bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Characteristics and Outcome of a Large Series of Patients with Chronic Lymphocytic Leukemia (CLL) According to ZAP-70 Expression.
Authors: Bosch Francesc , Crespo Marta , Villamor Neus , Muntañola Ana , Ferrer Ana , Domingo Abel , Rozman Maria , Rozman Ciril , Lopez-Guillermo Armando , Montserrat Emili 
Published: April 2020

Abstract
The prognosis of patients with CLL has been traditionally assessed by using clinical stages. Clinical stages, however, are a mere reflection of the biological diversity of CLL. In this regard, we and others have recently shown that ZAP-70 expression separates CLL into two clinical forms with different outcome. The aim of this study was to analyze the distribution of age, gender, and different prognostic parameters according to ZAP-70 expression in 222 pts with CLL (median age, 62 yrs; female/male: 89/133). ZAP-70 was determined by flow cytometry, a high expression being defined as &gt;20% ZAP-70 positive CLL cells. Median follow-up of the series was 7.1 years. Clinical stages at diagnosis were: Binet stage A, 187 pts; B, 21 pts; and C, 14 pts. Rai Stage 0, 123 pts; I, 53 pts; II, 28 pts; III, 7 pts; and IV, 11 pts. Overall median survival was 13 years. Parameters associated with a high ZAP-70 expression were lymphocyte doubling time &gt;12 mos., atypical morphology, bone marrow infiltration &gt; 60%, increased serum LDH and timidin kinase, CD38 expression &gt;20%, del(13q14), unmutated status of IgVH, and development of Richer syndrome. Interestingly, ZAP-70 expression distribution correlated with Rai’s stage (0 vs. 1 to 4). Also, CD38 expression was able to separate two subpopulations with different survival among CLL cases with low ZAP-70 expression (median survival 18 yrs vs. 13 yrs), but not in pts. with ZAP-70&gt;20%. About 50% of pts in Binet A progressed during the follow-up. Median time to progression for patients with high ZAP-70 expression was 3.3 years whereas it was not reached for patients with low ZAP-70 expression. Median survival of pts with low ZAP-70 expression was 16.3 years, whereas it was of 8.5 years in those with high ZAP-70 expression. In conclusion, ZAP-70 expression identifies a subgroup of patients with CLL with unfavorable prognostic factors related to the proliferation and progression of the disease.
Prognostic Parameters according to ZAP-70 expression
Variable ZAP-70 &gt;20% ZAP-70 &lt; 20% p= Median age 60 yrs 63 yrs Gender (female) 39% 41% LDT &lt; 12 mos 42% 23% 0.009 Atypical morphology 54% 12% 0.000 BM infiltration &gt;60% 50% 33% 0.03 Increased LDH 13% 4% 0.028 Increased TK 66% 28% 0.000 CD38 &gt; 20% 67% 32% 0.000 Del(13q14) 38% 55% 0.027 Unmutated IgVH 88% 11% 0.000 Richter Syndrome 8% 2% 0.039 Rai Stage &gt; 0 53% 37% 0.039 TTP (Binet A) 3.3 yrs NR 0.000 Median Survival 16.3 yrs 8.5 yrs 0.000
Anti-CD20 Antibody Rituximab and Anti-CD23 Antibody IDEC-152 Induce Apoptosis of Malignant B-Cells in Combination with Chemical Antagonists of XIAP.
Authors: Mangiola Massimo , Welsh Kate , Kitada Shinichi , Pedersen Irene M. , Pathan Nuzhat , Pinilla Clementia , Kipps Thomas J. , Reed John C. 
Published: April 2020

