bluuebunny/crossref_metadata_2025_split huggingface dataset:
Death Associated Protein Kinase 2 (DAPK2): A Novel Epo-Modulated Apoptotic Regulator of Late Erythropoiesis.
Authors: Menon Madhu , Vincent Bethany , Breggia Anne , Wojchowski Don M. 
Published: October 2019

Abstract
Death-associated kinase-1 (DAPK1) is a broadly expressed pro-apoptotic cytoplasmic S/T protein kinase that regulates cell proliferation and survival, modulates a p53 apoptotic checkpoint, and contributes to ALL, AML, and myelodysplastic syndromes. DAPK2, by comparison, is an under-studied (but likewise pro-apoptotic) DAPK1 orthologue that we have discovered to be expressed (via Affymetrix gene profiling) at high-levels in late-stage erythroid progenitor cells. In particular, and as examined in purified and developmentally-staged proerythroblasts, basophillic erythroblasts and orthrochromatic erythroblasts, DAPK2 gene expression was sharply up-modulated as progenitor cells developed to a Ter119(+), CD71-high stage. Using a DAPK2-specific antibody, this was confirmed at the protein level, and initial analyses of expression in cell lines further indicated lineage-restricted DAPK2 expression (e.g. high level in erythroid GIE2 cells but undetectable in pluripotent EML cells). To advance an initial understanding of DAPK2’s role in erythroid cells, its possible regulation via the Epo receptor (EpoR) also was studied. Here, primary erythroid progenitor cells from mice with knocked-in minimal EpoR alleles were used (PY-null and PY343-only EpoR-HM and EpoR-H forms, respectively). Interestingly, the point-mutation of a PY3434/Stat5 specific binding site (to F343) (EpoR-HM allele) resulted in a clear multi-fold de-repression of DAPK2 that also correlated with a decreased survival potential for EpoR-HM erythroblasts. This repressive effect of EpoR/PY343/Stat5 signaling on DAPK2 expression was highly stage-specific, and was exerted distinctly in advance of an observed EpoR/PY343/Stat5-dependent up-modulation of Bcl-xl expression. In addition, in wild-type EpoR pro-erythroblasts, DAPK2 levels increased with decreasing Epo concentrations. Investigations therefore reveal DAPK2 to be a late-stage erythroid- restricted, (and EpoR/PY343/Stat5- modulated) novel candidate regulator of red cell production.
Repetitive High-Dose Therapy with Dose Escalated CHOP + Etoposide Followed by Autologous Stem Cell Transplantation (Mega-CHOEP) in Younger Patients with Primary Diagnosis of Aggressive NHL and Elevated LDH at Diagnosis: Final Analysis.
Authors: Schmitz Norbert , Kloess Marita , Engert Andreas , Berdel Wolfgang E. , Metzner Bernd , Truemper Lorenz , Loeffler Marcus , Pfreundschuh Michael , Glass Bertram 
Published: October 2019

Abstract
As a novel approach to primary treatment of aggressive lymphoma, we tested the feasibility and efficacy of a four cycle high-dose chemotherapy protocol including autologous stem cell transplantation after cycles 2, 3 and 4. In a multicenter Phase II study patients with newly diagnosed aggressive NHL, age between 18–60 years, and LDH > N at diagnosis were included. At dose level 1, cycle 1 consisted of Cyclophosphamide (CY) 1500 mg/m2, Adriamycin (ADR) 70 mg/m2, Vincristine 2mg, Etoposide (ETO) 450 mg/m2, and Prednisone 500 mg/m2. In subsequent cycles doses of CY and ETO were increased: Cycle II and III : CY 4500 mg/m2 and ETO 600mg/m2, cycle IV: CY 6000 mg/m2 and ETO 1000 mg/m2. At dose level 2 ETO was further increased throughout all cycles to 600, 960, 960 and 1480 mg/m2, respectively. From February 97 to August 99, 124 patients were enrolled 14 patients had to be excluded mostly due to correction of initial diagnosis. 110 patients were evaluable with a median observation time of 55 months. 81.8% of patients completed therapy as per protocol. There were 5 cases of treatment related mortality (4.5%), and one of these deaths was due to secondary leukemia (0.9%). Overall survival at 5 years was 67.2 % and freedom from treatment failure was 62.1 %. The following factors were tested with respect to their impact on time to treatment failure (TTTF): age, sex, extranodal disease, bulky disease, performance status, B-symptoms, stage, age-adjusted IPI and LDH. In univariate analysis, only the risk factors of the age-adjusted IPI and IPI itself showed a significant impact on TTTF: see table 1. In a Cox regression multivariate analysis, LDH remained the only independent risk factor with a relative risk of 2.0 (p=0.046). Mega-CHOEP is feasible and effective treatment in younger pts. with aggressive lymphoma. Elevated LDH has major prognostic significance in patients receiving repetitive high-dose therapy and autologous stem cell transplantation. A phase III study comparing Mega-CHOEP + Rituximab to conventional chemotherapy in younger pts. with aggressive NHL is ongoing.
