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Search Results: 1 - 10 of 548 matches for " Siegfried Janz "
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Waldenstr?m Macroglobulinemia: Clinical and Immunological Aspects, Natural History, Cell of Origin, and Emerging Mouse Models
Siegfried Janz
ISRN Hematology , 2013, DOI: 10.1155/2013/815325
Abstract: Waldenstr?m macroglobulinemia (WM) is a rare and currently incurable neoplasm of IgM-expressing B-lymphocytes that is characterized by the occurrence of a monoclonal IgM (mIgM) paraprotein in blood serum and the infiltration of the hematopoietic bone marrow with malignant lymphoplasmacytic cells. The symptoms of patients with WM can be attributed to the extent and tissue sites of tumor cell infiltration and the magnitude and immunological specificity of the paraprotein. WM presents fascinating clues on neoplastic B-cell development, including the recent discovery of a specific gain-of-function mutation in the MYD88 adapter protein. This not only provides an intriguing link to new findings that natural effector IgM+IgD+ memory B-cells are dependent on MYD88 signaling, but also supports the hypothesis that WM derives from primitive, innate-like B-cells, such as marginal zone and B1 B-cells. Following a brief review of the clinical aspects and natural history of WM, this review discusses the thorny issue of WM’s cell of origin in greater depth. Also included are emerging, genetically engineered mouse models of human WM that may enhance our understanding of the biologic and genetic underpinnings of the disease and facilitate the design and testing of new approaches to treat and prevent WM more effectively. 1. Clinical Aspects of WM: A Brief Overview 1.1. Definition and Classification The 2008 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [1] defines Waldenstr?m macroglobulinemia (WM) as a type of lymphoplasmacytic lymphoma (LPL) that involves the bone marrow and is associated with a monoclonal immunoglobulin (Ig) of the M class in the serum. The monoclonal IgM is usually referred to as IgM paraprotein or “M spike”—or mIgM for short. LPL is a low-grade malignancy of the mature B-lymphocyte lineage that exhibits a cytological spectrum of lymphoplasmacytic differentiation that ranges from small B cells to fully differentiated plasma cells (PCs). Between these extremes lies a sizable, if not predominant, fraction of cells with intermediate features and, therefore, designated lymphoplasmacytoid or lymphoplasmacytic cells (LPCs) [2]. Sometimes these cells are referred to as plasmacytoid or plasmacytic lymphocytes. Although LPL is characteristically associated with an mIgM that can be readily detected by serum protein electrophoresis, LPL does not always lead to WM. This is because approximately 5% of LPLs either produce a paraprotein that is not of the M class (but instead belongs in most cases to the A class or
Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF
Ken-ichi Fujita, Siegfried Janz
Molecular Cancer , 2007, DOI: 10.1186/1476-4598-6-71
Abstract: We examined the impact of secreted Wnt inhibitors from the Dickkopf (Dkk) family on pluripotent mesenchymal cells undergoing BMP2-induced osteoblastic differentiation.We found that Dkk1 and -2 restored the Wnt3a-dependent reduction of alkaline phosphatase (ALP), Osterix and p53, indicating that mitigated Wnt/β-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis. Dkk1 and -2 increased the expression of the osteoclast differentiation factors, receptor activator of NF-κB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), upon stimulation with Wnt3a/1,25-dihydroxyvitamine D3 and Wnt3a/BMP2, respectively. The decoy receptor of RANKL, osteoprotegerin (OPG), was down regulated under the latter conditions. These findings indicated that Dkk1 and -2 facilitate osteoclastogenesis by enhancing RANKL/RANK and M-CSF/c-Fms interactions. Dkk4 weakly shared activities of Dkk-1 and -2, whereas Dkk3 was ineffective.Our results suggest that inhibited Wnt/β-catenin signaling in BMP2-induced osteoprogenitors in vivo promotes, on balance, the heightened formation of osteoclasts. Focally increased Dkk1 production by tumor cells in the bone may thus lead to focal bone loss.The development of bone-resorbing osteoclasts is strictly dependent upon bone-forming osteoblasts and the balanced activity of both cell types is crucial for skeletal homeostasis [1,2]. Excess osteoclastic activity leading to focal bone loss is a common feature of human cancer, notably multiple myeloma (MM) [3]. Two factors supplied by osteoblast lineage cells are of critical importance for osteoclastogenesis: macrophage-colony stimulating factor (M-CSF)1 and receptor activator of NF-κB ligand (RANKL) [2]. M-CSF is required for proliferation and survival of osteoclast precursors, while RANKL is critical for precursor differentiation into mature, multinucleated osteoclasts. In addition to these positive regulators, osteoblast lineage cells produce the ma
Interaction of Navigation with Minimal Access Surgery  [PDF]
Siegfried Beller
Surgical Science (SS) , 2012, DOI: 10.4236/ss.2012.36059
Abstract: Minimal access surgery (MAS) includes conventional minimally invasive laparoscopic and thoracoscopic surgery, single incision laparoscopic surgery (SILS) and natural orifice transluminal endoscopic surgery (NOTES). An end of the evolution of MAS is not foreseeable, but there are still limitations. In the most common fields of intestinal surgery (cholecystectomy, appendectomy, colo-rectal resection) limitations of MAS shook dogma for surgical strategy and procedure. Automation units and telesurgical systems try to assist the surgical action. Remaining limitations are caused by lack of tactile sense and spatial awareness. With expanding application of minimal access technique in surgery the need for navigation assistance will increase. Future expansion is basically reliant on the feasibility of navigated surgery. Navigation must respect the problems of organ shift and realise continuous localisation of the surgical target as well as spatial orientation of surgical instruments and camera view.
