Alagille syndrome: an uncommon cause of intrahepatic cholestasis in adults

Alagille syndrome (ALGS) is an autosomal-dominant multisystem disorder caused by mutations in Jagged 1 (JAG1) or NOTCH2. The penetrance is low but highly variable. It is almost exclusively diagnosed in children with cholestasis and, more rarely, in their adult relatives. Here, we report the case of a patient diagnosed with ALGS in adulthood. The patient was a 28-year-old male who presented with characteristic facial features, an eye abnormality, chronic cholestasis with bile duct paucity on liver biopsy, atrial defects and stenosis of the left internal carotid artery. A novel frameshift mutation, c.2087_2088insAAAAATGG (p. W697Kfs*49), in JAG1 was identified. To our knowledge, this is the first case of ALGS diagnosed in adulthood in China. ALGS should be considered as a differential diagnosis for intrahepatic cholestasis in adult patients with a wide variety of clinical manifestations, including cardiac disease, skeletal abnormalities, ocular abnormalities and characteristic facial features

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Jagged1 is Clinically Prognostic and Promotes Invasion of Glioma-Initiating Cells by Activating NF-κB(p65) Signaling.

BACKGROUND/AIMS: Jagged1 is the ligands of the Notch signaling and has been shown to promote glioma-initiating cells (GICs) in glioblastoma. The role of Jagged1 in GICs invasion and underlying molecular mechanisms remain unclear. METHODS: Survival data from R2 genomics analysis, the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA) and visualization platform database were used to evaluate the effects of Jagged1 on overall patient survival. we investigated Jagged1 induced the GICs cells' invasion by matrix degradation assays and Transwell cell invasion assays in vitro, then we further explored the underlying molecular mechanisms using Co-immunoprecipitation (co-IP) analysis. RESULTS: High expression of Jagged1 in human glioma was associated with poor survival. Clinical data analysis showed that the Jagged1 was positively correlated with NF-κB(p65). Jagged1-induced invasion of GICs cells through activation of NF-κB(p65) pathway. In vivo, knockdown of Jagged1 could suppress the tumorigenicity of GICs cells through NF-κB(p65) signaling. CONCLUSION: Insights gained from these findings suggest that Jagged1 plays an important oncogenic role in GICs malignancy by activation of NF-κB(p65) signaling, and Jagged1 could be employed as an effective therapeutic target for GICs.

Progressive and Prognosis Value of Notch Receptors and Ligands in Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Hepatocellular carcinoma (HCC) is not sensitive to radiotherapy and chemotherapy and experiences postoperative relapse extremely easy, which is the major cause of the high mortality rate. The Notch signaling pathway is expected to become a new target for the biological treatment of HCC. We searched databases for studies that evaluated the expression of Notch receptors and/or ligands in human HCC tissue. The search yielded 15 studies that enrolled 1643 patients. Compared with non-HCC tissues, Notch 1 was associated with a higher expression level (odds risk 1.59, 95% confidence interval 0.34 to 7.45), as well as Notch 3 (2.63, 0.69 to 10.02), Notch 4 (1.33, 0.74 to 2.38) and Jagged 1 (1.47, 0.23 to 9.53); however, Notch 2 showed the opposite result (0.60, 0.30 to 1.20). Larger tumor size (>5 cm), metastasis positive, and micro vascular invasion positive were features that were associated with over-expression in Notch 1 according to the clinicopathological features. The expression levels of Notch 1, 3, 4 and Jagged 1 were associated with higher expression in HCC tissues, while Notch 2 had the opposite result. This study is registered with PROSPERO (CRD42017055782).

[Xinfeng Capsule improves lung function by regulating Notch/Jagged-HES axis of type II alveolar epithelial cells in adjuvant arthritis rats].

