In mice, expression of a missense mutant of Jag1 (Jag1) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology. JAG1 does not bind NOTCH1, but binds NOTCH2, and elicits hypomorphic signaling. This mouse model can be used to study other features of Alagille syndrome and organ development.
Glioblastoma multiforme (GBM) is the most frequently occurring primary malignant brain tumor; patients with GBM often have a very poor prognosis and differing responses to treatment. Therefore, it is very important to find new biomarkers that can predict clinical outcomes and help in treatment decisions. MicroRNAs are small, non-coding RNAs that function as post-transcriptional regulators of gene expression and play a key role in the pathogenesis of GBM. In a group of 38 patients with primary GBM, we analyzed the expression of eight microRNAs (miR-21, miR-128a, miR-181c, miR-195, miR-196a, miR-196b, miR-221, and miR-222). In addition, we examined the methylation status of O-6-methylguanine-DNA methyltransferase (MGMT) promoter by high-resolution melting analysis, as this has been shown to be a predictive marker in GBM. MGMT methylation status correlated with progression-free survival (P = 0.0201; log-rank test) as well as with overall survival (P = 0.0054; log-rank test). MiR-195 (P = 0.0124; log-rank test) and miR-196b (P = 0.0492; log-rank test) positively correlated with overall survival. Evaluation of miR-181c in combination with miR-21 predicted time to progression within 6 months of diagnosis with 92% sensitivity and 81% specificity (P < 0.0001). Our data confirmed that the methylation status of MGMT but also miR-21, miR-181c, miR-195, and miR-196b to be associated with survival of GBM patients. Above all, we suggest that the combination of miR181c and miR-21 could be a very sensitive and specific test to identify patients at high risk of early progression after surgery. (Cancer Sci 2011; 102: 2186-2190 G lioblastoma multiforme (GBM) is the most frequently occurring primary malignant brain tumor of astrocytic origin.(1)Despite the introduction of modern therapeutic approaches, this cancer remains generally associated with very poor prognosis.(2) A significant benefit of overall survival (OS) has been achieved in patients treated with concomitant chemoradiotherapy with temozolomide (RT ⁄ TMZ), an alkylating agent. However, not all patients are sensitive to this therapy. (3,4) Because of an extremely short median survival time of glioblastoma patients and diversity in therapy response, it is very important to identify new biomarkers that can be used in prognosis and prediction of therapeutic response and ⁄ or clinical outcome in GBM patients in order to rationalize treatment decisions.MicroRNAs (miRNAs) are highly conserved, small, non-coding RNAs, 18-25 nucleotides in length, that function as posttranscriptional regulators of gene expression by silencing their mRNA targets. Bioinformatics tools estimate that miRNAs regulate up to one-third of human genes including a significant number of oncogenes, tumor suppressor genes, and genes associated with the invasion, dissemination, and chemoresistance of tumors.(5) Therefore, these molecules play significant roles in the pathogenesis of many cancers, including GBM. (6,7) In the context of this tumor, recent published reports have proposed that some miRNAs tha...
Objectives: The development of colorectal cancer (CRC) is characterized by multiple genetic alterations. Transcribed ultraconserved regions (T-UCRs) are a subset of 481 sequenc es longer than 200 bp, which are absolutely conserved between orthologous regions of human, rat and mouse genomes, and are actively transcribed. It has recently been proven in cancer systems that differentially expressed T-UCRs could alter the functional characteristics of malignant cells. Genome-wide profiling revealed that T-UCRs have distinct signatures in human leukemia and carcinoma. Methods: In our study, we examined the expression levels of uc.43, uc.73, uc.134, uc.230, uc.339, uc.388 and uc.399 in 54 samples of primary colorectal carcinomas and 15 samples of non-tumoral adjacent tissues by real-time PCR. T-UCR expression levels were also correlated with commonly used clinicopathological features of CRC. Results: Expression levels of uc.73 (p = 0.0139) and uc.388 (p = 0.0325) were significantly decreased in CRC tissue, and uc.73 indicated a positive correlation with overall survival (p = 0.0315). The lower expression of uc.388 was associated with the distal location of CRC (p = 0.0183), but no correlation of any evaluated T-UCR with clinical stage, grade and tumor diameter was observed. Conclusion: Our preliminary results suggest that uc.73 and uc.388 could be potential diagnostic and prognostic biomarkers in CRC patients.
