bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salvage Therapy of Progressive and Recurrent Hodgkin’s Disease: Results from a Multicenter Study of the Pediatric DAL/GPOH HD-Study Group.
Authors: Schellong Guenther , Doerffel Wolfgang , Claviez Alexander , Koerholz Dieter , Mann Georg , Scheel-Walter Hans G. , Boekkerink Jos P.M. , Riepenhausen Marianne , Lueders Heike , Poetter Richard , Ruehl Ursula 
Published: October 2019

Abstract
To evaluate the efficacy of a salvage therapy (ST-HD-86) developed for children and adolescents with progressive or relapsed Hodgkin’s disease (HD) who were primarily treated in the pediatric DAL/GPOH studies. The essential chemotherapeutic elements were ifosfamide, etoposide, prednisone (IEP) and doxorubicine, bleomycin, vinblastine, dacarbazine (ABVD). 176 patients with progression (N=51) or first relapse (N=125) were enrolled by 67 centers from six countries between 1986 and 2003. The median time from initial diagnosis to progression/relapse was 1.1 (range, 0.02–17.1) years and the median patients age at the diagnosis of progression/relapse was 14.7 (range, 4.3–24.5) years. Salvage therapy consisted of 3–5 alternating cycles of IEP and ABVD, supplemented in part by 1–2 cycles of cyclophosphamide, vincristine, procarbazine, prednisone (COPP) or CCNU, etoposide, prednimustine (CEP). Radiotherapy was given to involved areas using individualized dosages. In the 1990ies, high-dose high dose chemotherapy with stem cell support was introduced for patients with unfavorable prognostic criteria. Disease-free survival (DFS) and overall survival (OS) at 10 years after initiation of salvage therapy are 63±4% and 74±4%. Second events occurred in 70 of 176 pts (40%). Risk factor analysis revealed the time until progression/relapse as the most discriminating prognostic factor (p=.0001). Patients with progression had an inferior outcome (DFS 41±7%, OS 51±8%), whereas patients with late relapses (>12 months after end of therapy) do very well (DFS 87±4%, OS 90±4%). The result of study ST-HD-86 with a long-term survival of 74% in this large cohort of patients with progressive or relapsed HD can be considered favorable. While the salvage strategy for patients with progression has to be further optimized, a reduction of intensity might be considered for those patients with late relapses following HD in childhood or adolescence.
Chronic Myeloid Leukemia (CML) in Childhood - Results of the Multicenter-Trial CML-paed.
Authors: Suttorp Meinolf , Claviez Alexander , Martiniak Yvonne , Klingebiel Thomas , Niethammer Dietrich , Gadner Helmut , Peters Chris , Kabisch Hartmut , Kremens Bernhard , Zintl Felix , Henze Guenter , Goebel Ulrich 
Published: October 2019

Abstract
CML is a rare disease in childhood and hematopoietic stem cell transplantation (SCT) remains the only proven option for cure of young patients (pts). We here report the results of the GPOH-trial “CML-paed”. From December 1995 to June 2004 pts younger than 19 years (median age: 11.4 yrs) with Philadelphia-chromosome positive CML (n=193; 99 boys, 94 girls) were treated by hydroxyurea ± interferon and scheduled for SCT from an HLA-matched family donor within 6 months after diagnosis (Dx) and from an unrelated donor within 12 months. 85% of the pts were diagnosed in chronic phase (CP). Six pts (3%) died from disease without SCT with a median interval from Dx to death of 6.5 months (range 0.5–12 months) and 25 pts are still searching for a donor. 168 pts underwent SCT (n=50 HLA-matched related; n=69 HLA-matched unrelated (MUD); n=18 HLA-mismatched related; n=31 HLA mismached unrelated) in CP (n=139), in accelerated phase (AP, n=9), in blast crisis (BC, n=9), or in 2. CP (n=10). Probability of overall survival (OS) was 75 % if SCT was performed <7 months after Dx (n=53 pts) and 60 % (n=100 pts) if pts were transplanted later, however, this difference was statistically not significant. Conditioning regimens included either total body irradiation (n=82) or busulfan (n=80) resulting in no statistically different impact on OS. 5-year OS was 82 % for SCT from HLA-matched related and 55% for HLA-MUD-SCT reflecting a higher transplant-related mortality for the latter (p=.0017). After SCT from HLA-mismached unrelated and HLA-mismatched related donors, OS was 56% and 50%, respectively. 12 out of 168 pts (12%) relapsed following SCT after a mean interval of 11 months (range: 1–137 mos) and 9 of them so far have died of CML. Outcome was inferior if SCT was performed in advanced stages of CML (OS of all pts in CP: 67%; in AP: 55%, in BC: 21%, respectively). During the last decade the 3-year OS after SCT from HLA-matched unrelated donors improved gradually from 45 % before the year 1994, to 53 % in the period 1995 to 1999 and to 62 % after 2000, respectively. This large series of pts from a controlled trial shows an excellent OS of 82% for pediatric pts with CML undergoing SCT from matched sibling donors and constantly improving results during the last decade in the setting of MUD-SCT.
Characterization of Platelet Lipid Rafts Leads to the Identification of RGS-19, Which Forms a Phosphorylation-Dependent Complex with 14-3-3ζ.
Authors: Foy Martina , Treumann Achim , Fitzgerald Desmond J. , Maguire Patricia B. 
Published: October 2019