Table 1
Risk factor 2-years TTTF p-value LDH (< 2xONV/> 2xONV) 73.1 vs 48.2% p=0.004 Stage (I, II/III, IV) 76.5 vs 60.9% p=0.044 Performance status (ECOG 0, 1/>1) 73.2 vs 51.2% p=0.047 Age-adjusted IPI (1, 2/3) 72.4 vs 45.4% p=0.007
CHOP Improves Response Rates but Not Overall Survival in Follicular and Mantle Cell Lymphoma (MCL)- Results of a Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).
Authors: Nickenig Christina , Dreyling Martin H. , Schiegnitz Eva , Pfreundschuh Michael , Truemper Lorenz H. , Reiser Marcel , Wandt Hannes , Lengfelder Eva , Ludwig Wolf-Dieter , Berdel Wolfgang E. , Metzner Bernd , Hess Georg , Forstpointner Roswitha , Parwaresch Reza , Hasford Joerg , Unterhalt Michael , Hiddemann Wolfgang 
Published: October 2019

Abstract
In advanced stage follicular lymphoma conventional chemotherapy is non-curative and no major improvement in overall survival has been achieved by different regimens. Similarly, MCL, a lymphoma subtype with an especially poor clinical outcome, cannot be cured by conventional chemotherapy. In 1996, the German Low Grade Lymphoma Study Group (GLSG) started a randomized trial to evaluate the efficacy of two different anthracycline/anthrachinon containing regimens comparing CHOP (cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 2, adriamycine 50 mg/m2 day 1, prednisone 100 mg/m2 days 1–5) and MCP (mitoxantrone 8 mg/m2 days 1–2, chlorambucil 3x3 mg/m2 days 1–5; prednisone 25 mg/m2 days 1–5). 415 previously untreated patients with advanced stage indolent lymphoma were prospectively randomized to receive either 6–8 cycles of CHOP or MCP and are evaluable for induction therapy. 277 patients (67%) had a follicular lymphoma, 86 (21%) had a mantle cell lymphoma and 52 (13%) patients had another indolent histology. Responders up to 60 years were subsequently assigned to either myeloablative radiochemotherapy and autologous stem cell transplantation or to interferon-a maintenance (IFNa ), all other patients received IFNa. As stem cell mobilization was hampered in the MCP arm (only 44% sucessful mobilisations after MCP, 93% after CHOP; p=0.0003), from July 1998 all younger patients were asssigned to the CHOP arm. 86% complete and partial remissions (18% CR) were observed in the CHOP arm, whereas after MCP an overall response rate of 77% was obtained (14% CR, p=0.0094). In subgroup analysis similar improvement of remission rates were detected in follicular lymphoma (91% vs 82%, p=0.026) and mantle cell lymphomas (87% vs 73%, p=0.080). No differences, were observed, however, between both regimens for progression-free survival in both lymphoma subtypes. Overall survival was comparable for FL in both study arms (74% vs 69% at five years, p=0.29). In MCL, overall survival was slightly higher in the CHOP arm (5y OS: 57% vs. 31%; p=0.0578), but this difference was mostly due to unbalanced patient characteristics (IPI). In conclusion, CHOP appears superior to MCP in achieving a higher initial response rate but has no long term impact on response duration or overall survival.
Targeting the Insulin-Like Growth Factor-I Receptor (IGF-IR) in Multiple Myeloma Cells Using Selective IGF-IR Tyrosine Kinase Inhibitors.
