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1.
PLoS One ; 16(3): e0247074, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33647031

RESUMO

OBJECTIVE: To study the feasibility of use of radiomic features extracted from axillary lymph nodes for diagnosis of their metastatic status in patients with breast cancer. MATERIALS AND METHODS: A total of 176 axillary lymph nodes of patients with breast cancer, consisting of 87 metastatic axillary lymph nodes (ALNM) and 89 negative axillary lymph nodes proven by surgery, were retrospectively reviewed from the database of our cancer center. For each selected axillary lymph node, 106 radiomic features based on preoperative pharmacokinetic modeling dynamic contrast enhanced magnetic resonance imaging (PK-DCE-MRI) and 5 conventional image features were obtained. The least absolute shrinkage and selection operator (LASSO) regression was used to select useful radiomic features. Logistic regression was used to develop diagnostic models for ALNM. Delong test was used to compare the diagnostic performance of different models. RESULTS: The 106 radiomic features were reduced to 4 ALNM diagnosis-related features by LASSO. Four diagnostic models including conventional model, pharmacokinetic model, radiomic model, and a combined model (integrating the Rad-score in the radiomic model with the conventional image features) were developed and validated. Delong test showed that the combined model had the best diagnostic performance: area under the curve (AUC), 0.972 (95% CI [0.947-0.997]) in the training cohort and 0.979 (95% CI [0.952-1]) in the validation cohort. The diagnostic performance of the combined model and the radiomic model were better than that of pharmacokinetic model and conventional model (P<0.05). CONCLUSION: Radiomic features extracted from PK-DCE-MRI images of axillary lymph nodes showed promising application for diagnosis of ALNM in patients with breast cancer.

3.
Pathol Res Pract ; 218: 153318, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33370709

RESUMO

Dihydroartemisinin (DHA), an effective antimalarial drug, has been widely investigated as an anti-tumor agent. Although previous studies have indicated the potential therapeutic effects of DHA on multiple malignancies, its detailed molecular mechanisms in gastric cancer (GC) are still undocumented. In the present study, we applied network pharmacology and bioinformatics (gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses) to obtain the collective targets of DHA and GC and analyzed their involvement in constructing a protein-protein interaction (PPI) network. The top 10% hub targets in this network were identified, and TCGA database was utilized for the single gene analysis of their correlation with the prognosis of GC. CCK8, EdU, Transwell, and flow cytometry analyses were conducted, and subcutaneous xenograft tumor models were constructed to assess the effects of DHA on the tumorigenesis and invasion of GC. Furthermore, the targets of DHA were verified by molecular docking, quantitative real-time PCR (qPCR) and western blot analyses in GC cells. The results indicated that the common targets of DHA and GC were enriched in multiple cancer-related pathways including KDR, STAT1 and apoptosis signaling pathways, where the core genes included KDR, MMP9, STAT1, TP53, CASP3/7 and BCL2L1. The lowered expression of KDR and increased expression of TP53 and CASP7 harbored a favorable survival for patients with GC patients. CASP7 showed a positive correlation with CASP3 but a negative correlation with KDR and could be regarded as an independent protective factor for overall survival in GC. Moreover, DHA treatment induced cell apoptosis and suppressed the cell proliferation, DNA synthesis, cycle progression and invasive capabilities both in vitro and in vivo. DHA also upregulated p53, CASP3, and cleaved-CASP3 and downregulated BCL2L1, MMP9, KDR, p-KDR, STAT1 and p-STAT1 in GC cell lines. In conclusion, DHA could suppress the tumorigenesis and invasion of GC by regulating STAT1/KDR/MMP9 and p53/BCL2L1/CASP3/7 pathways. Our findings might provide a novel approach for the treatment of GC.

