bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting of mTOR in AML Is Associated with Decreased Growth of Leukemic Cells and Downregulation of VEGF.
Authors: Boehm Alexandra , Aichberger Karl J. , Mayerhofer Matthias , Krauth Maria-Theresa , Derdak Sophia , Pickl Winfried F. , Samorapoompichit Puchit , Sillaber Christian , Florian Stefan , Sonneck Karoline , Sperr Wolfgang R. , Valent Peter 
Published: April 2020

Abstract
The mammalian target of rapamycin (mTOR), a key-regulator of cell cycle progression, has recently been implicated in growth of neoplastic cells and tumor- and leukemia-associated angiogenesis. In addition, mTOR has been described as a regulator of expression of vascular endothelial growth factor (VEGF), a cytokine involved in tumor-related angiogenesis, in various neoplasms. We asked whether mTOR can be employed as a new therapeutic target in acute myeloid leukemia (AML) using the mTOR-targeting drug rapamycin and its derivatives RAD001 (everolimus) and CCI-779. As assessed by 3H-thymidine incorporation, rapamycin was found to counteract growth of AML cells in vitro in 9/11 patients examined as well as in the AML-derived cell lines U937, HL60, and KG1a. The effects of rapamycin on growth of AML cells were dose-dependent (primary AML cells: IC50: 10 pM - 1 nM; inhibition of 3H-thymidine uptake at 1 nM of rapamycin: 43±15 % of control; p&lt;0.05) and associated with G1 cell cycle arrest as well as apoptosis. The same results were obtained with RAD001 and CCI-779. In all responsive cells analyzed, rapamycin and its derivatives decreased expression of VEGF in AML cells at the mRNA- and protein level. Exogenously added VEGF was found to revert the rapamycin-induced inhibition of growth in HL60 cells, but did not revert rapamycin effects in KG1a cells, U937 cells, or primary AML cells. In summary, our data suggest that rapamycin and its derivatives act antileukemic in AML cells by two distinct mechanisms, namely direct inhibition of cell growth and suppression of proangiogenic VEGF. mTOR may be a new interesting target in AML.
Nucleophosmin Protects Hematopoietic Cells from Stress-Induced Apoptosis through Inhibition of P53.
Authors: Pang Qishen , Li June , Zhang Xiaoling , Sejas Daniel P. , Bagby Grover C. 
Published: April 2020

Abstract
Nucleophosmin (NPM) is a multifunctional protein frequently overexpressed in actively proliferating cells including tumor and hematopoietic stem cells. Here we report that NPM protects hematopoietic cells from stress-induced apoptosis through inhibition of the tumor suppressor p53. Specifically, we forced expression of wild-type (WT) NPM or a mutant variant with a deletion of the C-terminal 120 aa of NPM (NPMΔC) by retroviral gene transfer in the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent myeloid cell line MO7e (expresses low level of NPM) and the lymphoblast HSC536 cells derived from a Fanconi anemia (FA) patient in the C complementation group (expresses essentially undetectable NPM). Using a flow cytometric method for caspase 3 activation (early apoptosis), we demonstrated that overexpression of NPM but not the mutant NPMΔC confers MO7e and HSC536 cells resistance to apoptosis induced by growth factor deprivation and treatment with the chemotherapeutic drug etoposide. In addition, suppression of NPM expression by small interfering RNA targeting NPM in chronic myelogenous leukemia line K562 and FA-associated acute myelogenous leukemia cell line UoC-M1 increases etoposide-induced apoptosis, thus providing proof of concept evidence that the pathological elevations of NPM found in cancers and leukemias are important for maintaining cell survival and resistance to apoptosis. Because overexpression of the mutant NPMΔC, which lacks the p53-interacting domain, fails to confer cellular resistance to stress-induced apoptosis, we determined whether NPM protects cells from apoptotic cell death through a mechanism involving p53. We used the genetically matched p53 WT and null mouse bone marrow (BM) cells to show that overexpression of WT NPM protects against ionizing irradiation (IR)-induced apoptosis of wild-type but not p53-null BM cells. Moreover, NPM inhibits IR-induced p53 phosphorylation at Ser18 and transactivation, and interacts with p53 in bone marrow hematopoietic cells. Thus, this study not only demonstrates anti-apoptotic function of a proliferation-promoting protein but also suggests that cancer progression may require increased expression of NPM to suppress p53 activation and maintain cell survival.
