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Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke. Despite being the most prevalent vascular hereditary disease, clinical data regarding the Brazilian population are scarce. Considering that the Brazilian population has one of the most heterogeneous genetic constitutions in the world, knowledge about genetic and epidemiological profiles is mandatory. The present study aimed to elucidate the epidemiological and clinical features of CADASIL in Brazil. Methods We performed a case series study comprising 6 rehabilitation hospitals in Brazil and reported the clinical and epidemiological data from the medical records of patients admitted from 2002 to 2019 with genetic confirmation. Results We enrolled 26 (16 female) patients in whom mutations in exons 4 and 19 were the most common. The mean age at the onset of the disease was of 45 years. Ischemic stroke was the first cardinal symptom in 19 patients. Cognitive impairment, dementia, and psychiatric manifestations were detected in 17, 6, and 16 patients respectively. In total, 8 patients had recurrent migraines, with aura in 6 (75%) of them. White matter hyperintensities in the temporal lobe and the external capsule were found in 20 (91%) and 15 patients (68%) respectively. The median Fazekas score was of 2. Lacunar infarcts, microbleeds, and larger hemorrhages were observed in 18 (82%), 9, and 2 patients respectively. Conclusion The present is the most extensive series of Brazilian CADASIL patients published to date, and we have reported the first case of microbleeds in the spinal cord of a CADASIL patient. Most of our clinical and epidemiological data are in accordance with European cohorts, except for microbleeds and hemorrhagic strokes, for which rates fall in between those of European and Asian cohorts.
Resumo Antecedentes Arteriopatia cerebral autossômica dominante com enfartes subcorticais e leucoencefalopatia (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, CADASIL, em inglês) é uma causa genética de acidente vascular cerebral (AVC) isquêmico e a forma mais comum de acidente vascular cerebral não aterosclerótico. Apesar de ser a doença vascular hereditária mais prevalente que há, os dados clínicos para a população brasileira são escassos. Considerando que o Brasil tem uma das constituições genéticas mais heterogêneas do mundo, o conhecimento sobre perfis genéticos e epidemiológicos é obrigatório. Este estudo teve como objetivo elucidar as características clínicas e epidemiológicas de pacientes com CADASIL no Brasil. Métodos Apresentamos uma série de casos envolvendo 6 hospitais de reabilitação no Brasil, e relatamos dados clínicos e epidemiológicos de prontuários de pacientes admitidos entre 2002 e 2019 com confirmação genética. Resultados incluímos 26 pacientes (16 mulheres) em que as mutações nos éxons 4 e 19 eram as mais comuns. A idade média de início da doença foi de 45 anos. O AVC isquêmico foi o primeiro sintoma cardinal em 19 pacientes. Comprometimento cognitivo, demência e manifestações psiquiátricas foram detectados em 17, seis e 16 pacientes, respectivamente. Ao todo, 8 pacientes apresentavam enxaqueca, sendo com aura em 6 (75%) pacientes. Hiperintensidades de substância branca no polo temporal e na cápsula externa foram encontradas em 20 (91%) e 15 pacientes (68%), respectivamente. A pontuação mediana na escala de Fazekas foi de 2. Infartos lacunares, microssangramentos e macro-hemorragias foram observadas em 18 (82%), 9 (41%) e 2 (9%) pacientes, respectivamente. Conclusão O presente estudo representa a mais extensa série de pacientes brasileiros com CADASIL publicada até o momento, e relatamos o primeiro caso de micro-hemorragia na medula espinhal de um paciente com CADASIL. A maior parte dos nossos dados clínicos e epidemiológicos está de acordo com as coortes europeias, exceto para micro-hemorragias e macro-hemorragias, para as quais as taxas se enquadram entre as das coortes europeias e asiáticas.