Abstract
Lipid rafts are specialised membrane regions, rich in dynamic multi-protein complexes that are implicated in the regulation of platelet activation processes, particularly those mediated by GPVI and GPIb/IX/V. To elucidate the role of rafts in platelet function, we carried out a comprehensive characterization of the detergent-insoluble proteins associated with rafts from control and VWF-activated platelets using liquid chromatography coupled to tandem mass spectrometry. Over 160 proteins were identified including 72 proteins unique to platelet rafts and several novel platelet signaling and vesicle transport proteins e.g., rab 5, rab 8 and syntaxin 11. Indeed, the high level of signaling and trafficking proteins identified implicates rafts as concentrating platforms for the critical platelet functions of activation and secretion. Moreover, activation through GPIb-IX-V resulted in the translocation of many proteins into or out of rafts. Proteins recruited into rafts upon VWF-activation included GPIbαand regulator of G-protein signalling-19 (RGS-19). We confirmed that the novel platelet protein, RGS-19, upon VWF activation resides exclusively within the raft fraction and using confocal microscopy, RGS-19 co-localised with GPIbα and the raft-marker flottilin, to both the plasma and vesicle membranes of VWF-activated platelets. The phosphorylation-dependent interaction of RGS proteins with 14-3-3 leads to the inhibition of their GTPase-activating protein (GAP) activity. Aligning RGS-19 to other members of the RGS family, we identified that it contained a novel 14-3-3 binding motif. Immunoprecipitation with an antibody to 14-3-3ζ demonstrated that RGS-19 and GPIbα co-immunoprecipitated with 14-3-3ζ in VWF-activated rafts. Furthermore, we demonstrated that acid phosphatase treatment could significantly reduce the co-immunoprecipitation of RGS-19 with 14-3-3ζ from activated rafts. Thus, within 15 sec of VWF activation we are suggesting maximal suppression of the GAP activity of RGS-19 in rafts through a phosphorylation-dependent association with 14-3-3ζ. Our results provide the basis for a new hypothesis concerning how RGS proteins might govern signaling within platelet rafts.
AKT Activity Regulates Sensitivity of Multiple Myeloma Cells to mTor Inhibitors.
Authors: Frost Patrick , Hoang Bao , Gera Joseph , Sharma Anushree , Shi Yijiang , Yan Huajun , Lichtenstein Alan 
Published: October 2019

Abstract
Inhibitors of the mammalian target of rapamycin (mTOR), such as rapamycin and CCI-779, have potential as anti-tumor agents against multiple myeloma (MM). In a murine xenograft model, CCI-779 demonstrated efficacy against in vivo growth of OPM-2 and 8226 MM cells. In this model, OPM-2 tumors (ED50=2 mg/kg) were considerably more sensitive than 8226 (ED50=20 mg/kg) tumors. CCI-779-induced anti-tumor responses were associated with significant inhibition of proliferation and angiogenesis and concomitant upregulation of apoptosis. OPM-2 cells were also significantly more sensitive to these CCI-779-mediated effects. Other tumor models have demonstrated that heightened AKT activity induces hypersensitivity to mTOR inhibitors. As OPM-2 cells express high levels of activated AKT (due to PTEN mutations) and 8226 cells contain predominantly quiescent AKT, this regulatory role for AKT may be present in MM cells as well. To further test this, we stably expressed an activated AKT allele in U266 (U266myr-AKT) MM cells. The in vivo growth of U266myr-AKT cells was considerably more sensitive than control U266 cells to the anti-tumor effects of CCI-779. The differential sensitivity induced by AKT activation was mirrored in an enhanced sensitivity to CCI-779-mediated apoptosis and inhibition of angiogenesis. Since previous studies demonstrated the ability of AKT/mTOR to regulate the expression of vascular endothelial growth factor (VEGF), we hypothesized that MM cells with heightened AKT activity may be more sensitive to the CCI-779-mediated inhibition of this critical angiogenic factor. In vitro, mTOR inhibitor, rapamycin, was markedly more effective at inhibiting VEGF secretion from U266myr-AKT than control cells. Our results demonstrate that AKT regulates the sensitivity of MM cells to the anti-tumor effects of mTOR inhibitors and that this may be mediated through the inhibition of AKT-dependent survival and growth factors.
P-21 Activated Kinase 1 (Pak1) Is Critical for Normal Mast Cell Degranulation and Cytokine Production in Response to Antigen Stimulation of the High Affinity IgE Receptor.
Authors: Allen Jayme D. , Hoffman Clemens , Derr-Yellin Ethel , Bessler Waylan , Yang Fen-Chun , Ingram David A. , Jaffer Zahra , Tipton Amanda , Chernoff Johnathan , Clapp D. Wade 
Published: October 2019

