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1.
Rinsho Shinkeigaku ; 61(9): 588-593, 2021 Sep 28.
Artigo em Japonês | MEDLINE | ID: mdl-34433746

RESUMO

Recent progress in genetic analysis can provide a precision diagnosis for many hereditary neuromuscular diseases in daily practice. Moreover, disease-modifying therapies such as nucleic acid medicine for patients with several neuromuscular diseases (i.e., hereditary ATTR amyloidosis, spinal muscular atrophy, and Duchenne muscular dystrophy) have been approved in Japan. For all neurologists, knowledge and practical skills of genetic counseling, especially predictive testing, will increase in importance. To promote personalized medicine for patients with neuromuscular diseases and their families, it is necessary to develop of genetic counseling systems, including nurturing genetic professionals.

2.
Anticancer Res ; 41(8): 4047-4052, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281873

RESUMO

BACKGROUND/AIM: Tropomyosin-related kinase B (TrkB)/brain-derived neurotrophic factor (BDNF) signaling plays a role in inducing malignant phenotypes in several aggressive types of cancers. To create a conclusive therapy targeting TrkB/BDNF signaling in solid refractory cancers, the biological significance of TrkB/BDNF signaling was analyzed in pancreatic ductal adenocarcinoma (PDAC) cells. MATERIALS AND METHODS: Three PDAC cell lines were used as target cells to investigate proliferation and invasiveness. Small interfering RNA (siRNA) and the TrkB tyrosine kinase inhibitor k252a were used as TrkB/BDNF signaling inhibitors. RESULTS: All PDAC cell lines expressed TrkB and BDNF. When TrkB and BDNF were inhibited by siRNA or k252a, the invasiveness of PANC-1 and SUIT-2 cells significantly decreased. When TrkB was inhibited by siRNA or k252a, proliferation was significantly inhibited in PDAC cells. CONCLUSION: TrkB/BDNF signaling may be a new therapeutic target for PDAC. Therapies targeting TrkB/BDNF signaling may be a conclusive cancer therapy for refractory solid cancer.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor trkB/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Carbazóis/farmacologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Alcaloides Indólicos/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Transdução de Sinais/efeitos dos fármacos
3.
Transl Oncol ; 14(9): 101152, 2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34134073

RESUMO

In our previous study, we found that inhibition of protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is expressed in lymphocytes, enhances lymphocyte activation, suggesting PTPN3 may act as an immune checkpoint molecule. However, PTPN3 is also expressed in various cancers, and the biological significance of PTPN3 in cancer cells is still not well understood, especially for lung neuroendocrine tumor (NET).Therefore, we analyzed the biological significance of PTPN3 in small cell lung cancer and examined the potential for PTPN3 inhibitory treatment as a cancer treatment approach in lung NET including small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC). Experiments in a mouse xenograft model using allo lymphocytes showed that PTPN3 inhibition in SCLC cells enhanced the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In addition, PTPN3 was associated with increased vascularization, decreased CD8/FOXP3 ratio and cellular immunosuppression in SCLC clinical specimens. Experiments in a mouse xenograft model using autocrine lymphocytes also showed that PTPN3 inhibition in LCNEC cells augmented the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In vitro experiments showed that PTPN3 is involved in the induction of malignant traits such as proliferation, invasion and migration. Signaling from PTPN3 is mediated by MAPK and PI3K signals via tyrosine kinase phosphorylation through CACNA1G calcium channel. Our results show that PTPN3 suppression is associated with lymphocyte activation and cancer suppression in lung NET. These results suggest that PTPN3 suppression could be a new method of cancer treatment and a major step in the development of new cancer immunotherapies.

4.
Am J Med Genet A ; 185(7): 2175-2179, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33884742

RESUMO

Transient receptor potential channel C6 encoded by TRPC6 is involved in slit diaphragm formation in podocytes, and abnormalities of the TRPC6 protein cause various glomerular diseases. The first identified pathogenic variant of TRPC6 was found to cause steroid-resistant nephrotic syndrome that typically developed in adulthood and then slowly led to end-stage renal disease, along with a renal pathology of focal segmental glomerulosclerosis. Here, we report a patient with rapidly progressing infantile nephrotic syndrome and a heterozygous missense TRPC6 variant. The patient, a 2-year-old Japanese boy, developed steroid-resistant nephrotic syndrome at age 11 months. His renal function deteriorated rapidly, and peritoneal dialysis was introduced at age 1 year and 6 months. His renal pathology, obtained at age 1 year and 1 month, was consistent with diffuse mesangial sclerosis (DMS). Clinical exome analysis and custom panel analysis for hereditary renal diseases revealed a reported heterozygous missense variant in TRPC6 (NM_004621.5:c.523C > T:p.Arg175Trp). This is the first report of a patient with a TRPC6-related renal disorder associated with DMS.