Forced Overexpression of Ahi-1 Confers a Proliferative Advantage on Primitive Murine Hematopoietic Cells and Enhances the Effects of BCR-ABL.
Authors: Zhou Leon , Ringrose Ashley , Jiang Xiaoyan 
Published: April 2020

Abstract
Ahi-1 (Abelson helper integration site-1) is a novel gene that is commonly activated by proviral insertional mutagenesis in v-abl or myc-induced murine leukemias and lymphomas. Ahi-1 encodes a unique protein with known signaling features including SH3 and WD40-repeat domains but its normal function is unknown. Involvement of Ahi-1 in leukemogenesis is suggested by the high frequency of Ahi-1 mutations seen in certain virus-induced murine leukemias and by the gross perturbations seen in the expression of human AHI-1 and its isoforms in several human leukemic cell lines, as well as in the primary lin−CD34+CD38− leukemic stem cell-enriched population in patients with chronic phase CML. To further investigate the role of Ahi-1 as a potential co-operating oncogene relevant to BCR-ABL-mediated leukemogenesis, we compared the biological behavior of primitive murine hematopoietic cells from the bone marrow of 5-FU-treated adult C57BL/6 mice after their transduction with MSCV-Ahi-1-IRES-YFP, MSCV-BCR-ABL-IRES-GFP retroviruses, either alone or in combination. Quantitative real-time RT-PCR analysis of RNA from FACS-purified lin−YFP+ (Ahi-1+), lin−GFP+ (BCR-ABL+) and lin−YFP+GFP+ (Ahi-1+ + BCR-ABL+)-transduced bone marrow cells showed that Ahi-1 transcripts were present at 40-fold higher levels in the Ahi-1-transduced cells by comparison to the control cells transduced with the empty MIY vector. Immediately post-transduction, the Ahi-1-transduced cells produced a similar number of colonies as the MIY-transduced control cells in semi-solid cultures containing Steel factor (SF) + IL-3 + IL-6 + EPO, although a small proportion of the Ahi-1+ CFCs (~10%) were already growth factor-independent. In addition, the proliferative activity of the FACS-purified lin−YFP+ (Ahi-1+) cells (as indicated by the rate of expansion of viable cells in a week in liquid cultures containing SF, IL-3, and IL-6) was ~3-fold higher than in cultures initiated with control (lin−YFP+) cells. Moreover, after 4 weeks in longterm culture-initiating cell (LTC-IC) assays, the Ahi-1+ cells produced 2x more CFCs than the control cells. All of these endpoints (proliferative activity, growth factor-dependence and CFC output in LTC-IC assays) are also perturbed by BCR-ABL transduction. Interestingly, in cells that were co-transduced with Ahi-1 and BCR-ABL, all of these effects were further enhanced as compared to cells transduced with either BCR-ABL alone (2–4-fold) or Ahi-1 alone (3–6-fold). Thus, overexpression of Ahi-1 alone deregulates the proliferation control of primitive murine hematopoietic cells and this is additive with the effects of BCR-ABL, suggesting that Ahi-1 and BCR-ABL can cooperate to promote the progression of BCR-ABL-associated diseases like CML.
A Multicentre Study on 100 Cases with Thrombotic Thrombocytopenic Purpura: The Role of Adamts-13 Activity and Anti-Adamts-13 Antibodies.
Authors: Peyvandi Flora , Ferrari Silvia , Lavoretano Silvia , Canciani Maria T. , Mannucci Pier M. 
