bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presence of Unfavorable Cytogenetic Abnormalities Is the Strongest Predictor of Poor Survival in Secondary Myelofibrosis.
Authors: Dingli David , Schwager Schwager M. , Ruben Mesa A. , Li Chin Yang , Tefferi Ayalew 
Published: April 2020

Abstract
Post-polycythemic (PPMM) and post-thrombocythemic (PTMM) myeloid metaplasia are consensually referred to as secondary myelofibrosis (sMF). Prognostic variables in sMF are not as well defined as they are for agnogenic myeloid metaplasia (AMM). Such information is particularly crucial for management decisions in transplant-eligible patients. Accordingly, we examined the prognostic impact of several clinical and laboratory variables in 66 young patients (age &lt; 60 years) with sMF including 37 with PPMM and 29 with PTMM. Multivariate analysis of parameters other than cytogenetics identified older age (p=0.02), anemia (hemoglobin level &lt; 10 g/dL; p=0.007), and PPMM (p=0.009) as independent risk factors for shortened survival. However, when such analysis was restricted to patients in whom cytogenetic studies were performed (n=31), the presence of unfavorable cytogenetic abnormalities (i.e. clones other than 20q- and 13q-) became the one and only adverse prognostic factor for survival (p=0.001).
Figure Figure
The prognostic value of cytogenetics was independent of the Dupriez prognostic score (p=0.003).
Figure Figure
A similar analysis in a temporal cohort of 50 age-matched patients with AMM also identified unfavorable cytogenetics as an independent predictor of poor survival along with thrombocytopenia and anemia. The current study suggests an important prognostic role for cytogenetics in both de novo and secondary myelofibrosis.
Estrogen-Based Hormone Therapy and Thrombosis Risk in Women with Essential Thrombocythemia.
Authors: Gangat Naseema , Wolanskyj Alexandra P. , Schwager Susan M. , Mesa Ruben A. , Tefferi Ayalew 
Published: April 2020

Abstract
Background
Estrogen-based hormone treatment (EBHT), in the form of either oral contraceptives or hormone replacement therapy, is generally felt to be associated with an increased risk of thrombosis in women with essential thrombocythemia (ET). However, there is insufficient evidence to support or refute such a concern.
Methods
Data was abstracted from medical records of a consecutive cohort of women with ET seen at the Mayo Clinic. Thrombotic risk was determined by the occurrence of a major thrombotic event namely myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, peripheral arterial thrombosis, pulmonary embolism, or deep venous thrombosis at or after diagnosis of ET.
Results
i. Information regarding EBHT at or after the diagnosis of ET
The study cohort included 307 women with ET (median age, 55 years; range 16–88) with a median follow-up of 133 months from diagnosis (range, 0.2–397). EBHT at or after diagnosis was documented in 93 women (30%); 59 patients were on EBHT at time of diagnosis and treatment was initiated after diagnosis in 34 patients. Among the 59 patients who were receiving EBHT at the time of diagnosis, treatment was discontinued within one month of their ET diagnosis in 17 patients but continued in the other 42 patients for a median of 48 months (range, 2–168). In the 34 patients with EBHT that was initiated after the diagnosis of ET, median treatment period was 44 months (range, 1–144).
ii. Correlation between EBHT and thrombosis at diagnosis
At diagnosis, major thrombosis was documented in a total of 74 patients (24%) that included 11 of the 59 patients (19%) on EBHT and 63 of 248 patients (25%) that were not receiving such therapy at the time of diagnosis (p=0.28).
iii. Correlation between EBHT and thrombosis after diagnosis
A total of 95 patients (31%) experienced a subsequent (i.e. post-diagnosis) thrombotic episode during the study period. These occurred in 65 of 214 patients (30%) that were not exposed to EBHT at or after diagnosis, 5 of 17 patients (29%) in whom EBHT was discontinued with the diagnosis of ET, 13 of 42 patients (31%) in whom EBHT was continued despite the diagnosis of ET, and 12 of 34 patients (35%) in whom EBHT was started after the diagnosis of ET (p=0.95). Furthermore, duration of EBHT, using a cutoff value of 1 year, did not significantly affect the incidence of thrombotic events (p=0.67).
The different comparative groups were similar in age distribution as well as frequency of other cardiovascular risk factors including smoking, diabetes mellitus, hypertension, and hyperlipidemia.
Conclusion
The current study addresses the important issue of safety pertaining to the use of estrogen-based hormones in women with ET and did not reveal a significant alteration of thrombosis risk as a result of hormone therapy.
Protective Effect of Activated Protein C in Murine Endotoxemia: Mechanism of Action.
Authors: Kerschen Edward J. , Cooley Brian C. , Castellino Francis J. , Griffin John H. , Weiler Hartmut 
Published: April 2020