5.
Adv Exp Med Biol ; 1261: 153-163, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33783737

RESUMO

Oleaginous yeasts, Yarrowia lipolytica and Lipomyces starkeyi, can synthesize more than 20% of lipids per dry cell weight from a wide variety of substrates. This feature is attractive for cost-efficient production of industrial biodiesel fuel. These yeasts are also very promising hosts for the efficient production of more value-added lipophilic compound carotenoids, e.g., lycopene and astaxanthin, although they cannot naturally biosynthesize carotenoids. Here, we review recent progress in researches on carotenoid production by oleaginous yeasts, which include red yeasts that naturally produce carotenoids, e.g., Rhodotorula glutinis and Xanthophyllomyces dendrorhous. Our new results on pathway engineering of L. starkeyi for lycopene production are also revealed in the present review.


Assuntos
Lipomyces , Basidiomycota , Carotenoides , Rhodotorula , Leveduras/genética
6.
Intern Med ; 60(4): 557-561, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32999234

RESUMO

The patient was an 82-year-old Japanese man with no family history suggestive of amyloidosis. He developed bilateral leg edema and shortness of breath and was referred to our hospital. An electrocardiogram showed atrial fibrillation with right bundle branch block. Echocardiography showed concentric LV hypertrophy. An endomyocardial biopsy showed severe ATTR amyloid deposits. A genetic analysis of the transthyretin (TTR) gene revealed a heterozygous c.187C>T missense variant resulting in p.P63S (P43S). In silico analyses predicted that this variant only modestly altered the structure and function of the TTR protein. The p.P63S variant might be associated with an elderly-onset cardiac-dominant ATTRv phenotype.


Assuntos
Neuropatias Amiloides Familiares , Pré-Albumina , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Ecocardiografia , Testes Genéticos , Humanos , Masculino , Fenótipo , Pré-Albumina/genética
7.
Dysphagia ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33215265

RESUMO

Tongue-strengthening exercises (TSE) using a device have been proposed as an intervention for improving tongue strength and endurance. However, devices for TSE have been expensive and difficult to manipulate and are not commonly used in home or clinical settings. This study therefore aimed to investigate whether tongue-strengthening self-exercises (TSsE) using a tongue-strengthening self-exercise tool at home can improve tongue strength in healthy older adults. This study included 27 participants (exercise group, η = 16, 7 men, 9 women, median age 84.5 years; control group, n = 11, 2 men, 9 women, median age 79.0 years). Exercises in the exercise group consisted of pushing the anterior tongue against the hard palate 30 times, 3 times a day, 5 days a week, for 8 weeks using a tongue-strengthening self-exercise tool. This tool is available in five levels of hardness. The most suitable hardness of the tool for each participant was calculated based on 60% of maximum tongue pressure (MTP) during the first 2 weeks of the training period and 80% of MTP for the remainder of the training period, as assessed using a tongue pressure-measuring device. The exercise group showed a significant improvement of 4.1 kPa in MTP (an 11.53% increase) and 4.53 s in endurance of tongue pressure (ETP) (a 99.86% increase). Furthermore, adherence in the exercise group was 99.2%. In conclusion, performing TSsE for 8 weeks was effective for increasing MTP and ETP in healthy older adults. This indicates that TSsE may be useful in older individuals at home to prevent age-related tongue muscle weakness.

8.
Intern Med ; 59(20): 2587-2591, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32581172

RESUMO

A 61-year-old Japanese man with the pure spinal form of cerebrotendinous xanthomatosis developed dysesthesia of the lower limbs and gait disturbance at 57 years of age. At 61 years old, he was unable to walk without support. A neurological examination showed spasticity and sensory disturbance in the lower limbs. Spinal MRI showed long hyperintense lesions involving the lateral and posterior funiculus in the cervical and thoracic cord on T2-weighted images. His serum cholestanol level was markedly elevated. A CYP27A1 gene analysis identified two missense variants, p.R474W, and a novel p.R262C variant. Combination therapy with chenodeoxycholic acid and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase decreased his serum cholestanol level.