Published: April 2020

Abstract
Background: The metalloprotease ADAMTS-13 disposes physiologically of the unusually large molecular forms of the von Willebrand factor (VWF), that have the property to aggregate platelets in the microcirculation in the presence of high shear forces. The congenital or acquired deficiency of ADAMTS-13 has been specifically associated with a diagnosis of thrombotic thrombocytopenic purpura (TTP), a rare microangiopathy characterised by the massive formation of occlusive platelet thrombi in the microcirculation.
Aim of the study: To investigate the pathogenic mechanism of TTP in 100 patients referred from 6 different countries and diagnosed on the basis of the presence of at least 3 of the followings laboratory abnormalities or clinical signs: thrombocytopenia, hemolytic anemia, elevated serum level of lactadehydrogenase and neurological symptoms compatible with focal ischemia.
Materials and methods: ADAMTS-13 levels were measured in all patients’ plasma by Collagen Binding assay as previously described (Gerritsen et al., Thromb Haemost 1999); anti-ADAMTS-13 neutralizing antibodies was measured only in patients with low ADAMTS-13 levels, whereas candidate gene mutations were searched only in patients who had low ADAMTS-13 levels (less than 20%) not explained by detectable anti-ADAMTS-13 antibodies, whether or not there was a family history of TTP.
Results: Plasma levels of ADAMTS-13 were severely reduced (&lt;10% of normal) in 48% of the cases, moderately reduced (between 10 and 46%) in 24% and normal (&gt;46%) in 28%. An antibody was identified as the cause of the deficiency in 38% the cases: the great majority of the patients with detectable inhibitor (87%) had severe ADAMTS-13 deficiency but 5 (13%) had moderately reduced ADAMTS-13 activity (ranging from 11 to 25%). Mutation analysis of the ADAMTS13 gene, carried on 15 patients, revealed a genetic variant in only two patients born from consanguineous marriages. The first case was a double heterozygosity for a 29 base pair deletion in exon 3 (291–319del) and a single nucleotide insertion in exon 29 (4143insA). The 290–319del and 4143insA mutations lead to premature stops at codons 368 and 1387 respectively. The second one consisted in a homozygosity for a 6 base pair deletion in exon 23 (2930–2935del). This deletion leads to a substitution of Cys 977 by Trp, and a deletion of 2 aminoacids, Ala and Arg, at residues 978 and 979 respectively.
Conclusion: The study of this large series of patients with TTP indicates that in nearly one third of patients ADAMTS-13 levels were normal. In more than half of the patients with low plasma level of the protease, ADAMTS-13 deficiency was not due to the presence of inactivating antibodies or gene abnormalities. An unexpected observation was that an inhibitor was also found in 5 patients with moderately reduced levels of ADAMTS-13.
A Meta-Analysis to Determine the Risk of Heparin Induced Thrombocytopenia (HIT) and Isolated Thrombocytopenia in Prophylaxis Studies Comparing Unfractioneted Heparin (UFH) and Low Molecular Weight Heparin (LMWH).
Authors: Martel Nadine , Wells Philip S. 