5.
J Zhejiang Univ Sci B ; 21(11): 911-920, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33150774

RESUMO

OBJECTIVE: To investigate the value of optic disc retinal nerve fiber layer (RNFL) thickness in the diagnosis of diabetic peripheral neuropathy (DPN). METHODS: Ninety patients with type 2 diabetes, including 60 patients without DPN (NDPN group) and 30 patients with DPN (DPN group), and 30 healthy participants (normal group) were enrolled. Optical coherence tomography (OCT) was used to measure the four quadrants and the overall average RNFL thickness of the optic disc. The receiver operator characteristic curve was drawn and the area under the curve (AUC) was calculated to evaluate the diagnostic value of RNFL thickness in the optic disc area for DPN. RESULTS: The RNFL thickness of the DPN group was thinner than those of the normal and NDPN groups in the overall average ((101.07± 12.40) µm vs. (111.07±6.99) µm and (109.25±6.90) µm), superior quadrant ((123.00±19.04) µm vs. (138.93±14.16) µm and (134.47±14.34) µm), and inferior quadrant ((129.37±17.50) µm vs. (143.60±12.22) µm and (144.48±14.10) µm), and the differences were statistically significant. The diagnostic efficiencies of the overall average, superior quadrant, and inferior quadrant RNFL thicknesses, and a combined index of superior and inferior quadrant RNFL thicknesses were similar, and the AUCs were 0.739 (95% confidence interval (CI) 0.635-0.826), 0.683 (95% CI 0.576-0.778), 0.755 (95% CI 0.652-0.840), and 0.773 (95% CI 0.672-0.854), respectively. The diagnostic sensitivity of RNFL thickness in the superior quadrant reached 93.33%. CONCLUSIONS: The thickness of the RNFL in the optic disc can be used as a diagnostic method for DPN.

7.
Front Pharmacol ; 11: 566060, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33041807

RESUMO

Carbapenem-resistant enterobacteriaceae (CRE) bloodstream infections have been rapidly spreading worldwide with a high mortality and pose a challenge to therapeutic decision-making, especially in premature neonates because insufficient empirical antimicrobial therapy is independently associated with high mortality. This case reported that a premature infant with CRE bloodstream infection was treated successfully with high-dose meropenem treatment with model-based therapeutic drug monitoring (TDM). In clinical settings, treatment target attainment of meropenem can be improved by increasing the frequency of administration, prolonging the infusion time, and using a high dose. This case report shows a successful regimen for CRE infection in a premature neonate and emphasizes the utility of model-based TDM of high-dose meropenem treatment. The adequate antimicrobial benefit provided by innovative techniques could ensure the efficacy and safety of high-dose meropenem therapy for CRE infection.

8.
Cell Transplant ; 29: 963689720958656, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907379

RESUMO

8-Chloro-adenosine (8-Cl-Ado) has been shown to exhibit its antitumor activity by inducing apoptosis in human lung cancer A549 and H1299 cells or autophagy in chronic lymphocytic leukemia, and MDA-MB-231 and MCF-7 breast cancer cells. Adenosine deaminases acting on RNA 1 (ADAR1) is tightly associated with cancer development and progression. The aim of this study was to investigate the role of ADAR1 in the proliferation of MDA-MB-231 and SK-BR-3 breast cancer cell lines after 8-Cl-Ado exposure and its possible mechanisms. After 8-Cl-Ado exposure, CCK-8 assay was performed to determine the cell proliferation; flow cytometry was used to analyze the cell cycle profiles and apoptosis; and the protein levels of ADAR1, p53, p21, and cyclin D1 were measured by western blotting. The results showed that the cell proliferation was greatly inhibited, G1 cell cycle was arrested, and apoptosis was induced after 8-Cl-Ado exposure. ADAR1 and cyclin D1 protein levels were dramatically decreased, while p53 and p21 levels were increased after 8-Cl-Ado exposure. Moreover, the cell growth inhibition was rescued, apoptosis was reduced, and p53 and p21 protein levels were downregulated, while cyclin D1 was upregulated when cells were transfected with plasmids expressing ADAR1 proteins. More importantly, RNA-binding domain of ADAR1 is critical to the cell growth inhibition of breast cancer cells exposed to 8-Cl-Ado. Together, 8-Cl-Ado inhibits the cell proliferation, induces G1 phase arrest and apoptosis at least by targeting ADAR1/p53/p21 signaling pathway. The findings may provide us with insights into the role of ADAR1 in breast cancer progression and help us better understand the effects of 8-Cl-Ado in the treatment of breast cancer.

