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1
Yao, A. C., P. M. Gootman, P. P. Frankfurt, and S. M. DiRusso. "Age-related superior mesenteric arterial flow changes in piglets: effects of feeding and hemorrhage." American Journal of Physiology-Gastrointestinal and Liver Physiology 251, no. 5 (November 1, 1986): G718—G723. http://dx.doi.org/10.1152/ajpgi.1986.251.5.g718.
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Cardiovascular (CV) responses to feeding before and after 15% blood volume hemorrhage (H) were studied in lightly anesthetized piglets less than or equal to 2-days and greater than 2-wk-old. Superior mesenteric (Mes) and renal (Ren) arterial flows (F) were registered by electromagnetic probes before and continuously for 2 h after milk feeding (26 ml/kg) by gavage. Postprandially, in piglets less than or equal to 2-days-old MesF tended to increase (maximum change, mean +/- SE, 16.0 +/- 4.7%) at 30 min, whereas Mes vascular resistance (R) significantly decreased at 30, 90, and 120 min (17.3 +/- 6.2%). In piglets greater than 2-wk-old, MesF significantly increased by 30 min, which lasted 120 min (37.7 +/- 11.7%); MesR decreased by 20.0 +/- 5.8% at 90-120 min. Compared with the less than or equal to 2 days olds, the older piglets demonstrated greater and more sustained postprandial MesF increase. After H, regional F and pulse pressure (PP) decreased, heart rate and R increased in both groups. After stabilization, feeding induced insignificant CV changes in less than or equal to 2-day-old piglets. In contrast, increased MesF (44 +/- 14.4%) and PP (24 +/- 8.5%) and decreased MesR (31 +/- 8.9%) were observed in the greater than 2-wk-olds. MesF changes differed significantly between the age groups. The Ren vascular bed showed no consistent response in both age groups. Thus Mes vascular responses to feeding with or without preceding H in developing piglets were age related.
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Li, T., Y. Xie, X. Zhang, S. Wang, and W. Ji. "190FEEDERS FROM RHESUS MONKEY SUPPORT PROLONGED DIFFERENTIATED GROWTH OF RHESUS MONKEY EMBRYONIC STEM CELLS." Reproduction, Fertility and Development 16, no. 2 (2004): 216. http://dx.doi.org/10.1071/rdv16n1ab190.
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Previous study demonstrated that feeders are important for growth and differentiation of rhesus monkey embryonic stem cells (rES)(Thomson JA et al., 1995 PNAS \bf 92, 7844–7848). In this study, we developed 5 rhesus monkey feeder cell lines for rES culture: MESF (ear skin fibroblasts from 2-week-old neonatal monkeys), MAF (adult Fallopian tube cells), MGF (adult follicular granulose fibroblast-like cells), MGK (adult follicular granulose kidney-like cells), and MSC (single-cell cloning from MESF), all of which were fibroblast-like cells. Two experiments were designed to investigate rES cell growth and differentiation potentials. In experiment 1, rES (R366.4) was cultured on MESF, MAF, MGF, MGK, and MSC, with MEF (mouse embryonic fibroblasts) as control. In experiment 2, rES was cultured on the mixed feeders: MSC: MGK at 1:1, 7:3, 8:2 and 9:1, depending on the results of experiment 1. Results of experiment 1 showed that the rES underwent undifferentiated growth on MESF, MAF, MGF and MSC (cultured for 15 passages), but not on MGK, with morphology typical of rES on MEFs, and exhibiting positive alkaline phosphatase staining, positive expression of Oct-4 and GAPDH, and negative expression of PAX6, AFP, BMP4 and hCG of rES as well as normal karyotypes. Embryonic bodies (EBs) were formed on Day 7 to 8 from the rES cultured on MESF, MAF, MGF and MSC. The EBs showed positive expression of hCG, AFP and BMP4. Differentiation of neuron, epithelium and muscle cells was observed after 21 days of continuous culture of the rES. The colonies of rES cultured on MESF, MAF, MGF and MSC were higher than on MEF (1.5 to 3 times). Interestingly, expansion speeds and differentiation rates on MSC were less than on MESF. These results also indicated that fibroblast cells, on the one hand, were alone sufficient for supporting prolonged undifferentiated growth of rES, and on the other hand, other mixed cells except fibroblast cells had the ability to promote the growth and differentiation of R366.4 rES. Results of experiment 2 showed that the mixed feeders (MSC:MGK) at 8:2 or 9:1 supported undifferentiated growth of rES but not feeders at 7:3 or 1:1. Our work demonstrated that the rhesus monkey feeders were better able to support undifferentiated growth and maintain differentiation potentials of rES than were MEFs feeders. The rES could grow if the ratio of mixed other cells serving as the feeders exceeded 20%.