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Background: The potential involvement of Notch signaling pathway in cell fate decision, tumor heterogeneity and angiogenesis in solid tumors can be explored in colorectal cancer (CRC). This might further help to improve outcomes in CRC. Here, the promoter methylation of Notch receptor gene (Notch2 and Notch3) and their co-expression with its downstream transcription factor Hes1 has been analyzed. Methods: Seventy-two CRC patients were enrolled to study the role of Notch2, Notch3 and Hes1 genes in colorectal cancer. Promoter methylation and mRNA expression in tumor and adjoining normal tissue were assessed by Methylation Specific PCR and quantitative Real time PCR respectively. Statistical correlation was done by using SPSS. Results: We found that Notch2 and Notch3 were hypomethylated in 52/72 (72.22%) and 54/72 (75%) cases respectively. Hypomethylation of Notch 2 and Notch 3 showed significant association with advanced stage (p=0.001) and (p=0.003) and nodal metastasis (p=0.036) and (p=0.012) respectively. Both Notch 2 and Notch 3 showed increased mRNA expression in 49 (68.05%) and 51(70.84%) patients with a fold change of 3.37 and 5.43 respectively. Positive correlation between hypomethylation and expression was observed for both genes. High expression of Hes1 was found in 53(73.61%) of cases which was highly relatable with over expression of notch receptor genes. Upregulation of Notch 2, Notch 3 and Hes1 showed significant association with high grade tumors, advance stage and presence of LN metastasis, additionally Notch 3 and Hes1 showed significant association with distant metastasis. Conclusion: Hypomethylation of Notch 2 and 3 receptors is playing crucial role in regulating the expression of these genes in CRC. Overexpression of Notch 2, Notch 3 and Hes1 are associated with disease progression in CRC.
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Objective:To report the clinical features, imaging findings and gene mutation features of a Chinese family with cerebral autosomal dominant arteriopathy with subcritical infarcts and leukoencephalopathy (CADASIL).Methods:We summarized the clinical and imaging features of a CADASIL family confirmed by gene sequencing. NOTCH3 gene sequencing was conducted for the proband, and the structure of the protein encoded by the mutant gene was predicted. Results:The patients in this family mainly presented with recurrent lacunar infarction and hypertension, without headache and emotional disorders such as anxiety or depression. Head MRI of the proband showed multiple lacunar infarctions and extensive white matter degeneration. Susceptibility-weighted imaging showed multiple small intracranial hemorrhages. The analysis of NOTCH3 gene showed that the proband had c.697T>A mutation. The 3D structure prediction of the protein encoded by this mutation locus showed that this locus could lead to the conversion of cysteine to serine at the 233rd position. Conclusions:The patients of this CADASIL family have a c.697T>A mutation of NOTCH3 gene. This mutation may cause the change of amino acid in the structure of the wild type Notch3 protein, which may lead to increased formation of β-folding structures in the surrounding region, thus changing the structure and function of protein and causing disease.
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CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary small vessel disease originated from adult onset, which is caused by the mutation of NOTCH3 gene located in the region of chromosome 19p13. Its clinical features include recurrent ischemic stroke, progressive cognitive impairment, migraine and mental disorders. Recent studies have shown that the mutations in the EGFr region of NOTCH3 gene are associated with the course, clinical manifestations and imaging features of CADASIL. This article reviews the research progress of the NOTCH3 gene EGFr region mutation genotype, clinical phenotype of CADASIL and their correlation, hoping to provide ideas for the early diagnosis and pathogenesis of CADASIL.
