bluuebunny/crossref_metadata_2025_split huggingface dataset:
Working capital dynamics
Authors: Chauhan Gaurav Singh 
Published: April 2020

We assess short-run variations in firms’ working capital allocations in light of finding persistence in these allocations in the recent literature. Specifically, we study the extent and speed of mean reversion in firms’ working capital allocations to evaluate if firms tend to follow firm-specific value-maximizing optimal allocations. Furthermore, we assess whether and to what extent firms trade off their working capital to accommodate capital expenditure shocks. While we find frequent inter-temporal offsetting movements in working capital allocations in the short run, we do not find evidence of a systematic trade-off between working capital and fixed asset investments. JEL Classification: G30, G31, G32
Is the Proposed World Health Organization (WHO) Classification for Chronic Myeloid Leukemia (CML) of Clinical Value in the Imatinib Era?.
Authors: Cortes Jorge , O’Brien Susan , Garcia-Manero Guillermo , Faderl Stefan , Shan Jenny , Giles Francis , Verstovsek Srdan , Rios Mary Beth , Talpaz Moshe , Kantarjian Hagop 
Published: April 2020

Abstract
The criteria to define chronic (CP), accelerated (AP) and blast phase (BP) CML vary in the literature. The WHO recently proposed, based on the literature and collective experience of the clinical advisory committee, new criteria for myeloid malignancies including CML in an attempt to provide more uniform criteria (Blood2002; 100:2292). Imatinib is the current standard therapy for CML, and the criteria used in most studies using imatinib are shown below in contrast to the WHO proposal:
Phase Criteria Imatinib WHO *Unrelated to therapy (Rx), **Unresponsive to Rx, Plts=platelets, BM=bone marrow AP Blasts 15–29% 10–19% Blasts + promyelocytes ≥ 30% NA Basophils ≥ 20% ≥ 20% Plts &lt;100 x 109/L* Yes Yes Plts &gt;1000 x 109/L** No Yes Increasing spleen size and WBC** No Yes CE At any time Not at diagnosis (Dx) BP Blasts ≥ 30% ≥ 20% Extramedullary disease Yes Yes Large clusters of blasts in BM NA Yes
We investigated the clinical validity of the WHO proposal among 809 patients (pts) with CML in all stages treated with imatinib at MDACC since 1999. According to the imatinib classification, 537 (66%) pts were in CP, 196 (24%) in AP, and 76 (9%) in BP. When analyzing the specific subsets of pts where the classifications differ, major findings are: 1) Pts with CE at Dx (n=14) have similar cytogenetic (CG) complete remission (CR) rate (86%) than pts (n=477) with imatinib CP (75%, p=.53), but it is lower when CE develops after Dx (34/64, 53%; p=.0005). Similar results are found for overall survival (OS) and progression-free survival (PFS). 2) CG CR rate among pts with 20%–29% blasts (4/19, 21%) is more similar to that of AP (37/99, 37%)(p=0.19) than to pts with ≥30% blasts (5/76, p=0.07). This trend is more significant for OS and PFS. 3) Pts with increasing WBC and spleen, or plts &gt;1000 x109/L unresponsive to Rx have a CG CR rate (9/42, 21%; p=.07) lower than others with AP, but there is no difference in OS or PFS. 4) Pts with plts &gt;1000 x109/L without prior Rx have similar outcome as those with CE developing on therapy. In conclusion, based on results imatinib therapy, AP can be defined as blasts ≥10%, basophils ≥20%, plt &lt;100 x109/L (unrelated to Rx) or &gt;1000 x109/L (unresponsive to Rx), increasing WBC and spleen (unresponsive to Rx), and CE not at diagnosis; BP is defined by blasts ≥30% or extramedullary disease; pts who develop CE during the course of Rx of with plts &gt;1000 x109/L not related to Rx constitute an intermediate group between CP and AP; all others are CP.
Frequency of Blast Crisis after Achieving Complete Cytogenetic Remission in First Chronic Phase CML Patients Who Recieved Imatinib Therapy within Six Months of Diagnosis.
Authors: Laurence Arian , Marin David , Clark Richard , Shepherd4 Patricia , Mackinnon Stephen 
Published: April 2020