Assuntos
Ácido Quenodesoxicólico/uso terapêutico , Colestanotriol 26-Mono-Oxigenase/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças da Coluna Vertebral/genética , Xantomatose Cerebrotendinosa/genética , Medula Cervical/patologia , Colestanol/sangue , Quimioterapia Combinada , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Medula Espinal/patologia , Doenças da Coluna Vertebral/diagnóstico , Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/tratamento farmacológico
9.
Cerebellum Ataxias ; 7: 7, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32587707

RESUMO

Background: Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (PDYN). The frequency of PDYN variants is reportedly very low (~ 0.1%) in several ataxia cohorts screened to date. Case presentations: We found five cases of SCA23 in two families (mean age at onset: 37.8 ± 5.5 years; mean age at examination: 64.2 ± 12.3 years) with a novel PDYN variant (c.644G > A:p.R215H). We identified marked heterogeneity in the clinical features in Family 1: the proband showed clinical and neuroimaging features suggestive of multiple system atrophy with predominant parkinsonism (MSA-P). Conversely, the proband's mother with the PDYN p.R215H variant had no subjective symptoms; she had not come to medical attention before our survey, although she showed apparent cerebellar atrophy on brain magnetic resonance imaging (MRI). The other two patients in Family 1 and a patient in Family 2 showed slowly progressive cerebellar ataxia. Conclusions: We here report two Japanese families with SCA23, one of which showed considerable phenotypic variation in affected members. Our findings support that SCA23 can phenotypically overlap with MSA.

11.
Neuron ; 105(4): 645-662.e11, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31831332

RESUMO

The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.


Assuntos
Esclerose Amiotrófica Lateral/genética , Anticorpos Monoclonais/genética , Proteína C9orf72/genética , Demência Frontotemporal/genética , Terapia Genética/métodos , Proteína ran de Ligação ao GTP/metabolismo , Idoso , Esclerose Amiotrófica Lateral/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/metabolismo , Encéfalo/metabolismo , Proteína C9orf72/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Demência Frontotemporal/metabolismo , Marcação de Genes/métodos , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Distribuição Aleatória , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteína ran de Ligação ao GTP/antagonistas & inibidores
13.
Anticancer Res ; 39(3): 1179-1184, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842147

RESUMO

BACKGROUND/AIM: Small-cell lung cancer (SCLC) remains one of deadliest types of cancers. Cis-diamminedichloroplatinum (CDDP) is a key chemotherapeutic agent for SCLC, however, its therapeutic effect is limited. Recently, hypoxia in the cancer microenvironment has been suggested to influence the effect of cancer therapy. MATERIALS AND METHODS: Using small interfering RNA inhibition of leukocyte common antigen-related interacting protein alpha 4 (liprin-α4), and of hypoxia-inducible factor (HIF)-1α, proliferation, invasion, migration and chemosensitivity were investigated in SBC-5 SCLC cells, under normoxia and hypoxia. RESULTS: Liprin-α4 was found to contribute to proliferation, but not migration and invasion of SBC-5 cells both under normoxia and hypoxia. Inhibition of liprin-α4 increased chemosensitivity of SBC-5 cells under hypoxia. Liprin-α4 signaling occurs through mitogen-activated protein kinase pathways via activation of HIF1α expression. Inhibition of HIF1α reduced proliferation and increased chemosensitivity of SBC-5 cells under hypoxia. CONCLUSION: Liprin-α4 inhibition may enhance the effect of CDDP and liprin-α4 might be a novel therapeutic target in SCLC.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/terapia , RNA Interferente Pequeno/administração & dosagem , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Carcinoma de Pequenas Células do Pulmão/terapia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Tirosina Fosfatases Semelhantes a Receptores/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo
14.
Anticancer Res ; 38(8): 4543-4547, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30061220

RESUMO

BACKGROUND/AIM: Small cell lung cancer (SCLC) is still a deadly type of cancer for which there are few effective therapeutic strategies. Development of a new molecule targeting agent is urgently desired. Previously we showed that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) are new therapeutic targets for pancreatic cancer. In the present study, we analyzed whether RBPJ/MAML3 inhibition could also be a new therapeutic strategy for SCLC. MATERIALS AND METHODS: Using silencing of RBPJ/MAML3, proliferation, invasion, migration and chemosensitivity of SBC-5 cells were investigated. RESULTS: RBPJ/MAML3 inhibition reduced Smoothened and HES1 expression, suggesting that RBPJ/MAML3 signaling was through Hedgehog and NOTCH pathways. In the analysis of cell functions, RBPJ/MAML3 inhibition significantly reduced proliferation and invasiveness via reduction of expression of matrix metalloproteinases. On the other hand, RBPJ/MAML3 inhibition also reduced chemosensitivity to cis-diamminedichlo-roplatinum and gemcitabine. CONCLUSION: These results suggest that RBPJ and MAML3 could be new therapeutic targets for SCLC, however, chemosensitivity may be reduced in combinational use with other chemo-therapeutic agents.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Fatores de Transcrição/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinases da Matriz/metabolismo , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Transativadores
15.
J Neurol Sci ; 384: 30-35, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29249373

