bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ca 15-3 a Marker for the Megaloblastic Anaemia?.
Authors: Mettivier Vincenzo , Pezzullo Luca , Finizio Olimpia , Rocco Stefano , Bene Lucia , De Rosa Carlo 
Published: October 2019

Abstract
Ca 15-3 is a glycoprotein present in the cells of the mammary carcinoma and in some epithelial cells. Is a marker used for the monitoring of the breast and gastrointestinal carcinoma. The megaloblastic anaemia is an anaemia characterized by deficit of absorption of Vitamin B12 and is associated with gastritis atrophic and the target cell is the parietal gastric cell.
In our institution, from June 2003 to December 2004, the level of Ca15-3 and of others tumour markers (CEA; Ca125; Ca19.9; alfa-FETO) they have been tested in the serum of 16 patients (9 male and 7 female with median age of 64,5 and range of 37–80 years) with de novo megaloblastic anaemia, 2 patients were gastrectomized. In all patients has been effected: esophagogastroduodenoscopy and control anti-parietal gastric cells antibody (APCA).
Increase level in the serum of CA 15-3 with normal level of other tumour markers have been found in 14/16 patient with median value of 61 U/ml (range 35–100 U/ml) in two patients (gastrectomized) the value of CA 15-3 was normal. Besides in 12/14 patients have shown positivity for the APCA, only in two patients has been diagnosed a gastritis atrophic, in the other patients has been observed a normal gastric mucous.
After a median observation of 24 months any patient has developed a mammary or gastro-intestinal carcinoma
These results indicate what the increased level of CA 15-3 antigen in patient with megaloblastic anaemia is positively correlated with APCA and with the presence of a normal gastric mucous. These clinical conditions make to suppose the destruction from the APCA of the parietal gastric cells with the liberation of this glycoprotein and this is shown in two patients gastrectomized with presence of APCA and not increased level of the CA 15-3.
In conclusion the CA15-3 antigen is probably an specific marker for the diagnosis of megaloblastic anaemia and is probably associated with the destruction of parietal gastric cells.
MP4, a Human Hemoglobin Modified with Maleimide-Peg, Reduces Sickling of Red Blood Cells in an In Vitro Model.
Authors: Winslow Robert , Oliva Mariana , Intaglietta Marcos , Vandegriff Kim , Baker Dale , Malavalli Ashok 
Published: October 2019

Abstract
Human hemoglobin surface-modified with maleimide polyethylene glycol (MP4) has been shown to be effective in transporting O2 and maintaining tissue perfusion in several animal models. MP4 appears to be free of vasoconstriction, and clinical trials have shown MP4 to be free of the side-effects commonly associated with hemoglobin-based products. Since MP4 is effective in delivering O2 to capillaries in the hamster microcirculation, our hypothesis is that it would be of therapeutic benefit in Sickle Cell Disease. In order to test this hypothesis, we measured pressure that develops as dilute sickle cells pass through a filter with and without MP4. Cells from patients with sickling disorders were washed with phosphate-buffered saline (PBS) containing 1% bovine serum albumin (BSA) and suspended at 1% hematocrit in the presence and absence of MP4 (2 g/dL). The suspension was then pumped through a hollow fiber oxygenator (Living Systems Instrumentation, Model Number OXR) using an array of 162 polypropylene fibers, 300 mm OD, 240 mm ID, surface area 0.0115 m2. After emerging from the oxygenator the suspension passed through a filter (Millipore Isopore, pore size 5.0 mm, 13 mm diameter) at a pump rate of 1 mL/min. All experiments were performed at 21oC. After achieving a steady flow rate, the oxygenator gas was abruptly changed to N2, and the PO2 and pressure of the prefilter suspension was continuously monitored. As PO2 fell, pressure began to rise in all experiments, but in the presence of MP4, the pressure rise was offset, being lower by about 10 mm Hg, indicating a favorable effect on sickling at constant PO2. If MP4 was saturated with CO, sickling was inhibited, even in the absence of O2. These results indicate that MP4 has a significant effect on sickling, apart from any effect it might have in promoting capillary perfusion. Furthermore, the results confirm that despite its low P50 (~5 mm Hg), MP4 does not “steal” O2 from sickle cells. Supported by grants HL64395 and HL076163 from the NHLBI
Inter-Site Validation of a Single Breath Hold T2* MR Technique for Heart and Liver Iron Measurement.
Authors: Kirk Paul , Anderson Lisa J. , Tanner Mark A. , Galanello Renzo , Matta Gildo , Tan Ru S. , Ng Ivg , Lai Angie , Chen Kevin , Firmin David N. , Pennell Dudley J. 
Published: October 2019