9.
Mol Cancer ; 19(1): 121, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32767982

RESUMO

N6-methyladenosine (m6A) is one of the most common RNA modifications in eukaryotes, mainly in messenger RNA (mRNA). Increasing evidence shows that m6A methylation modification acts an essential role in various physiological and pathological bioprocesses. Noncoding RNAs (ncRNAs), including miRNAs, lncRNAs and circRNAs, are known to participate in regulating cell differentiation, angiogenesis, immune response, inflammatory response and carcinogenesis. m6A regulators, such as METTL3, ALKBH5 and IGF2BP1 have been reported to execute a m6A-dependent modification of ncRNAs involved in carcinogenesis. Meanwhile, ncRNAs can target or modulate m6A regulators to influence cancer development. In this review, we provide an insight into the interplay between m6A modification and ncRNAs in cancer.

10.
J Dig Dis ; 21(8): 454-461, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32621394

RESUMO

OBJECTIVE: To clarify the pathological characteristics of granuloma and granulomatous lymphangitis in patients with non-neoplastic bowel diseases and to compare their significance in the differential diagnosis of Crohn's disease (CD) and intestinal tuberculosis (ITB). METHODS: Altogether 78 cases with CD, 11 with ITB and 33 suffering from other non-neoplastic bowel diseases were included. All patients underwent a partial enterectomy and histopathological examination. Pathological sections were reviewed retrospectively. Detailed morphological features and the distribution of granulomas and granulomatous lymphangitis in the three groups were analyzed and compared. RESULTS: Significant differences in the features of granuloma were observed in CD compared with ITB, including the presence of Langhans giant cells, caseous necrosis, coalescence, hyaline change, onionskin changes, and their frequency and size. Granulomatous lymphangitis was significantly more frequent in CD than in other non-neoplastic bowel diseases (P < 0.0001). The rate was also higher than that of granuloma in CD (P = 0.0004). It more often manifested within the mucosal layer of the small bowel (55.4%) in CD whereas it tended to be located within the deep layers of the intestinal wall in other diseases. It can be divided into four types, but types 1 and 2 appeared relatively specific to CD. CONCLUSIONS: Granuloma and granulomatous lymphangitis were not specific in CD. However, by combining morphology and distribution, their manifestations could assist in the differentiation of CD from other non-neoplastic bowel diseases. Furthermore, granulomatous lymphangitis showed better diagnostic performance than granulomas in the mucosal layer of the small bowel.

11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(3): 937-941, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32552961

RESUMO

OBJECTIVE: To investigate the effects of different routes in placental mesenchymal stem cells (PMSC) on serum expression levels of IL-4, IL-17, TNF-α and IFN-γ in aplastic anemia (AA) rats. METHODS: The rat model of aplastic anemia (AA rats) was established by 5-fluorouracil combined with busulfan. The rats was divided into four groups: control, experimental, PMSC-injected into the tail vein, and PMSC-injected into the medullary cavity. The general state of rats in each group was observed in detail before and after treatment. The serum levels of interleukin-4 (IL-4) , interleukin-17 (IL-17), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) were measured by enzyme-linked immunosorbent assay (ELISA) at week 1, 3 and 5 after treatment. RESULTS: The serum levels of TNF-α, IFN-γ and IL-17 in the experimental group were significantly higher than those in the control group, while the level of IL-4 was significantly decreased (P<0.05). The levels of TNF-α, IFN-γ and IL-17 gradually decreased after treatment while the level of IL-4 increased. By the fifth week, the above indexes were closed to the control group (P>0.05), and the levels of TNF-α, IFN-γ and IL-17 in the group with PMSCs injected via the medullary cavity decrease more significantly than those group with PMSC injected via the tail vein, but level of IL-4 was not significantly different between two groups. CONCLUSION: The level of serum hematopoietic negative regulators increase significantly, and the level of hematopoietic promoting factors decreases significantly in aplastic anemia rats. PMSC can down-regulate the level of hematopoietic negative regulators and up-regulate the level of hematopoietic promoting factors in the rats with aplastic anemia, and the inhibition of hematopoietic negative regulators by intramedullary injection is more significant than that by caudal vein injection.