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ObjectiveTo observe the effects of Bufei Yishen prescription on airway mucus hypersecretion and Notch signaling pathway related protein Notch3 and enhancer of split homologue 1 （HES1） in rats with chronic obstructive pulmonary disease （COPD） and to explore its action mechanism. MethodForty-eight SD rats were randomly divided into the control group， model group， Bufei Yishen prescription group， and aminophylline （APL） group，with 12 rats in each group. The stable COPD rat model was established via cigarette smoking exposure combined with Klebsiella bacterial infection for 12 weeks， and the corresponding drugs （3.7 g·kg-1·d-1 Bufei Yishen prescription and 54 mg·kg-1·d-1 APL） were administered by gavage during the next eight weeks. After the last administration at week 20， the lung tissue was sampled for observing the pathological changes and the rat lung function was detected. The tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and mucoprotein 5AC （MUC5AC） in bronchial alveolar lavage fluid and the mRNA and protein expression levels of Notch3， HES1， and MUC5AC in lung tissues were assayed. ResultCompared with the control group， the model group exhibited significantly weakened pulmonary function （P<0.05，P<0.01）， reduced average number of alveoli （P<0.01）， elevated mean linear intercept （P<0.01）， and up-regulated TNF-α， IL-6， and MUC5AC in bronchial alveolar lavage fluid and Notch3， HES1， and MUC5AC mRNA and protein expression in lung tissue （P<0.05，P<0.01）. Compared with the model group， Bufei Yishen prescription and APL remarkably enhanced pulmonary function， alleviated its pathological injury （P<0.05，P<0.01）， and down-regulated TNF-α， IL-6， and MUC5AC in bronchial alveolar lavage fluid and the mRNA and protein expression levels of Notch3， HES1， and MUC5AC in lung tissues （P<0.05，P<0.01）. ConclusionThe mechanism of Bufei Yishen prescription in inhibiting airway mucus hypersecretion of COPD rats was related to its regulation of Notch3 and HES1.
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Objective This study aimed at describing the frequency of rare variants of monogenic cerebral small vessel diseases (CSVD) in a cohort of patients with CSVD, and to explore its clinical relevance. Methods This study included CSVD patients visiting the Neurology Department of Peking Union Medical College Hospital(PUMCH) from March 2017 to January 2022, collecting their demographic and clinical information and DNA samples for whole-exome sequencing. Descriptive analysis and statistical analysis were conducted exploring the differences between monogenic CSVD-related gene mutation carriers and noncarriers. Results A total of 292 patients were included, 51.03% of whom carried one or more rare variants of monogenic CSVD-related genes. The most common rare low-frequency variants were located in the NOTCH3 gene (70 patients, 23.97%), followed by HTRA1 and COL4A1/COL4A2 (22 patients, 7.53%) respectively. Among the subgroup of patients without a family history of stroke (n=176), the frequency of rare variants was as high as 47.16%. Compared with non-carriers, the carriers were diagnosed at a younger age (58.76±13.71 vs. 63.46±13.21, P=0.003). No difference was found in phenotypes among single-SNP carriers, multiple-SNPs carriers, and noncarriers. Conclusions The frequency of rare mutation of monogenic CSVD-related genes were relatively high in Chinese CSVD cohort. The most common rare variant was within the NOTCH3, followed by HTRA1 and COL4A1/COL4A2 genes. For CSVD patients of unknown causes, genetic screening should not be neglected even if there is not a family history of the disease.
