JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia

JAK2 abnormalities may serve as target for precision medicines in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for JAK2 mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP-ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy. JAK2 mutations mainly occurred in the poor prognostic subtypes BCR-ABL1-like and non- BCR-ABL1-like B-other (negative for sentinel cytogenetic lesions). JAK2 translocations were restricted to BCR-ABL1-like cases. Momelotinib and ruxolitinib were cytotoxic in both JAK2 translocated and JAK2 mutated cells, although efficacy in JAK2 mutated cells highly depended on cytokine receptor activation by TSLP. However, our data also suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and microenvironment-induced resistance. Furthermore, inhibitors induced accumulation of phosphorylated JAK2Y1007, which resulted in a profound re-activation of JAK2 signaling upon release of the inhibitors. This preclinical evidence implies that further optimization and evaluation of JAK inhibitor treatment is necessary prior to its clinical integration in pediatric BCP-ALL

Signaling Pathways as Therapeutic Targets in Pediatric B-cell Precursor Acute Lymphoblastic Leukemia

Intra- and inter-cellular signaling pathways have become promising candidates for cancer therapy, because they are frequently affected by oncogenic aberrations and specific small molecule inhibitors are available. The aim of this thesis is to identify and evaluate signaling pathways that may be targeted by novel therapeutic approaches in children with BCP-ALL

Technology assessment at universities of applied sciences: On closing the gap between knowledge for action and implementation competence

Technology assessment (TA) has become an essential tool for dealing with wicked problems. TA institutions cover many areas of the research landscape; however, the question arises to what extent TA is incorporated by universities of applied sciences. These are supposed to act as local drivers of innovation in addition to providing education. This article examines the dissemination of TA approaches at technically oriented state universities of applied sciences in German-speaking countries. Using a systematic content analysis of online information, it provides an overview of the different manifestations. The aim is to review the current state of TA embedding and to identify needs for and potential opportunities through a thorough implementation of TA instruments in education and research.Technology assessment (TA) has become an essential tool for dealing with wicked problems. TA institutions cover many areas of the research landscape; however, the question arises to what extent TA is incorporated by universities of applied sciences. These are supposed to act as local drivers of innovation in addition to providing education. This article examines the dissemination of TA approaches at technically oriented state universities of applied sciences in German-speaking countries. Using a systematic content analysis of online information, it provides an overview of the different manifestations. The aim is to review the current state of TA embedding and to identify needs for and potential opportunities through a thorough implementation of TA instruments in education and research