Assuntos
Anemia Aplástica , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Animais , Feminino , Interferon gama , Placenta , Gravidez , Ratos , Fator de Necrose Tumoral alfa
12.
Artigo em Inglês | MEDLINE | ID: mdl-32513801

RESUMO

Data of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for meropenem. Population PK data were analyzed using NONMEM software. Fifty-seven patients (mean age, 2.96 years [range, 0.101 to 14.4]; mean body weight, 15.8 kg [range, 5.0 to 65.0]) were included. A total of 135 meropenem concentrations were obtainable for population PK modeling. The median number of samples per patients was 2 (range, 1 to 4). A two-compartment model with first-order elimination was optimal for PK modeling. Weight and creatinine clearance (estimated by the Schwartz formula) were significantly correlated with the PK parameters of meropenem. The probabilities of target attainment for pathogens with low MICs of 1 and 2 µg/ml were 87.5% and 68.6% following administration of 40 mg/kg/dose (every 8 h [q8h]) as a 4-h infusion and 98.0% and 73.3% with high MICs of 4 and 8 µg/ml following administration of 110 mg/kg/day as a continuous infusion in critically ill infants and children under 70% fT >MIC (the free time during which the plasma concentration of meropenem exceeds the MIC), respectively. The standard dosage regimens for meropenem did not meet an appropriate PD target, and an optimal dosing regimen was established in critically ill infants and children. (This study has been registered at ClinicalTrials.gov under identifier NCT03643497.).

13.
Artigo em Inglês | MEDLINE | ID: mdl-32478040

RESUMO

The development of non-invasive, inexpensive, and effective early diagnosis tests for gastric and small-bowel lesions is an urgent requirement. The introduction of magnetically guided capsule endoscopy (MGCE) has aided examination of the small bowel for diagnoses. However, the distribution of the fecal microbiome in abnormal erosions of the stomach and small bowel remains unclear. Herein, alternations in the fecal microbiome in three groups [normal, small-bowel inflammation, and chronic gastritis (CG)] were analyzed by metagenomics and our well-developed method [individual-specific edge-network analysis (iENA)]. In addition to the dominant microbiota identified by the conventional differential analysis, iENA could recognize novel network biomarkers of microbiome communities, such as the genus Bacteroide in CG and small-bowel inflammation. Combined with differential network analysis, the network-hub microbiota within rewired microbiota networks revealed high-ranked iENA microbiota markers, which were disease specific and had particular pathogenic functions. Our findings illuminate the components of the fecal microbiome and the importance of specific bacteria in CG and small-bowel erosions, and could be employed to develop preventive and non-invasive therapeutic strategies.