CDDO-Imidazolide inhibits growth and survival of c-Myc-induced mouse B cell and plasma cell neoplasms
Seong-Su Han, Liangping Peng, Seung-Tae Chung, Wendy DuBois, Sung-Ho Maeng, Arthur L Shaffer, Michael B Sporn, Siegfried Janz
Molecular Cancer , 2006, DOI: 10.1186/1476-4598-5-22
Abstract: Morphological features and surface marker expression of iMycEμ-2 cells were evaluated using cytological methods and FACS, respectively. mRNA expression levels of the inserted MycHis and normal Myc genes were determined by allele-specific RT-PCR and qPCR. Myc protein was detected by immunoblotting. Cell cycle progression and apoptosis were analyzed by FACS. The expression of 384 "pathway" genes was assessed with the help of Superarray? cDNA macroarrays and verified, in part, by RT-PCR.Sub-micromolar concentrations of CDDO-Im caused growth arrest and apoptosis in iMycEμ-1 and iMycEμ-2 cells. CDDO-Im-dependent growth inhibition and apoptosis were associated in both cell lines with the up-regulation of 30 genes involved in apoptosis, cell cycling, NFκB signaling, and stress and toxicity responses. Strongly induced (≥10 fold) were genes encoding caspase 14, heme oxygenase 1 (Hmox1), flavin-containing monooxygenase 4 (Fmo4), and three members of the cytochrome P450 subfamily 2 of mixed-function oxygenases (Cyp2a4, Cyp2b9, Cyp2c29). CDDO-Im-dependent gene induction coincided with a decrease in Myc protein.Growth arrest and killing of neoplastic mouse B cells and plasma cells by CDDO-Im, a closely related derivative of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid, appears to be caused, in part, by drug-induced stress responses and reduction of Myc.2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and closely related derivatives, such as CDDO-imidazolide (CDDO-Im) [1], are novel synthetic triterpenoids that exhibit potent in vitro activity against a wide range of human cancers including lung and ovarian carcinoma [2], acute myeloid leukemia [3], cutaneous T-cell lymphoma [3], chronic lymphocytic leukemia (CLL) [4] and multiple myeloma (MM) [5]. CDDO's anti-neoplastic activity involves a complex set of biochemical pathways that can lead, depending on cell type and context, to induction of cell differentiation and apoptosis [3,5-7], inhibition of
Molecular and cytological features of the mouse B-cell lymphoma line iMycEμ-1
Seong Su Han, Arthur L Shaffer, Liangping Peng, Seung Chung, Jae Lim, Sungho Maeng, Joong Su Kim, Nicole McNeil, Thomas Ried, Louis Staudt, Siegfried Janz
Molecular Cancer , 2005, DOI: 10.1186/1476-4598-4-40
Abstract: The morphological features and the surface marker expression profile of the iMycEμ-1 cells were evaluated using cytological methods and FACS, respectively. The cytogenetic make-up of the iMycEμ-1 cells was assessed by spectral karyotyping (SKY). The expression of the inserted MycHis gene was determined using RT-PCR and qPCR. Clonotypic immunoglobulin gene arrangements were detected by Southern blotting. The global gene expression program of the iMycEμ-1 cells and the expression of 768 "pathway" genes were determined with the help of the Mouse Lymphochip? and Superarray? cDNA micro- and macroarrays, respectively. Array results were verified, in part, by RT-PCR and qPCR.Consistent with their derivation from LBL, the iMycEμ-1 cells were found to be neoplastic IgMhighIgDlow lymphoblasts that expressed typical B-cell surface markers including CD40, CD54 (ICAM-1), CD80 (B7-1) and CD86 (B7-2). The iMycEμ-1 cells harbored a reciprocal T(9;11) and three non-reciprocal chromosomal translocations, over-expressed MycHis at the expense of normal Myc, and exhibited gene expression changes on Mouse Lymphochip? microarrays that were consistent with MycHis-driven B-cell neoplasia. Upon comparison to