Authors: Stromberg Thomas , Ekman Simon , Girnita Leonard , Lennartsson Johan , Hellman Ulf , Carlson Kristina , Osterborg Anders , Vanderkerken Karin , Axelson Magnus , Larsson Olle , Nilsson Kenneth , Jernberg-Wiklund Helena 
Published: October 2019

Abstract
In multiple myeloma (MM) emerging evidence suggest the IGF-1R as an important mediator of tumor cell survival and thus resistance to cytotoxic therapy. Since IGF-1R is not an absolute requirement for maintenance of normal cell homeostasis, interfering with IGF-1R signaling at the receptor tyrosine kinase (RTK) level represents an attractive strategy to improve anti-cancer treatment. However, most IGF-1 RTK inhibitors do not fully discriminate between the IGF-1 RTK and the insulin RTK, i.e. are diabetogenic. Recently, members of the cyclolignan family have been shown to selectively inhibit the phosphorylation of the IGF-1R β-chain without down regulating the RTK activity of the insulin R1. The effect of two of these compounds, picropodophyllin (PPP) and deoxypodophyllotoxin (DPPT), was studied in vitro using a panel of nine MM cell lines and primary tumor cells from MM patients, and in vivo using the 5TMM mouse MM model2. Both IGF-1 RTK inhibitors effectively inhibited growth in all MM cell lines providing increased apoptosis and cell cycle arrest in the G2/M-phase. Notably, the two drug-resistant subclones of the MM cell line RPMI 8226/Dox40 (doxorubicin) and RPMI 8226/LR5 (melphalan), were highly sensitive to the IGF-1 RTK inhibitors. In addition, PPP and DPPT showed inhibitory effects on primary MM cells cultured in vitro with bone marrow stromal cells. Inhibition of the IGF-1 RTK with PPP has been shown to be non-competitive with ATP suggesting interference with the IGF-1R at the substrate level1. To identify tyrosine phosphorylation site(s) on the IGF-1R β-chain potentially regulated by the IGF-1 RTK inhibitors, IGF-1R extracted from RPMI 8226 cells was analyzed by tryptic phosphopeptide mapping following 32P-labeling and treatment with PPP or DPPT. Cleaved phosphopeptides were separated by thin layer chromatography and analyzed by a modified radio-Edman degradation. The results show that the IGF-1 RTK inhibitors do not down regulate any specific tyrosine phosphorylation site of the IGF-1R in MM cells. In vitro kinase assay suggests that PPP/DPPT-induced inhibition of the IGF-1R instead is conducted via a general down regulation of the tyrosine kinase activity of the receptor. Extraction of tyrosine phosphorylated proteins followed by electrophoresis and mass spectrometric analysis revealed additional signaling molecules affected by treatment with the IGF-1 RTK inhibitors e.g. impaired tyrosine phosphorylation of CDK1/cdc2, a cell cycle associated protein known as a potent regulator of apoptosis. Taken together, we show that treatment of MM cells with selective IGF-1 RTK inhibitors decreases survival/proliferation and affects the function of crucial intracellular signaling proteins, thus emphasizing the pivotal role for IGF-1R signaling in MM.
Gene Expression Profiling Defines a Set of New Molecular Markers for Sporadic and Familial Myeloproliferative Disorders.
Authors: Kralovics Robert , Teo Soon-Siong , Passamonti Francesco , Buser Andreas S. , Tichelli Andre , Cazzola Mario , Skoda Radek C. 