Abstract
We tested the effects of Rituximab (anti-CD20) and IDEC-152 (anti-CD23) on apoptosis of B-cell malignancies, using established non-Hodgkin’s B-Cell lymphoma cell lines and freshly isolated Chronic Lymphocytic Leukemia (CLL) B-cells. We used monolayers of stably transfected CHO-cells expressing FcRγIII-A to present antibody to B-cells and promote crosslinking. Established B-cell lymphomas (n = 3) were cultured in the presence of FcRγIIIA-expressing CHO monolayer with or without MAbs and apoptosis was measured by annexin V/propidium iodide staining at various times thereafter. Both antibodies induced time-dependent apoptosis of B-cell lymphoma cell lines. After 48 hrs of treatment with either Rituximab or IDEC-152, the majority of the malignant B-cells were apoptotic (remaining viable cells = 28.7% ± 0.2137% for Rituximab and 30.87% ± 0.7332% for IDEC-152). Rituximab and IDEC-152 also induced marked increases in caspase activity in B-cell lymphoma cell lines, with fold-increases above baseline control cells of 25 ± 0.9031 and 24 ± 0.3839, respectively. In contrast, neither Rituximab nor IDEC-152 induced striking effects on primary CLL B-cells (n = 6). We therefore tested the combination of Rituximab or IDEC-152 with other agents that target anti-apoptotic proteins, exploring whether more efficient induction of apoptosis can be achieved. We cultured lymphoma cell lines and primary CLL specimens with chemical antagonists of XIAP (Schimmer, et al. Cancer Cell5: 25, 2004), an anti-apoptotic protein that inhibits effector caspases. When used at concentrations where XIAP antagonists alone were non-apoptotic (approximately 2.5 μM), a significant increase in apoptosis was achieved in cultures of lymphoma and CLL cells treated with either Rituximab or IDEC-152. These findings suggest that Rituximab or IDEC-152 may more efficiently induce apoptosis of malignant B-cells when combined with an apoptosis-sensitizing agent. (Supported by CA-81534; CA-78040; and an unrestricted grant from Genentech, Inc.).
Fusion of NUP214 to ABL1 on Amplified Extrachromosomal Elements in T-ALL.
Authors: Cools Jan , Graux Carlos , Melotte Cindy , Quentmeier Hilmar , Ferrando Adolfo A. , Levine Ross , Vermeesch Joris R. , Stul Michel , Dutta Binita , Boeckx Nancy , Bosly Andre , Heimann P. , Uyttebroeck Anne , Mentens Nicole , Somers Riet , MacLeod Roderick A.F. , Drexler Hans G. , Look A. Thomas , Gilliland D. Gary , Michaux Lucienne , Vandenberghe Peter , Wlodarska Iwona , Marynen Peter , Hagemeijer Anne 
Published: April 2020

Abstract
The Philadelphia translocation, encoding the BCR-ABL1 (BCR-ABL) fusion gene, is typically found in chronic myeloid leukemia (CML) and precursor B-cell acute lymphoblastic leukemia (B-ALL), but is exceptionally rare in T-cell acute lymphoblastic leukemia (T-ALL). To study the potential involvement of ABL1 gene rearrangements in T-cell malignancies, we screened 90 T-ALL cases by fluorescence in situ hybridization (FISH), using BCR and ABL1 probes. No BCR-ABL1 fusion signals were observed, confirming the low frequency of this rearrangement in T-ALL, but we did observe marked amplification (&gt; 10 signals per nucleus) ABL1 of in 5 of 90 (5.5 %) T-ALL patients.
Amplification of ABL1 occurred on small extrachromosomal elements that were not detectable by conventional cytogenetics. and hence are referred to as episomes. FISH, and array-CGH analyses delineated the amplicon as a 500 kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (CAN). Molecular analysis led to the identification of a NUP214-ABL1 fusion gene, which is generated as result of the circularization of the genomic region between ABL1 and NUP214 to form the episomes. This is the first example of an oncogenic fusion gene generated by extrachromosomal amplification. The NUP214-ABL1 transcript was detected in 5 patients with ABL1 amplification, in 5 of 85 (5.8 %) additional T-ALL patients, and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib mesylate (STI-571). The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased expression TLX1 of (HOX11) or TLX3 (HOX11L2), and with deletion of CDKN2A (p16), consistent with a multi-step pathogenesis of T-ALL. Our results identify a novel mechanism for the generation of a fusion gene on extrachromosomal elements, and indicate the importance of activated tyrosine kinase signaling in the pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of T-ALL patients that could benefit from imatinib treatment.
Dysregulated Apurinic/Apyrimidinic Endonucleases (Ape1 and Ape2) Lead to Genetic Instability in Multiple Myeloma.
Authors: Shammas Masood A. , Koley Hemant , Shah Sima , Batchu Ramesh B. , Tassone Pierfrancesco , Anderson Kenneth C. , Munshi Nikhil C. 
Published: April 2020

