Recurrent gain-of-function mutations in the transcription factors
and much more in
were found in hematopoietic malignancies with the highest proportion in mature T- and natural killer-cell neoplasms ...(peripheral T-cell lymphoma, PTCL). No targeted therapy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for PTCL, we mimicked graded STAT5A or STAT5B activity by expressing hyperactive
or
variants at low or high levels in the hematopoietic system of transgenic mice. Only mice with high activity levels developed a lethal disease resembling human PTCL. Neoplasia displayed massive expansion of CD8
T cells and destructive organ infiltration. T cells were cytokine-hypersensitive with activated memory CD8
T-lymphocyte characteristics. Histopathology and mRNA expression profiles revealed close correlation with distinct subtypes of PTCL. Pronounced STAT5 expression and activity in samples from patients with different subsets underline the relevance of JAK/STAT as a therapeutic target. JAK inhibitors or a selective STAT5 SH
domain inhibitor induced cell death and ruxolitinib blocked T-cell neoplasia
We conclude that enhanced STAT5A or STAT5B action both drive PTCL development, defining both STAT5 molecules as targets for therapeutic intervention.
Nanocomposite polyHIPE foams with open-cellular morphology were obtained using nanoparticles (γFe2O3/Fe3O4), surfactant (Pluronic L121) or nanoparticle/surfactant stabilized dicyclopentadiene high ...internal phase emulsions (DCPD HIPEs). Upon curing, cavity sizes were found to vary drastically between 950 ± 360 µm down to 7 ±3 µm depending on the HIPE formulations. As-obtained nanocomposite polyHIPE foams were functionalized using elemental bromine in THF. Upon bromination the nanoparticles are moved from the cavities surfaces into the bulk phase of the polymer scaffold, which affects the inductive-heating capability of the magnetic nanocomposite foams decreasing it by the factor of 2.
Summary
The p21‐activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers ...and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1+ haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by shPAK2‐ but not shPAK1‐expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix. PAK2‐deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo. PAK2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome‐mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the PAK2 isoform represents a promising target for the treatment of haematological diseases.
Summary
The p21‐activated kinases (
PAK
s) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers ...and is associated with poor prognosis. To date,
PAK
deregulation has mainly been studied in solid tumours, where
PAK
1 and
PAK
4 are the main isoforms deregulated. We show that
PAK
1 and
PAK
2 are the critical isoforms in a
BCR
/
ABL
1
+
haematopoietic malignancy. In suspension, leukaemic cells deficient for
PAK
1 and
PAK
2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by sh
PAK
2‐ but not sh
PAK
1‐expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing
PAK
2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require
PAK
2 to grow towards an extracellular matrix.
PAK
2‐deficient cells fail to form colonies in methylcellulose and to induce lymphomas
in vivo
.
PAK
2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome‐mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the
PAK
2 isoform represents a promising target for the treatment of haematological diseases.
Background: Single cases of aggressive B-cell non-Hodgkin lymphomas upon treatment with the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib in patients with myeloproliferative disorders (MPD) have ...been reported (Pardanani, Mayo Clin.Proc. 2011 ; Bhatt VR et al. J Natl Compr Canc Netw . 2015;13(3):281-28; Palmason et al. BMC Hematology 2015). However, incidence and pathogenesis remain enigmatic.
Methods: We investigated 626 patients with myeloproliferative neoplasms diagnosed at the Medical University of Vienna between 1997 and 2016. Of these, 69 patients with primary or secondary myelofibrosis were treated with JAK2 -inhibitors since 2009. Data on secondary malignancies were retrieved from our MPN database. Detailed clinical, pathologic and genetic data were obtained in patients developing lymphoma. These observations were recapitulated in a Stat1 knock-out mouse model (Stat1-/- mice).