14.
Brain Behav ; 10(6): e01589, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32324340

RESUMO

OBJECTIVE: Dickkopf-1 (DKK-1), an inhibitor of the canonical/-catenin cascade of the Wnt pathway, was upregulated in brain tissues of hemorrhagic stroke rats, and its rising circulating levels were associated with poor prognosis of acute ischemic stroke patients. We attempted to ascertain the relationship between serum DKK-1 levels and 30-day death after severe traumatic brain injury (sTBI). MATERIALS AND METHODS: Serum DKK-1 levels were gauged in a total of 94 sTBI patients and 94 healthy controls. Trauma severity was assessed using Glasgow Coma Scale (GCS) and Rotterdam classification based on head computerized tomography scan. Prognostic variable was 30-day death. RESULTS: Compared with controls, serum DKK-1 levels were substantially elevated in patients (median value, 3.7 versus 1.0 ng/ml). Area under receiver operating characteristic curve was 0.802 (95% confidence interval (CI), 0.708-0.877) for predicting 30-day death. Adjusted logistic regression showed that serum DKK-1 levels above 3.7 ng/ml remained as an independent marker of 30-day death (odds ratio, 8.573; 95% CI, 1.386-53.020) and overall survival (hazard ratio, 7.322; 95% CI, 1.320-40.622). An intimate correlation existed between DKK-1 levels and GCS scores (r = -.649) in addition to Rotterdam classification (r = .664). CONCLUSIONS: High serum levels of DKK-1 are closely associated with increasing severity and rising short-term mortality of sTBI.

15.
Brain ; 143(1): 222-233, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819945

RESUMO

Essential tremor is one of the most common movement disorders. Despite its high prevalence and heritability, the genetic aetiology of essential tremor remains elusive. Up to now, only a few genes/loci have been identified, but these genes have not been replicated in other essential tremor families or cohorts. Here we report a genetic study in a cohort of 197 Chinese pedigrees clinically diagnosed with essential tremor. Using a comprehensive strategy combining linkage analysis, whole-exome sequencing, long-read whole-genome sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal GGC repeat expansion in the 5' region of the NOTCH2NLC gene that co-segregated with disease in 11 essential tremor families (5.58%) from our cohort. Clinically, probands that had an abnormal GGC repeat expansion were found to have more severe tremor phenotypes, lower activities of daily living ability. Obvious genetic anticipation was also detected in these 11 essential tremor-positive families. These results indicate that abnormal GGC repeat expansion in the 5' region of NOTCH2NLC gene is associated with essential tremor, and provide strong evidence that essential tremor is a family of diseases with high clinical and genetic heterogeneities.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Tremor Essencial/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Feminino , Sequência Rica em GC , Ligação Genética , Humanos , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/ultraestrutura , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Linhagem , Reação em Cadeia da Polimerase , Pele/ultraestrutura , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
16.
Pathol Res Pract ; 215(11): 152677, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31591052

RESUMO

Sanguinarine (SAG), a benzophenanthridine alkaloid extracted from Sanguinaria canadensis, exerts antioxidant, anti-inflammatory and antiproliferative activities in a variety of malignancies. However, the underlying mechanisms by which SAG affects the tumorigenesis of gastric cancer (GC) are unclear. The common targets of SAG and GC were identified by network pharmacology, and the association of thymocyte selection-associated high mobility group box (TOX) with the clinicopathological characteristics and prognosis of patients with GC was analyzed by using datasets from The Cancer Genome Atlas (TCGA). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays, colony formation assays, flow cytometry analysis, and a xenograft tumor model were conducted to assess the effects of SAG on the growth of GC cells, and Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were used to determine the effects of SAG on the TOX/DNA-PKcs/KU70/80 signaling pathway. We identified 9 collective targets of SAG and GC, of which TOX expression levels were dramatically downregulated in GC tissues compared with adjacent normal tissues, and a low expression of TOX served as an independent prognostic factor of poor survival in patients with GC. SAG suppressed cell viability, colony formation and in vivo tumorigenesis and induced cell apoptosis and cell cycle arrest. Furthermore, SAG increased the expression levels of TOX but decreased those of DNA-PKcs and KU70/80 in GC cells. Our findings indicate that SAG inhibits the tumorigenesis of GC cells by regulating TOX/DNA-PKcs/KU70/80 signaling and may provide therapeutic strategies for the treatment of GC.