Abstract
Background
Approximately 60,000 people are born with thalassaemia major every year. The average life expectancy of thalassaemia major patients is 35 years due to iron overload Cardiomyopathy. The cardiomyopathy is reversible when treated early, but once heart failure is established it is often rapidly progressive, and unresponsive to treatment. The single breath hold (SBH) T2* technique has been validated as the most robust and reproducible non-invasive measurement of myocardial and iron load. Our aim in this study was to validate the transferability and reproducibility of this technique in different scanners worldwide.
Methods
We aim to compare the reproducibility in six different sites worldwide as part of an NIH funded grant (R01-DK66084-01). So far, two of these sites have been validated: Singapore (Siemens Sonata, 1.5T scanner) and Cagliari, Italy (GE Signa, 1.5 T scanner). At both validation sites, 10 patients were scanned for heart and liver T2*, and scans were repeated for interstudy reproducibility. All patients then flew to London to be rescanned on our reference Siemens Sonata scanner.
Results
Of the 20 patients scanned, 70% had myocardial iron loading (T2* <20ms) and in 10% the myocardial iron loading was severe.
Liver iron loading was present in 65% of patients and in 30% this was severe.
The coefficient of variation (COV) for the heart T2* measurements between the local sites and London was 5.9% and 4.9% yielding an average coefficient of variation across both sites of 5.4% (figure 1).
The coefficient of variation (COV) for the liver T2* measurements between the local sites and London was 11.3% and 3.9% yielding an average coefficient of variation across both sites of 7.6% (figure 2).
There was no significant correlation between liver and myocardial loading.
Conclusion
These are the first data demonstrating the transferability of the SBH T2* technique and the clinical validation from the 2 collaborating centers were excellent for both heart and liver measurements. Further MR sites confirmed for validation include Children’s Hospital of Philadelphia (USA); Ramathibodi Hospital, Bangkok (Thailand); and Chinese University Hong Kong.
Figure 1 Figure 1. Figure 2 Figure 2.
Modulation of Platelet Adhesion by Antithrombin.
Authors: Loncar Robert , Stoldt Volker , Thomas Volker , Zotz Reiner B. , Scharf Rudiger E. 
Published: October 2019

Abstract
In this study, we evaluated the influence of antithrombin on platelet adhesion onto immobilized fibrinogen using an in vitro system simulating venous and arterial flow. Platelets in anticoagulated whole blood (PPACK, 40μM) were labeled with mepacrine (10μM). Adhesion of platelets onto fibrinogen-coated glass cover slips was assessed in a rectangular flow chamber (shear rates of 13 s−1 to 1500 s−1). Platelets were visualized at 15 sec, 1 and 5 min following perfusion using a fluorescence laser-scan microscope. In parallel, the effects of supraphysiological supplementation of blood with antithrombin (2.8 IU/ml of blood) on platelet adhesion rates was evaluated. During perfusion, platelet adhesion onto fibrinogen linearly increased with exposure time and shear rates. Within the first min of perfusion, an inverse correlation between platelet adhesion and plasma antithrombin activity was observed at shear rates of 13 s−1 and 50 s−1 (r=−0.48 and r=−0.7, p each <0.05). Significant differences in platelet adhesion (1786±516 U vs. 823±331 U, p<0.05) related to low (92±3.3%) and high (117±4.1%) antithrombin activity was observed at a flow rate of 13s−1 within first minute. Further supplementation of anticoagulated whole blood with antithrombin (activity up to 280 %) decreased the rate of platelets adhesion (ratio of adhesion at 1 and 5 min) about 35% when compared to nonsupplemented blood (1.25 ± 0.17 vs. 1.95 ± 0.4, p=0.008). Application of heparine as anticoagulant did not enhance the antiadhesion properties of antithrombin. Our findings are in accordance with the “low shear phenomenon” of arterial thrombus progression, i.e. thrombus enlargement at distal areas with reduced flow or even stasis. Moreover, the observation that antithrombin significantly suppressed platelet adhesion onto immobilized fibrinogen under low flow conditions is of therapeutic interest and needs further evaluation.
New Coagulation Assays Reference Ranges for Healthy Adults Using the Modern Sysmex CA-1500 Coagulometer.
Authors: Wakeman Lisa , Munro Roger , Dorward Nick , Benton Ann , Gibb Andy , Al-Ismail Saad 
Published: October 2019