Results: B-cell lymphomas developed in 4 out of 69 patients (5.8%) upon ruxolitinib treatment compared to only 2 of 557 (0.36%) in the control group (16-fold increased risk, p=0.0017). The median time to lymphoma diagnosis was 25 months after ruxolitinib initiation (Table 1). Two lymphoma patients had been pre-treated with alkylating agents before ruxolitinib, one with hydroxyurea, the JAK -inhibitor fedratinib and ruxolitinib, and one received ruxolitinib only. All lymphomas were of aggressive CD19+ B-cell type (3 DLBCL, 1 HG BCL NOS) and showed distinct features with extranodal involvement and/or bone marrow infiltration (3/4), IPI of 2 or greater, and high MYC, and TP53 expression. Genetic analysis revealed abnormalities in MYC, BCL2, BCL6 or TP53 genes (Table 1). Targeted sequencing in 2 patients showed inactivating mutations in the B2M, CDKN2A, or TP53 genes. No JAK2 -mutation was found in the lymphomas. Three of four patients responded to anti-lymphoma therapy, but 3 patients eventually died from lymphoma or sAML. Of note, the clinical, and pathogenetic features closely resembled those of the published cases and 2 cases seen at a different institution (Paris, Hospital Saint-Louis).
Mice deficient for the JAK kinase target STAT1 mirrored the course of the human disease: 16 of 24 Stat1-/- mice developed myeloid hyperplasia with splenomegaly and a massive expansion of myeloid blasts in bone marrow and peripheral blood. Lowering the load of myeloid blasts by ATRA or ruxolitinib led to B-cell proliferation. Transplantation of bone marrow from diseased Stat1-/- mice resulted in aggressive B-cell lymphomas displaying strikingly similar features to the human lymphomas with upregulation of c-Myc and Bcl-2 and downregulation of B2m (ß2-microglobulin) and Cdkn2a . STAT3 and STAT5 were not activated in these B-cell lymphomas indicating that the JAK/STAT pathway is dispensable for B cell transformation. B cells from diseased Stat1-/- mice gave rise to stable growth-factor independent cell lines, underlining their high grade of transformation.
Conclusion. Inhibition of the JAK/STAT1 pathway in myeloproliferative diseases appears to provoke the development of a distinct type of aggressive B-cell lymphoma. In myelofibrosis treated with a JAK2 inhibitor 5 to 6% of patients are affected. Further investigations to identify potential risk factors are ongoing.
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Sperr:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Phadia: Research Funding; Meda: Research Funding; Teva: Honoraria; Novartis: Other: Register. Staber:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Abbie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; MSD: Honoraria; Amgen: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Valent:Blueprint: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Incyte: Honoraria; BMS: Honoraria; Ariad: Honoraria, Research Funding; Pfizer: Honoraria; Teva: Honoraria; Deciphera: Honoraria, Research Funding. Hoermann:Gilead: Honoraria, Research Funding; Ariad: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Krauth:Novartis: Honoraria; Celgene: Honoraria; AOP Orphan Pharmaceuticals AG: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen Cilag: Honoraria; Amgen: Honoraria. Jaeger:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gisslinger:PharmaEssentia: Consultancy, Honoraria; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Shire: Honoraria; Janssen Cilag: Honoraria; Takeda: Honoraria.
In this paper a global vision scheme for estimation of positions and orientations of mobile robots is presented. It is applied to robot soccer application which is a fast dynamic game and therefore ...needs an efficient and robust vision system implemented. General applicability of the vision system can be found in other robot applications such as mobile transport robots in production, warehouses, attendant robots, fast vision tracking of targets of interest and entertainment robotics. Basic operation of the vision system is divided into two steps. In the first, the incoming image is scanned and pixels are classified into a finite number of classes. At the same time, a segmentation algorithm is used to find corresponding regions belonging to one of the classes. In the second step, all the regions are examined. Selection of the ones that are a part of the observed object is made by means of simple logic procedures. The novelty is focused on optimization of the processing time needed to finish the estimation of possible object positions. Better results of the vision system are achieved by implementing camera calibration and shading correction algorithm. The former corrects camera lens distortion, while the latter increases robustness to irregular illumination conditions.
Documenting underwater cultural heritage is a challenging undertaking. Underwater environment is not a man's natural habitat and special equipment and devices had to be invented so that he could ...enter and study this environment. Several decades of underwater research and many sacrifices were needed to fully understand the importance of underwater heritage and its protection. The means for accurate documentation underwater are very limited and demanding, due to required technical equipment it is also expensive. Emergence of modern 3D methods and accompanying software tools for processing of 3D data is therefore of utmost importance for documenting and protection of underwater cultural heritage. In comparison to manual and analog methods, 3D methods offer much better accuracy, they substantially shorten the necessary time spent underwater and in this way improve the safety at work as well as lower the entire cost of field work. For illustration of the above development we discuss archeological case studies from the North East Adriatic.
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