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Alam, Najmul, Naureen Banu, Nobi ul Alam, Umme Ruman, Zidan Khan, Md Arfin Ibn Aziz, Niloy Barua, et al. "Deciphering the Pharmacological Potentials of Methanol Extract of Sterculia foetida Seeds Using Experimental and Computational Approaches." Evidence-Based Complementary and Alternative Medicine 2022 (April 23, 2022): 1–13. http://dx.doi.org/10.1155/2022/3403086.
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The edible herb Sterculia foetida L. has potential nutraceutical and medicinal effects. The present study is performed to assess the possible antidiabetic, neuropharmacological, and antidiarrheal activity of the methanolic extract of S. foetida seeds (MESF) through in vitro, in vivo, and in silico approaches. When compared to standard acarbose, the results of the antidiabetic study provided strong proof that the glucose level in the MESF was gradually decreased by inhibiting the function of α-amylase enzymes. The sedative potential of MESF (200 and 400 mg/kg) was determined by employing open field, hole cross, and thiopental sodium-induced sleeping time tests, which revealed significant reductions in locomotor performance and increased sleep duration following MESF treatment. In addition, mice treated with MESF exhibited superior exploration during elevated plus maze and hole board tests. MESF also showed good antidiarrheal activity in castor oil-induced diarrhea and intestinal motility tests. Previously isolated compounds (captan, 1-azuleneethanol, acetate, and tetraconazole) exhibited good binding affinity in docking studies and drug-likeliness properties in absorption, distribution, metabolism, excretion/toxicity (ADME/T), and toxicological studies. Collectively, these results indicate the bioactivity of S. foetida, which represents a potential candidate in the food and pharmaceutical industries.
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Arellano-Rodrigo, Eduardo, Alberto Alvarez-Larran, Francisco Cervantes, Juan-Carlos Reverter, Neus Villamor, and Emili Montserrat. "Increased Granulocyte CD11b and Monocyte Tissues Factor Expression in Patients with Essential Thrombocythemia and Thrombosis." Blood 104, no. 11 (November 16, 2004): 1526. http://dx.doi.org/10.1182/blood.v104.11.1526.1526.
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Abstract The mechanisms accounting for the increased risk of thrombosis in patients with essential thrombocythemia (ET) are not well known. Recently, a possible role for the granulocytes in the development of thrombosis in ET has been suggested. To analyze the possible relationship between granulocyte activation and a history of thrombosis in ET, granulocyte activation was studied in 53 ET patients (26 with a previous history of thrombosis and 27 without) and 26 healthy controls. Neutrophil and monocyte CD11b expression, monocyte tissue factor (mTF) expression, and platelet-neutrophil (PNC) and platelet-monocyte (PMC) complexes were studied using whole blood cytometry and the results were expressed as percentages and in MESF (molecules of equivalent soluble fluorochrome) units. Granulocyte CD11b and mTF expression were measured at baseline and after activation with lipopolysaccharide (LPS). The results are as follows: 1) ET patients had significantly higher baseline percentages of circulating PNC and PMC as well as neutrophil CD11b MESF expression than the controls (p=0.0001); 2) monocyte CD11b expression was higher in patients with ET and thrombosis (mean 151241 MESF) than in those without (127191 MESF) and in the controls (65717 MESF) (p= 0.0001); 3) mTF baseline surface expression was increased in ET patients as compared with the controls (15635 vs 9385 MESF, p= 0.0001); 4) following LPS activation, patients with ET and previous thrombosis had significantly higher mean percentage of mTF expression than those without thrombosis and the controls (48%, 36% and 25%, respectively) (p= 0.0001). No differences were noted when the results were analysed according to the treatment that the patients were receiving at the time of study. In conclusion, patients with ET and a history of thrombosis show a marked increase in granulocyte activation, especially in monocyte activation, and therefore such alteration might play a role in the pathogenesis in these patients.
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Kimlinger, Teresa K., Thomas E. Witzig, and S. Vincent Rajkumar. "Expression of Cytoplasmic and Surface VEGF by Plasma Cells in Myeloma and Related Disorders." Blood 104, no. 11 (November 16, 2004): 3655. http://dx.doi.org/10.1182/blood.v104.11.3655.3655.
