OBJECTIVETo analyze the clinical features and genetic cause for a family affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

METHODSClinical manifestations, neuroimaging, and genetic analysis were performed.

RESULTSThe main clinical features have included stroke, emotional disturbance and history of migraine without progressive memory impairment. A positive family history was confirmed. Cranial MRI has revealed multi-infarct lesions and white matter hyperintensity involving bilateral basal ganglia, subcortex and brain stem. All such features were in keeping with the diagnosis of CADASIL. A rare 2182C>T mutation in exon 14 of the NOTCH3 gene was identified in all available cases.

CONCLUSIONBoth clinical and molecular features suggested that the family has been affected with CADASIL.

Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Migraine Disorders ; genetics ; Receptor, Notch3 ; Receptors, Notch ; genetics

Animals ; Cells, Cultured ; Collagen Type I ; Gene Expression ; Mice ; Pancreatic Stellate Cells ; RNA, Small Interfering/genetics* ; Receptor, Notch3 ; Signal Transduction

OBJECTIVETo investigate the expressions and the role of Notch signaling-associated proteins in esophageal squamous cell carcinoma (ESCC).

METHODSFifty patients with ESCC were included in this study. The expressions of Notch signaling-associated protein (4 receptors: Notch1, Notch2, Notch3, Notch4; 5 ligands: Dll1, Dll3, Dll4, Jagged1, Jagged2) in cancer foci and adjacent normal tissues (5 cm distance to cancer) were examined by immunohistochemitry. Correlations of these proteins with cancer cell proliferation(Ki-67 index) and clinicopathologic features were investigated.

RESULTSHigher levels of Notch1 and Notch2 were measured in cancer foci compared with adjacent tissues (all P<0.05). There were no differences in the expressions of Notch3, Dll1 and Dll3 (all P>0.05). Notch4, Dll4 and Jagged2 were not detected in both cancer foci and adjacent tissues. Notch1 expression was negatively correlated with lymph node metastasis and TNM staging (all P<0.01). Jagged 1 expression was positively correlated with TNM staging (P<0.01). Ki-67 index was obviously higher in cancer foci, while it was negatively correlated with Notch1 and Notch3 (all P<0.01) and positively correlated with Dll1 and Jagged 1 (all P<0.01).

CONCLUSIONNotch signaling path may act as tumor suppressive gene in the pathogenesis of esophageal squamous cell cancer, in which Notch1 protein plays an important role.

Carcinoma, Squamous Cell ; metabolism ; Esophageal Neoplasms ; metabolism ; Genes, Tumor Suppressor ; Humans ; Lymphatic Metastasis ; Neoplasm Staging ; Receptor, Notch1 ; metabolism ; Receptor, Notch2 ; metabolism ; Receptor, Notch3 ; Receptors, Notch ; metabolism ; Signal Transduction

OBJECTIVETo investigate a cerebral autosomal dominant arteriopathy with the subcortical infarcts and leukoencephalopathy (CADASIL) case with clinical manifestations of baldness, lumbago and Parkinson's symptoms.

METHODSClinical and imaging data of the patient were analyzed. The patient and his family members were also subjected to genetic testing.

RESULTSThe symptoms of the patient included recurrent stroke, dementia, and mood disturbance, in addition with lumbago, baldness and Parkinson's symptoms but no migraine. Cranial MRI of the patient showed bilateral symmetric leukoencephalopathy and multiple small subcortical lacunar infarcts. A point mutation in exon 11 of the NOTCH3 gene (R558C) was discovered in the proband and four asymptomatic relatives.

CONCLUSIONCADASIL is characterized by recurrent subcortical ischemic stroke, dementia, pseudobulbar palsy, and mood disturbance. Baldness, lumbago and Parkinson's symptoms may also be seen in such patients.

Alopecia ; etiology ; CADASIL ; complications ; diagnostic imaging ; genetics ; Humans ; Low Back Pain ; etiology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Mutation ; Parkinsonian Disorders ; etiology ; Receptor, Notch3 ; genetics

OBJECTIVETo analyze potential mutations of the NOTCH3 gene in two Chinese families featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy (CADASIL).

METHODSThe two probands and related family members and 100 healthy controls were recruited. Potential mutations of the NOTCH3 gene were screened by PCR and direct sequencing. PolyPhen-2 and SIFT software were used to predict the protein function.