Published: October 2019

Abstract
The description of new molecular markers, such as PRV-1, has revived the interest in myeloproliferative disorders (MPD). To gain information on gene expression in cells derived from the MPD clone, we performed Affymetrix U133A microarray analysis on granulocyte RNA from MPD patients and healthy controls. Granulocytes are relevant for expression profiling in MPD, because they originate from the MPD stem cell clone in all PV, IMF, and in a proportion of ET patients. By analyzing 10 patients with PV, 9 patients with ET and 6 healthy controls we identified more than 300 genes with a significantly altered expression (P<0.05). Both PV and ET samples were clearly separated from healthy controls in unsupervised cluster analysis. The expression profiles of PV and ET showed partial overlap. In addition, we analyzed 4 affected individuals from 3 unrelated families with hereditary MPD-like phenotypes. Interestingly, 2 affected individuals from the same family with a PV-like phenotype clustered with the sporadic PV group, whereas 2 patients with familial ET-like phenotype had an expression profile closely resembling sporadic ET. Together with our finding that the family with PV displays clonal hematopoiesis, these results support the concept that studying familial MPDs, i.e. positional cloning of the mutated genes, could be relevant to advancing our understanding of sporadic MPD. From the 300 genes which displayed altered expression in MPD patients, we selected 15 for a detailed quantitative PCR analysis in a Swiss cohort of 42 MPD patients, 3 patients with chronic myelogenous leukemia, 7 patients with secondary erythrocytosis and 14 healthy controls. These markers include genes encoding transcription factors (KLF4, ETS2), a growth factor (FGF13) and proteins involved in signaling (SOCS3, FYB). A combination of three markers (HP, HRP, and ETS2) was sufficient to detect all PV patients that displayed endogenous erythroid colonies, including PV patients with normal levels of PRV-1. MPD patients with a history of complications, such as bleeding, secondary fibrosis or leukemic transformation, exhibited significantly higher levels of expression in a subset of these markers. In contrast, there was no difference in expression levels between MPD patients who received hydroxyurea and patients without cytoreductive treatment, suggesting that hydroxyurea does not alter the phenotypic characteristics of the MPD clone. We are now validating the usefulness of these markers on an independent test cohort of 93 individuals from Italy. The conclusions from this comparison will be presented.
Effect of Human Plasma-Derived Protein C and Murine Recombinant Protein C on Severe Neonatal Sepsis in Mice.
Authors: Muchitsch Eva-Maria , Schwarz Hans Peter , Varadi Katalin , Esmon Charles , Mancuso Giuseppe , Teti Giuseppe 
Published: October 2019

Abstract
Neonatal sepsis is a leading cause of infant morbidity and mortality frequently associated with activation of the coagulation system. Reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death. Although activated protein C is indicated for the treatment of severe sepsis in adults, the risk of severe bleeding may limit its use in neonates. Because the likelihood of inducing bleeding with the zymogen form of protein C is reduced we assessed both human and murine protein C zymogen in a murine neonatal sepsis model. In this model neonatal mice were challenged with viable group B streptococci (GBS). The effect of this septic condition on endogenous protein C levels was evaluated and the effect of treatment with either recombinant murine protein C or human plasma-derived (non-activated) protein C (Ceprotin) investigated. During severe GBS sepsis murine endogenous protein C levels decreased over time in neonatal mice, resulting in a maximum decrease of −30 % at 16 hours after GBS challenge and returned towards baseline at 30 hours. Concomitantly, there was an increase in endogenous protein C activation up to 59 % at 6 hours after GBS challenge, returning to baseline levels at 16 hours. Blocking endogenous murine protein C with an anti-mouse monoclonal antibody increased the mortality rate significantly from 62 to 91 %. Treatment of neonatal septic mice (n=36) with 300 U/kg murine protein C subcutaneously 4 hours before GBS challenge decreased the mortality rate significantly in severe sepsis (LD90) to 64 % (p=0.002). Similarly pretreatment with human plasma-derived protein C (200 IU/kg) 4 hours before GBS challenge increased survival rate significantly in severe septic mice. Treatment with 200 IU/kg (Ceprotin) was even effective given 18 hours after GBS challenge, leading to a decrease in the mortality rate in severe sepsis from 87.5 to 48 %. Despite this species difference and the septic condition, human protein C zymogen was activated to activated protein C and detectable in the circulation of mice. This is the first preclinical study were a beneficial effect of a non-activated protein C could be shown in an animal model of severe neonatal sepsis.
A Factor VII Deficiency Protects Against Lethal Endotoxemia in Mice.
Authors: Xu Haifeng , Ploplis Victoria A. , Joyce David E. , Castellino Francis J. 