Abstract
Recombinant activated protein C (APC) reduces mortality of patients with severe inflammatory disease associated with multi-organ failure. APC exerts anticoagulant, anti-inflammatory, and cytoprotective effects. The contribution of these distinct APC activities to the overall therapeutic efficacy in septic patients is unknown. The aim of the study is to delineate the mechanism underlying the protective effect of APC in mouse endotoxemia. We first establish an experimental mouse model to demonstrate that recombinant murine APC reduces 6 day mortality of mice subjected to LPS-induced endotoxemia. APC treatment did not alter the extent of inflammatory cytokine release. Recombinant human APC did not exhibit therapeutic efficacy in this model. In contrast, recombinant human and mouse APC reduced to a similar extent experimentally induced arterial thrombus formation. The therapeutic efficacy of wild type recombinant murine APC was abolished in genetically engineered mice with reduced expression of the endothelial protein C receptor (EPCR). Recombinant mutant murine APC with greatly reduced anticoagulant potency was as effective as wild type murine APC in reducing mortality of mice subjected to LPS-induced septicemia. Mice homozygous for the Leiden polymorphism in the factor V (fV) gene, which renders coagulation factor V partially resistant to the anticoagulant effect of APC secondary to blocked fV proteolysis at R504 (R506 in humans), were refractory to the therapeutic benefit conveyed by administration of recombinant wild type mouse APC. In summary, these findings provide evidence that the therapeutic efficacy of recombinant APC is predominantly based on the ability of APC to interact with the endothelial protein C receptor, and that the anticoagulant activity of APC is not sufficient for achieving protection against mortality in a mouse model of endotoxemia. On the other hand, cleavage of fV at R506 appears necessary for retaining therapeutic efficacy in carriers of the fV Leiden allele.
Two Oncogenic Hits Are Required To Initiate Lymphomagenesis in Adult, but Not Neonatal Hosts.
Authors: Fan Alice C. , Giuriato Sylvie , Karlsson Asa , Padua Rose Ann , Felsher Dean W. 
Published: April 2020

Abstract
The hallmark (8:14) translocation of Burkitt’s lymphoma causes MYC overexpression, a primary event in the development of Burkitt’s lymphoma. While Burkitt’s lymphoma comprises nearly one third of childhood malignancies, it is rare in adults. Among many explanations is the possibility that the capacity for a lymphocyte to undergo malignant transformation by MYC activation is influenced by factors related to the developmental state of the host. To address this possibility, we used transgenic mice in which the MYC proto-oncogene is conditionally regulated via the Tetracycline Regulatory System (Tet system). When MYC was activated in cohorts of mice less than 3 weeks of age, mice universally succumbed to lymphoma within 23 weeks. However, when MYC was activated in adult mice (over 7 weeks of age) the mice failed to develop lymphoma within 50 weeks. We were not able to detect differences in the effects of MYC on the proliferation or apoptosis in lymphocytes from adult versus neonatal hosts. We next explored whether the concomitant activation of MYC with a second oncogene could induce lymphomagenesis in adult mice. When we conditionally induced both MYC and BCL2 or MYC and RAS in adult hosts, mice succumbed to lymphoma with a mean latency of 24–27 weeks. Our results suggest that in adult hosts, concurrent activation of at least two oncogenes is required for MYC to initiate tumorigenesis.
Surface-Enhanced Laser Desorption/Ionization Mass Spectral Plasma Profiles Distinguish Individuals of a Protein C-Deficient Family with a Thrombotic Episode before the Age of 40 from Age-Matched Family Members without a History of Thrombosis.
Authors: Svensson Annika , Whiteley Gordon , Callas Peter , Bovill Edwin 
Published: April 2020