The liver fulfills central roles in metabolic control and detoxification and, as such, is continuously exposed to a plethora of insults. Importantly, the liver has a unique ability to regenerate and can completely recoup from most acute, non-iterative insults. However, multiple conditions, including viral hepatitis, non-alcoholic fatty liver disease (NAFLD), long-term alcohol abuse and chronic use of certain medications, can cause persistent injury in which the regenerative capacity eventually becomes dysfunctional, resulting in hepatic scaring and cirrhosis. Calcium is a versatile secondary messenger that regulates multiple hepatic functions, including lipid and carbohydrate metabolism, as well as bile secretion and choleresis. Accordingly, dysregulation of calcium signaling is a hallmark of both acute and chronic liver diseases. In addition, recent research implicates calcium transients as essential components of liver regeneration. In this review, we provide a comprehensive overview of the role of calcium signaling in liver health and disease and discuss the importance of calcium in the orchestration of the ensuing regenerative response. Furthermore, we highlight similarities and differences in spatiotemporal calcium regulation between liver insults of different etiologies. Finally, we discuss intracellular calcium control as an emerging therapeutic target for liver injury and summarize recent clinical findings of calcium modulation for the treatment of ischemic-reperfusion injury, cholestasis and NAFLD.
Organ function depends on tissues adopting the correct architecture. However, insights into organ architecture are currently hampered by an absence of standardized quantitative 3D analysis. We aimed to develop a robust technology to visualize, digitalize, and segment the architecture of two tubular systems in 3D: double resin casting micro computed tomography (DUCT). As proof of principle, we applied DUCT to a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice), characterized by intrahepatic bile duct paucity, that can spontaneously generate a biliary system in adulthood. DUCT identified increased central biliary branching and peripheral bile duct tortuosity as two compensatory processes occurring in distinct regions of Jag1Ndr/Ndr liver, leading to full reconstitution of wild-type biliary volume and phenotypic recovery. DUCT is thus a powerful new technology for 3D analysis, which can reveal novel phenotypes and provide a standardized method of defining liver architecture in mouse models.
Spontaneous bleeds are a leading cause of death in the pediatric JAG1‐related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non‐invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1Ndr/Ndr mice, using retina as a model. Jag1Ndr/Ndr mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex‐specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non‐invasive vascular analysis in patients. Finally, Jag1Ndr/Ndr mice represent a new model for vascular compromise in ALGS.
The liver is the biggest internal organ in humans and mice, and high auto-fluorescence presents a significant challenge for assessing the three-dimensional (3D) architecture of the organ at the whole-organ level. Liver architecture is characterized by multiple branching lumenized structures, which can be filled with resin, including vascular and biliary trees, establishing a highly stereotyped pattern in the otherwise hepatocyte-rich parenchyma. This protocol describes the pipeline for performing double resin casting micro-computed tomography, or "DUCT". DUCT entails injecting the portal vein and common bile duct with two different radiopaque synthetic resins, followed by tissue fixation. Quality control by clearing one lobe, or the entire liver, with an optical clearing agent, allows for pre-screening of suitably injected samples. In the second part of the DUCT pipeline, a lobe or the whole liver can be used for micro-computed tomography (microCT) scanning, (semi-)automated segmentation, and 3D rendering of the portal venous and biliary networks. MicroCT results in 3D coordinate data for the two resins allowing for qualitative as well as quantitative analysis of the two systems and their spatial relationship. DUCT can be applied to postnatal and adult mouse liver and can be further extended to other tubular networks, for example, vascular networks and airways in the lungs.
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