Abstract
Multiple myeloma (MM) is associated with significant genomic instability. Homologous recombination (HR), which is elevated in MM, is considered to be responsible for this instability. As endonucleases play an important role in mediating HR, here we have evaluated the role of endonuclease in biology and progression of MM. Gene expression profile using Affymetrix U133 array showed &gt; 2 fold elevation of Ape1 or Ape2 or both in 5 of 6 MM cell lines and 12 of 15 patient samples. Immunocytochemistry confirmed upregulation of Ape1 protein in MM cell lines. A Plasmid degradation assay confirmed significantly elevated endonuclease activity in MM cells compared to normal plasma cells. To identify the pre-dominating endonuclease activity, the degradation assay was carried out in the presence of specific endonuclease inhibitors. Harmane and methoxyamine (MA), specific inhibitors of apurinic/apyrimidinic endonucleases effectively inhibited significant endonuclease activity, while other endonuclease inhibitors ACPD and FK506 had minimal effects, confirming predominant role of apurinic/apyrimidinic endonucleases (APE) in mediating increased endonuclease activity in MM. We investigated the role of elevated APE endonuclease activity on DNA recombination and subsequent genomic re-arrangements. Using a plasmid-based assay we have previously demonstrated significantly elevated homologous recombination (HR) in MM. Inhibition of endonuclease by methoxyamine suppressed HR activity by 85 ± 2% in MM cells. Next, we evaluated whether inhibition of HR by methoxyamine can affect the frequency of acquisition of new genetic changes in MM cells using single nucleotide polymorphism (SNP) arrays (Affymetrix) as indicator of genomic instability. In three independent experiments, methoxyamine reduced the acquisition of new loss of heterozygocity (LOH) loci by an average of 71%. These data suggest that the dysregulated APE endonucleases contribute significantly to the genomic instability, acquisition of new mutations and progression of MM and provides the rationale for targeting endonuclease activity to prevent disease progression including development of drug resistance.
Constitutively Activated FGFR3 Mutants Signal through PLCγ- Dependent and -Independent Pathways for Hematopoietic Transformation.
Authors: Chen Jing , Williams Ifor R. , Lee Benjamin H. , Duclos Nicole , Huntly Brian J.P. , Donoghue Daniel J. , Gilliland D. Gary 
Published: April 2020

Abstract
Ectopic expression of FGFR3 associated with t(4;14), frequently containing the activating mutation K650E (TDII), has been implicated in the pathogenesis of human multiple myeloma. To investigate the role of autophosphorylated tyrosine residues in FGFR3 signal transduction and transformation, we characterized a series of FGFR3 TDII mutants with single or multiple Y→F substitutions. Phenylalanine substitution of a non-activation loop tyrosine residue Y760, essential for PLCγ binding and activation, significantly attenuated FGFR3 TDII-mediated PLCγ activation, as well as transformation in Ba/F3 cells and a murine bone marrow transplant (BMT) leukemia model. In contrast, single substitution of other non-activation loop tyrosine residues Y577, Y724 or Y770 had minimal to moderate effects on TDII-dependent transformation. Substitution of all the four non-activation loop tyrosine residues significantly attenuated, but did not abolish FGFR3 TDII transforming activity. However, substitution of both activation loop tyrosine residues Y647/Y648 resulted in complete abrogation of FGFR3 TDII kinase activity and transforming activity in vitro and in vivo. Similar observations were obtained in the context of constitutively activated fusion TEL-FGFR3 associated with peripheral T-cell lymphomas (PTCL) with chromosomal translocation t(4;12)(p16;p13). Moreover, two independent EμSR-FGFR3 TDII transgenic mouse lines developed pro-B cell lymphoma, and PLCγ was highly activated in primary lymphoma cells as assessed by tyrosine phosphorylation, along with elevated activation of STAT3 and expression of Bcl-XL in the tumor tissues. These data indicate that engagement of multiple signaling pathways, including PLCγ-dependent and PLCγ-independent signaling pathways, are required for full hematopoietic transformation by constitutively activated FGFR3 mutants.
Allogeneic Transplant in Patients with Poor Prognosis B-Chronic Lymphocytic Leukemia (B-CLL): Comparative Study between Myeloablative(M) and Non-Myeloablative(NM) Conditioning Regimen.
Authors: Caballero M.D. , García-Marco J.A. , Martino R. , Esteve J. , Mateos M.V. , León A. , Sarrá J. , Ribera Josep Maria , Sanz G. , de la Serna J. , Díez J.L. , San Miguel11 J.F. 
Published: April 2020