Abstract
Stem cell transplantation (SCT) remains the only proven curative therapy for chronic myeloid leukemia (CML) but is limited by significant procedure related morbidity. Imatinib is the first of a new generation of specifically targeted drugs for this disorder based on the ubiquitous presence of the BCR-ABL kinase. The success of Imatinib therapy to induce a cytogenetic remission (CCyR) raises questions over the suitability and timing of SCT as a treatment for CML. Of importance is the degree of protection CCyR infers from developing a blast crisis. We report a total of 68 patients from five centres all of whom started Imatinib within six months of diagnosis of 1st chronic phase CML and subsequently achieved a complete cytogenetic remission. In this group, five cases spontaneously developed blast crisis despite achieving a CCyR. In the affected patients CCyR was achieved between 97 and 254 days (mean 148 days) and BC developed between 177 and 875 days (mean 446 days). The BC was myeloid in three cases and lymphoid in the remaining two. Statistical analysis of this group predicts a 91% freedom from blast crisis at two years (figure 1). The development of acute leukemia is assumed to derive from further mutations within the BCR-ABL expressing stem cell pool. The success of SCT therapy in curing CML drops significantly if the patient has previously progressed to a blast crisis. The finding that cytogenetic remission is no guarantee of protection from developing a blast crisis suggests that for young patients with a sibling match, stem cell transplantation may be considered as an early therapy in the management of CML.
The Resusciatative Fluid You Chose May Potentiate Bleeding.
Authors: Brummel-Ziedins Kathleen E. , Whelihan Matthew F. , Ziedins Eduards G. , Mann Kenneth G. 
Published: April 2020

Abstract
Trauma is the leading cause of death in the younger population in the United States, frequently from the development of hemorrhagic shock. Controversy exists over the type of volume resuscitation to be used (dilutions ranging up to 66%) in hemorrhagic shock for restoring hemodynamic stability. Trauma results in massive exposure of tissue factor to the circulation and explosive amounts of thrombin being generated. We studied the effect of various resuscitative formulas to blood coagulation, specifically thrombin generation and fibrin formation, in a controlled setting using corn trypsin inhibited whole blood initiated with a 5pM stimulus of tissue factor. Thrombin generation measured as its complex with antithrombin III (TAT) was evaluated periodically over a time course of 20 min. Fibrin clots were collected and weighed. We investigated four diluents (0.9% NaCl (NS), lactated Ringer’s solution (LR), 6% hydroxyethyl starch (HES) and 3% NaCl (HS)) each at a 0,10, 20, 30, 40, 50 and 60% blood dilution. At a 10% dilution TAT generation was in the order of LR (−4%) &lt; HES (−8%)&lt; NS and HS (−12%). Diluting by 20% resulted in further decreases of TAT formation. The fibrin clot mass decreased dramatically with a 20% dilution for NS (−42%) and HES (−30%). Conversely, HS produced no change in fibrin mass but effected the largest change in thrombin generation rate (−56%). At a 50% dilution, comparable thrombin generation profiles were obtained for LR, HES and NS (~35% decrease). However, the fibrin masses decreased by 27% with LR, 46% with NS and 74% with HES. No clot formation or thrombin generation was seen with HS at &gt; 20% dilution. This in vitro study shows that: 1) LR has the least effect on thrombin generation and gave higher than anticipated clot weights; 2) HES reduced the fibrin clot mass at higher dilutions; 3) HS abolishes coagulation after a 20% dilution. Overall, both the extent and nature of hemodilution cause profound alterations in the hemostatic mechanism.
The Predictive Value of hs-C-Reactive Protein Is Based on the Presence of Antiphospholipid Antibodies.
Authors: Miesbach Wolfgang A. , Boehm Martina , Claus Detlef , Scharrer Inge 
Published: April 2020