RESULTSThe conditions of both probands were adult-onset, with main clinical features including recurrent transient ischemic attacks and/or strokes, cognitive impairment. MRI findings suggested multiple cerebral infarcts and severe leukoencephalopathy. A heterozygous mutation c.328C>T (p.Arg110Cys), which was located in exon 3 of the NOTCH3 gene and known as a causative mutation, was identified in proband 1. A novel heterozygous mutation c.1013 G>C (p.Cys338Ser) located in exon 6 of the NOTCH3 gene was identified in the proband 2, which was not reported previously. The same mutations were not detected among the 100 unrelated healthy controls. Function analysis suggested that heterozygous mutation c.1013G>C can severely affect the functions of NOTCH3 protein.

CONCLUSIONTwo heterozygous missense mutations in the NOTCH3 gene have been identified in two families affected with CADASIL. The novel heterozygous Cys338Ser mutation in exon 6 of the NOTCH3 gene probably underlies the CADASIL.

Adult ; Brain ; diagnostic imaging ; CADASIL ; diagnostic imaging ; genetics ; Female ; Heterozygote ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Mutation ; Receptor, Notch3 ; genetics

OBJECTIVE: To report a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifesting as lumbago, hunchback and Parkinson's syndrome. METHODS: A 49-years-old male CADASIL patient was reported. Results of clinical examination, neuroimaging and genetic testing were analyzed. His family members were also subjected to genetic testing. Related literature was reviewed. RESULTS: The patient had no typical symptoms of CADASIL such as headache, repeated stroke, dementia and emotional disorders, but progressive Parkinson's syndrome, late onset lumbago, hunchback, dysphagia, and diplopia. Brain MRI showed left basal ganglia and external capsule lacunar infarction. Genetic testing revealed a point mutation c.1630C>T (p.R544C) in exon 11 of the NOTCH3 gene. A heterozygous mutation was detected in the same gene in his mother, elder sister and younger brother, all of whom showed different clinical phenotypes. CONCLUSION The clinical features of CADASIL are heterogeneous. Lumbago, humpback, and Parkinson's syndrome may be a rare clinical phenotype of CADASIL.
CADASIL ; complications ; genetics ; Humans ; Low Back Pain ; etiology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Mutation ; Parkinson Disease ; etiology ; Receptor, Notch3 ; genetics

OBJECTIVE: To examine the expression of notch3 in the kidneys of patients with primary hypertension and rats with spontaneous hypertension, and to explore the relationship of notch3 and hypertension renal fibrosis. METHODS: Thirteen patients with primary hypertension served as a primary hypertension group (HP group), and 15 patients with kidney tumor served as a control group (CP group). The spontaneous hypertensive rats served as a primary hypertension group (SHR group, n=6), and WKY rats served as a control group (WKY group, n=6). Masson stainning was used to examine the collagen in the kidneys in the SHR group and the WKY group. Immunohistochemical staining was used to detect the levels of Notch3 in kidneys of the patients and the rats. The expression of snail mRNA in the kidneys in the SHR group and the WKY group was examined by real-time PCR. RESULTS: Masson staining showed much more collagen in the SHR group than that in the WKY group (P<0.05); the expression of Notch3 in the HP group was much higher than that in the CP group ( 6.741±0.231 vs 0.763±0.358, P<0.01). The expression of Notch3 in the SHR group was much higher than that in the WKY group (5.487±0.774 vs 0.421±0.163, P<0.01), and The expression of snail mRNA was much higher in the SHR group than that in the WKY group (0.996±0.120 vs 0.208±0.090, P<0.01 ). CONCLUSION Notch3 may be related to the occurrence of hypertension renal fibrosis.
Animals ; Arteriosclerosis ; Essential Hypertension ; Fibrosis ; Humans ; Hypertension ; metabolism ; pathology ; Kidney ; pathology ; Kidney Diseases ; metabolism ; pathology ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Receptor, Notch3 ; Receptors, Notch ; metabolism

Cadherins ; metabolism ; Female ; Gene Expression Profiling ; Humans ; Inflammatory Breast Neoplasms ; genetics ; metabolism ; pathology ; NF-kappa B ; metabolism ; Receptor, ErbB-2 ; metabolism ; Receptor, Notch3 ; Receptors, CCR7 ; metabolism ; Receptors, CXCR4 ; metabolism ; Receptors, Notch ; metabolism

