed to provide updated estimates for the trends and the effects attributable to age, period, and cohort by gender in urban and rural areas in China. The data were based on the vital registration system in China from 2003 to 2012. The annual percentage change used Joinpoint Regression Analysis. Spline functions were fitted to the age-period-cohort analysis. The average age-adjusted diabetes mortality rate was higher in women than in men, and it was higher in urban than in rural residents among both genders. The trend analysis of diabetes showed a favorable pattern among urban residents in both genders. Mortality increased with age, and compared with period and cohort effects, age effects were the most important risk factor in diabetes mortality. Although the overall trends in diabetes mortality decelerated, aging and rural-urban differences could still be driving the epidemic underlining a continued need for the priorities for health care programs to focus on predictors in diabetes mortality.
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Diabetes Mellitus/mortalidad , Población Rural/estadística & datos numéricos , Población Urbana/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , China/epidemiología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mortalidad/tendencias , Factores de Riesgo , Distribución por Sexo , Adulto JovenRESUMEN
BACKGROUND: Dyslipidemia contributes to the risk of many diseases, including stroke, cardiovascular disease and metabolic-related diseases. Previous studies have indicated that single nucleotide polymorphisms (SNPs) are associated with different levels of serum lipid. Therefore, this study explored the relationship between the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster gene polymorphisms and dyslipidemia in the total sample population and stratified by genders in a northeast Chinese population. METHODS: A total of 3,850 participants from Jilin Province, China, were enrolled in our study, and their serum lipid levels were measured. Six functional SNPs (APOA1 rs5072, APOC3 rs5128, APOA4 rs5104, APOA5 rs651821, ZPR1 rs2075294 and BUD13 rs10488698) were genotyped using polymerase chain reaction and MALDI-TOF-MS. Logistic regression analysis was performed to explore the relationship of APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster gene polymorphisms with dyslipidemia. Linkage disequilibrium and haplotype analyses were performed with the SNPStats program and Haploview software. RESULTS: All SNPs conformed to Hardy-Weinberg equilibrium. Logistic regression analysis revealed that rs5072, rs5128 and rs651821 were associated with hypertriglyceridemia, rs5104 and rs651821 were associated with low-HDL cholesterolemia in overall group. rs651821 was associated with hypertriglyceridemia and low-HDL cholesterolemia in both the male and female group. However, among females, rs5072 was observed to be associated with hypertriglyceridemia. Haplotype analysis showed that haplotypes TGCCGC and CAGCGC were associated with dyslipidemia in the overall, male and female groups. CONCLUSION: SNPs in the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster were associated with dyslipidemia. Furthermore, the association of APOA1 rs5072 in this gene cluster with dyslipidemia differed between genders; thus, additional studies are needed to confirm this conclusion, and the mechanisms underlying these results warrant further exploration.
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BACKGROUND: The prevention of suicidal ideation plays a key role in reducing suicide rates. This study aimed to determine the prevalence of suicidal ideation among college students in Jilin Province, China, and to analyse the risk factors associated with suicidal ideation. METHODS: A total of 6284 valid data collection sheets were collected using the stratified cluster sampling method. The data collected were divided into four sections, namely, socio-demographic information, family and social interactions, daily habits, and mental health self-rating scales. RESULTS: The prevalence of suicidal ideation in the past 12 months was 9.2%. A multivariate logistic regression analysis showed that being a senior (ORâ¯=â¯1.769, 95%CI:1.225-2.555), general family relationships (ORâ¯=â¯1.641, 95%CI:1.172-2.298), frequent parental quarrels (ORâ¯=â¯1.398, 95%CI:1.027-1.902)/parental separation (ORâ¯=â¯2.497, 95%CI:1.414-4.408), the level of satisfaction with motherly love (ORâ¯=â¯2.261, 95%CI:1.454-3.515), having only one or two friend(s) (ORâ¯=â¯1.530, 95%CI:1.038-2.254), frequent excursions to bars/ karaoke halls/ song and dance halls (ORâ¯=â¯1.673, 95%CI:1.257-2.229) or billiard halls with friends (ORâ¯=â¯1.865, 95%CI:1.270-2.740), smoking (ORâ¯=â¯2.175, 95%CI:1.603-2.951), moderate sleep quality (ORâ¯=â¯1.636, 95%CI:1.115-2.402), and depressive symptoms (ORâ¯=â¯2.078, 95%CI: 1.710-2.525) were risk factors for suicidal ideation. Family factors had the most influence on suicidal ideation, whereas depression symptoms were identified to be a mediating factor between family, social interactions, or daily habits and suicidal ideation, and it only exerted direct effects. LIMITATIONS: This cross-sectional study cannot provide causal interpretations. CONCLUSION: Our findings showed the prevalence of suicidal ideation among college students in Jilin province. Among all the risk factors associated with suicidal ideation, family factors should be the main concern in the prevention of suicidal ideation, and interventions that target depression symptoms are key to reducing suicidal ideation.