normal B cells using eight different Superarray? cDNA macroarrays, the iMycEμ-1 cells showed the highest number of changes on the NFκB array.The iMycEμ-1 cells may provide a uniquely useful model system to study the growth and survival requirements of Myc-driven mouse LBL in vitro.Gene-targeted iMycEμ mice contain a single-copy mouse MycHis (c-myc) cDNA that has been inserted in opposite transcriptional orientation in the mouse immunoglobulin heavy-chain gene cluster, Igh. The specific insertion site of the MycHis transgene is in the intervening region of the Igh joining gene locus, JH, and the intronic heavy-chain enhancer, Eμ. The inserted transgene encodes a C-terminal His6 tag that is useful to distinguish message and protein encoded by MycHis and normal Myc [1]. The iMycEμ mice prov
Position Determination of a Robot End-Effector Using a 6D-Measurement System Based on the Two-View Vision  [PDF]
Alexej Janz, Christian Pape, Eduard Reithmeier
Open Journal of Applied Sciences (OJAppS) , 2013, DOI: 10.4236/ojapps.2013.37049

A mechatronic system based on the micro-macro-kinematic consists of an industrial robot and a piezoelectric stage mounted on the robot’s end-effector and has to carry out operations like micro-assembly or micro-milling. The piezoelectric stage has to compensate the positioning error of the robot. Therefore, the position of the robot’s end-effector has to be measured with high accuracy. This paper presents a high accuracy 6D-measurement system, which is used to determine the position and orientation of the robot’s end-effector. We start with the description of the operational concept and components of the measurement system. Then we look at image processing methods, camera calibration and reconstruction methods and choose the most accurate ones. We apply the well-known pin-hole camera model to calibrate single cameras. Then we apply the epipolar geometry to describe the relationship between two cameras and calibrate them as a stereo vision system. A distortion model is also applied to enhance the accuracy of the system. The measurement results are presented in the end of the paper.

Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms
Chen-Feng Qi,Yong-Soo Kim,Shao Xiang,Ziedulla Abdullaev,Ted A. Torrey,Siegfried Janz,Alexander L. Kovalchuk,Jiafang Sun,Delin Chen,William C. Cho,Wei Gu,Herbert C. Morse III
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms13056204
Abstract: Transcriptional activation of MYC is a hallmark of many B cell lineage neoplasms. MYC provides a constitutive proliferative signal but can also initiate ARF-dependent activation of p53 and apoptosis. The E3 ubiquitin ligase, ARF-BP1, encoded by HUWE1, modulates the activity of both the MYC and the ARF-p53 signaling pathways, prompting us to determine if it is involved in the pathogenesis of MYC-driven B cell lymphomas. ARF-BP1 was expressed at high levels in cell lines from lymphomas with either wild type or mutated p53 but not in ARF-deficient cells. Downregulation of ARF-BP1 resulted in elevated steady state levels of p53, growth arrest and apoptosis. Co-immunoprecipitation studies identified a multiprotein complex comprised of ARF-BP1, ARF, p53, MYC and the multifunctional DNA-binding factor, CTCF, which is involved in the transcriptional regulation of MYC, p53 and ARF. ARF-BP1 bound and ubiquitylated CTCF leading to its proteasomal degradation. ARF-BP1 and CTCF thus appear to be key cofactors linking the MYC proliferative and p53-ARF apoptotic pathways. In addition, ARF-BP1 could be a therapeutic target for MYC-driven B lineage neoplasms, even if p53 is inactive, with inhibition reducing the transcriptional activity of MYC for its target genes and stabilizing the apoptosis-promoting activities of p53.
Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia
Eun Sung Park, John D Shaughnessy, Shalu Gupta, Hongyang Wang, Ju-Seog Lee, Hyun Goo Woo, Fenghuang Zhan, James D Owens, Michael Potter, Siegfried Janz, J Frederic Mushinski
BMC Genomics , 2007, DOI: 10.1186/1471-2164-8-302
Abstract: Unsupervised hierarchical cluster analysis exhibited two main sub-clusters of samples: a B-cell lymphoma cluster and a plasma cell tumor cluster with subclusters reflecting mechanism of induction. This report represents the first step in using global gene expression to investigate molecular signatures related to the role of cooperating oncogenes in a model of Myc-induced carcinogenesis. Within a single subgroup, e.g., ABPCs, plasma cell tumors that contained typical T(12;15) chromosomal translocations did not display gene expression patterns distinct from those with variant T(6;15) translocations, in which the breakpoint was in the Pvt-1 locus, 230 kb 3' of c-Myc, suggesting that c-Myc activation was the initiating factor in both. When integrated with previously published Affymetrix array data from human multiple myelomas, the IL-6-transgenic subset of mouse plasma cell tumors clustered more closely with MM1 subsets of human myelomas, slow-appearing plasma cell tumors clustered together with MM2, while plasma cell tumors accelerated by v-Abl clustered with the more aggressive MM3-MM4 myeloma subsets. Slow-appearing plasma cell tumors expressed Socs1 and Socs2 but v-Abl-accelerated plasma cell tumors expressed 4–5 times as much. Both v-Abl-accelerated and non-v-Abl-associated tumors exhibited phosphorylated STAT 1 and 3, but only v-Abl-accelerated plasma cell tumors lost viability and STAT 1 and 3 phosphorylation when cultured in the presence of the v-Abl kinase inhibitor, STI-571. These data suggest that the Jak/Stat pathway was critical in the transformation acceleration by v-Abl and that v-Abl activity remained essential throughout the life of the tumors, not just in their acceleration. A different pathway appears to predominate in the more slowly arising plasma cell tumors.Gene expression profiling differentiates not only B-cell lymphomas from plasma cell tumors but also distinguishes slow from accelerated plasma cell tumors. These data and those obtained from th
NF-κB/STAT3/PI3K signaling crosstalk in iMycEμ B lymphoma
Seong-Su Han, Hwakyung Yun, Dong-Ju Son, Van S Tompkins, Liangping Peng, Seung-Tae Chung, Joong-Su Kim, Eun-Sung Park, Siegfried Janz
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-97
Abstract: Nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) were constitutively activated in iMycEμ mice, not only in LBLs but also in the splenic B-lymphocytes of young animals months before tumors developed. Moreover, inhibition of either transcription factor in iMycEμ-1 cells suppressed growth and caused apoptosis, and the abrogation of NF-κB activity reduced DNA binding by both STAT3 and Myc, as well as Myc expression. Inhibition of STAT3 signaling eliminated the activity of both NF-κB and Myc, and resulted in a corresponding decrease in the level of Myc. Thus, in iMycEμ-1 cells NF-κB and STAT3 are co-dependent and can both regulate Myc. Consistent with this, NF-κB and phosphorylated STAT3 were physically associated with one another. In addition, LBLs and iMycEμ-1 cells also showed constitutive AKT phosphorylation. Blocking AKT activation by inhibiting PI3K reduced iMycEμ-1 cell proliferation and caused apoptosis, via downregulation of NF-κB and STAT3 activity and a reduction of Myc levels. Co-treatment with NF-κB, STAT3 or/and PI3K inhibitors led to additive inhibition of iMycEμ-1 cell proliferation, suggesting that these signaling pathways converge.Our findings support the notion that constitutive activation of NF-κB and STAT3 depends on upstream signaling through PI3K, and that this activation is important for cell survival and proliferation, as well as for maintaining the level of Myc. Together, these data implicate crosstalk among NF-κB, STAT3 and PI3K in the development of iMycEμ B-cell lymphomas.Deregulated NF-κB activity plays a critical role in the survival and radiation resistance of tumor cells in a variety of human neoplasias including B cell lymphomas (BCLs) [1-5]. NF-κB comprises a family of transcription factors that control genes implicated in B-cell activation, proliferation and resistance to apoptosis [6]. Five known, structurally conserved members of the NF-κB/Rel family function as dimers in various combinations:
Identification of Candidate B-Lymphoma Genes by Cross-Species Gene Expression Profiling
Van S. Tompkins, Seong-Su Han, Alicia Olivier, Sergei Syrbu, Thomas Bair, Anna Button, Laura Jacobus, Zebin Wang, Samuel Lifton, Pradip Raychaudhuri, Herbert C. Morse, George Weiner, Brian Link, Brian J. Smith, Siegfried Janz
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076889
Abstract: Comparative genome-wide expression profiling of malignant tumor counterparts across the human-mouse species barrier has a successful track record as a gene discovery tool in liver, breast, lung, prostate and other cancers, but has been largely neglected in studies on neoplasms of mature B-lymphocytes such as diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We used global gene expression profiles of DLBCL-like tumors that arose spontaneously in Myc-transgenic C57BL/6 mice as a phylogenetically conserved filter for analyzing the human DLBCL transcriptome. The human and mouse lymphomas were found to have 60 concordantly deregulated genes in common, including 8 genes that Cox hazard regression analysis associated with overall survival in a published landmark dataset of DLBCL. Genetic network analysis of the 60 genes followed by biological validation studies indicate FOXM1 as a candidate DLBCL and BL gene, supporting a number of studies contending that FOXM1 is a therapeutic target in mature B cell tumors. Our findings demonstrate the value of the “mouse filter” for genomic studies of human B-lineage neoplasms for which a vast knowledge base already exists.
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