Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia

Purpose: Aberrant PI3K/AKT/mTOR signaling has been linked to oncogenesis and therapy resistance in various malignancies including leukemias. In Philadelphia chromosome (Ph) positive leukemias, activation of PI3K by dysregulated BCR-ABL tyrosine kinase (TK) contributes to the pathogenesis and development of resistance to ABL-TK inhibitors (TKI). The PI3K pathway thus is an attractive therapeutic target in BCR-ABL positive leukemias, but its role in BCR-ABL negative ALL is conjectural. Moreover, the functional contribution of individual components of the PI3K pathway in ALL has not been established. Experimental design: We compared the activity of the ATP-competitive pan-PI3K inhibitor NVP-BKM120, the allosteric mTORC1 inhibitor RAD001, the ATP-competitive dual PI3K/mTORC1/C2 inhibitors NVP-BEZ235 and NVP-BGT226 and the combined mTORC1 and mTORC2 inhibitors Torin 1, PP242 and KU-0063794 using long-term cultures of ALL cells (ALL-LTC) from patients with B-precursor ALL that expressed the BCR-ABL or TEL-ABL oncoproteins or were BCR-ABL negative. Results: Dual PI3K/mTOR inhibitors profoundly inhibited growth and survival of ALL cells irrespective of their genetic subtype and their responsiveness to ABL-TKI. Combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2. Conclusions: Inhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with ALL. Greater antileukemic activity of dual PI3K/mTORC1/C2 inhibitors appears to be due to the redundant function of PI3K and mTOR. Clinical trials examining dual PI3K/mTORC1/C2 inhibitors in patients with B-precursor ALL are warranted, and should not be restricted to particular genetic subtypes

Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis

anus kinase 2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib, are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the antifibrotic role of the JAK2 inhibitor pacritinib on activated hepatic stellate cells (HSCs) in vitro and in two animal models of liver fibrosis in vivo.Jonel Trebicka is supported by the German Research Foundation project ID 403224013–SFB 1382 (A09); by the German Federal Ministry of Education and Research (BMBF) for the DEEP‐HCC project; by the Hessian Ministry of Higher Education, Research, and the Arts (HMWK) for the ENABLE cluster project; and by Eurostars (Grant ID 12350). The MICROB‐PREDICT (project ID 825694), DECISION (project ID 847949), GALAXY (project ID 668031), LIVERHOPE (project ID 731875), and IHMCSA (project ID 964590) projects have received funding from the European Union's Horizon 2020 research and innovation program. The manuscript reflects only the authors' views, and the European Commission is not responsible for any use that may be made of the information it contains. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript

Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease

Contains fulltext : 96924.pdf (publisher's version ) (Open Access)BACKGROUND: We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD. METHODS: mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn's colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn's disease (CD) and 1193 UC) and in 853 healthy controls. RESULTS: mRNA expression of SHP in the ileum is reduced in patients with Crohn's colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD. CONCLUSIONS: FXR activation in the ileum is decreased in patients with Crohn's colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients

Smart vehicles, smart traffic: naar een nieuwe mobiliteit

In ons kleine en drukke Nederland is vlot en veilig verkeer belangrijk. Daarin is nog veel te verbeteren. Nederlanders staan samen zo’n 43 miljoen uur per jaar in file, het equivalent van 26 duizend full-time banen. Het aantal verkeersdoden neemt af, maar het aantal ernstig gewonden neemt juist toe. Emissies door rijdend en stilstaand verkeer zorgen op veel plaatsen voor een slechte luchtkwaliteit. Afgezien van immateriële schade kost dit jaarlijks zo’n 20 miljard Euro

On the choice of basis functions in FIR feed-forward design for wafer stages

In view of the increasing demands on scanning resolution and wafer throughput, control perfor- mance in the presence of disturbances is considered important for lithograpic systems. These sys- tems consist of various positioning modules that need to be synchronized at nano-scale accuracy while being exposed to large acceleration forces. The goal of this project was to establish this nano- scale accuracy by optimizing the coefficients in a Finite Impulse Response (FIR) filter feed-forward structure. The gradients used in the optimization are reconstructed via basis functions. Two types of basis functions are compared throughout this report, namely time delay and time derivative ba- sis functions. The time delay function is a more steady function gives a reasonable estimation of the gradient of the error at a low number of coefficients, but also at a high number of coefficients. Contrarily, the time derivative function, which is not constant over the considered interval of co- efficients, gives a better result at a low number of coefficients, but a worse result at a high number of coefficients. The choice therefore is dependent on the number of coefficients. This is one of the main conclusions of this work

A comparison of the battery electric TU/e Lupo EL and VW Lupo 3L diesel

To gain more insight in different aspects of electric vehicles, the Dynamics and Control group of the Eindhoven University of Eindhoven has developed the Lupo Electric Lightweight (EL) as a research platform for electric mobility. A model of the powertrain of the Lupo EL is created and gives fairly accurate indications of the real-life performance of the Lupo EL. The deviation between the model and DC measurement results is less than 10%. According to the measurements results, the electric Lupo EL has significant lower carbon dioxide emissions than the Lupo 3L equipped with a diesel engine. The difference in CO2 emissions between the EL and 3L at constant speed is at least 8.9%. Batteries make the vehicle more expensive and result in additional CO2 emissions during production. The break-even distance is 82300 km for the CO2 emissions and 326400 km for the investments, if normal power grid electricity is used. If solar energy is used, the break-even distance would be 38600 km for the CO2 emissions and 243600 km for the investments. The range of the Lupo EL is between 150 and 200 km, depending on the driving conditions. Comparing the Lupo EL with other electric vehicles, like the Nissan Leaf and Smart ForTwo, the energy usage is fairly low

Experimental Output Regulation for a Nonlinear Benchmark System

Research on the nonlinear output regulation problem is mainly focused on theoretical developments and studies on simulation level. In this brief, we present experimental results on the local output regulation problem for a nonlinear benchmark mechanical system, the so-called translational oscillator with a rotational actuator system. The presented results show the effectiveness of the nonlinear output regulation theory in practice. As follows from the conducted experiments, issues such as the convergence rate, stability, and performance robustness with respect to (non) parametric uncertainties, the size of the region of attraction, and actuator saturation should be accounted for in tuning the controller gains. This design problem has not been addressed in the existing literature on the nonlinear output regulation problem and it, therefore, raises a new direction for research crucial to the future application of output regulation theory in practice