Published: April 2020

Abstract
HIT is an uncommon but potentially devastating complication of anticoagulation with UFH or LMWH. The absolute risk of HIT and thrombocytopenia are not clearly defined and no summary data to provide odds ratio is available. We conducted a meta-analysis to determine and compare the incidences of HIT in surgical or medical patients receiving thromboprophylaxis with either UFH or LMWH. We searched MEDLINE-OVID and MEDLINE-PubMed using and combining the following terms: heparin induced thrombocytopenia, low molecular weight heparin, prophylaxis, randomized controlled trials, prospective studies. The function Explode was used. Search was limited to humans from 1984 to 2004. Over 400 abstracts were reviewed and then 91 articles were independently reviewed by two authors, without any restriction of article language. Included studies were those comparing prophylactic UFH and LMWH and measuring HIT (defined as platelets drop &gt; 50% or &lt; 100 X 109/L AND positive laboratory HIT assay) or thrombocytopenia (defined as platelets drop &gt; 50% or &lt; 100 X 109/L) as outcomes. Studies defining thrombocytopenia with lower thresholds were excluded because cases could have been missed. Extracted data included patient characteristics, drug regimens, HIT, thrombocytopenia and venous thromboembolism rates. Disagreements were resolved by consensus. Eligible studies were included into the meta-analysis using a random-effects model to determine the odds ratio for the incidences of HIT and thrombocytopenia between UFH and LMWH. Funnel plots were made to assess possible publication bias. 17 articles were eligible with a total of 8500 patients: 2 RCTs measuring HIT; 10 RCTs measuring thrombocytopenia, and 5 prospective non-randomized studies with comparison groups measuring HIT. Three analysis were performed and all favoured the use of LMWH: 1) 2 RCTs measuring HIT showed an OR of 0.10 (95% confidence interval [CI] 0.01–0.77; p=0.03); 2) all 7 studies measuring HIT showed an OR of 0.11 (95%CI= 0.05–0.26; p&lt; 0.00001); 3) 12 RCTs measuring thrombocytopenia showed an OR of 0.45 (95% CI= 0.26–0.80; p=0.006). Comparing the rates in the 7 studies measuring HIT UFH resulted in HIT in 3.4% (95%CI=2.6% to 4.3%) of cases and LMWH resulted in HIT in 0.2% (95% CI=0.1% to 0.6%), a statistically significant difference (p&lt;0.0001). This meta-analysis confirms the lower incidences of HIT and thrombocytopenia with LMWH prophylaxis compared to UFH. Absolute rates of HIT with LMWH are very low. The HIT rates should be considered when determining the drug of choice for thromboprophylaxis in surgical and medical patients.
The Association between Tissue Factor-Exposing Microparticles and the Activation of the Coagulation System in Cancer Patients.
Authors: Weltermann Ansgar , Hron Gregor , Kollars Marietta , Kornek Gabriela , Quehenberger Peter , Eichinger Sabine , Kyrle Paul Alexander 
Published: April 2020

Abstract
Background: Malignancy is a major risk factor of venous thromboembolism. In addition to circumstantial factors such as chemotherapy, the pathogenesis of thrombosis in cancer patients is directly influenced by tumor related factors. In this respect, the expression of tissue factor (TF) on tumor cells is considered to play an important role. Besides its cellular expression, more recent studies focused on TF exposure on circulating microparticles. The role of these TF exposing microparticles with regard to the pathogenesis of VTE in cancer patients, however, has not yet been investigated. We therefore conducted a prospective case control study in order to determine (a) the number and cellular origin of TF exposing microparticles in cancer patients and (b) the association between these microparticles and the activation of the coagulation system.
Materials and Methods: A total of 20 patients with advanced colorectal cancer (Dukes D) and 20 healthy, age- and sex-matched controls were included. Microparticles were isolated from plasma, stained with annexin V, cell-specific antibodies and analysed by flow cytometry. The activation of the coagulation system was measured by D-dimer (ELISA).
Results: Compared to the controls, the total number of TF exposing microparticles was significantly higher in the patient group (32.5 ± 23.9 vs. 18.1 ± 10.0 k/ml plasma, p = 0.007). These finding was due to a higher number of TF exposing microparticles originating from thrombocytes (12.9 ± 7.9 vs. 6.5 ± 2.9 k/ml plasma, p = 0.017) and from monocytes (9.1 ± 6.5 vs. 5.5 ± 1.4 k/ml plasma, p = 0.11) in cancer patients. Likewise, D-Dimer levels were higher among cancer patients as compared to the controls (1.61 ± 1.58 vs. 0.40 ± 0.36 μg/ml, p = 0.001). The number of TF exposing microparticles correlated with D-dimer (r = 0.67, p &lt; 0.001).
Conclusion: Both the significant elevation of TF exposing microparticles in the circulation of cancer patients and the association between these microparticles and the activation of the coagulation system suggest a potential role of TF exposing microparticles in the pathogenesis of venous thromboembolism in cancer patients.