Abstract
Mast cells participate in normal and pathogenic inflammatory processes, including innate host defense, allergy, and asthma. Stimulation of the mast cell high-affinity IgE receptor (FcεR) by receptor cross-linking activates multiple downstream signaling pathways resulting in degranulation and de novo synthesis of multiple cytokines. However, the molecular mechanisms underlying these processes are incompletely defined. It is known that Rac2 deficient murine bone marrow derived mast cells (BMMCs) have impaired degranulation, but the downstream effectors that modulate this function are unknown. We hypothesized that p-21 activated kinase 1 (Pak1), a downstream effector of Rac proteins, is important in degranulation and de novo cytokine synthesis. Mature BMMCs from wild-type (WT) and Pak1 KO mice were sensitized with anti-DNP IgE then stimulated with DNP-HSA to stimulate FcεR. Interestingly, Pak1 KO BMMCs showed significant impairment in degranulation, as demonstrated by a 3-fold reduction in the percent of B-hexosaminidase released upon IgE stimulation. IgE stimulation of mast cell results not only in degranulation, but also in the production of TNFα, which is critical in the early recruitment of neutrophils to sites of acute inflammation. TNFαsynthesis is influenced by a number of transcription factors, many which are regulated by Erk. Since Pak1 has been shown, in overexpression systems, to phosphorylate Raf and Mek to activate Erk, we examined Erk activation in WT and Pak1 KO BMMCs in response to IgE stimulation. Pak1 KO BMMCs have a 50% reduction in phospho-Erk as compared to controls. We then tested another MAPK member important in mast cell cytokine synthesis, p38, and found phospho-p38 to be decreased in Pak1 KO BMMCs as well. Further, IgE-stimulated Pak1 KO BMMCs produce only 20–30% as much TNFαas controls. To define the role of Pak1 in cytokine production as specific for TNFαversus a more global defect, we also studied IL-6 synthesis and are able to report a 50% reduction in IL-6 production by Pak1 KO BMMCs. Our results indicate that Pak1 is important in BMMC degranulation, cytokine production, and MAPK activation in response to FcεR stimulation. These studies identify Pak1 as a potential therapeutic target in pathologic inflammation. Mechanisms by which Pak1 may be influencing mast cell degranulation as well as further study of transcription factors important in mast cell cytokine production are under current investigation.
HOXB9 Is Overexpressed in Blast Cells from a Subset of Acute Myeloid Leukemia Patients and Supports Proliferation of AML Cell Lines.
Authors: Heinrichs Stefan , Schoch Claudia , Neuberg Donna S. , Look A. Thomas 
Published: October 2019