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Objective:To investigate the clinical characteristics and pathogenic gene mutation of lateral meningocele syndrome(LMS).Methods:We retrospectively collected the clinical manifestations, laboratory examination, imaging examinations, and genetic analysis of a neonate with LMS which was diagnosed at the Department of Neonatology of the Second Affiliated Hospital of Wenzhou Medical University in May 2020. Relevant literature up to February 2021, retrieved from PubMed, OMIM, CNKI, Wanfang, and CQVIP database with the terms of "lateral meningocele syndrome", " NOTCH3", were reviewed to summarize the clinical characteristics, pathogenesis, and genetic etiology of this disease. Results:A full-term male newborn was admitted to our hospital due to feeding difficulty 7 d after birth. The clinical characteristics included hypotonia, dysphagia, hypertension, lateral spinal meningocele, craniofacial anomaly, and cryptorchidism. Abnormal spinal MRI and brainstem evoked potential were also observed. Whole exome sequencing revealed a heterozygous frameshift variation c.6667_6686del(p.Ala2223Profs*12) of NOTCH3 gene located in 19p13.12, which was not detected in the parents. Only 12 English literature were retrieved, with 17 patients from 15 pedigrees. Out of the 18 patients including the index case, 10 were genetically diagnosed as LMS. The age at diagnosis ranged from 15 d to 55 years. Regarding the clinical features, multiple lateral thoracolumbar spinal meningoceles (18/18) was the most common one, followed by retrognathia and low-set ears (16/18), eyelid ptosis and down slanting palpebral fissures (15/18), hypotonia (13/18), hypertension (11/18), developmental delay (9/18), mixed or conductive hearing loss (9/18), cardiovascular dysplasia (7/18), and cryptorchidism (7/10). A total of nine NOTCH3 gene variants were detected, all were heterozygous variants, including six frameshift and three nonsense variants. Conclusions:LMS is caused by NOTCH3 gene mutation with the clinical characteristics including multiple lateral thoracolumbar spinal meningoceles, craniofacial dysmorphisms, hypotonia, hypertension, developmental delay, difficulty in feeding, cryptorchidism, etc.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common single gene hereditary cerebral small vessel disease in adults. With the development of gene sequencing technology and imaging, the disease is more and more recognized by people. In this paper, according to the research progress in recent years, the mutation types of NOTCH3 gene in CADASIL patients, the hot spot regions and sites of mutation in different populations, and the relationship between genotype and phenotype were summarized from the perspective of genetics. The future gene therapy of the disease was prospected.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3 gene mutation. The main manifestations of the disease are migraine,cerebral ischemic stroke, progressive cognitive impairment, psychological abnormality which developed at different stage of disease. Multiple cerebral lacunar infarctions, white matter T 2 hyperintensities and cerebral microbleeds can be seen on brain magnetic resonance imaging. The definite diagnosis evidence of CADASIL is the presence of granularosmiophilic material on the surface of arteriolar smooth muscle cells and (or) the identification of pathogenic variants of NOTCH3 gene. With the wide application of second-generation sequencing, more and more patients with CADASIL have been diagnosed. This article will give a summary on the pathogenesis mechanism, clinical manifestations, diagnostic workup, and management of CADASIL.
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Objective To explore the relationship between exon mutations of NOTCH3 gene and clinical phenotype in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods We consecutively included 30 CADASIL patients with clinical symptoms in 15 pedigrees, who visited Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine from May 2015 to Dec. 2017, and collected the clinical data and genetic analysis results. Furthermore, we analyzed the relationship between the exon mutations of NOTCH3 gene and clinical phenotypes, including age at onset, first clinical symptoms and frequency of symptomatic ischemic stroke. Results Twelve mutation sites of NOTCH3 gene were detected in the 15 pedigrees. Seven of them were located in exon 4, 3 in exon 11, 1 in exon 19, and 1 in exon 20. The onset age of the patients carrying exon 11 mutations was the latest ([53.6±13.3] years, n＝7), followed by the patients carrying exon 4 mutations ([42.7±5.7] years, n＝15). The onset age of 8 patients with mutations in other exons (exon 19 and 20) was (33.5±7.5) years, which was significantly earlier compared with the patients with exon 4 and 11 mutation (P0.01 and P0.05). Most of the patients with mutations of exon 4 had motor and speech disorders (11/15, 73.3%), while ones with mutations of exon 19 and 20 had cognitive impairment (7/8, 87.5%). Most of the patients (11/15, 73.3%) carrying mutations in exon 4 had motor and speech disorders at onset, while 7 of 8 patients (87.5%) with mutations in exon 19 and exon 20 had impaired cognition at onset. The times of symptomatic ischemic stroke in patients with mutations in exon 4 was 3 (median) and in patients with mutations in exon 11 was 2 (median), and no symptomatic ischemic stroke occurred in the patients with mutations in exon 19 and 20. Conclusion Exon 4 and exon 11 of NOTCH3 gene are hotspots of mutations in the cohort of CADASIL cases, and the mutations in different exons are associated with onset age, first symptoms and symptomatic ischemic stroke.