Assuntos
Antineoplásicos/farmacologia , Benzofenantridinas/farmacologia , Carcinogênese/efeitos dos fármacos , Isoquinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Proteínas de Grupo de Alta Mobilidade/efeitos dos fármacos , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Autoantígeno Ku/efeitos dos fármacos , Autoantígeno Ku/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
ACS Omega ; 4(14): 16121-16124, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31592480

RESUMO

Efficient analytical representations of the thermodynamic properties for carbon disulfide remain open challenges in the communality of science and engineering. We present two analytical representations of the entropy and Gibbs free energy for gaseous carbon disulfide which we find to be of satisfactory accuracy and convenient for future use. The proposed two analytical representations merely rely on five molecular constants of the carbon disulfide molecule and avoid applications of a large number of experimental spectroscopy data. In the temperature range from 300 to 6000 K, the average relative deviations of the predicted molar entropy and reduced Gibbs free energy values from the National Institute of Standards and Technology database are 0.250 and 0.108%, respectively.

18.
Oncol Lett ; 18(4): 3880-3886, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31516599

RESUMO

Melanoma is the most malignant type of skin cancer and is resistant to numerous chemotherapeutic and radiotherapy-based treatment approaches due to the activation of rapid and reversible pro-survival signaling pathways. As a result, patients will often present with a poor prognosis. Therefore, novel preventive methods and treatments are urgently required for patients with melanoma. Vitamin C (also known as L-ascorbic acid) is a water-soluble vitamin that is widely used as a dietary additive and has been demonstrated to exhibit anti-cancer properties. In the present study, the effects of vitamin C in human melanoma A375 cells, and the mechanisms underlying these effects were investigated. Vitamin C potently suppressed human melanoma A375 cell proliferation by inducing apoptosis in A375 cells. Induction of apoptosis was related to caspase-9 and caspase-3 activation and the mitochondrial membrane potential of A375 cells significantly decreased in the presence of vitamin C. Furthermore, vitamin C induced apoptosis in A375 cells by activating the Bax- and Bcl-2-mediated mitochondrial pathway. These results indicate that vitamin C may be a potentially useful clinical anti-tumor drug for treating patients with melanoma.

19.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(7): 680-684, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31315768

RESUMO

OBJECTIVE: To preliminarily investigate the relationship between stimulatory G protein α subunit (GNAS) and thyroid hormone receptor α (THRA) gene mutations and clinical phenotypes in children with congenital hypothyroidism (CH). METHODS: A total of 70 children with CH diagnosed by neonatal screening were enrolled. Their peripheral blood samples were collected to extract genomic DNA. GNAS and THRA genes were screened for mutations using next-generation sequencing. Bioinformatics software was used to analyze the pathogenicity of gene mutations. RESULTS: Of the 70 children with CH, nine missense mutations (three known mutations and six novel mutations) in the GNAS gene were detected in three patients (4%), and one gene polymorphism, c.508A>G(p.I170V), in the THRA gene was detected in four patients. The analysis results of bioinformatics software and ACMG/AMP guidelines showed that the two GNAS gene mutations [c.301C>T(p.R101C) and c.334G>A(p.E112K)] were more likely to be pathogenic. Three children with GNAS gene mutations showed different degrees of hypothyroidism. CONCLUSIONS: GNAS gene mutations are related to the development of CH, and children with CH have different clinical manifestations. THRA gene mutations may not be associated with CH.


Assuntos
Cromograninas/genética , Hipotireoidismo Congênito , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Receptores alfa dos Hormônios Tireóideos/genética , Genes erbA , Humanos , Recém-Nascido , Mutação , Fenótipo
20.
Am J Hum Genet ; 105(1): 166-176, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178126

RESUMO

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.


Assuntos
Corpos de Inclusão Intranuclear/patologia , Doenças Neurodegenerativas/patologia , Receptores Notch/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Feminino , Humanos , Corpos de Inclusão Intranuclear/genética , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Linhagem , Sequenciamento Completo do Exoma
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