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Estudiantes/psicología , Ideación Suicida , Adolescente , Adulto , China/epidemiología , Estudios Transversales , Femenino , Encuestas Epidemiológicas , Humanos , Modelos Logísticos , Masculino , Salud Mental , Prevalencia , Factores de Riesgo , Universidades , Adulto JovenRESUMEN
BACKGROUND: Intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) are two of the main treatment techniques for cervical cancer. Whether either technique significantly reduces irradiated volumes of organs at risk (OARs) remains controversial. The aim of this study was to explore which of these treatment paradigms is the superior technique in cervical treatment, taking clinical outcomes and treatment efficiency from published findings into consideration. MATERIALS AND METHODS: PubMed, EMBASE, and Cochrane Library databases were utilized. The average percent irradiated volumes of OAR were extracted from all included studies. Dual arc results were extracted due to their superiority to single arc methods in terms of plan quality. Standard mean deviations and 95% CIs were calculated for delivery time, monitor units, and average percent irradiated volumes of OAR. Assessment of publication bias and sensitivity analyses were performed. All statistical analyses were conducted using R 3.5.0 software. RESULTS: Eight studies were included in this meta-analysis. For irradiated volumes of OARs, irradiated volume of rectum receiving 40 Gy (rectum V40) was significantly decreased in VMAT compared with IMRT. However, no significant differences were observed between IMRT and VMAT plans in bladder V40 or small bowel V40/V30. In addition, delivery times and monitor units were significantly lower in the VMAT plan than in the IMRT plan. CONCLUSION: Compared with IMRT, VMAT is significantly more protective for the rectum, suggesting that it may be an optional therapy technique for patients with cervical cancer.
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BACKGROUND: DNA demethylase is a crucial enzyme in the epigenetic modification and regulation mechanisms of gene transcription. Based on previous assertions that the pathophysiology of schizophrenia is associated with epigenetics, we aimed to explore whether DNA demethylase activity might be related to schizophrenia in northeast China. METHODS: We recruited 25 patients with first-episode schizophrenia and 29 normal controls from a northeast Chinese Han population. The diagnostic criteria of schizophrenia were determined according to diseases and related health problems, the tenth revision (ICD-10), and criteria of mental disorders, the third revised edition (CCMD3). DNA demethylase activity in human peripheral blood mononuclear cells (PBMCs) was measured using a DNA demethylase activity colorimetric assay ultra kit. RESULTS: Using Student's t-test, activation of DNA demethylase and its activity were higher in schizophrenia patients compared to healthy individuals (p < 0.001). Furthermore, the level of DNA demethylase activity in male and female subjects with schizophrenia significantly increased (all p < 0.05). CONCLUSIONS: Our data showed that DNA demethylase might play a role in the pathophysiology of schizophrenia, and individuals with higher DNA demethylase activity were susceptible to schizophrenia in a northeast Chinese Han population. To the best of our knowledge, this is the first time directly measured human blood samples to examine the association between first-episode schizophrenia patients and DNA demethylase activity, which will provide new insight to explore the effect on the mechanism of schizophrenia.