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Objective To investigate the expression of Notch3,DLL1 and CD133 in human colorectal adenocarcinoma and its clinical pathology meaning.Methods Immunohistochemical staining was used to detect the expression of Notch3,DLL1 and CD133 in 12 cases of normal colorectal mucosa tissue,30 cases of colorectal adenoma tissue and 50 cases of colorectal adenocarcinoma tissue,and the relationship between them and clinicopathological data wereanalyzed.Results The positive rates of Notch3,DLL1 and CD133 were 64.0 ％ (32/50),68.0 ％ (34/50) and 54.0 ％ (27/50) in colorectal carcinoma tissues,respectively,which were remarkably higher than those in colorectal adenoma tissue(26.7 ％,33.3％％,36.7 ％)and those in normal colorectal mucosa tissue (8.3％,16.7％,8.3％) (P＜0.05).There was no significant difference between the adenoma group and the normal group(P＞0.05).The expression levels of Notch3,DLL1 and CD133 were not correlated to age,gender,tumor location,degree of differentiation and the tumor size,except lymph node metastasis,in addition,the expression of Notch3 and DLL1 were also associated with Dukes staging,and The expression of DLL1 were also associated with tumor infiltration depth (P＜0.05).The expression of Notch3 protein was positively related to that of DLL1 protein(r=0.478,P=0.000).Conclusion The positive expression rates of Notch3,DLL1 and CD133 in colorectal adenocarcinoma tissue are remarkably higher than those in the normal colorectal mucosa and colorectal adenoma tissue,which prompts that the high expression of Notch3,DLL1 and CD133 may all participate in the process and metastasis of colorectal adenocarcinoma.Moreover Notch3 signalling pathway may act through the cancer stem cells and eventually regulate the initiation and development of colorectal adenocarcinoma.
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Background and purpose: Abnormal expression and amplification of transforming growth factor beta 1 (TGF-β1) and Notch3 in ovarian carcinoma tissues are associated with metastasis and low survival rate, respectively. The crosstalk between TGF-β1 and Notch3 signaling pathway promotes invasion and metastasis in various cancers. However, the mechanism is still under debate. Therefore, this study was designed, using in vitro cytological assays, to investigate the effects of TGF-β1 and Notch3 signaling pathway on ovarian cancer cell biological behavior and the potential mechanisms in terms of the crosstalk between TGF-β1 and Notch3 signaling pathway. Methods: Hey A8 and Hey cell lines were used as models in the study. The levels of TGF-β1 in supernatants from culture media were measured by ELISA. Both cell lines were treated with 500 ng/mL TGF-β1 neutralizing antibody (control group), 10 ng/mL TGF-β1, 50 μmol/L DAPT, 10 ng/mL TGF-β1 and 50 μmol/L DAPT, 50 μmol/L tumor necrosis factor receptor-associated factor 6 (TRAF6) peptide inhibitor, 10 ng/mL TGF-β1 and 50 μmol/L TRAF6 peptide inhibitor, respectively. The protein expression levels of TGF-β1 and Notch3 signaling pathway molecules as well as TRAF6 from cell lines with different treatments were detected by Western blot. Cell proliferation, migration and invasion were tested by cell counting kit-8 (CCK-8), scratch and Transwell assays, respectively. Results: The levels of TGF-β1 were timedependently increased in supernatants of culture media from Hey A8 and Hey cell lines. Compared with control group, TGF-β1 treatment increased the expression levels of Notch3-ICD and Hes1, while no obvious change was observed in the group treated with DAPT and TGF-β1. Moreover, TGF-β1 promoted cell proliferation, migration and invasion while DAPT decreased the proliferation, migration and invasion in cell lines treated with TGF-β1. These results indicated that TGF-β1 might promote proliferation, invasion and migration of ovarian epithelial cancer cells through activating the Notch3 signaling pathway. Further study showed that TGF-β1 up-regulated TRAF6 and activated the Notch3 signaling pathway. The activation of the Notch3 signaling pathway by TGF-β1 was inhibited in cells treated with the TRAF6 specific inhibitor. Conclusions: TGF-β1 may promote the proliferation, invasion and migration of ovarian epithelial carcinoma cells through TRAF6-mediated activation of the Notch3 signaling pathway.