Abstract
Reference ranges (RRs) in coagulation are applicable only to specific analyser and reagent combinations and frequently need to be re-established if any of these are changed. In no other sphere of clinical laboratory practice are RRs more affected by such a wide range of multiple demographic and pre-analytical variables. For most routine clinical laboratories therefore, the collection of multiple, separate RRs is not feasible so a representative group of healthy adults such as laboratory staff frequently constitute the reference population from which these limits are calculated. Early morning venous samples were collected into glass B-D Vacutainers (Ref: 367691) from 221 healthy laboratory personnel (F= 159; M = 62) aged 20–63 yrs for both gender. Age groups were equally represented. Samples were processed on a Sysmex CA-1500 analyser within 1 hour of collection. Appropriate NCCLS guidelines were followed throughout. Reagents employed were - Actin FSL (APTT); Innovin (PT); Dade-Behring reference, calibration and deficient plasmas (factor assays); Dade-Behring kit ref: OWWR15 (ATIII); Chromogenix kit ref: 82209863 (Protein C). Outliers were excluded, data examined for normal distribution from histograms and significance levels calculated from the Anderson - Darling test of normality. RRs for normally distributed parameters were calculated using means ± 2SDs. RRs for non-normally distributed parameters were calculated using the log natural transformation and the antilog of 2.5- and 97.5- percentiles. Italicised parameters shown below are non-normally distributed.
Parameter Reference Range Anderson Darling P-Value P-value for normal distribution Mann Whitney U-test (M versus F) *=significant difference PT sec 10.0 – 11.8 <0.005 0.003* APTT sec 24.7 – 31.7 0.006 0.232 TCT sec 13.8 – 17.4 0.035 0.198 Fib g/L Clauss 1.6 – 4.2 0.190 t-test not significant Fib g/L Derived 2.1 – 4.9 0.200 t-test not significant II % 82 – 133 <0.005 0.019* V% 70 – 150 0.021 0.303 VII % 60 – 164 0.008 0.037* X% 75 – 147 0.539 t-test not significant VIII % 48 – 204 <0.005 0.520 IX % 65 – 142 <0.005 0.275 XI % 61 – 142 <0.005 0.394 XII % 59 – 133 0.088 t-test not significant Protein C % 75 – 160 0.036 0.024* ATIII % 86 – 128 0.329 t-test not significant
Kruskal Wallis tests on our data indicate that all coagulation factors are positively associated with age except factors IX and XII. Significant differences (p=0.014) in factor VIIIc was found between those of blood group O and non group O. Significant correlation was found between declining APTTs and associated increasing factor VIIIc when measured in individual volunteers.
Cooperative Action of 1alpha,25-Dihydroxyvitamin D3 and Retinoic Acid in NB4 Acute Promyelocytic Leukemia Cell Differentiation Is Transcriptionally Controlled.
Authors: Bastie Jean-Noel , Balitrand Nicole , Guillemot Isabelle , Chomienne Christine , Delva Laurent 
Published: October 2019

Abstract
All-trans-retinoic acid (RA) and 1alpha,25-dihydroxyvitamin D3 (1,25D3) are involved in the control of hematopoiesis and have been suggested to play a role in cellular differentiation and are as such potent inducers of differentiation of myeloid leukemia cells. In this study, we have shown that in promyelocytic NB4 cells, addition of 1,25D3 enhances terminal granulocytic RA-dependent differentiation concomitant with the enhanced activation of the RA-transcriptional activity through an RARbeta promoter. By EMSA and ChIP assays, we further demonstrate that while both VDR and RAR are bound to the RARbeta promoter in NB4 cells, addition of 1,25D3 increases VDR binding to this promoter while that of RA induces the release of VDR and increases the binding of RAR. Thus, contrary to normal myeloid cells, 1,25D3 does not act as a transrepressor of RA-transcriptional activity in leukemic cells suggesting that transcriptional regulation of RA-target genes may be modified in malignant cells. In promyelocytic leukemic cells the combination of 1,25D3 and RA results in both enhanced transactivation and differentiation.
Simultaneous Administration of AMN107 and Imatinib in the Treatment of Imatinib-Sensitive and Imatinib-Resistant Chronic Myeloid Leukemia.
Authors: Griffin James D. , Weisberg Ellen L. 
Published: October 2019