Abstract
Emerging evidence from studies in mice and humans suggests that HOX genes integrate the myelodysplastic and leukemogenic activities of different oncogenes. Translocations involving the MLL gene, a major upstream regulator of the HOXA cluster, have been identified in AML and define a specific cytogenetic subgroup of this disease. Recently, amplification of MLL was found in AML and MDS cases, revealing a second mechanism of deregulation of MLL and its downstream targets. However, additional leukemogenic upstream pathways have to be postulated, since upregulation of specific HOX genes, particularly HOXA9, is more frequent than MLL deregulation. Given the fact that HOXA9 is targeted by several yet to be identified mechanisms, we asked whether other members of the HOX9 paralog group are also highly expressed in myeloid malignancies. Our analysis of 449 AML patients by gene expression microarray revealed that besides HOXA9 (61% of all cases), HOXB9 is upregulated in 15% of the cases, whereas the overexpression of HOXC9 and HOXD9 expression is a very rare event (>1% of all cases). High levels of HOXB9 expression did not correlate with low levels of HOXA9 expression ruling out the possibility that HOXB9 compensates for a lack of HOXA9 activity in the leukemogenesis of a HOXA9 negative AML cases. Interestingly, within the cytogenetically defined subgroups (inv(16), t(15;17), t(8;21)) that have no HOXA9 expression at all, HOXB9 was also low or absent. To test if HOXB9 has the potential to contribute to the leukemogenic phenotype we analyzed a panel of human AML cell lines. The finding that 6 out of 24 cell lines express high levels of HOXB9 further indicates the significance of HOXB9 in myeloid malignancies. We chose K-562 and HEL as model cell lines since they express high levels of HOXB9, but lack HOXA9 expression. To reveal HOXB9 dependent pathways we designed two highly efficient siRNAs to target HOXB9 and knocked down its expression by retroviral transduction. In comparison to cells expressing a control siRNA, the resulting cell lines showed <5% of the control HOXB9 protein levels and a reduction in the cellular growth rate. Consequently, HOXB9 expression is required for the rapid growth of these AML cells. To gain insight into the molecular mechanisms underlying this phenotype we are performing global gene expression analysis. Preliminary results of our nearest neighbor analysis in K-562 cells revealed the upregulation of genes associated with erythroid differentiation upon HOXB9 knockdown. Our results indicate that HOXB9 expression inhibits the differentiation of leukemic myeloid progenitor cells, consistent with a role for the aberrant expression of this major HOX protein in leukemogenesis, by maintaining cells of the leukemic clone in an undifferentiated and rapidly proliferative state.
The Osteo-Hematon: Modeling the Ontogenic Development of Stem-Cell Niches into Discrete Organotypic Proliferative Units.
Authors: Blazsek Istvan , Oberlin Estelle , Souyri Michele , Peault Bruno 
Published: October 2019

Abstract
Hemogenic stem cells (HSC) emerge at distinct allocation territories during ontogenesis. They irrigate freely the whole body by the blood stream, but the adult HSC expand and differentiate exclusively in the bone marrow (BM). This implies that stem cells are not autonomous units of development; rather, tissue specific niches control their destiny. We investigated the spatio-temporal emergence of stem cells and nest-forming cells, and basic mechanisms by which they shape together the functional-proliferative units in the liver and BM during ontogenesis. Video microscopy in gut/liver primordium cultures provided direct evidence for intrinsic emergence of a primitive vasculo-hemogenic meshwork guided by pulsative, cardiomyogenic cells around nascent hepatic cords in E8.75-E10 mouse embryos. Gain-of-competence and development of hepatic units required firm aggregation of cholangio-hepatic (CK19+/CK18+), hemogenic (CAFC) and vasculogenic stem/progenitor cells and nest-forming cells into compact 3-D structures, similarly to BM hematons. Colonization and expansion of HSC in the mouse liver at E12, then in the BM at postnatal d2, numerically correlated with the increase in isolatable niches/hematons. Time-lapse video microscopy, quantitative colony assays, FACS and immunocytochemistry analyses of the adult human BM showed that the hematon is enriched in mesenchymal stem cells, preadipocytes/adipocytes, contractile myogenic cells, a vascular meshwork, guardian macrophages and hemopoietic stem/progenitor cells (Sca-1/c-kit/CD34/Thy-1/CD31+). A hematon module plays the role of an organizing center that emits growth signalling factors and accumulates morphogen/differenciator factors, retinoids and 1,25-di(OH)-vitaminD3. The physical attachment of many hematons to spongy bone suggests that they form the basic structural-functional units in the ultimate, fully competent BM. We suggest designating these units osteo-hematons. A comparative analysis of BM aspirates from healthy donors (n=75) and patients (n=210) revealed the disorganization of osteo-hematon modules in AML prior to therapy and in CML during all stages of the disease.
High Cyclin D1 Expression Is Associated with Increased Proliferation Rate and Decreased Survival in Mantle Cell Lymphoma (MCL) and Is Caused by Genomic Deletions and Mutations that Enhance Stability of Cyclin D1 mRNA.
Authors: Wiestner Adrian , Chiorazzi Michael , Lai Raymond , Rosenwald Andreas , Muller-Hermelink H. Konrad , Ott German , Chan Wing C. , Greiner Timothy C. , Weisenburger Dennis D. , Vose Julie , Armitage James O. , Gascoyne Randy D. , Connors Joseph M. , Campo Elias , Montserrat Emilio , Bosch Francesc , Smeland Erlend B. , Kvaloy Stein , Holte Harald , Delabie Jan , Fisher Richard I. , Grogan Thomas M. , Miller Thomas P. , Wilson Wyndham H. , Jaffe Elaine S. , Staudt Louis M. 
Published: October 2019