Abstract
Sustained complete remissions (CR) have been reached with allogeneic transplant in patients with poor prognosis B-CLL; however, mortality rates are high (20–50%); in order to reduced TRM, NM conditioning are widely used in haematological malignancies; however it is not clear if the use of NM regimens can maintain the efficacy reducing the toxicity. IN this report we performed a retrospective comparison between 30 patients (group A) who have received myeloablative conditioning consisted of TBI plus Cy in 23 pts (74%), TBI, Cy plus VP-16 in 6 pts (19%) and BuCy in 1 patient and 31 patients (Group B) who have received a NM transplant. Conditioning regimens in Group B included: Fludarabine plus Melphalan, 20 pts (64%), Fludarabine, Busulphan and ATG, 5 pts (16%), Fludarabine, TBI and ATG, 4 pts (13%) and Fludarabine plus TBI, 1 patient. All patients received peripheral blood stem cells from a HLA related identical donor. T-cell depletion was performed in 14 patients of the group A. Median age at transplant was significantly higher in the group B patients (53 versus 45, respectively) (p&lt;0,005); no differences were observed in terms of status at transplant and n° of previous chemotherapy lines as well in the risk of graft versus host disease (GVHD) and transplant related mortality (TRM) (See Table, below).
With a median follow-up of 71 and 36 months for groups A and B respectively,Overall Survival and Event Free Survival are similar for both groups (53% versus 64% and 60% versus 68%, respectively). Although patients in the NM transplant group were older toxicity was similar in both groups; moreover a similar efficacy has been observed suggesting the clear role of graft versus tumour effect in B-CLL probably more important that the type ofconditining.
Table 1
GROUP A Myeloablative Group B Non-myeloablative p Number of previuous chemotherapy lines 2 (1-6) 2 (1-8) NS Acute GVHD 15/30 (48%) 20/31 (64%) NS Grade II-IV 11/30 (35%) 12 /31(38%) NS Chronic GVHD 12/26pts at risk (46%) 18/27 pts at risk (66%) NS Extense 8 pts (30%) 9 pts (33%) NS TRM 7/30 (23%) 7/31 (22%) NS
Molecular Composition of Intercellular Contacts in Human Mesenchymal Stem Cells.
Authors: Wuchter Patrick , Boda Judit , Straub Beate , Krause Ulf , Seckinger Anja , Grund Christine , Kuhn Caecilia , Gottschling Sandra , Franke Werner W. , Ho Anthony D. 
Published: April 2020

Abstract
The long-term fate of stem cells depends on their interaction with the niche. Mesenchymal stem cells (MSC) from human bone marrow have been demonstrated to differentiate into various tissues, such as bone, cartilage, muscle and fat. As the interaction with the microenvironment plays a major role in differentiation, we have characterized the cell-cell contact among MSC. We have demonstrated the occurrence of a novel kind of adhering junction, consisting of slender, villiform-to-vermiform cell projections (processus adhaerentes). In this study, we have systematically analyzed the molecular composition of these junctions.
A panel of antibodies specific for various components of tight junctions, gap junctions, adherens junctions and desmosomes was used. The expression of these antigens was verified by light and electron microscopy and by biochemical analysis, including immunoprecipitation and RT-PCR. MSC from two different sources were analyzed: MSC obtained from bone marrow aspirates from healthy voluntary donors and additionally MSC originating from umbilical cord blood donated for scientific research. We have also shown the presence of vimentin-positive retothelial cells (which are probably the source of MSC) in situ in fresh bone marrow samples.
We demonstrate that MSC were interconnected by occasional gap junctions and frequent adhering junctions. Additionally, we found a unique molecular composition of these adhering junctions, as they comprise the transmembrane glycoproteins cadherin 11, N-cadherin and syndecan-1, together with the cytoplasmic plaque proteins α- and β-catenin and p120ctn. Constitutive complexes of these molecules have been identified.
Our data indicate that MSC communicate with each other through junctions and junctional complexes. We hypothesize that MSC can embark on alternative differentiation pathways with specific junctional and cytoskeletal patterns. Characterization of and understanding the role of such intercellular contacts and their correlation to specific differentiation programs are being conducted.
Blood from Mesenchymal Stem Cell.
Authors: Lange Claudia , Gehling Ursula , Moosmann Sabine , Huss Ralf , Zander Axel R. 
Published: April 2020