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Objective To investigate the correlation between NOTCH3 polymorphic locus rs1043994 and white matter lesions (WML). Methods The enrolled subjects were elderly in the outpatient clinic for health check-up from January 2015 to January 2017. According to the results of cranial MR examination, 337 elderly people were divided into the WML group (n=172) and normal control group (n=165). The inclusion criteria were: (1) age ≥ 50 years old; (2) those who can cooperate with head MRI examination; (3) those who understand the study and agree to retain blood samples for SNP testing. Exclusion criteria were: (1) previous neurological diseases such as cerebrovascular disease, intracranial infection, dementia, and trauma; (2) having a history of mental illness; (3) suffering from serious diseases such as liver and kidney dysfunction, heart disease, tumors. The clinical data of the subjects were collected and the peripheral venous blood was extracted for DNA extraction. The cognitive function was evaluated by the Mini-mental State Examination. The genotyping of the subjects was carried out by restriction endonuclease. The correlation between rs1043994 polymorphism and WML was analyzed by Logistic regression. Results There was no significant difference in gender, education level, diabetes, hyperlipidemia, smoking, uric acid and Hcy between the two groups (P>0.05). Compared with the control group, the WML group had a higher average age and a higher proportion of hypertension (P<0.05), and the Mini-mental State Examination scores between the two groups were statistically significant different (P<0.01). The genotypes (AA, AG, GG) frequency and allele (A, G) frequency distribution of rs1043994 were statistically different between the two groups (P<0.05). Multivariate Logistic regression analysis showed that age (P=0.001), hypertension (P=0.012) and AA genotype (P=0.019) were independent risk factors of WML (P<0.05). The risk of WML in AA genotype is 2.512 times higher than that in AG/GG genotype. Conclusions The rs1043994 polymorphism of NOTCH3 gene is associated with WML in the elderly population, and the A allele is a susceptibility gene for WML. The rs1043994 polymorphism of the NOTCH3 gene may be a genetic risk factor for WML in the Chinese elderly population.
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Objective To explore the function of Notch-3 in epithelial-mesenchymal transition(EMT) and prognosis of pancreatic cancer patients.Methods Patients who received radical resection for pancreatic cancer in our hospital between January 2004 and October 2012 were included in this study.Immunohistochemical staining was performed with Notch-3,E-cadherin and Vimentin antibodies.Imaging pro plus 3.0 was used for analyzing the staining intensity.Survival analysis was performed using Kaplan-Meier method.Results Sixty-seven patients were included.Low expression of E-cadherin was detected in 61.2％ (41/67) of patients,while high expression of Vimentin and Notch-3 was found in 65.6％ (44/67) and 59.7％ (40/67),respectively.Notch-3 expression was proportional to Vimentin expression (R2 =0.872,P ＜ O.05),while inversely proportional to E-cadherin expression (R2 =0.570,P ＜ 0.05).Median overall survival time in high expression group of E-cadherin,Vimentin and Notch-3 was (25.2 ± 2.3) months,(14.8 ±0.9) months and (15.8 ±0.8) months.While in low expression group,the median overall survival time was (14.3 ± 1.0) months,(25.5 ± 2.4) months and (25.1 ± 2.9) months,respectively.There were significant differences between these two groups (all P ＜ 0.05).Conclusions Notch-3 expression was associated with EMT process in pancreatic cancer patients.Low expression of E-cadherin and high expression of Vimentin and Notch-3 predicated poor prognosis of pancreatic cancer.