Abstract
High-sensitive C-reactive protein (hs-CRP) is a marker of inflammation which has been shown in several prospective studies to predict independently myocardial infarction, stroke or peripheral artery disease. Patients with antiphospholipid antibodies (aPL) are at increased risk of recurrent thromboembolic events but the possibility to predict such risk seems rather limited. Recently, similarities were found in the pathology of thrombosis between elevated levels of hs-CRP and the presence of aPL.We studied the predictive role of hs-CRP levels in patients with the presence of aPL of a cohort of patients with neurological manifestations compared to those where aPL could be excluded.
Patients A follow-up investigation was done in 55 aPL-positive and 61 aPL -negative, sex- and age matched patients of the same cohort of patients with acute manifestations of neurological diseases. Hs-CRP levels were measured in all patients at enrollment and were related to the outcome of the patients after a median time of 32 months.
Methods Lupus anticoagulants were detected according to the SSC of the ISTH. Anticardiolipin tests were performed by a ß2-glycoprotein I-dependent enzyme-linked immunsorbent assay (Pharmacia ELISA). Hs-CRP was measured by latex enhanced turbidometry (dimension RXL, Dade Behring).
Results Cerebral infarctions and transient ischemic attacks were the most common cerebral manifestations of the patients. In APS patients elevated levels of hs-CRP could be measured significantly more frequently than in patients where aPL could be excluded (44 % vs. 16 %, p&lt;0.005). The rate of recurrences or severe residual symptoms was higher in patients with aPL (45 %) compared to 32 % in aPL-negative patients. In non APS patients hs-CRP levels were not associated to the occurrence of future neurological events. In patients with aPL elevated levels of hs-CRP were highly associated to an increased rate of recurrent or residual symptoms (OR, 12.5; 95 % CI, 3.72 to 41.94) and not related to other risk factors, except of smoking (p&lt;0.05).
Conclusion Elevated levels of hs-CRP were associated to the presence of aPL and related to the risk of recurrences in these patients but not in patients where the presence of aPL could be excluded. In patients with APS elevated levels of hs-CRP may identify a group of patients at high risk of recurrent or residual neurological symptoms who may benefit from a more careful follow-up and antithrombotic therapy.
Inhibition of Factor Xa in Prothrombinase Is Enhanced by Covalent Linkage of Antithrombin to Heparin.
Authors: Kentner Taryn A. , Berry Leslie R. , Chan Anthony K.C. 
Published: April 2020

Abstract
Prothrombinase is the surface-bound complex in which factor Xa (Xa) converts prothrombin to thrombin in vivo. Studies have shown that Xa within prothrombinase is resistant to inhibition by antithrombin + heparin (AT+H). Previously we found that, unlike AT+H, a covalent conjugate of AT and H (ATH) was able to neutralize fibrin-bound thrombin. In this study, AT+H and ATH were compared in their reaction with Xa in prothrombinase. Mixtures of CaCl2, PCPS vesicles, factor Va (Va) and prothrombin in TSP buffer were combined with either AT+H or ATH. Following addition of Xa, time samples were neutralized with Na2EDTA + polybrene + substrate (S-2222) and residual Xa activity measured. Second order rate constants (k2) were calculated from plots of activity versus time. Results were compared to those in corresponding experiments with Xa alone. Inhibition of Xa in prothrombinase by AT+H had a k2 (x 108 M−1min−1) of 0.688 +/− 0.030. Conversely, free Xa neutralization by AT+H was significantly more rapid (k2 = 1.53 +/− 0.35, p = 0.041). ATH reaction with prothrombinase Xa proceeded at a rate that was insignificantly different from that with Xa alone (2.36 +/− 0.31 and 2.83 +/− 0.83, respectively) and similar to AT+H reaction with free Xa. Varying concentrations of prothrombinase components showed similar effects. We conclude that covalently linked complexes of AT + H undergo unhindered reaction with Xa in prothrombinase, while non-covalently linked AT+H encounters resistance. It is possible that ATH may effectively prevent plasma thrombin generation by neutralization of Xa in prothrombinase and thus may prohibit feedback activation of coagulation.
Minimal Residual Disease Detection Identifies Differences between the Risk Groups Defined by the ALL IC-BFM 2002 and the ALL-BFM 2000 Protocols.
Authors: Fronkova Eva , Reznickova Leona , Muzikova Katerina , Mejstrikova Ester , Hrusak Ondrej , Schrappe Martin , Stary Jan , Trka Jan 
Published: April 2020