RESUMO

Cortical cerebellar atrophy (CCA) and multiple system atrophy with predominant cerebellar ataxia (MSA-C) are the two major forms of adult-onset sporadic ataxia. Contrary to MSA-C, there are neither diagnostic criteria nor neuroimaging features pathognomonic for CCA. Therefore, it is assumed that the category of CCA in the Japanese national registry include heterogeneous cerebellar ataxic disorders. To refine this category in more detail, we here used a clinical-based term, "idiopathic cerebellar ataxia (IDCA)", and proposed its diagnostic criteria. We collected 346 consecutive patients with the core features of the criteria (sporadic, insidious-onset and slowly progressive cerebellar ataxia in adults, and cerebellar atrophy on brain imaging). Of these, 212 (61.3%) were diagnosed with probable or possible MSA, and 30, who did not meet the diagnostic criteria for MSA at examination, were also excluded because of MRI findings suggestive of MSA. Twenty two were proven to have hereditary spinocerebellar ataxias by genetic testing, and 19 had secondary ataxias. Finally, the remaining 63 (18.2%) were diagnosed with IDCA. The mean (standard deviation) age at onset was 57.2 (10.8) years. Of these, 25 (39.7%) showed pure cerebellar ataxia, and the remaining 38 (60.3%) had some of extracerebellar features including abnormal tendon reflexes (46.0%), positive Babinski sign (9.5%), sensory disturbance (12.7%), cognitive impairment (9.5%), and involuntary movements (7.9%). Our results show that IDCA refined by the diagnostic criteria still includes clinically and genetically heterogeneous ataxic disorders. More extensive genetic analyses will be of significance for further clarification of this group.


Assuntos
Ataxia Cerebelar/diagnóstico , Idoso , Encéfalo/diagnóstico por imagem , Ataxia Cerebelar/fisiopatologia , Diagnóstico Diferencial , Feminino , Humanos , Japão , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/fisiopatologia , Estudos Retrospectivos
16.
Hum Genome Var ; 4: 17052, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29081981

RESUMO

A Japanese family with autosomal recessive cerebellar ataxia type 8 (SCAR8, MIM 610743) is described. We identified a novel SYNE1 frameshift deletion (c.6843del, p.Q2282Sfs*3). This family shared similar clinical manifestations characterized by adult-onset, relatively pure cerebellar ataxia with mild eye movement abnormality. Intelligence and bulbar and respiratory functions were unaffected. This study suggests the clinical utility of using panel-based exome sequencing for genetic diagnosis in hereditary ataxias in a cost-efficient manner.

17.
Anticancer Res ; 37(9): 4987-4992, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28870922

RESUMO

BACKGROUND/AIM: Previously we have shown that tropomyosin-related kinase B (TRKB) and Hedgehog (Hh) signalling pathways induce malignant phenotypes in many cancer types. However, results from small cell lung cancer (SCLC) clinical trials using TRK and Hh inhibitors have been disappointing. One reason for this may be the existence of crosstalk between TRKB and Hh signalling pathways. In this study, we detected negative crosstalk between the TRKB and Hh-GLI1 signalling pathways. MATERIALS AND METHODS: The human small cell lung carcinoma cell line, SBC-5, was used. Using small interfering RNA to inhibit TRKB and Hh signalling, whether TRKB and Hh signaling contribute to proliferation and invasiveness in SBC-5 cells were investigated. RESULTS: TRKB expression in GLI1 siRNA-transfected SBC-5 cells was higher than that of control cells. GLI1-knockdown alone did not affect invasiveness of SBC-5 cells. However, combined knockdown of TRKB and GLI1 significantly decreased invasiveness. Moreover, combined TRKB and GLI1 knockdown inhibited proliferation and migration to a greater extent than when either was inhibited alone. CONCLUSION: These results suggest that Hh inhibition increases TrkB expression to counter tumor suppression in SBC-5 cells. The combined use of TRKB and Hh inhibitors may, therefore, be useful for the treatment of refractory SCLC.


