bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preoperative Fibrin Monomer Allows Prediction on Excessive Intraoperative Blood Loss - Finally a Preoperative Coagulation Screening That Works?.
Authors: Korte Wolfgang C. , Wettstein Patrick , Gabi Konrad , Rohner Mirjam , Corbetta Cinzia , Schnider Thomas 
Published: April 2020

Abstract
We recently demonstrated that patients with intraoperative coagulopathy and increased blood loss show a persistent pre-, intra- and postoperative increase in fibrin monomer concentration as well as an excessive intraoperative consumption of fibrinogen and F. XIII. We therefore wanted to test the hypothesis that preoperative fibrin monomer concentrations can be used as a risk indicator for intraoperative blood loss.
In 168 patients admitted to the surgical service of our hospital, median intraoperative blood loss increased significantly with preoperative fibrin monomer (FM) quartiles (50, 100, 200 and 400 ml in preoperative FM quartiles 1 to 4; p&lt;0.001, ANOVA on ranks and p&lt;0.05 for group wise comparison, Rank Sum test). Stratification in FM quartile groups was unrelated to diagnoses with the exception of laparoscopic cholecystectomy (found significantly less frequent in quartile 4 than 1). Most importantly, accuracy evaluation showed that preoperative fibrin monomer concentration &lt; 3 μg/l excluded intraoperative blood loss &gt; 500 ml with 92% sensitivity, 95% negative predictive value and 41% exclusion rate. This compares well to other exclusion strategies such as the exclusion of deep venous thrombosis with the help of D-dimer and probability scores. In contrast, blood loss was unrelated to preoperative values of prothrombin time, platelet count and actived partial thromboplastin time. The FM ROC curve compared to the PT ROC curve is shown in the figure; the area under the curve for the FM ROC curve was significantly greater than the one for the PT ROC curve (0.743, 95% CI 0.655 – 0.811 vs. 0.555, 95% CI 0.473 – 0.635).
These results - obtained in a second, independent and prospective study - confirm the hypothesis generated from our first study that preoperative fibrin monomer concentrations allow prediction on excessive intraoperative blood loss. We suggest that preoperative fibrin monomer concentrations be further studied for identification of patients that might benefit from intensified intraoperative monitoring.
Figure Figure
Coagulation Abnormalities in Patients with Noonan Syndrome - a Single Centre Case Series.
Authors: Stoffman Jayson M. , Chodirker Bernard N. , Israels Sara J. 
Published: April 2020

Abstract
Noonan syndrome (NS) is an autosomal dominant disorder that includes short stature, characteristic facies, congenital heart defect, webbed neck, and developmental delay. A mutation in the PTPN11 gene can be identified in 50% of patients. A bleeding tendency is included in the phenotypic spectrum, with factor XI deficiency and platelet abnormalities described most frequently. At Winnipeg’s Health Sciences Centre, 24 patients with features typical of NS have been studied by the Special Haemostasis Laboratory. Four patients in whom the diagnosis was suspected but not considered definite are also included in this analysis. Clinical complaints included easy bruising (9), epistaxis (2), menorrhagia (1), and a family history of bleeding problems (3). Sixteen patients were referred for investigation following the diagnosis of NS. All 28 patients had coagulation screening tests: 16 patients had an abnormal PT and 12 had an abnormal aPTT. Thrombin time was slightly prolonged in 6 of 23 patients. Reptilase time was normal in 8 patients, and fibrinogen concentration was normal in 20 patients.
Factor XI levels were measured in 14 patients, with a mean value of 62% (range 32–99%). Only 2 patients had levels below the normal range. One of 13 patients evaluated for FXII levels was deficient (FXII 25%), and 2 of 19 patients evaluated for FIX levels had mild FIX deficiency (FIX 40 and 49%) without symptomatic bleeding. No other factor deficiencies were identified. Twenty-four patients had determinations of von Willebrand Factor antigen and activity; 2 had results consistent with mild Type 1 von Willebrand Disease.
Platelet aggregation studies were done in 22 patients. A variety of abnormalities were noted, with the most frequent being abnormal aggregation with epinephrine (7/22). Dense granule number was decreased in 2 of 7 samples studied by electron microscopy. Lupus anticoagulants were detected in 3 of 13 patients screened. Thrombophilia investigations in 4 patients detected decreased protein S in one patient who had been diagnosed previously with protein S deficiency.
This unselected case series, the largest reported to date in the literature, illustrates the heterogeneity of coagulation abnormalities that may occur in NS. Symptoms, when present, were mild, and often did not correlate with laboratory abnormalities. Non-specific platelet aggregation defects were the most commonly identified abnormalities. In contrast to the literature, factor XI deficiency was not prevalent. A specific etiology for the variable bleeding tendency has not yet been identified in NS.
Activation of the Coagulation System Should Be Considered in the Initial Phase of Chemotherapy in Acute Myeloid Leukemia.
Authors: Astermark Jan , Strandberg Karin , Sallerfors Bengt , Stenflo Johan , Berntorp Erik 
Published: April 2020