Abstract
Minimal residual disease (MRD) testing based on a unique Ig/TCR gene rearrangement pattern of each patient’s leukaemia turned out to be an independent tool to determine treatment response and the risk of relapse in paediatric acute lymphoblastic leukaemia (ALL). Since 07/2000, MRD information at week 5 and 12 of therapy has been used for stratification in ALL-BFM 2000 trial. In parallel, ALL IC-BFM 2002 has been designed by the International-BFM Group to test the morphological assessment of the early treatment response. Patients are stratified according to the blast proportion in peripheral blood (PB) at day 8 and in bone marrow (BM) at day 15 and 33 of therapy, age, initial WBC and the presence of BCR/ABL and MLL/AF4 fusion. One of the goals of the study is the comparison of this risk group assessment to the MRD-based criteria used in ALL-BFM 2000. In the Czech Republic, 73 patients were treated according to ALL IC-BFM 2002 protocol from 11/2002 to 12/2003, 29 in the standard-risk (SR), 35 in the intermediate-risk (IR) and 9 in the high-risk (HR) group. The SR, HR and all T-cell ALL patients were examined for clonal Ig/TCR rearrangements. RQ-PCR patient-specific systems were designed for each of these patients according to the ESG-MRD-ALL criteria. For 39 of the 40 patients tested (97.5%) at least one target with minimal sensitivity of 10(−4) was identified. MRD was evaluated in BM samples from 34 patients at several time points inclusive of the mandatory 5 and 12 week ones. Simultaneously the PB specimens of the T-ALL patients were tested. In total, 205 BM and 64 PB specimens were included. In 7 patients of 24 in the SR group, MRD positivity at week 5 and/or at week 12 was observed (ranging between 9.7x10(−4) and 1.5x10(−2)), thus identifying patients who would not qualify to the MRD-based SR group in ALL-BFM 2000 despite the identical induction regimen. In T-ALL patients, PB-MRD levels paralleled those in BM. MRD results showed no separation of MRD levels between IR- and HR-stratified T-ALL patients. These preliminary findings reveal a significant difference between the stratification results of ALL IC-BFM 2002 and ALL-BFM 2000. A fast response as measured by the morphology criterion (M1 or M2 bone marrow at day 15) together with other low-risk features does not necessarily correspond with rapid MRD clearance. The complete analysis of MRD is planned for the international consortium participating in the ALL IC-BFM 2002 protocol.
IRTA2 Protein on Lymphoma Cell Lines and Hairy Cell Leukemia Cells Detected by Novel Monoclonal Antibodies.
Authors: Ise Tomoko , Nagata Satoshi , Maeda Hiroshi , Kreitman Robert , Stetler-Stevenson Maryalice , Pastan Ira 
Published: April 2020