Abstract
We tested the hypothesis that differences in the low molecular weight (500–20.000 Da) proteomic profile of plasma may be detectable between members of a protein C-deficient thrombophilic family who have suffered thrombotic events before age &lt;40 compared to family members without a history of venous thrombosis.
Unfractionated plasma samples from members of a previously described large thrombophilic kindred with type I protein C deficiency were applied to ProteinChip weak cation exchange interaction chips (WCX2; Ciphergen Biosystems, Fremont, CA) and subjected to SELDI-TOF (surface-enhanced laser desorption/ionization time-of-flight) mass spectrometry using the Ciphergen PBSII ProteinChip System (Ciphergen Biosystems, Freemont, CA, USA). Profiles were analyzed by a boosted decision-tree algorithm. When individuals who had presented with deep venous thrombosis before the age of 40 (n=21) were compared to age-matched, healthy family members (n=50), the proteomic patterns defined by the decision-tree analysis could classify the entity of DVT before age 40 with 66% sensitivity, at a specificity of 86%. When a small group of cases with history of superficial venous thrombosis (n=6) was added to the case group, the sensitivity was 87.5% at a specificity of 80%. These data support the hypothesis that members of the protein C deficient Vermont kindred II who suffer a thrombotic event before age 40 display significant differences in low-molecular weight proteomics profile compared to those who remain disease-free. This is the first study to apply SELDI-TOF technology in conjunction with a bioinformatics tool to analyze low molecular weight proteomic patterns in patients with venous thrombosis. We are presently pursuing higher resolution analysis with the prOTOF, MALDI orthogonal time of flight mass spectrometer system in order to identify specific peptides
The Role of p53 in C-myc Induced Lymphomagenesis Mediated by the IgH 3′ Enhancers.
Authors: Wang Jinghong , Boxer Linda M. 
Published: April 2020

Abstract
Translocation of the c-myc oncogene to the immunoglobulin heavy chain gene (IgH) locus is the most common chromosomal abnormality in Burkitt’s lymphoma. Our mouse model (IgH-3′E-myc) with the IgH 3′ enhancers integrated 5′ of the c-myc gene demonstrated that the IgH 3′ enhancers play an important role in c-myc deregulation and B cell lymphomagenesis. In this study, we examined the role of the tumor suppressor p53 in c-myc-induced B cell lymphomagenesis by developing IgH-3′E-myc mice with only a single p53 allele (p53+/−-mycE mice). We found that lymphoma development and death were significantly accelerated in these mice compared to the IgH-3′E-myc mice. p53+/−-mycE mice developed Burkitt-like B cell lymphomas at about 5 months of age, and the lymphomas had a clonal origin. In premalignant B cells, p53 expression was comparable to that in wildtype B cells; however, significantly decreased p53 levels were observed in malignant lymphoma cells. In addition, p53 expression was not up-regulated in response to etoposide in lymphoma cells. The remaining p53 allele was present, and no mutations were detected in the coding region. Increased expression of Mdm2 was observed in half of the lymphomas. Premalignant B cells from p53+/−-mycE mice showed higher induced and spontaneous apoptosis due to increased c-myc expression. However, malignant lymphoma cells had a greatly increased survival rate in culture and were more resistant to chemotherapeutic agents. The majority of the lymphomas showed increased expression of the anti-apoptotic protein Bcl-xL. We found that p53 could negatively regulate the bcl-xL promoter in lymphoma cells, and a region that was responsive to p53 in the bcl-xL promoter was identified. These data support the conclusion that decreased p53 levels and overexpression of Bcl-xL play an important role in c-myc-induced lymphomagenesis mediated by IgH 3′ enhancers.
An Activating Mutation (Ser525Pro) within the Transactivation Domain of REL in Two Patients with Human B-Cell Lymphomas Enhances REL’s In Vitro Transforming Activity.
Authors: Trautmann Heiko , Starczynowski Daniel T. , Pott Christiane , Harder Lana , Arnold Norbert , Siebert Reiner , Kneba Michael , Gilmore Thomas D. 
Published: April 2020