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Desmetilación del ADN , ADN-Citosina Metilasas/metabolismo , Leucocitos Mononucleares/enzimología , Esquizofrenia/enzimología , Adulto , Pueblo Asiatico/genética , Células Cultivadas , China , ADN-Citosina Metilasas/genética , Femenino , Predisposición Genética a la Enfermedad/etnología , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Esquizofrenia/sangre , Esquizofrenia/genética , Adulto JovenRESUMEN
BACKGROUND: Ovarian sex cord-stromal tumors (OSCST) include juvenile granulosa cell tumors (JGCT), Sertoli-Leydig cell tumor (SLCT) and gynandroblastoma (GAB) among others. These ovarian sex cord-stromal tumors as well as other tumors including pleuropulmonary blastoma (PPB) may be associated with DICER1 mutations. We sought to describe the clinical and genetic findings from the first 107 individuals enrolled in the International Ovarian and Testicular Stromal Tumor Registry. METHODS: Medical and family history were obtained for individuals consecutively enrolled in the International Ovarian and Testicular Stromal Tumor Registry. Pathology was centrally reviewed. DICER1 sequencing was performed on blood and tumor tissue. RESULTS: Of the 107 participants, 49 had SLCT, 25 had JGCT and 5 had GAB. Nearly all (36/37) SLCTs and 4/4 GAB tested had a DICER1 mutation in an RNase IIIb domain hotspot; approximately half of these individuals had a predisposing germline DICER1 mutation. Metachronous SLCTs were seen in 3 individuals with germline DICER1 mutations. Other DICER1-associated conditions were seen in 19% of patients with SLCT or GAB. Three children of women with SLCT were diagnosed with PPB based on genetic testing and clinical screening during the course of this study. All were diagnosed with PPB in its earliest and most curable form (Type I), were treated with surgery alone, and are alive without evidence of disease. CONCLUSIONS: Recognition of the distinct genetic basis for a group of these tumors improves precise classification in difficult cases and promotes mutation-based screening and early detection.
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ARN Helicasas DEAD-box/genética , Neoplasias Ováricas/genética , Ribonucleasa III/genética , Tumor de Células de Sertoli-Leydig/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Lactante , Persona de Mediana Edad , Mosaicismo , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Pronóstico , Sistema de Registros , Tumor de Células de Sertoli-Leydig/enzimología , Tumor de Células de Sertoli-Leydig/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/enzimología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Adulto JovenRESUMEN
CONTEXT: -The placenta is an important component in understanding the fetal response to intrauterine Zika virus infection, but the pathologic changes in this organ remain largely unknown. Hofbauer cells are fetal-derived macrophages normally present in the chorionic villous stroma. They have been implicated in a variety of physiological and pathologic processes, in particular involving infectious agents. OBJECTIVES: -To characterize the fetal and maternal responses and viral localization in the placenta following Zika virus transmission to an 11 weeks' gestation fetus. The clinical course was notable for prolonged viremia in the mother and extensive neuronal necrosis in the fetus. The fetus was delivered at 21 weeks' gestation after pregnancy termination. DESIGN: -The placenta was evaluated by using immunohistochemistry for inflammatory cells (macrophages/monocytes [Hofbauer cells], B and T lymphocytes) and proliferating cells, and an RNA probe to Zika virus. The fetal brain and the placenta were previously found to be positive for Zika virus RNA by reverse transcription-polymerase chain reaction. RESULTS: -The placenta demonstrated prominently enlarged, hydropic chorionic villi with hyperplasia and focal proliferation of Hofbauer cells. The degree of Hofbauer cell hyperplasia gave an exaggerated immature appearance to the villi. No acute or chronic villitis, villous necrosis, remote necroinflammatory abnormalities, chorioamnionitis, funisitis, or hemorrhages were present. An RNA probe to Zika virus was positive in villous stromal cells, presumably Hofbauer cells. CONCLUSIONS: -Zika virus placental infection induces proliferation and prominent hyperplasia of Hofbauer cells in the chorionic villi but does not elicit villous necrosis or a maternal or fetal lymphoplasmacellular or acute inflammatory cell reaction.
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Proliferación Celular , Macrófagos/virología , Placenta/patología , Placenta/virología , Infección por el Virus Zika/patología , Infección por el Virus Zika/virología , Virus Zika/fisiología , Adulto , Animales , Vellosidades Coriónicas/diagnóstico por imagen , Vellosidades Coriónicas/patología , Vellosidades Coriónicas/virología , Femenino , Feto/diagnóstico por imagen , Feto/patología , Feto/virología , Edad Gestacional , Interacciones Huésped-Patógeno , Humanos , Hiperplasia , Macrófagos/patología , Imagen por Resonancia Magnética , Placenta/diagnóstico por imagen , Embarazo , Ultrasonografía Prenatal , Infección por el Virus Zika/diagnóstico por imagenRESUMEN
Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific "hotspot" codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of PBB patients lack predisposing germline or mosaic mutations and have sporadic (rather than syndromic) disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development.