Abstract
The immunoglobulin superfamily receptor translocation associated 2 (IRTA2) gene encodes a cell surface receptor homologous to the family of Fc receptors. Because of the restricted expression of the mRNA in B cell-linage cells, IRTA2 is a new potential target for the immunotherapy of B cell malignancies. To study the function and expression of the IRTA2 gene product, we produced monoclonal antibodies (MAbs) specific to IRTA2. We successfully made 36 MAbs from a mouse immunized with IRTA2-encoding plasmid DNA. All the MAbs reacted with IRTA2-extracellular domain-Fc fusion protein in ELISA and 293T cells expressing IRTA2 in a fluorescence-activated cell sorter (FACS) analysis. Binding of each MAb to a series of deletion mutants of IRTA2-Fc fusion protein and mutual competition of the MAbs to the binding to the whole extracellular domain of IRTA2-Fc fusion protein revealed that the panel of MAbs recognizes more than 10 epitopes on IRTA2. There are at least 1, 1, 2, 4, and 2 epitopes on extracellular domain 1 (ED1), ED3, ED1-3, ED4-9, and whole extracellular domain, respectively. Twenty five out of the 36 MAbs are specific to IRTA2 but 11 others showed cross reactivity to other members of the IRTA family. Among 36 MAbs produced, 3 MAbs (F25, F56 and F119) were used for further analysis based on their specific reactivity with recombinant IRTA2 expressed on 293T cells and lack of cross reactivity with other IRTA family members. In a FACS analysis, MAbs F56 and F119 detected IRTA2 expression on 6/7 B-cell non-Hodgkin’s lymphoma and 1/6 Burkitt’s lymphoma cell lines. Reverse transcriptase-polymerase chain reaction experiments and Western blotting using MAb F25 confirmed the expression profile. We also analyzed blood samples of 11 patients with hairy cell leukemia (HCL), 11 patients with chronic lymphocytic leukemia (CLL), and 4 patients with follicular lymphomas (FL) by FACS. We detected IRTA2 expression on 100% HCL (11/11), 55% CLL (6/11) and 0% of FL cells (0/4). Our results provide the first evidence that the IRTA2 is expressed on the surface of HCL and CLL cells as well as some human lymphoma cell lines. We expect IRTA2 will be established as a new target for immunotherapy.
Array CGH Analysis for Target Genes at 6p21 Amplification Region in Diffuse Large B-Cell Lymphoma.
Authors: Kasugai Yumiko , Tagawa Hiroyuki , Kameoka Yoshihiro , Karnan Sivasundaram , Suzuki Ritsuro , Tsuzuki Shinobu , Hosokawa Yoshitaka , Seto Masao 
Published: April 2020

Abstract
Amplification of 6p21 has been detected in various solid tumor and hematological neoplasms. These include hepatoma, osteosarcoma, pancreatic cancer, bladder cancer, and mantle cell lymphoma . However, no candidate target genes in this amplified region have been identified. In diffuse large B-cell lymphoma (DLBCL), no amplification has been reported. Recently, we established genome-wide array comparative genomic hybridization (array CGH) consisting of 2300 BAC clones that can survey a whole genome at the density of an average size of 1.3 Mb. The array CGH detected amplification at 6p21 in 12 of 70 (24%) DLBCL patients (Tagawa et al., Cancer Res. in press) and one DLBCL cell line, SUDHL-9. We next made high density array glass for 6p21 region with 23 BAC clones covering 3 Mb. We found that the minimal common region of amplification was approximately 2Mb in size. In this region, there are 27 known genes including cyclin D3. The cyclin D3 has been reported to be overexpressed in a case of DLBCL with t(6;14)(p21.1;q32.3). We have analyzed expression level of those genes in the minimal common region of amplification, and found that five genes, BYSL, cyclin D3, TBN, KIAA0240, and TBCC were overexpressed. These results indicate that not only cyclin D3 but also other genes are also possible target genes for the 6p21 amplification.
Critical and Complementary Role of FLT3 and Interleukin 7-Receptor Alpha Signaling in T Lymphocyte Development.
Authors: Buza-Vidas Natalija , Ahlenius Henrik , Cilio Corrado M. , Svensson Marcus , Agace William , Jacobsen Sten Eirik W. , Sitnicka Ewa 
Published: April 2020