Abstract
REL/NF-κB transcription factors are implicated in the control of apoptosis and cell growth particular in hematopoetic lineages. The REL locus at chromosomal region 2p13–16 is frequently amplified in B-cell lymphomas including diffuse-large B-cell lymphoma (DLBCL) and may play a role in lymphomagenesis. Overexpression of wild-type REL can transform chicken lymphoid cells in culture, and several experimentally-generated mutations within the REL C-terminal transactivation domain (TAD) have been previously shown to enhance REL’s transforming ability.
We analysed 83 B-cell lymphomas included in the ‘Deutsche Krebshilfe’ funded network „Molecular Mechanisms in Malignant Lymphoma“ for the presence of activating mutations in the coding region of REL. We performed a systematic dHPLC screening for mutation discovery and identified an identical point mutation in two human B-cell lymphomas (a t(14;18)-positive follicular lymphoma and a mediastinal B-cell lymphoma) that changes Ser525 to Pro within the REL TAD. In the mediastinal B-cell lymphoma, the mutation in REL was proven to be of germline origin. FISH showed an amplification of the REL locus in the tumor cells of this case. Quantitative allelic discrimination of S525P indicates that the mutant REL gene was over-represented in both cases. By in vitro experiments we could show that the S525P mutation enhances the in vitro transforming ability of REL in chicken spleen cells. In addition, REL-S525P differs from wild-type REL in its ability to activate certain κB site-containing reporter plasmids in transient transfection assays. In particular, REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein is over-expressed in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 of REL falls within a sequence that is similar to other known phosphorylation sites of the IκB kinase, and REL-S525P shows a reduced ability to be phosphorylated by IKKα in vitro. The S525P mutation reduces IKKα- and TNFα-stimulated transactivation by REL, as measured in GAL4 reporter assays. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNFα-induced cell death than cells transformed by wild-type REL. These results represent the first identification of a tumor-derived activating mutation in the REL proto-oncogene, and they suggest that the S525P mutation contributes to the development of human B-cell lymphomas by altering REL’s ability to induce target gene expression by affecting an IKKα-regulated transactivation activity.
Lymphoblastic Leukemia/Lymphoma in Mice Overexpressing the Mer Receptor Tyrosine Kinase.
Authors: Salzberg Dana B. , Keating Amy K. , Anwar Adil , Sawczyn Kelly , Hill Kimberley , Sather Susan , Park Jane , DeRyckere Deborah , Everett Doug , Graham Douglas K. 
Published: April 2020

Abstract
Mer is a transmembrane tyrosine kinase receptor that belongs to a subfamily of tyrosine kinases including Axl and Tyro-3. Within the hematopoietic lineages, Mer is expressed in monocytes/macrophages, dendritic cells and platelets. Normal thymocyte subsets and mature lymphocytes do not express Mer. However, Mer RNA transcript and Mer protein is ectopically expressed in a subset of B cell and T cell acute lymphoblastic leukemia (ALL) cell lines and patient samples. Previous in vitro studies have suggested that constitutive expression of Mer has anti-apoptotic properties and transforming potential. The overexpression of Mer in ALL suggests that this tyrosine receptor kinase may play an important role in leukemogenesis. In an attempt to investigate the oncogenic potential of Mer in vivo, we created a transgenic mouse model in which the expression of the full-length murine Mer cDNA was placed under the control of the Vav promoter. Ectopic expression of Mer has been demonstrated in thymocytes and lymphocytes of the transgenic mice. The ability to activate the ectopic Mer protein with the ligand Gas 6 has confirmed that the protein is functional. Gas 6 stimulation of Mer in lymphocytes from transgenic mice lead to activation of downstream anti-apoptotic signaling pathways including AKT and ERK 1/2. At 12–24 months of age, 60% of the Mer transgenic mice developed lymphadenopathy, hepatosplenomegaly and the presence of circulating lymphoblasts. Histopathological analysis was consistent with a diagnosis of lymphoblastic leukemia/lymphoma. The majority of the lymphomas characterized by flow cytometry were identified as T cell lymphomas with a small subset having co-expression of both T cell and B cell markers. Tumor-free survival in Mer transgenic mice were significantly decreased as compared to the wild type mice (p=0. 003). These data suggest that Mer may play a cooperative role in leukemogenesis and is an attractive candidate marker for biologically targeted leukemia/lymphoma therapy.
Bcl2 Flexible Loop Domain Positively and Negatively Regulates Survival Function through Direct Interaction with p53.
Authors: Deng Xingming , Gao Fengqin , Flagg Tammy , Anderson Jessica , May W. Stratford 
Published: April 2020