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Objective To investigate the expression of Notch1,Notch3 and Hes1 in gastrointestinal stromal tumors(GIST) and their clinical significance.Methods Quantitative real-time polymerase chain-reaction(Q-PCR) and Western blot were applied to detect the mRNA and the expression of Notch1,Notch3 and Hes1 in 135 matched GIST specimens and adjacent tissues.Meanwhile,the expression of Notch1,Notch3 and Hes1 was detected by immunohistochemistry,and the relationship between their expression and clinicopathological factors in GIST patients was analyzed.In addition,a total of 40 wild type mice(WT) and Notch1 knockout mice(KO) was divided into WT group,KO group,WT+ GIST group and KO+GIST group,and the expression of Notch1,Notch3 and Hes1 in each group was detected.Results Compared with adjacent tissues,the mRNA andthe expression of Notch1,Notch3 and Hes1 were up-regulated in GIST tissues(P＜0.05).The positive rates of Notch1,Notch3 and Hes1 in the GIST specimens (59.26 ％,65.19 ％ and 62.22 ％) were higher than those in the adjacent tissues(17.780％,22.22 ％ and 17.78 ％),and the difference was statistically significant(P＜0.05).Statistical analysis showed that the expression of Notch1 was significantly correlated with the NIH grade of GIST(x2 =8.532,P=0.002);the expression of Notch3 was significantly related with tumor metastasis of GIST (x2 =7.532,P=0.003);the expression of Hes1 was significantly associated with the tumor size of GIST(x2 =6.781,P=0.012).The expression of Notch1,Notch3 and Hes1 was higher in WT+GIST group compared to the expression found in WT group(all P＜0.05).There were no significant differences in the expression of Notch1,Notch3 and Hes1 between WT+ GIST group and KO+GIST group.The expression of Notch1,Notch3 and Hes1 was lower in KO+ GIST group compared to the expression found in WT+GIST group(all P＜0.05).Conclusion The expression of Notch1,Notch3 and Hes1 related to Notch signaling pathway is elevated in GIST tissues,and the activation of Notch signaling pathway may play an important role in the occurrence and progression of GIST.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cerebral small vessel disease.Migraine,recurrent subcortical ischemia,progressive cognitive impairment,and emotional disorders are the main features.The diagnosis of CADASIL depends on typical clinical symptoms and neuroimaging findings,and it is confirmed by skin biopsyz and gene testing.In recent years,some new insights have been obtained in the clinical and imaging features of CADASIL This article reviews the research progress in this field.
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Objective To study the expression of Notch3 in pancreatic ductal adenocarcinoma (PDAC) and to find out its relationship with clinical features and overall survival in patients with pancreatic ductal adenocarcinoma.Methods PDAC and adjacent non-cancerous tissues from 80 patients who under went surgery for primary PDAC in the Affiliated Tumor Hospital of Zhengzhou University were collected between 2008 and 2015.The specimens were divided into two subgroups by immunohistochemical staining of Notch3:the low expression group (0-4 points) and the high expression group (5-12 points).Correlations between expression of Notch3 with clinical features and prognosis of patients with PDAC were analyzed.Results A high expression of Notch3 gene was significantly associated with tumor grade,metastasis,venous invasion and TNM staging.Univariate Cox regression analysis showed that metastasis,venous invasion,TNM stage and protein expression of Notch3 were strongly correlated with overall survival of patients.Multivariate analysis showed that metastasis,TNM stage and Notch3 were independent risk factors of overall survival in patients with PDAC.Kaplan-Meier survival curves indicated that a high expression of Notch3 was an important risk factor of poor survival.Conclusions A high expression of Notch3 was significantly associated with progression and poor prognosis of PDCA.Notch3 may serve as a new indicator of PDAC progression and patient survival outcomes.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy(CADASIL)is a common hereditary disease caused by NOTCH3 gene. The major clinical manifestations includerecurrent small-vessel ischaemic events, migraine, dementia and mood disturbance. Herein, wereport a 32-years-old male presented with right leg weakness and persistent migraine. We carried outneurological exams, genetic testing, blood and cerebrospinal fluid analysis (CSF) as well as magneticresonance imaging (MRI) for the brain and spinal cord. There were no anti-aquaporin-4 antibodiesand oligoclonal bands in the CSF and blood investigations were within the normal range. MRI scansrevealed multiple hyperintense regions in the brain and longitudinally hyperintense signal in spinal cord.Further, we identified a c.383G>A(p.Cys128Tyr) mutation in NOTCH3 gene. Therefore, the patientwas diagnosed with CADASIL concurrent with spinal cord lesion. The patient’s condition slightlyimproved after two weeks treatment with daily dosage of 0.5 g citicoline and 75 mg clopidogrel.