Abstract
Chronic myelogenous leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) are caused by the Bcr-Abl tyrosine kinase oncogene. The Abl inhibitor imatinib is an effective, frontline therapy for early, chronic phase CML. However, accelerated or blast crisis phase CML and Ph+ ALL patients often relapse because of drug resistance that results from the emergence of imatinib-resistant point mutations within the Bcr-Abl kinase domain. The aminopyrimidine ATP-competitive inhibitor, AMN107, was designed to fit into the ATP-binding site of the Bcr-Abl protein in such a way as to exhibit higher efficacy against imatinib-resistant Bcr-Abl point mutants. AMN107 is active against many imatinib-resistant Bcr-Abl mutants in vitro and in vivo, and is significantly more potent than imatinib against wild-type Bcr-Abl. AMN107 is currently showing promise in phase I/II clinical trials involving CML patients who are unresponsive to imatinib, and thus could potentially be used as a single agent in selected patients resistant or intolerant to imatinib. Alternatively, the use of more than one inhibitor of Abl should effectively lower the number of residual Bcr-Abl-expressing cells having the potential to undergo mutation, and therefore could potentially suppress the emergence of drug-resistant Bcr-Abl mutations. Thus, AMN107 and imatinib could be administered together to achieve higher responsiveness in CML patients. In the current study, we investigated the combination of imatinib and AMN107 in a panel of wild-type and imatinib-resistant Bcr-Abl-expressing cell lines, including 32D.p210, K562, F486S-Ba/F3, F317L-Ba/F3, M351T-Ba/F3, and T315I-Ba/F3. We found evidence of additive to synergistic effects in several of the cell lines examined. In addition, the combination of AMN107 and imatinib was studied in vivo using a bioluminescent Bcr-Abl model of CML. Mice harboring murine 32D.p210 cells engineered to stably express firefly luciferase were treated with vehicle, AMN107 alone (15mg/kg), imatinib alone (75mg/kg), or both AMN107 and imatinib at their respective doses. Mice treated with both agents were observed to carry an overall lower tumor burden (as measured by levels of total body bioluminescence and percent spleen weights) than vehicle-treated mice and mice treated with each agent alone. These results suggest that the combination of imatinib and AMN107 may be a more effective treatment for CML than either agent alone.
Complement-Induced Cell Death by Rituximab Depends on CD20-Expression Level and Acts Complementary to Antibody-Dependent Cell-Mediated Cytotoxicity.
Authors: van Meerten Tom , van Rijn Rozemarijn S. , Hagenbeek Anton , Ebeling Saskia B. 
Published: October 2019

Abstract
The CD20-specific monoclonal antibody rituximab (RTX) has significantly enhanced the overall survival of B-cell non-Hodgkin’s lymphoma but not of chronic lymphocytic leukemia. The level of CD20 expression on tumors has been related to response, but results of several studies are contradictory and no clear relationship could be established. The main effector mechanisms of RTX are thought to be complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), but the exact mechanism is still unknown. Part of the lack of a clear relationship may be explained by the absence of data on the combined contribution of CDC and ADCC.
To study the impact of CD20-expression level on CDC, ADCC and their relative contribution, we developed a system to manipulate CD20-expression levels on cells by transducing the CD20-negative CEM T cell line and developed a new assay to investigate the combined contribution of RTX-mediated CDC and ADCC. By limiting dilution of the transduced and selected cells, clonally-related CEM-CD20 cells were obtained with the number of CD20 molecules as the only variable parameter (mean fluorescence intensity range: 256–693, N=90). These were then subjected to RTX and human serum as a complement source. The results show that the CDC activity clearly depends on CD20-expression level and there is a linear correlation of CD20-expression level to RTX-mediated killing by CDC (p<0.001, r2=0.9125). To further strengthen the importance of CD20-expression level to RTX-mediated CDC, we transduced the already CD20-postive Raji Burkitt’s lymphoma cell line with the CD20-encoding retrovirus. The extra CD20 molecules thus obtained made the cells significantly more sensitive to human serum and RTX (p<0.001).
For ADCC, the CEM-CD20 clones were subjected to effector cells and RTX, which, in contrast to CDC, showed no correlation between CD20-expression level and cell kill via ADCC (p=0.1402, r2=0.1869).
For the combination of CDC and ADCC, as with CDC alone, results showed a correlation between CD20 expression and cell kill (p<0.0201, r2=0.6214). Importantly, CDC-resistant cells were sensitive to ADCC and vice versa. These findings indicate that CDC and ADCC act complementary.
In summary, these data show the importance of CD20-expression level for RTX-mediated cell kill and give new insights into the development of novel strategies to increase RTX-efficacy and the possibility to predict tumor response.
Cocktail Therapy Increased the Survival Rate of APL.
Authors: Zhou Jin , Meng Ran , Li Limin , Yu Jie , Yang Baofeng 
Published: October 2019