Abstract
p53 not only functions as a transcription factor but also has a direct extranuclear apoptogenic role at the mitochondria. We have discovered that DNA damage-induced p53/Bcl2 binding is associated with decreased Bcl2/Bax interaction and increased apoptotic cell death in a mechanism regulated by Bcl2’s flexible loop regulatory domain (FLD) in IL3-dependent myeloid NSF/N1.H7 cells. Purified p53 protein can disrupt the Bcl2/Bax complex by directly binding to a negative regulatory region of the FLD (aa32–68). Deletion of the negative regulatory region (aa32–68) abolishes Bcl2/ p53 binding and enhances its antiapoptotic function. Removal of aa69–87 of the FLD, which contains Bcl2’s phosphorylation site(s) (T69, S70 and S87), enhances Bcl2/p53 binding and abrogates Bcl2’s potent survival activity, indicating this is a positive regulatory region. Phosphorylation of Bcl2 in the FLD inhibits p53 binding since the phosphomimetic T69E/S70E/S87E (EEE) but not the nonphosphorylatable T69A/S70A/S87A (AAA) Bcl2 mutant displays a reduced capacity to bind p53 and more potently inhibits p53-induced cytochrome c release. A full-length Bcl2 loop-only protein (aa32–87) can directly bind p53 to impede Bcl2/p53 binding in vitro. Either DNA damage or expression of p53 targeted to mitochondria results in Bcl2/p53 binding followed by exposure of Bcl2’s BH3 domain and inactivation of Bcl2’s antiapoptotic function. Therefore, Bcl2’s FLD contains both a positive and negative regulatory regions which functionally regulate Bcl2’s antiapoptotic activity via differential binding of Bax and p53, respectively.
Phosphorylation of the MCT-1 Oncogene Protein by p42/44 MAPK Is Required for Transformation.
Authors: Nandi Suvobroto , Reinert Line S. , Hachem Ali , Gartenhaus Ronald B. 
Published: April 2020

Abstract
The MCT-1 oncogene has been shown to decrease cell doubling time, dramatically shorten the duration of G1 transit time and/or G1-S transition, as well as transform NIH3T3 fibroblasts. We subsequently demonstrated that there are significantly increased levels of MCT-1 protein in a subset of primary diffuse large B-cell lymphomas (DLBCL) as well as some T-cell lymphomas compared with normal lymphoid tissue. We have mapped MCT-1 to chromosome Xq22-24, a region that has been previously shown to contain amplified DNA in a variety of primary B-cell lymphoid neoplasms using comparative genomic hybridization (CGH). Recent data has shown that MCT-1 is involved in protection against serum-starvation induced apoptosis involving enhanced AKT activity. Phosphorylation is one potential mechanism by which the activity of molecules involved in cell cycle regulation/survival is rapidly modulated. The RAS/MEK/ERK signal transduction cascade plays a prominent role in the regulation of cell growth and proliferation. The MCT-1 protein is predicted to have several putative phosphorylation sites including, a p42/p44 MAPK and cyclinB/cdc2 kinase substrate site. These cdc2 and MAPK phosphorylation sites have been mutated through site-directed mutagenesis and expressed in human dermal fibroblasts (HDF) in order to examine the role of these kinase sites on cell growth and transformation. We demonstrated that the phosphorylation of MCT-1 by p42/p44 MAPK is critical for its ability to stimulate cell proliferation as well as cellular transformation. Our data suggest that targeting the RAS/MEK/ERK signal transduction cascade may be a useful therapeutic approach in those lymphomas and related disorders overexpressing MCT-1.