Published: October 2019

Abstract
The formation of FVIIa:TF complex is a main contributor to the coagulopathy associated with acute bacterial infection and sepsis. In this study, the role of FVII has been investigated in a murine model of lethal endotoxemia induced by LPS using genetically altered mice expressing low FVII (FVIItTA/tTA). The results demonstrated that FVIItTA/tTA mice had reduced mortality, coagulation, and inflammatory responses compared to wild-type (WT) mice. The reduced thrombin generation in FVIItTA/tTA mice at early stages of post-LPS challenge correlated with less fibrin formation, which was characterized by diminished fibrin deposition in the liver and lower D-Dimer levels in the plasma. Fibrin deposition at late stages of endotoxemia was, however, similar between WT and FVIItTA/tTA mice. There was an apparent increased activation of the intrinsic coagulation pathway in FVIItTA/tTA mice as exhibited by an increased consumption of FXII and FXI zymogen in blood, which appeared to compensate for the diminished thrombin generation characteristic of the low FVII state. Fibrinolytic potential during endotoxemia remained the same between WT and FVIItTA/tTA mice. Reduced inflammatory responses were prominent in FVIItTA/tTA mice, as demonstrated by lower IL-6, MIP-2, and higher IL-10 plasma protein levels, which correlated with the total RNA expression levels in various tissues as determined by Quantitative RT-PCR. These reduced inflammatory responses could be directly due to less FVIIa:TF:PAR-2 signaling, and/or indirectly by less thrombin:PARs signaling in FVIItTA/tTA mice. Additionally, a slight increase in parenchymal organ bleeding was observed in FVIItTA/tTA mice challenged with LPS. Results from these studies indicate that low FVII benefits survival mainly through attenuation of coagulation and inflammatory responses as the result of potentially less coagulation protease signaling. Protection by mechanisms associated with regulation of fibrin formation appears to be limited to early stages of the disease.
Cytogenetic and FISH Study of 92 Patients with Splenic Marginal Zone B-Cell Lymphoma (SMZBCL).
Authors: Salido Marta , Sole Francesc , Espinet Blanca , Gimeno Eva , Florensa Lourdes , Granada Isabel , Astier Laura , Domingo Alicia , Mollejo Manuela , Martinez-Climent Jose A. , Garcia Juan L. , Benet Isana , Hernandez Jesus M. , Martinez Pedro , Piris Miguel A. , Perez-Vila Encarna , Woessner Soledad , Campo Elias , Serrano Sergio 
Published: October 2019

Abstract
Background. In the World Health Organization classification system (WHO), Splenic Marginal Zone B-cell Lymphoma (SMZBCL) is described as an indolent B-cell lymphoma, which generally presents as splenomegaly with involvement of the bone marrow and peripheral blood. The immunophenotype is usually IgM+, IgD+/−, cytoplasmic-Ig−/+, pan B antigens+, CD5−, CD10−, CD23−, CD43−/+ and cyclin D1−. A minority of cases (< 20%) express CD5 antigen. The most frequent cytogenetic aberrations are deletions at 7q22–q32, gains of chromosome 3/3q and involvement of chromosomes 1 and 8. The objective of this study is the genetic characterization of SMZBCL by conventional cytogenetics and FISH.
Patients and methods. We present 92 patients with SMZBCL from a multicenter study after being diagnosed morphologically and immunologically. Conventional cytogenetic studies were carried out on lymphoid cells from 72 hour-peripheral blood and/or spleen cultures stimulated with TPA. FISH was performed with centromeric probes from chromosome 3 and 12 and locus specific probes from P53 gene and 7q31 loci. Cross-species color banding FISH (RxFISH) probe was applied in 11 patients and SKY in 4 patients to redefine/confirm G-banding karyotype.
Results. A clonal chromosome abnormality was found in 62/92 patients (67%) being identified in 37 (60%) as a complex karyotype. The most frequent recurrent abnormalities were deletions of 7q (30 cases) and gains of chromosome 3 (20 cases). 6/20 cases with gains #3, were gains of 3q arm, in three of them resulting from an unbalanced translocation. Thirteen cases showed rearrangements of 3q without gain of material. The chromosomes most frequently involved were: 7q, 3q, 14q, 8q and 1q (in more than 10 cases). Four cases presented gain of chromosome 3/3q and 7q deletion in the same karyotype. Four novel cytogenetic aberrations involving 14q32 were found in this series: t(6;14)(p12;q32) in two cases, t(14;19)(q32;q13) in two cases and t(10;14)(q24;q32), t(1;14)(q21;q32) and t(9;14)(pter-p22::14q32-14q11::9q22) in one case respectively.
Conclusions.
-In our series, the most frequent cytogenetic aberration in SMZBCL is a deletion at 7q (48%) and could be considered as a cytogenetic marker of these entity. -Gains of chromosome 3 or partial gains affecting only 3q arm are frequently observed in SMZBCL (32%) being chromosome 3 commonly rearranged. -RxFISH ans SKY techniques help us to define new aberrations not detected by conventional cytogenetics. -We describe translocations involving 14q32 that could help us to identify novel oncogenes related to SMZBCL.