12 research outputs found
Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4-/- mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients
Proteomic analysis of liver diseases: molecular mechanisms and biomarker discovery
Liver diseases afflict more than 10% of the world population. Although the main risk factors are known and the population at risk is monitored, new biomarkers are urgently needed to allow early diagnosis and hence more effective therapeutic interventions. Here, we revise the contribution of proteomics to the study of liver diseases and its potential impact in the clinical practice is evaluated
Methodology and key performance indicators (KPIs) for railway on-board positioning systems
The European Union (EU) is bolstering the railway sector with the aim of making it a direct competitor of the aviation sector. For that to occur, railway efficiency has to be improved by means of increasing capacity and reducing operational expenditure. Tracks are currently used below their maximum capacity. Given this fact and the EU's goals for the railway sector, research on solutions for on-board positioning system based on global navigation satellite systems (GNSS) have arisen in recent years. By taking advantage of GNSS, safety critical positioning systems will be able to use the infrastructure more efficiently. However, GNSS based positioning systems still cannot fulfill current normative validation processes, mainly, due to the fact that GNSS based positioning performance evaluation is not compatible with the key performance indicators (KPIs) used to assess railway systems performance: reliability, availability, maintainability, and safety. This paper proposes a methodology and unified key performance indicators (KPIs). Additionally, it shows real examples to address this issue. It aims to fill the gap between the current railway standardization process and any on-board positioning system
Prioritizing Popular Proteins in Liver Cancer: Remodelling One-Carbon Metabolism
Primary liver cancer
(HCC) is recognized as the fifth most common
neoplasm and the second leading cause of cancer death worldwide. Most
risk factors are known, and the molecular pathogenesis has been widely
studied in the past decade; however, the underlying molecular mechanisms
remain to be unveiled, as they will facilitate the definition of novel
biomarkers and clinical targets for more effective patient management.
We utilize the B/D-HPP popular protein strategy. We report a list
of popular proteins that have been highly cocited with the expression “liver
cancer”. Several enzymes highlight the known metabolic remodeling
of liver cancer cells, four of which participate in one-carbon metabolism.
This pathway is central to the maintenance of differentiated hepatocytes,
as it is considered the connection between intermediate metabolism
and epigenetic regulation. We designed a targeted selective reaction
monitoring (SRM) method to follow up one-carbon metabolism adaptation
in mouse HCC and in regenerating liver following exposure to CCl<sub>4</sub>. This method allows systematic monitoring of one-carbon metabolism
and could prove useful in the follow-up of HCC and of chronically
liver-diseased patients (cirrhosis) at risk of HCC. The SRM data are
available via ProteomeXchange in PASSEL (PASS01060
Prioritizing Popular Proteins in Liver Cancer: Remodelling One-Carbon Metabolism
Primary liver cancer
(HCC) is recognized as the fifth most common
neoplasm and the second leading cause of cancer death worldwide. Most
risk factors are known, and the molecular pathogenesis has been widely
studied in the past decade; however, the underlying molecular mechanisms
remain to be unveiled, as they will facilitate the definition of novel
biomarkers and clinical targets for more effective patient management.
We utilize the B/D-HPP popular protein strategy. We report a list
of popular proteins that have been highly cocited with the expression “liver
cancer”. Several enzymes highlight the known metabolic remodeling
of liver cancer cells, four of which participate in one-carbon metabolism.
This pathway is central to the maintenance of differentiated hepatocytes,
as it is considered the connection between intermediate metabolism
and epigenetic regulation. We designed a targeted selective reaction
monitoring (SRM) method to follow up one-carbon metabolism adaptation
in mouse HCC and in regenerating liver following exposure to CCl<sub>4</sub>. This method allows systematic monitoring of one-carbon metabolism
and could prove useful in the follow-up of HCC and of chronically
liver-diseased patients (cirrhosis) at risk of HCC. The SRM data are
available via ProteomeXchange in PASSEL (PASS01060