Role of Congenital and Acquired Thrombophilic Factors in the Failure of Thrombolysis in Patients with Acute Myocardial Infarction.
Authors: Fossati Carolina , Patti Giuseppe , Pasceri Vincenzo , Giannetti Barbara , Nusca Annunziata , Mega Simona , Annibali Ombretta , Di Sciascio Germano , Avvisati Giuseppe 
Published: April 2020

Abstract
In patients with acute myocardial infarction, a persistently occluded infarct related coronary artery, despite a correct thrombolysis, is associated with an unfavourable prognosis. Therefore, identification of variables predictive of ineffective thrombolysis is crucial to identify patients at higher risk of thombolysis failure. To investigate whether or not acquired or congenital thrombophilic factors had a role in the ineffective thrombolysis we designed this study in which patients treated with intravenous thrombolysis for a ST segment elevation myocardial infarction were blind tested for the thrombophilic factors on the occasion of the coronary angiography performed within 30 days from the thrombolytic treatment. Patients with known factors influencing metabolism and circulating levels of homocysteine were excluded from this study. From October 2003 to May 2004, 104 consecutive patients treated with intravenous thrombolysis for a ST segment elevation myocardial infarction were available for this study, 3of these refused to participate in the study All patients underwent,within 30 days from thrombolysis, a coronary angiography and of the 101 participating in the study, 40 resulted occluded while 61 had a patent artery. In these 101 patients we blind tested the levels of ATIII,PC,PS; moreover, we determined also the levels of homocysteine, the presence of Lupus Anticoagulant (by mean of DRVVT and Silica Clotting Time) and ACA of IgG type as well as the Plasminogen levels. Furthermore, blood samples were also analysed by PCR technique for the presence of Factor V Leiden, the G20210A Factor II mutation and the C677T mutation in the MTHFR gene. Surprisingly, patients with MTHFR 677TT homozygosis had a significantly higher prevalence of occluded infarct artery (73%) vs those with MTHFR 677CT/CC genotype (30%, P=0.0008); frequency of MTHFR 677TT homozygosis was 4-fold higher in patients with occluded vs those with a patent vessel (40% vs 10%, P=0.0008). MTHFR 677TT genotype predicted the risk of failed thrombolysis with a specificity of 90% and multivariate analysis showed that MTHFR 677TT homozygosis was independently associated with an occluded artery (odds ratio 3.8, 95% confidence interval 1.1–9.1; P=0.03). None of the other studied factors at multivariate analysis influenced the thrombolysis failure. Moreover, patients with occluded infarct vessel and MTHFR 677TT genotype had the highest homocysteine levels (P=0.011). Our findings indicate that in patients with acute myocardial infarction, MTHFR 677TT homozygous is independently associated with a persistently occluded infarct-related artery after thrombolysis.
Efficacy and Safety of Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) Therapy with Rituximab Maintenance in Patients with Untreated Low-Grade Follicular Lymphoma.
Authors: Sweetenham John William , Dicke Karel , Arcaroli John , Kogel Karen , Rana Tahir M. , Rice Laura L. 
Published: April 2020

Abstract
Background: Recent trials have demonstrated the efficacy of rituximab induction therapy, when followed by maintenance rituximab, in patients with untreated low-grade follicular NHL. Earlier studies, employing low-dose total-body irradiation as an initial treatment for follicular lymphoma (FL), have previously shown the inherent radiosensitivity of the disease. Based on these findings, we evaluated the efficacy and safety profile of frontline 90Y ibritumomab tiuxetan (Zevalin®) delivered prior to maintenance rituximab in patients with low-grade FL.