Abstract
Background Arsenic trioxide provides significant benefits in newly diagnosed and relapsed acute promyelocytic leukemia (APL) respectively. However, the high relapsed rate is still threatened the life of APL patients. Which regimen should be used to overcome or reduce the relapse in consolidated treatment is a key problem at present. We performed a pilot study about that.
Objective To Compare the effectiveness and security of cocktail therapy with single arsenic trioxide therapy in APL consolidated treatment.
Methods Sixty-Five APL patients, who once received arsenic trioxide treatment and obtained complete remission, were enrolled in this study. Patients were divided into two groups according to the different consolidated regimens. After reinforced treated with DA (daunomycin and cytarabine) or HOAP (harringtonine, vincristin, cytarabine and prednisone) for two course, Group A involved twenty cases received single arsenic trioxide consolidated, Group B included forty-five cases treated with the cocktail therapy, alternatively treated with arsenic trioxide, all trans-retinoic acid and chemotherapy (DA or HOAP). The relapse rates, the survival rates and the central nervous system infiltration rates in 3 years followed up were compared.
Results The relapsed rate of Group A was 55%, which was higher than that of Group B(17.8%). The re-remission rate after the first relapse in Group A was 22%, which was lower than that of Group B(42.8%). The central nervous system infiltration rate of Group A was 28%, which was higher than that of Group B(6%). The average survival time of Group A was 10.5±4.2months, which was shorter than that of Group B (22.5±5.5 months). The three-year survival rate of Group A was 15%, which was less than that of Group B (65.8%).
Conclusions Cocktail therapy —alternatively treated with arsenic trioxide, all trans-retinoic acid and chemotherapy will be the reasonable regimen for APL consolidated treatment. Which provided benefited on inhibiting relapse and central nervous system infiltration of APL.
Suppressor of Cytokine Signaling 3 (SOCS3) Regulates CXCL12-Induced Adhesion to VCAM1 during B Cell Development.
Authors: Silberstein Leslie , Le Yi 
Published: October 2019

Abstract
CXCL12 (SDF-1) induces prolonged FAK phosphorylation in bone marrow (BM) progenitor B cells, but only induces transient FAK phosphorylation in peripheral B cells. In addition, FAK signaling is tightly correlated with CXCL12-induced adhesion to VCAM-1. Given that the CXCR4 receptor expression is similar at all B cell stages, we hypothesized that progenitor and mature B cells possess different mechanisms to control FAK phosphorylation. Here we demonstrate that SOCS3 regulates CXCL12-induced FAK signaling through the ubiquitin-proteosome pathway. First we show that CXCL12 triggers increased FAK ubiquitination in human peripheral B cells and mouse spleen B cells, but not in human and mouse BM B cells. In accordance with this finding, SOCS3 expression is relatively low in progenitor BM B cells and high in peripheral blood and splenic B cells. Through over-expression of SOCS3 in the progenitor B cell line, REH, we demonstrate that SOCS3 co-associates with FAK following CXCL12 stimulation. Moreover, over-expression of SOCS3 results in decreased FAK phosphorylation (intensity and duration), and impaired CXCL12- induced chemotaxis and adhesion to VCAM1. Next, we isolated splenic B cells from MMTV-Cre SOCS3 fl/fl mice and found that SOCS3 deficient mature B cells have increased and prolonged FAK phosphorylation and also show enhanced chemotaxis and sustained adhesion to VCAM-1, similar to progenitor B cells. Flow cytometric analysis revealed that MMTV-Cre SOCS3 fl/fl mice have an increased number of IgM+, Ig D-, mature B cells in the BM compared to wild type mice. Taken together, our results suggest that regulation of FAK signaling through SOCS3 may be important for B cell maturation in the BM and for the egress of mature B cells into the circulation.