Abstract
Most MCLs harbor the t(11;14) translocation resulting in overexpression of cyclin D1 that promotes tumor proliferation. Gene expression profiling of 92 cyclin D1 positive MCL biopsy samples defined a gene expression signature of tumor proliferation that provided strong prognostic information: the quartile of patients with the highest proliferation gene expression signature had a 0.8 year median survival whereas the quartile with the lowest expression had a 6.7 year median survival (Cancer Cell 2003, 3:185). Sixteen of the 23 MCL samples in the highest proliferation quartile displayed exceptionally high cyclin D1 levels and preferentially expressed short cyclin D1 mRNA forms that lacked parts of the 3′UTR known to harbor RNA-destabilizing elements. To test whether expression of short cyclin D1 mRNA is due to genomic deletions, we screened DNA from all samples in the highest proliferation quartile by quantitative genomic PCR. We found genomic deletions of the 3′UTR region in 6 of the 10 samples that expressed short mRNAs. We next sequenced the proximal 400bp region of the 3′UTR in those samples with high expression of short mRNAs that did not have genomic deletions. In 2 samples, we found 2 distinct mutations: a 3bp deletion and an A insertion. Both of these mutations created a premature polyadenylation signal (AATAAA) about 300bp 3′ of the stop codon, giving rise to a predicted mRNA of 1.5kb that lacks the destabilizing elements present in the full-length form. We identified two MCL cell lines, Jeko-1 and Z138, that also showed high-level expression of the short cyclin D1 form. In Jeko-1 we found a deletion of the 3′UTR similar to that observed in the MCL patient samples, whereas the mechanism responsible for expression of the short cyclin D1 mRNA in Z138 remains unclear. In both lines, we confirmed that the half-life of the short cyclin D1 mRNA is longer than that of the full length mRNA. Our results demonstrate that MCLs increase cyclin D1 expression not only through the t(11;14), but also by the additional mechanisms of genomic deletions and mutations that create alternative polyadenylation sites that yield more stable mRNAs. Higher cyclin D1 expression increases proliferation and decreases survival, suggesting that strategies aimed at reducing cyclin D1 expression in MCL could have therapeutic promise.
Incidence of Recurrent Venous Thromboembolism According to Duration of Vitamin K Antagonists: Results of a Meta-Analysis on Individual Data.
Authors: Boutitie Florent , Pinede Laurent , Schulman Sam , Agnelli Giancarlo , Rascob Gary , Jullian Jim , Hirsh Jack , Kearon Clive 
Published: October 2019

Abstract
Objective: 1) to describe the incidence of recurrent venous thromboembolism (VTE) after stopping treatment with vitamin K antagonists (VKA); 2) to determine if the incidence of recurrent VTE is influenced by the duration of VKA therapy.
Methods: We performed a meta-analysis on the individual data of patients included in five randomized controlled trials (ODAC, DURAC 1, LAFIT, WODIT DVT, DOTAVK studies) that assessed several durations of oral treatment with VKA after an episode of VTE. A Poisson linear regression model was used to estimate the rate of recurrent VTE over time in patients off treatment with VKA, according to the duration of treatment (1.5, 3, 6 and ≥12 months).
Results: 2365 patients were followed for an average of 24.5 months after stopping therapy, and 330 recurrent VTE were observed. Estimation of the hazard functions in patients off treatment revealed that the rate of recurrent VTE decreased rapidly over the first year following the index event, independently of the duration of treatment with VKA, and stabilized afterwards. In addition, a peak of recurrences was observed in the first 1 to 3 months after stopping therapy, in all treatment duration groups. The rate of recurrent VTE after the short-term peak did not seem to be modified by the duration of therapy, after accounting for the time elapsed since the index event.
Discussion: After a treated episode of VTE, the rate of recurrence declined exponentially over time. This result may be explained by 1) the natural evolution of recurrence rate after an acute VTE; 2) the heterogeneity of recurrence rate among patients (with higher risk patients experiencing recurrences sooner than lower risk patients). The peak of recurrent VTE observed in the first 1 to 3 months after stopping treatment regardless of the duration of anticoagulant therapy may suggest that some patients are exposed to a very high risk of recurrence as soon as the protective effect of treatment is released.