Methods: Patients were eligible for treatment if they presented with histologically confirmed, previously untreated low-grade FL. Additional eligibility criteria included stage III or IV disease and a need for therapeutic intervention because of constitutional symptoms, evidence of disease progression, or organ dysfunction directly attributable to NHL. Patients were excluded if there was evidence of histologic transformation to aggressive disease. On day 1, patients received an initial infusion of rituximab (250 mg/m2) followed by an imaging dose of Indium 111 (111In) ibritumomab tiuxetan (5 mCi). One week later, a second infusion of rituximab (250 mg/m2) was given, proceeded by an injection of 90Y ibritumomab tiuxetan (0.3 or 0.4 mCi/kg, depending upon platelet count). Rituximab maintenance therapy (375 mg/m2 x 4) was scheduled at 6-month intervals over 2 years. Endpoints included clinical response rates using standard International Workshop Response Criteria (IWRC) and toxicity.
Results: Ten patients, presenting with grade I or II FL, have been treated with 90Y ibritumomab tiuxetan, and 8 are evaluable for treatment response. The median age of patients was 58 years (range, 40–82) and 50% (5/10) of patients had stage IV disease. Delivered doses of 90Y ibritumomab tiuxetan ranged from 21–32 mCi. Toxicities were primarily hematologic with grade 3 cytopenia occurring in 38% (3/8) of patients. Of the 8 patients qualifying for evaluation, 5 (62%) had complete responses and 3 (38%) had partial responses to 90Y ibritumomab tiuxetan induction.
Conclusions: These data illustrate that frontline 90Y ibritumomab tiuxetan therapy produces high rates of response (100% in this small population) in patients with low-grade FL. Toxicities following administration of radiolabeled antibody were manageable. Further follow-up is needed to determine the long-term efficacy of combining frontline radioimmunotherapy with antibody-based maintenance.
SGN-30 (Anti-CD30 Monoclonal Antibody) Is Active and Well Tolerated in Patients with Refractory or Recurrent Systemic Anaplastic Large Cell Lymphoma.
Authors: Forero-Torres Andres , Bernstein Steven , Gopal Ajay , Foss Francine , Leonard John , Rosenblatt Joseph , Bartlett Nancy , Younes Anas , Fisher David , Cheson Bruce , Carabasi Matthew , Bociek Gregory , Hart Bruce , McDonald Michael 
Published: April 2020

Abstract
SGN-30 is a chimeric mAb which recognizes the CD30 antigen found on tumor cells from patients (pts) with Hodgkin’s disease (HD) and anaplastic large cell lymphoma (ALCL). In preclinical experiments, SGN-30 was shown to have antitumor activity in both in vitro and in vivo models of HD and ALCL. The results of a multi-dose phase I study showed minimal toxicity associated with doses of 2–12 mg/kg as six weekly IV infusions. One complete response (CR) was seen in the three non-Hodgkin’s lymphoma patients (2 ALCL, 1 diffuse large B-cell lymphoma) accrued to the study and two patients demonstrated stable disease (SD) over time. A phase II multi-dose study was initiated to further evaluate the safety, antitumor activity and pharmacokinetics of six weekly IV infusions of 6 mg/kg of SGN-30 in pts with relapsed or refractory HD or systemic ALCL (sALCL). Five patients (2M, 3F) with ALCL have been enrolled, with a median age of 52 (range 33–75) and 3 median prior therapies (range 2–5). Multiple doses of SGN-30 have been well tolerated in all of the pts. Drug-related adverse events have been typically mild and consistent with mAb administration. No drug-related grade 3/4 events have been observed. Two patients have had objective responses with one patient achieving a CR. The patient’s baseline CT scan showed a 5.1 x 2.0 cm chest wall mass in the lower left anterior lateral chest wall representing local lymphoma recurrence. After six doses of SGN-30 the mass disappeared completely with some edema in the chest wall but no obvious residual mass. The duration of response is pending at this time, and it will be presented in the meeting. Another patient experienced a partial response. The patient, who entered the study with constitutional symptoms and extensive cutaneous and nodal disease, had resolution of all skin lesions, significant reduction in adenopathy and improvement in constitutional symptoms after completion of her SGN-30 therapy. The patient progressed after discontinuation of therapy. Of the other three patients, one had SD and two progressed. These early results are promising and accrual to the trial continues.