Abstract
Malignant hematologic disorders may be associated with coagulopathy causing bleeding or thromboembolic complications. Severe infections as well as chemotherapy may augment this risk by the action of inflammatory mediators and the release of proteases. We evaluated the hemostatic process in 10 patients with acute myeloid leukemia (no acute promyelocytic leukemia) before the start of induction therapy with IDA-C and daily during the following two weeks of treatment. Various hemostatic parameters were studied, including the complex between activated protein C and the protein C inhibitor (APC-PCI) with a newly developed method, thrombin generation, protein C, prothrombin fragment 1+2 (F1+2), antithrombin and factor VIII. The APC-PCI concentration was relatively high in all patients at start of treatment (mean 0.81 ± SEM 0.27 μg/L; normal range 0.07–0.26 μg/L) reflecting an activation of the coagulation system, and further increased during the initial phase of chemotherapy reaching the highest level on Day 3 to 5 of 1.67±0.53 μg/L (p=0.0047). The concentration of the complex then declined during the following 10 days to 0.10±0.03 μg/L on Day 14, i.e. to a concentration significantly lower than that at start of treatment (p=0.005). The concentration of F1+2 varied in a similar way with a concentration of 2.17±0.51 nM at start of treatment and an increase on Day 3–5 to 4.17±0.93 nM (p=0.005) followed by a decline to 1.09±0.22 nM on Day 14. Thrombin generation was relatively high in the initial phase of chemotherapy (319.0±44.5 nM) and then declined to 154.6±17.2 nM on Day 14 (p=0.008). The protein C activity was relatively low at start (0.70±0.05 IU/mL) indicating a state of consumption, but showed a trend towards normalization during treatment reaching an average level of 0.78±0.05 IU/mL for all patients on Day 14 (p=0.103). The factor VIII level was high and relatively stable during the two weeks of treatment with a range of 1.73±0.16 to 1.89±0.17 IU/mL, indicating a reactive state. The level of antithrombin was normal at start of treatment (1.00±0.05 IU/mL) and throughout the study period. Our data show that acute myeloid leukemia may be associated with a significant coagulopathy and that the activity in the coagulation process is increased during the initial phase of chemotherapy. This should be considered in patients at start of treatment, in particular, in patients with septicemia and/or signs of disseminated intravascular coagulation.
Elevated Prothrombin Fragment F1+2 Levels during Pregnancy in Women with Previous Venous Thromboembolism.
Authors: Zotz Rainer B. , Gerhardt Andrea , Marzotko Steffi , Wagner Karl J. , Bender Hans G. , Scharf Rudiger E. 
Published: April 2020