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AIM: To investigate the effect of suberoylanilide hydroxamic acid (SAHA) on the apoptosis of hu-man small-cell lung cancer H446 cells and its possible mechanism.METHODS: H446 cells were incubated in the medi-um containing SAHA.CCK-8 assay was used to detect the anti-tumor effect of SAHA on the H446 cells, and IC50 values of SAHA were calculated.Flow cytometry was used to analyze the apoptosis.After Notch3 gene was silenced, the pro-apopto-tic effect of SAHA on the H446 cells was inhibited ( P <0.05).Eukaryotic expression plasmid containing N3ICD was transfected into the H446 cells, so that N3ICD was expressed in the H446 cells.The mRNA expression of Notch3 was measured by RT-PCR.The protein levels of Notch3, N3ICD, Puma and cleaved caspase-3 were determined by Western blot.RESULTS: SAHA remarkably reduced the cell viability in a dose-dependent manner (P <0.05), and the IC50 value of SAHA was 1.91 μmol/L.SAHA induced apoptosis in a dose-dependent manner (P <0.05).The expression of Notch3 gene was negative in the H446 cells, SAHA reactivated Notch3 gene and Notch3 pathway in a dose-dependent manner (P <0.05).Notch3 knockdown inhibited apoptosis induced by SAHA (P <0.05).Over-expression of N3ICD up-regula-ted the protein levels of Puma and cleaved caspase-3.CONCLUSION: SAHA induces apoptosis in human small-cell lung cancer H446 cells by activating Notch3 pathway and up-regulating the protein level of Puma.
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BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most-common single gene disorder of cerebral small vessel disease. There is no definite evidence of genotype-phenotype correlation in CADASIL. However, recent studies have shown the unique phenotypic feature of NOTCH3 R544C mutation. METHODS: We investigated the phenotypic spectrum of NOTCH3 R544C mutation in 73 CADASIL patients in Jeju between April 2012 and January 2014. RESULTS: Of the 73 subjects from 60 unrelated families included in this study, 40 (55%) were men. The mean age of the subjects was 62.2±12.2 (range 34-86 years). Cerebral infarction was the most frequent manifestation (37%), followed by cognitive impairment (32%), headache (17%), psychiatric symptom (16%), intracerebral hemorrhage (12%), transient ischemic attack (7%), and seizure (1%). The mean age of the subjects with ischemic or hemorrhagic episodes was 64.9±10.9 (range 41-86 years). A diagnosis of dementia was made in 12 subjects (16%). The mean age of the subjects with dementia was 75.6±6.5 (range 62-86 years). About 3% of subjects were unable to walk without assistance at assessment. Only one subject had developed chronic headache before the 40s. CONCLUSIONS: Our data support the hypothesis that CADASIL patients with R544C mutation in Jeju have relatively late onset disease.