The aim of this study is to investigate the effects of hypoxia inducible factor-2α (HIF-2α) and Notch3 on CoCl-induced migration and invasion of human breast cancer cell line MCF-7. MCF-7 cells were exposed to normoxia (21% O) or chemical hypoxia (21% Oplus CoCl). Short hairpin RNA (shRNA) was used to knock down HIF-2α and Notch3 in MCF-7 cells. The mRNA expression levels of HIF-2α, Notch3 and Hey1 were measured by RT-PCR. Western blot was performed to determine the protein expression levels of HIF-2α, Notch3, Hey1, Snail and E-cadherin. CoCltreatment resulted in higher protein expression levels of HIF-2α, Notch3, Hey1, Snail (P < 0.05) and lower levels of E-cadherin (P < 0.05), and promoted migration and invasion of MCF-7 cells (P < 0.05). shRNA-HIF-2α suppressed CoCl-induced mRNA expression of Notch3 and Hey1. Notch3 knockdown down-regulated Snail and up-regulated E-cadherin at protein level under simulated hypoxia (P < 0.05), and inhibited CoCl-induced migration and invasion of MCF-7 cells (P < 0.05). In conclusion, our data provide evidence that HIF-2α may promote the migration and invasion of MCF-7 cells under chemical hypoxic conditions by potentiating Notch3 pathway.
Basic Helix-Loop-Helix Transcription Factors ; Breast Neoplasms ; Cadherins ; Cell Hypoxia ; Cell Line, Tumor ; Cell Movement ; Down-Regulation ; Humans ; MCF-7 Cells ; Neoplasm Invasiveness ; RNA, Small Interfering ; Receptor, Notch3 ; Signal Transduction ; Up-Regulation

BACKGROUNDCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small artery disease caused by NOTCH3 gene mutation. We performed enhanced depth imaging optical coherence tomography (EDI-OCT) to evaluate the retinal vessel changes in CADASIL patients and assessed their consonance with brain magnetic resonance imaging (MRI) findings.

METHODSOf 27 genetically confirmed patients and an equal number of controls were recruited at the Peking University First Hospital from January 2015 to August 2016. All patients underwent 7T-MRI of the brain. Fazekas score, number of small infarcts and microbleeds were evaluated. All patients and controls underwent EDI-OCT to measure subfoveal choroidal thickness (SFCT), inner and outer diameters as well as arterial and venous wall thickness, and arterial venous ratio of the inner (AVRin) and outer diameters (AVRout). The relation between retinal vessel changes and Fazekas scores, numbers of small infarcts, or microbleeds was analyzed. Paired t-test was used to compare the SFCT and retinal vessel measurement data between patients and controls. Spearman's correlation was used to investigate the correlation between retinal vessel changes and MRI lesions.

RESULTSIn CADASIL patients, mean SFCT (268.37 ± 46.50 μm) and mean arterial inner diameter (93.46 ± 9.70 μm) were significantly lower than that in controls (P < 0.001,P = 0.048, respectively). Mean arterial outer diameter (131.74 ± 10.87 μm), venous inner (128.99 ± 13.62 μm) and outer diameter (164.82 ± 14.77 μm), and mean arterial (19.13 ± 1.85 μm) and venous (17.91 ± 2.76 μm) wall thickness were significantly higher than that in controls (P = 0.023,P = 0.004,P < 0.001,P < 0.001, respectively). Arterial inner diameter (rs= -0.39, P= 0.044), AVRin (rs= -0.65,P < 0.001), and AVRout (rs= -0.56, P= 0.002) showed a negative correlation with the number of small infarcts. Venous inner diameter (rs = 0.46, P= 0.016) showed a positive correlation with the number of small infarcts. Venous inner diameter (rs = 0.59, P= 0.002), outer diameter (rs = 0.47, P= 0.017), showed a positive correlation with the number of cerebral microbleeds (CMBs). AVRin (rs= -0.52, P= 0.007) and AVRout (rs= -0.40, P= 0.048) showed a negative correlation with the number of CMBs.

CONCLUSIONSMeasurement of retinal vessels using EDI-OCT correlates moderately well with MRI parameters. EDI-OCT might be a useful evaluation tool for CADASIL patients.

Adult ; Brain ; metabolism ; CADASIL ; Cerebral Infarction ; pathology ; Female ; Humans ; Leukoencephalopathies ; pathology ; Magnetic Resonance Imaging ; methods ; Male ; Middle Aged ; Mutation ; Receptor, Notch3 ; genetics ; Retinal Vessels ; metabolism ; Tomography, Optical Coherence ; methods