Abstract
Changes in blood coagulation and fibrinolysis during pregnancy create a state of hypercoagulability. This phenomenon predisposes to venous thromboembolism. Indicators of hypercoagulation in normal pregnancy are circulating thrombin-antithrombin complexes and increased levels of prothrombin fragment 1+2. A significant positive correlation between gestational age and elevated prothrombin fragment 1+2 has been shown. We hypothesized that women with previous venous thromboembolism are at a higher hypercoagulable state during subsequent pregnancies than women without prior thrombotic complications.
In a prospective study, we determined prothrombin fragment F1+2 over pregnancy among 109 women (175 measurements) with previous venous thromboembolism, and among 75 pregnant women (75 measurements) without previous venous thromboembolism. The prothrombin fragment F1+2 levels were statistically analyzed over time using a Mixed Model. This model allows a longitudinal analysis of the influence of a between-subjects factor (e.g. history of thrombosis) on prothrombin fragment F1+2 levels, the influence of a within-subjects factor (weeks of gestation) on prothrombin fragment F1+2 levels, and the interaction of the history of thrombosis and weeks of gestation representing a change of risk factor-dependent differences over time (weeks of gestation).
Among women with a previous history of venous thrombosis, prothrombin fragment F1+2 values were significantly higher during the course of pregnancy than among pregnant women without venous thromboembolism (p=0.0014). The results were adjusted for the physiological increase of prothrombin fragment F1+2 over pregnancy and were independent of heparin prophylaxis. Thus, determination of indicators of hypercoagulation like prothrombin fragment F1+2 represent an additional approach independent of known and unknown risk determinants of thrombosis to identify women at risk for venous thromboembolism during pregnancy.
Gains on Chromosome Band 9q34 Could Represent a Novel Independent Prognostic Marker in Multiple Myeloma Patients Receiving High-Dose Chemotherapy with Autologous Stem Cell Transplantation.
Authors: Liebisch Peter , Goldschmidt Hartmut , Tschajka Kathrin , Wendl Christiane , Benner Axel , Dohner Hartmut 
Published: April 2020

Abstract
Introduction: Genomic aberrations represent important prognostic markers in many hematological cancers. In multiple myeloma (MM), chromosome 13q deletion (13q-) has emerged as one of the most important outcome predictors and indicates a dismal prognosis. Other chromosomal abnormalities have been discussed as prognostic markers in this disease but came not out as independent variables when they were tested in a multivariate fashion. However, the complexity of genomic rearrangements and the clinical heterogeneity seen in malignant plasma cell disorders argue against 13q- as the sole genomic change of prognostic relevance.
Material and Methods: In a retrospective analysis, 109 patients (pts.) treated with one or two cycles of high-dose chemotherapy (HD-CTX) followed by autologous stem cell transplantation (ASCT) at a single center were analyzed by tri-color FISH and four DNA probes mapping to chromosome bands 1q21, 9q34, 11q25, and 13q14. The selection of DNA probes based upon previous data from a comprehensive molecular cytogenetic study that revealed a high incidence of chromosomal gains (+) and losses (−) involving these four loci. The Cox proportional hazards regression model was applied to correlate molecular cytogenetic markers with clinical data.
Results: The most frequent chromosomal abnormalities in the present series were +9q (49%), +1q (48%), +11q (47%), and 13q- (42%). The median follow-up time was 30 months (m) and the median event free survival (EFS) and overall survival (OS) time (calculated from first ASCT) of the entire cohort was 30 m and 71 m, respectively. There were 52 events (31 deaths). In a multivariable analysis including the four most frequent chromosomal abnormalities, +9q (hazard ratio 2.49, 95% CI 1.20-5.18; p=.01) and 13q- (2.34, 1.17–4.68; p=.02) were statistically significant risk factors for shorter EFS. The median EFS in pts. lacking both genomic changes was 3.6 years , while it was 2.5 years in pts. with either +9q or 13q- and only 1.5 years in pts. that exhibited both chromosomal abnormalities. Of note, when other potential prognostic factors ß2-microglobulin, albumin, number of chemotherapy cycles prior to first ASCT) were included in the multivariable analysis, +9q and 13q- remained independent risk factors for shorter EFS (p=.008 and p=.03, respectively). Due to the diversity of salvage treatment protocols applied after relapse, OS was not analyzed in this study.
Conclusions: +9q34 could represent a novel independent marker of adverse prognosis in MM pts. receiving HD-CTX with ASCT. The prognostic significance of +9q34 and other molecular cytogenetic aberrations is currently investigated within large multicenter trials on more homogenously treated cohorts of pts.
Inclusion of HOXA Genes in Genetic and Biological Networks Defining Human Acute T-Cell Leukemia.
Authors: Soulier Jean , Clappier Emmanuelle , Cayuela Jean-Michel , Regnault Armelle , Garcia-Peydro Marina , Dombret Herve , Baruchel Andre , Toribio Maria-Luisa , Sigaux Francois 
Published: April 2020