Objective To observe the effect of Xinfeng Capsule (XFC) on Notch/Jagged-HES of type II alveolar epithelial cells (AECII). Methods Rats were divided for four groups: normal control (NC) group, model control (MC) group, leflunomide (LEF) group, XFC group, with 10 rats in each group. Complete Freund's adjuvant (CFA) was injected in the right foot plantar skin of each rat except for the NC group. After adjuvant arthritis was successfully induced, LEF group was given LEF (0.5 mg/100 g), and XFC group was treated with XFC (0.034 g/100 g), once a day from the 13th day to the 42th day. The NC and MC groups were given normal saline instead. Swelling degree (SD), arthritis index (AI) and pulmonary function were observed. AECII was observed by transmission electron microscopy (TEM). The expressions of transforming growth factor ß1 (TGF-ß1), Notch1, Notch3, Jagged1 and HES1 proteins in AECII were detected by Western blotting. Results The pulmonary function parameters such as forced expiratory volume in 1 second (FEV1), maximum expiratory flow rate at 50% FVC (FEF50), instantaneous flow at 75% of expired volume (FEF75), peak expiratory flow (PEF) in the MC group were significantly lower than those in the NC group, and the expressions of TGF-ß1, Notch1, Notch3, Jagged1 and HES1 in AECII increased. The ultrastructure of AECII was damaged. Compared with the MC group, FEV1, FEF50, FEF75 and PEF increased, and TGF-ß1, Notch1, Notch3, Jagged1 and HES1 decreased in the XFC group. Compared with LEF group, the lung function was better in XFC group. Conclusion XFC can inhibit pulmonary fibrosis and improve pulmonary function by down-regulating TGF-ß1, Notch1, Notch3, Jagged1 and HES1 in rats with adjuvant arthritis.

The clinicopathological significance of Jagged1 and DLL4 in gallbladder cancer.

PURPOSE: Gallbladder cancers (GBCs) are highly aggressive gastrointestinal cancers with high mortality. Biological markers for the diagnosis, prognosis, and targeted therapy of GBCs have not been established. METHODS: The protein expression of Jagged1 and DLL4 in 80 adenocarcinomas (AC) and 46 squamous cell/adenosquamous carcinomas (SC/ASCs) was measured using immunohistochemistry. RESULTS: Positive Jagged1 and DLL4 expression in both SC/ASC and AC was significantly associated with poor differentiation, large tumor size, invasion, metastasis, and low surgical curability. Univariate Kaplan-Meier analysis showed that positive Jagged1 and DLL4 expression was significantly associated with mean survival of SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive Jagged1 and DLL4 expression, as well as poor differentiation, large tumor size, high TNM stage, invasion, lymph node metastasis, and low surgical curability are independent poor prognostic factors in both SC/ASC and AC patients. CONCLUSIONS: Positive Jagged1 and DLL4 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in patients with SC/ASC and patients with AC.

Jagged1 and DLL4 expressions in benign and malignant pancreatic lesions and their clinicopathological significance.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis. Despite intensive research, markers for the early diagnosis, prognosis, and targeting therapy of PDAC are not available. This study aimed to investigate the protein expressions of Jagged1 and DLL4 in PDAC tumor, benign pancreatic and normal pancreatic tissues, and analyze the associations of the two proteins with the clinical and pathological characteristics of PDAC. METHODS: A total of 106 PDAC tumor tissues and 35 peritumoral tissues were collected from January 2000 to December 2011 at our hospitals. Thirteen normal pancreatic tissues and 55 benign pancreatic specimens were collected at the same period. Immunohistochemical staining was used to measure Jagged1 and DLL4 protein expressions in these tissues. RESULTS: The percentage of positive Jagged1 and DLL4 was significantly higher in PDAC than in normal pancreatic tissues, benign pancreatic tissues, and peritumoral tissues (P<0.01). The higher Jagged1 and DLL4 expressions in PDAC were significantly associated with poor differentiation, maximum tumor size >5 cm, invasion, regional lymph node metastasis, and TNM III/IV disease (P<0.05). In PDAC, Jagged1 expression positively correlated with DLL4 expression. Univariate Kaplan-Meier analysis showed that positive Jagged1 and DLL4 expressions were significantly associated with shorter survival in patients with PDAC. Multivariate Cox regression analysis showed that positive Jagged1 and DLL4 expressions were independent prognostic factors for poor prognosis of patients with PDAC. CONCLUSION: Positive Jagged1 and DLL4 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in patients with PDAC.