Assuntos
Movimento Celular , Proliferação de Células , Proteínas Hedgehog/antagonistas & inibidores , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/antagonistas & inibidores , Receptor trkB/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/patologia , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Apoptose , Proteínas Hedgehog/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , RNA Interferente Pequeno/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Células Tumorais Cultivadas
18.
J Hum Genet ; 62(10): 923-925, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28638142

RESUMO

The causative mutation for spinocerebellar ataxia type 31 (SCA31) is an intronic insertion containing pathogenic pentanucleotide repeats, (TGGAA)n. We examined to what degree the inserted repeats were unstable during transmission. In 14 parent-child pairs, the average change of onset age was -6.4±7.3 years (mean±s.d.) in the child generation when compared with the parent generation. Of the 11 pairs analyzed, six showed expansion of inserted repeat length during transmission, and five showed contraction. On average, the inserted repeats expanded by 12.2±32.7 bp during transmission, but their mean length (with a 95% confidence interval) was not significantly different between parent and child generations. We consider that the length of the inserted repeats in SCA31 is changeable during transmission, but inter-generational instability is not marked, as far as the current sizing method can determine.


Assuntos
Instabilidade Genômica , Repetições de Microssatélites/genética , Mutagênese Insercional , Ataxias Espinocerebelares/genética , Idade de Início , Idoso , Feminino , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico
19.
Lab Invest ; 97(11): 1332-1342, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28604655

RESUMO

The tropomyosin-related kinase (Trk) family consists of TrkA, TrkB, and TrkC, which play essential roles in tumor progression and/or suppression in various cancers. Little is known about the biological significance of the Trk family in human lung squamous cell carcinoma (SCC). Here we investigated the clinical significance of the protein expression of Trk family members in samples from 99 SCC patients, and we explored the relationship between invasion/proliferation activities and Trk expression using lung SCC cell lines to clarify the biological significance of the Trk family in lung SCC. Immunohistochemical high expression of TrkB was significantly correlated with vascular invasion (P=0.004), lymph node metastasis (P<0.001), and advanced stage (P=0.0015). The overall survival of the patients with TrkB-high expression was significantly shorter than those with TrkB-low expression (P=0.0110). TrkA/TrkC expressions were not predictors of poor prognosis. An in vitro assay demonstrated that the inhibition of brain-derived neurotrophic factor (BDNF) (a TrkB ligand) and TrkB by K252a (a Trk inhibitor) or siRNA (BDNF-siRNA, TrkB-siRNA) suppressed the invasion, migration, and proliferative activities of lung SCC cells. The administration of recombinant human BDNF (rhBDNF) enhanced the invasion, migration, and proliferation activities, which were abrogated by K252a. TrkB-siRNA transfection increased the protein expression of E-cadherin and decreased vimentin expressions in lung SCC cells. Matrix metalloproteinase-2 (MMP-2)-mediated gelatin degradations were decreased in lung SCC cells transfected with TrkB-siRNA. Thus, TrkB-high expression is an indicator of poor prognosis in lung SCC, probably due to invasion/proliferation activities promoted by the BDNF/TrkB signaling pathway, which could become a therapeutic target for lung SCC.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmão/metabolismo , Glicoproteínas de Membrana/agonistas , Proteínas de Neoplasias/agonistas , Receptor trkB/agonistas , Transdução de Sinais , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Prognóstico , Interferência de RNA , Receptor trkA/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkB/metabolismo , Receptor trkC/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Estudos Retrospectivos
20.
J Hum Genet ; 62(7): 665-670, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28275245

RESUMO

Fabry disease is an important underlying disease in young cryptogenic stroke patients. However, little is known regarding the frequency of Fabry disease in the general stroke population, especially in elderly patients. A total of 588 stroke patients (61.7% men; average age 74.1±12.5 years) were enrolled in this prospective study. Blood samples were obtained to produce blood spots to determine α-galactosidase A (α-GalA) activity and for GLA gene analysis. One 65-year-old female patient had a known GLA gene mutation, c.2T>C (p.M1T), causing Fabry disease. Five male patients and two female patients had GLA c.196G>C (p.E66Q) variant, which is not associated with the full clinical manifestations of Fabry disease. The allele frequency of GLA c.196G>C was significantly higher in male patients with small-vessel occlusion (odds ratio 3.95, P=0.048) and non-cardioembolism (odds ratio 4.08, P=0.012) than that in the general Japanese population. Fabry disease is rare in the general Japanese stroke population. However, screening identified one elderly female patient with Fabry disease. GLA c.196G>C variant is a genetic risk factor for cerebral small-vessel occlusion and non-cardioembolism in Japanese males but not in females.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doença de Fabry/enzimologia , Doença de Fabry/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/complicações , alfa-Galactosidase/genética , Idoso , Demografia , Ensaios Enzimáticos , Doença de Fabry/complicações , Doença de Fabry/genética , Feminino , Frequência do Gene/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Linhagem , Prevalência
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