Abstract
We have identified a new recurrent chromosomal translocation, targeting the major homeobox gene cluster HOXA in human T-cell acute lymphoblastic leukemia (T-ALL). Four cases were characterized using a combination of FISH, Southern blot, breakpoint region sequencing, and a large scale expression analysis of a series of T-ALL. Specific RQ-PCR analysis of the HOXA1 to HOXA13 transcripts showed that the whole HOXA gene cluster expression was dramatically deregulated in the HOXA-rearranged cases, and also in the MLL and CALM-AF10-related T-ALL, strongly suggesting that HOXA genes are oncogenic in these types of leukemia. The HOXA-rearranged cases were included in a general portrait of T-ALL based on large scale expression analysis, showing that a new homogeneous T-ALL subgroup is defined by this chromosomal rearrangement. Moreover, patterns of gene expression associated to the distinct T-ALL oncogenic subgroups were compared with gene expression in normal human thymic sub-populations (11 purified sub-populations). Inappropriate use or perturbation of some specific molecular networks involved in thymic differentiation could be detected in the T-ALL cells. Also, we found that abnormal, frequently ectopic, expression of at least one developmental gene, including HOXA, TLX1/HOX11, TLX3/HOX11L2 and a few more, could be identified in most of the T-ALL cases. Our data strongly support the view that the abnormal expression of developmental genes, including the prototypical major homeobox genes HOXA in some cases, is critical in T-ALL oncogenesis.
Multiple Myeloma Oncogene 1 (MUM1)/Interferon Regulatory Factor 4 (IRF4) Upregulates Monokine Induced by Interferon-gamma (MIG) Gene Expression in B-Cell Malignancy.
Authors: Iida Shinsuke , Uranishi Miyuki , Sanda Takaomi , Ishida Takashi , Tajima Emi , Ito Masato , Komatsu Hirokazu , Inagaki Hiroshi , Ueda Ryuzo 
Published: April 2020

Abstract
MUM1(multiple myeloma oncogene 1)/IRF4(interferon regulatory factor 4) is a transcription regulatory factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas/leukemias and has been reported to predict an unfavorable outcome in some lymphoma subtypes including diffuse large B-cell lymphoma (DLBCL) and B-cell chronic lymphocytic leukemia (B-CLL). To elucidate its role in B-cell malignancies, we prepared stably MUM1-expressing Ba/F3 cells, which proliferated at a higher rate than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the Monokine induced by interferon-gamma (MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1 in inducible MUM1 expressing system. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed in chromatin immunoprecipitation assay. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and its receptor CXCR3 was also coexpressed in B-CLL cell lines that were positive for MUM1. Interestingly, treatment with neutralizing antibodies against MIG and its receptor, CXCR3, partially inhibited the proliferation of two MUM1-expressing B-CLL cell lines. These results suggest that MUM1 plays certain roles in the progression of B-cell lymphomas/leukemias by regulating the expression of various genes including MIG.
Knockdown of the Transcription Factor PU.1 Causes Characteristic Transcriptional Changes in Hematopoietic Stem Cells Prior to Leukemic Transformation.
Authors: Steidl Ulrich , Rosenbauer Frank , Gu Xuesong , Owens Bronwyn , Klippel Steffen , Wagner Katharina , Aivado Manuel , Libermann Towia A. , Tenen Daniel G. 
Published: April 2020