Abstract
We recently demonstrated that signaling through the cytokine tyrosine kinase receptor flt3 and interleukin-7 receptor a (IL-7Ra) is indispensable for fetal and adult B cell commitment and development (Sitnicka et al., J. Exp. Med. 198: 1495, 2003). These receptors are also implicated to be important in regulation of T cell development, but their potential interdependence remains unexplored. We recently showed that flt3 ligand (FL)-deficient mice have reduced levels of early thymic progenitors as well as the common lymphoid progenitor (CLP) (Sitnicka et al., Immunity, 17:463, 2002). In the present study we investigated T cell development in mice deficient in FL and IL-7Ra expression. Strikingly, when compared to FL−/− and IL-7Ra−/− mice, FL−/−xIL-7Ra−/− (double deficient) mice (8-10 week old) lack visible lymph nodes and Peyer’s Patches. Thymic cellularity was dramatically reduced to only 0.3% of FL−/− and wild type (WT) controls and to only 4% of IL-7Ra−/− mice. In agreement with previous studies, IL-7Ra−/− thymocytes revealed a partial block at the progression from the DN2 (CD4−CD8−CD44+CD25+) to DN3 (CD4−CD8−CD44−CD25+) stage, while in FL−/−xIL-7Ra−/− mice DN1 (CD4−CD8−CD44+CD25−), DN2 and DN3 thymic progenitors were undetectable. Thus, severe reductions in early thymocyte development in FL−/−xIL-7Ra−/− mice support a similar role for cross talk between these two signaling pathways in T cell development as recently demonstrated for B cell genesis.
Hematopoiesis in the Ts65Dn Mouse Model of Down Syndrome (DS) Recapitulates Many Features of Human DS.
Authors: Mundschau Gina , Jilani Sarah , Le Beau Michelle , Crispino John 
Published: April 2020

Abstract
Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL) is a complex malignancy that evolves in hematopoietic progenitors with trisomy 21 that acquire a somatic mutation in the blood transcription factor GATA1. The mechanistic relationship between these two genetic factors that leads to leukemia is poorly understood. In order to study the interplay between trisomy 21 and GATA1 mutations, we are developing a mouse model of this malignancy. The Ts65Dn mouse, which contains a segmental trisomy for mouse chromosome 16, homologous to human 21, has been reported to display several of the cognitive and craniofacial phenotypes seen in humans with DS, but the hematopoietic system has not been assessed as a model for blood development in humans with DS. We have evaluated adult hematopoiesis in the Ts65Dn strain by comparing monthly complete blood counts (CBC) of peripheral blood from 14 trisomic and 20 disomic littermates. Similar to humans with DS, Ts65Dn trisomic mice display persistent erythrocyte macrocytosis, with values at the high end of the normal range. Trisomic mice also harbor decreased numbers of red blood cells, mildly elevated platelet counts, a higher percentage of monocytes and a lower hemoglobin concentration. Interestingly infants with DS frequently display thrombocytosis. In addition, we have characterized fetal liver hematopoiesis in the Ts65Dn strain by FACS analysis of hematopoietic precursors and by performing colony assays. In general, we did not detect any significant differences in erythroid, myeloid, or megakaryocytic colony formation between trisomic or disomic fetuses. Likewise flow cytometry for CD34, TER119, and CD41 demonstrated overall similar numbers of cells in these compartments for Ts65Dn mice and disomic littermates. However, one of seven trisomic embryos displayed a significant increase in the proportion of CD34+ cells with concomitant decrease in both Ter119+ and CD41+ populations. In addition, cells from this fetal liver gave rise to seven-fold and three-fold increases in BFU-E and CFU-Mk colonies respectively, with no change in the CFU-GM. Although the sample size is small, these findings suggest that a subset of Ts65Dn trisomic fetuses exhibit aberrant hematopoiesis. Taken together, our study indicates that the Ts65Dn trisomic mouse may be an excellent model to study human DS hematopoiesis.