Abstract
Mesenchymal stem cells (MSC) have been described to support the maintainance and expansion of clonogenic hematopoietic cells in vitro and as progenitors for nonhematopoietic tissues. They clearly can be distinguished from hematopoietic cells by the surface markers CD45 and CD34. We investigated the potential of human MSC to form blood and endothelial cells. Human MSC in expansion cultures expressed RNA for CD117 and EpoR but not for other hematopoietic antigens. Many transcription factors essential for blood cell differentiation, e.g. c-mpl, Notch-1, Gata-2 and -3, Runx-1 and SCL, were detected in these cells. We used different differentiation strategies: A) Hematopoietic differentiation: 1. Prestimulation in IMDM + fetal calf serum (FCS) + horse serum (HS), mixed with methylcellulose (MC, containing cytokines SCF, IL-3, IL-6, G-CSF, GM-CSF and Epo) and differentiation in MC; 2. Prestimulation in serum free medium supplemented with SCF, TPO, GM-CSF and flt.- 3 ligand and differentiation in serum free MC; B) Endothelial differentiation: Prestimulation in serum free medium supplemented with SCF, TPO, and flt-3L and differentiation in medium + VEGF + bFGF + IGF. Using FACS-analysis, we detected up to 1.8 % CD34-positive cells within 2 weeks. Immunochemically we observed cells positive for CD45, CD34, CD133, CD14, CD16 and CD41. Although hMSC do not form colonies after seeding in MC, after prestimulation we observed colonies with the typical appearance of BFU-E which were GlycophorinA positive. Under endothelial conditions we detected cells positive for CD34 and KDR or CD31 and vWF. However, cell numbers of positive cells were low and therefore RT-PCR results were not very reliable. To confirm the differentiation capacity of MSC we generated CD45.2 mouse MSC (P9 what took about 6 month) and transplanted into lethally irradiated CD45.1 recipient mice. Four weeks after transplantation mice showed normal white blood cell counts but still decreased platelet counts. Analysis of donor chimerism 29 weeks after transplantation revealed up to 36 % (14.3±7.9%) donor cells in peripheral blood, mainly in the CD11b positive myeloid population but not in lymphoid cells. In thymus and bone marrow, marginal donor chimerism (3±0.8%) was detected, but the number in c-kit+ cells reached up to 28.2% (7.9±6.8%). In B-cells and erythroid progenitors chimerism was low but stable, but not in CD3+ cells. Taken together, we have shown that under the right conditions MSC are able to form blood and endothelial cells and reconstitute animals. We suggest that MSC could be an yet unrecognised precursor for both cell types and may contain the long searched hemangioblast in adult organisms.
TGF-β Receptor I Kinase Inhibitor Downregulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment.
Authors: Hayashi Toshiaki , Hideshima Teru , Podar Klaus , Richardson Paul , Munoz Olivier , Hamasaki Makoto , Ishitsuka Kenji , Yasui Hiroshi , Murphy Alison , McEnroe Glenn , Chakravarty Sarvajit , Dugar Sundeep , Higgins Linda S. , Chauhan Dharminder , Anderson Kenneth C. 
Published: April 2020

Abstract
Transforming growth factors (TGFs) have pleiotropic biologic effects on tumor cells and their environment. In multiple myeloma (MM), we have reported that bone marrow stromal cells (BMSCs) from MM patients produce more TGF-β1 than BMSCs from healthy donors, which in turn induces interleukin-6 (IL-6) secretion. In this study, we delineate the functional squelae of TGF-β1 in MM, and importantly, show that the TGF-β receptor I kinase inhibitor SD-208 significantly decreases secretion of both IL-6 and vascular endothelial growth factor (VEGF) from BMSCs, as well as tumor cell growth triggered by MM cell adhesion to BMSCs. Cytokine production and MM cell proliferation triggered by TGF-β1 or adhesion to BMSCs were examined in the presence or absence of SD-208 using ELISA and 3H thymidine incorporation assay, respectively. Effects of SD-208 on TGF-β1-induced signaling pathways triggering IL-6 and VEGF transcription in BMSCs were delineated using immunofluorescence staining, immunoblotting and DNA-binding assay. We here show that adhesion of MM cells to BMSCs triggers secretion of TGF-β1, which further upregulates IL-6 and VEGF secretion in BMSCs. These cytokines in turn mediate MM cell growth, survival, drug resistance, and migration. Importantly, SD-208 significantly inhibits not only transcription but also secretion of both IL-6 and VEGF from BMSCs triggered by either TGF-β1 or adhesion of MM cells to BMSCs. Moreover, SD-208 decreased tumor cell growth triggered by MM cell adhesion to BMSCs. SD-208 works, at least in part, by blocking TGF-β1-triggered nuclear accumulation of Smad2/3 and hypoxia-inducible factor 1α, as well as related production of IL-6 and VEGF, respectively. These studies indicate that SD-208 inhibits production of cytokines mediating MM cell growth, survival, drug resistance, and migration in the BM milieu, thereby providing the preclinical rationale for clinical evaluation of SD-208 to improve patient outcome in MM.