Abstract
Knockdown of the expression of the transcription factor PU.1 in mice results in an initial preleukemic expansion of myeloid progenitors and subsequent transformation to an immature acute myeloid leukemia (AML). Recent reports suggest that functional inactivation of PU.1 might also play a role in human AML. However, the molecular mechanisms underlying the malignant transformation are unknown. Examining the bone marrow of leukemic PU.1 knockdown mice we found an expansion of lin−, c-kit+, Sca1+ hematopoietic stem cells (HSC) as compared to wildtype animals. This finding prompted us to examine the transcriptome of HSC of PU.1 knockdown mice in the initial phase to look for early transcriptional changes underlying the malignant transformation. After lineage-depletion and FACS sorting of lin−, c-kit+, Sca1+ HSC we performed linear amplification of RNA which was then hybridized with Affymetrix Mouse Genome 430 2.0 arrays covering ~39,000 transcripts. Unsupervised hierarchical cluster analysis clearly distinguished PU.1 knockdown and wildtype HSC, demonstrating that reduced PU.1 expression levels lead to characteristic transcriptional changes in the stem cell compartment preceding the malignant transformation. 55 transcripts were upregulated, and 143 transcripts were downregulated in PU.1 knockdown HSC (&gt;1.5-fold, p&lt;0.05), reflecting the role of PU.1 as a transcriptional activator. We corroborated differential expression of 16 genes by quantitative real-time RT-PCR. Among the downregulated genes were c-fes, Bruton’s tyrosine kinase, transcription factor EC, and GM-CSF receptor α, demonstrating that those in-vitro targets of PU.1 are also affected in stem cells in vivo. BAFF-R and TACI, two members of the tumor necrosis factor receptor superfamily, receptor tyrosine kinase TEK and toll-like receptor 4 were downregulated, whereas PDGF receptor was upregulated, suggesting disturbed signaling in PU.1 knockdown HSC. We are currently investigating the causal contribution of these deregulated genes to the leukemic phenotype. In summary, our data delineate a distinct transcriptional pattern that precedes the leukemic transformation in PU.1 knockdown HSC, and provide novel insight into PU.1-mediated molecular pathways in vivo.
Ki23819 (KRN383•HCl) Inhibits Kinase Activity of Wild Type and Mutant FLT3 Receptor Tyrosine Kinase In Vitro.
Authors: Komeno Yukiko , Kurokawa Mineo , Imai Yoichi , Takeshita Masataka , Matsumura Tomoko , Kubo Kazuo , Yoshino Tetsuya , Nishiyama Uichi , Kuwaki Tomoaki , Kubo Kinya , Osawa Tatsushi , Ogawa Seishi , Chiba Shigeru , Miwa Atsushi , Hirai Hisamaru 
Published: April 2020

Abstract
[Background] FLT3 is a class III receptor tyrosine kinase which is widely expressed on hematopoietic stem/progenitor cells. Two types of constitutively active FLT3 mutations have been reported to be expressed on a subset of leukemic cells; internal tandem duplications (ITD) and kinase domain mutations. The former are associated with poor prognosis in acute myeloid leukemia (AML) patients. Although several inhibitors targeting FLT3-ITD are tested in clinical trials, their cytotoxic effects are still unsatisfactory. Innate and acquired resistance is also a problem to be solved. [Purpose] To screen a novel potent FLT3 inhibitor and characterize its in vitro activity. [Materials and Methods] MOLM13 and MV4-11 cells, human leukemia cell lines expressing FLT3-ITD, were exposed to candidate compounds for 48 hours, and cytotoxic effect was assessed by colorimetric assay. Inhibitory effect on autophosphorylation was evaluated by immunoprecipitation and Western blotting. These effects were also tested in 32D cells engineered to express wild type FLT3 (FLT3-WT) or FLT3-ITD. FLT3-WT was activated with 50 ng/ml FLT3 ligand for 15 min. Proapoptotic effect was confirmed by flow cytometry with Annexin V staining. In vitro kinase assay was performed to demonstrate direct inhibition of tyrosine kinase activity of FLT3-ITD. Inhibitory effects on downstream signaling molecules, ERK and STAT5, were assessed by Western blotting. [Results] Among candidates for VEGFR inhibitors from a library, a quinoline-urea derivative Ki23819 (KRN383•HCl) was identified to specifically inhibit proliferation and induce apoptosis to MOLM13 and MV4-11 cells. Ki23819 inhibited proliferation of MV4-11 cells more effectively than SU11248, a precedent FLT3 inhibitor (IC50 &lt;1 nM vs 3~10 nM). Similar results were obtained when MOLM13 cells were used. Ki23819 inhibited autophosphorylation of both ligand-activated FLT3-WT and FLT3-ITD (IC50 30 nM and 3 nM, respectively), and abrogated IL-3-independent proliferation of 32D cells expressing FLT3-ITD (IC50 3~10 nM). In vitro kinase assay demonstrated direct inhibition of kinase activity of FLT3-ITD (IC50 7.8 nM). This compound also inhibited ERK and STAT5 constitutively activated by FLT3-ITD. The IC50 for inhibition of phosphorylation in 32D FLT3-ITD cells was 3 nM for both proteins, which is equivalent to that for inhibition of FLT3-ITD autophosphorylation. [Conclusion] Ki23819 is a novel and potent candidate for antileukemic agents against FLT3-ITD positive AML. In vivo activity of KRN383, the free base of Ki23819, is also to be reported in this ASH meeting (Nishiyama et al.).