PneuAct-II: Hybrid manufactured electromagnetically stealth pneumatic stepper actuator

Additive manufacturing (AM) is one of the emerging production methodologies transforming the industrial landscape. However, application of the technology in fluidic power transmission and actuation is still limited. AM pneumatic stepper motors have been previously introduced to the field of image-guided surgical robotics, where their disposability and customizability are considered a significant advantage over conventional manufacturing. However, intrinsic dimensional limitations of AM parts and their poor surface quality affect mechanical performance. In this letter, a novel design, PneuAct-II, is presented combining AM, subtractive machining, and off-the-shelf components to achieve higher mechanical performance and resolution. Moreover, a motor identification setup has been built to automatically measure different aspects of the PneuAct motors, including wear, friction, leakage, and stall behavior at various boundary conditions. The effects of input pressure, stepping frequency, signal-width, and external torque on the stall behavior of motors with different clearances are studied. A maximum torque of 0.39 N$\cdot$m at an input pressure of 6.5 bar is achieved for a motor with a total volume of 90 cm$^3$, and a clearance of 156 $\mu$m. A nominal resolution of 2.25$^{\circ }$ at full-pitch and 1.125$^{\circ }$ at half-pitch is accomplished. Both resolution and mechanical performance (667 N$\cdot$m/bar $\cdot$ m$^3$) outperform the state-of-the-art (240 N$\cdot$m/bar $\cdot$ m$^3$ by PneuAct-I)

Pioglitazone Reduces Hepatocellular Carcinoma Development in Two Rodent Models of Cirrhosis

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide due to the lack of effective treatments. Chemoprevention in high-risk patients is a promising, alternative strategy. In this study, pioglitazone was investigated for its ability to prevent hepatocarcinogenesis in two rodent models of cirrhosis. METHODS: In the first model, male Wistar rats were given repeated, low-dose injections of diethylnitrosamine (DEN) to accurately recapitulate the progression of fibrosis to cirrhosis and HCC. In the second model, a single dose of DEN was administered to male C57Bl/6 pups at day fifteen followed by administration of a choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) at week six for 24 weeks. Pioglitazone treatment started at the first signs of fibrosis in both models. RESULTS: Pioglitazone effectively reduced fibrosis progression and HCC development in both models. Gross tumor nodules were significantly reduced after pioglitazone treatment (7.4 +/- 1.6 vs. 16.6 +/- 2.6 in the rat DEN model and 5.86 +/- 1.82 vs. 13.2 +/- 1.25 in the mouse DEN+CDAHFD model). In both models, pioglitazone reduced the activation of mitogen-activated protein kinase (MAPK) and upregulated the hepato-protective AMP-activated protein kinase (AMPK) pathway via increasing circulating adiponectin production. CONCLUSION: Pioglitazone is an effective agent for chemoprevention in rodents and could be repurposed as a multi-targeted drug for delaying liver fibrosis and hepatocarcinogenesis

Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis

Lgr5 marks adult stem cells in multiple adult organs and is a receptor for the Wnt-agonistic R-spondins (RSPOs). Intestinal, stomach and liver Lgr5(+) stem cells grow in 3D cultures to form ever-expanding organoids, which resemble the tissues of origin. Wnt signalling is inactive and Lgr5 is not expressed under physiological conditions in the adult pancreas. However, we now report that the Wnt pathway is robustly activated upon injury by partial duct ligation (PDL), concomitant with the appearance of Lgr5 expression in regenerating pancreatic ducts. In vitro, duct fragments from mouse pancreas initiate Lgr5 expression in RSPO1-based cultures, and develop into budding cyst-like structures (organoids) that expand five-fold weekly for >40 weeks. Single isolated duct cells can also be cultured into pancreatic organoids, containing Lgr5 stem/progenitor cells that can be clonally expanded. Clonal pancreas organoids can be induced to differentiate into duct as well as endocrine cells upon transplantation, thus proving their bi-potentiality

Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation

Hepatocellular carcinoma (HCC) is a leading cause of death among cirrhotic patients, for which chemopreventive strategies are lacking. Recently, we developed a simple human cell-based system modeling a clinical prognostic liver signature (PLS) predicting liver disease progression and HCC risk. In a previous study, we applied our cell-based system for drug discovery and identified captopril, an approved angiotensin converting enzyme (ACE) inhibitor, as a candidate compound for HCC chemoprevention. Here, we explored ACE as a therapeutic target for HCC chemoprevention. Captopril reduced liver fibrosis and effectively prevented liver disease progression toward HCC development in a diethylnitrosamine (DEN) rat cirrhosis model and a diet-based rat model for nonalcoholic steatohepatitis–induced (NASH-induced) hepatocarcinogenesis. RNA-Seq analysis of cirrhotic rat liver tissues uncovered that captopril suppressed the expression of pathways mediating fibrogenesis, inflammation, and carcinogenesis, including epidermal growth factor receptor (EGFR) signaling. Mechanistic data in liver disease models uncovered a cross-activation of the EGFR pathway by angiotensin. Corroborating the clinical translatability of the approach, captopril significantly reversed the HCC high-risk status of the PLS in liver tissues of patients with advanced fibrosis. Captopril effectively prevents fibrotic liver disease progression toward HCC development in preclinical models and is a generic and safe candidate drug for HCC chemoprevention

Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma

Objective Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention. Design Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivo and ex vivo validation were used to identify chromatin modifiers and readers for HCC chemoprevention. Results In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients. Conclusion Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases

Tailored Chemical Reactivity Probes for Systemic Imaging of Aldehydes in Fibroproliferative Diseases

During fibroproliferation, protein-associated extracellular aldehydes are formed by the oxidation of lysine residues on extracellular matrix proteins to form the aldehyde allysine. Here we report three Mn(II)-based, small-molecule magnetic resonance probes that contain α-effect nucleophiles to target allysine in vivo and report on tissue fibrogenesis. We used a rational design approach to develop turn-on probes with a 4-fold increase in relaxivity upon targeting. The effects of aldehyde condensation rate and hydrolysis kinetics on the performance of the probes to detect tissue fibrogenesis non-invasively in mouse models were evaluated by a systemic aldehyde tracking approach. We showed that, for highly reversible ligations, off-rate was a stronger predictor of in vivo efficiency, enabling histologically validated, three-dimensional characterization of pulmonary fibrogenesis throughout the entire lung. The exclusive renal elimination of these probes allowed for rapid imaging of liver fibrosis. Reducing the hydrolysis rate by forming an oxime bond with allysine enabled delayed phase imaging of kidney fibrogenesis. The imaging efficacy of these probes, coupled with their rapid and complete elimination from the body, makes them strong candidates for clinical translation

Tailored Chemical Reactivity Probes for Systemic Imaging of Aldehydes in Fibroproliferative Diseases

During fibroproliferation, protein-associated extracellular aldehydes are formed by the oxidation of lysine residues on extracellular matrix proteins to form the aldehyde allysine. Here we report three Mn(II)-based, small-molecule magnetic resonance probes that contain α-effect nucleophiles to target allysine in vivo and report on tissue fibrogenesis. We used a rational design approach to develop turn-on probes with a 4-fold increase in relaxivity upon targeting. The effects of aldehyde condensation rate and hydrolysis kinetics on the performance of the probes to detect tissue fibrogenesis non-invasively in mouse models were evaluated by a systemic aldehyde tracking approach. We showed that, for highly reversible ligations, off-rate was a stronger predictor of in vivo efficiency, enabling histologically validated, three-dimensional characterization of pulmonary fibrogenesis throughout the entire lung. The exclusive renal elimination of these probes allowed for rapid imaging of liver fibrosis. Reducing the hydrolysis rate by forming an oxime bond with allysine enabled delayed phase imaging of kidney fibrogenesis. The imaging efficacy of these probes, coupled with their rapid and complete elimination from the body, makes them strong candidates for clinical translation