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The ability of neuroepithelial cells to generate a diverse array of neurons is influenced by locally secreted signals. In the spinal cord, Sonic Hedgehog (Shh) is known to induce distinct cell fates in a concentration-dependent manner by regulating the activities of the three Gli transcription factors in neural precursors. However, whether Gli-mediated Shh signaling is also required to induce different cell types in the ventral telencephalon has been controversial. In particular, loss of Shh has little effect on dorsoventral patterning of the telencephalon when Gli3 is also removed. Furthermore, no ventral telencephalic phenotypes have been found in individual Gli mutants. To address this issue, we first characterized Shh-responding ventral telencephalic progenitors between E9.5 and E12.5 and found that they produce neurons migrating to different layers of the cortex. We also discovered a loss of Nkx2.1 and Nkx6.2 expression in two subgroups of progenitors in embryos lacking major Gli activators. Finally, we analyzed the telencephalic phenotypes of embryos lacking all Gli genes and found that the ventral telencephalon was highly disorganized with intermingling of distinct neuronal cell types. Together, these studies unravel a role for Gli transcription factors in mediating Shh signaling to control specification, differentiation and positioning of ventral telencephalic neurons.
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Tipificación del Cuerpo/fisiología , Factores de Transcripción de Tipo Kruppel/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Telencéfalo/crecimiento & desarrollo , Animales , Embrión de Mamíferos/metabolismo , Femenino , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Ratones , Ratones Endogámicos , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenotipo , Telencéfalo/embriología , Factor Nuclear Tiroideo 1 , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína con Dedos de Zinc GLI1 , Proteína Gli2 con Dedos de Zinc , Proteína Gli3 con Dedos de ZincRESUMEN
The identity of distinct cell types in the ventral neural tube is generally believed to be specified by sonic hedgehog (Shh) in a concentration-dependent manner. However, recent studies have questioned whether Shh is the sole signaling molecule determining ventral neuronal cell fates. Here we provide evidence that canonical Wnt signaling is involved in the generation of different cell types in the ventral spinal cord. We show that Wnt signaling is active in the mouse ventral spinal cord at the time when ventral cell types are specified. Furthermore, using an approach that stabilizes beta-catenin protein in small patches of ventral spinal cord cells at different stages, we show that Wnt signaling activates different subsets of target genes depending on the time when Wnt signaling is amplified. Moreover, disruption of Wnt signaling results in the expansion of ventrally located progenitors. Finally, we show genetically that Wnt signaling interacts with Hh signaling at least in part through regulating the transcription of Gli3. Our results reveal a novel mechanism by which ventral patterning is achieved through a coordination of Wnt and Shh signaling.
Asunto(s)
Linaje de la Célula , Transducción de Señal , Médula Espinal/citología , Médula Espinal/metabolismo , Proteínas Wnt/metabolismo , Animales , Embrión de Mamíferos/embriología , Embrión de Mamíferos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/deficiencia , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células Madre/metabolismo , Factores de Tiempo , Proteína Gli2 con Dedos de Zinc , Proteína Gli3 con Dedos de Zinc , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
NogoA, a myelin-associated component, inhibits neurite outgrowth. Nogo66, a portion of NogoA, binds to Nogo66 receptor (NgR) and induces the inhibitory signaling. LINGO-1 and p75 neurotrophin receptor (p75), the low-affinity nerve growth factor receptor, are also required for NogoA signaling. However, signaling mechanisms downstream to Nogo receptor remain poorly understood. Here, we observed that NgR and p75 were colocalized in low-density membrane raft fractions derived from forebrains and cerebella as well as from cerebellar granule cells. NgR interacted with p75 in lipid rafts. In addition, disruption of lipid rafts by beta-methylcyclodextrin, a cholesterol-binding reagent, reduced the Nogo66 signaling. Our results suggest an important role of lipid rafts in facilitating the interaction between NgRs and provide insight into mechanisms underlying the inhibition of neurite outgrowth by NogoA.