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Abstract Background: Previous studies quantitating VEGF in plasma cells from multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and smoldering myeloma (SMM) have found no significant difference in expression between the groups. These studies have been done using immunohistochemistry, quantitative RT-PCR, and Western Blots using material from isolated CD138+ plasma cells. These studies may have been limited by specificity of reagents, low numbers of plasma cells, or heterogeneity within the plasma cell population. Asosingh et al have shown that 5T2MM murine myeloma cells show greater VEGF expression in the CD45- compared to the CD45+ plasma cell compartment (Asosingh K, Blood2004;103:3131–7). Quantitative flow cytometric methods allow for the quantitation of antigen expression with high sensitivity and allow discrimination among cell subsets. Flow studies have suggested that myeloma patients have both CD45+ and CD45 - plasma cell subsets and that each compartment may contain phenotypic and functionally different types of clonal plasma cells. This two part study evaluated bone marrow plasma cells for intracellular and surface levels of VEGF in MM, MGUS, SMM, amyloid, and normal controls. Methods: Cytoplasmic VEGF expression (cVEGF) was measured on lysed and permeabilized (FACSTM Permeabilizing Solution, BD Biosciences, San Jose, CA) whole bone marrow samples using anti-VEGF PE (R and D Systems, Minneapolis, MN). With each run, QuantumTM Simply Cellular Beads (Bangs Laboratories, Fishers, IN) were stained with the same VEGF antibody to create a standard curve for calculation of MESF/ABC (antibody binding capacity) values. A median VEGF MESF value was calculated for the plasma cells, lymphocytes, and granulocytes from each patient sample. Surface expression of VEGF (sVEGF) was determined using CD138 FITC/ VEGF PE/ CD45 Percp/ CD38 APC staining on ACK lysed whole bone marrow cells. sVEGF expression was determined on the plasma cell population as a whole and on the individual CD45 fractions. Median expression and proportion of cases with plasma cells expressing >20% sVEGF were calculated. Cytoplasmic kappa and lambda staining was also done to determine clonality. Results: cVEGF MESF differences within the plasma cell populations were greater than in the other cell types. The MESF was higher in MM (n=14 patients, median MESF 247,866) compared to MGUS/SMM (n=14, median MESF 89,794) and amyloid (n=5, median MESF 134,429)(p=0.038). The lymphocytes and granulocytes in each group had similar MESF values, but the median MESF was lower than in the plasma cells (median 41,485 for lymphocytes, and 24,227 for granulocytes). sVEGF was expressed by less than 20% of plasma cells in all groups studied. Similar results were also seen in the CD45- plasma cell fraction. In the CD45+ plasma cell fraction, all groups showed varying levels of positive expression: MM (n=15 patients; median, 52% cells positive), normal controls (n=4; 51%), MGUS/SMM (n=11; 34%). Conclusions: cVEGF expression was significantly higher in MM compared to SMM/MGUS in this study. On the other hand, sVEGF expression was confined to the CD45+ plasma cell compartment in all groups studied, with a trend to higher % positive cells in the MM group compared to MGUS. We are working on studying levels of secreted VEGF in various human plasma cell subsets, both alone and in conjunction with stromal cell contact.
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Alam, Najmul, Naureen Banu, Md Arfin Ibn Aziz, Niloy Barua, Umme Ruman, Israt Jahan, Farhana Jahan Chy, et al. "Chemical Profiling, Pharmacological Insights and In Silico Studies of Methanol Seed Extract of Sterculia foetida." Plants 10, no. 6 (June 3, 2021): 1135. http://dx.doi.org/10.3390/plants10061135.
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Sterculia foetida, also known as jangli badam in Bangladesh, is a traditionally used plant that has pharmacological activities. A qualitative phytochemical analysis was performed to assess the metabolites in a methanolic extract of S. foetida seeds (MESF), and the cytotoxic, thrombolytic, anti-arthritics, analgesic, and antipyretic activities were examined using in vitro, in vivo, and in silico experiments. Quantitative studies were performed through gas chromatography-mass spectroscopy (GC-MS) analysis. The brine shrimp lethality bioassays and clot lysis were performed to investigate the cytotoxic and thrombolytic activities, respectively. The anti-arthritics activity was assessed using the albumin denaturation assay. Analgesic activity was determined using the acetic acid-induced writhing test and the formalin-induced paw-licking test. A molecular docking study was performed, and an online tool was used to perform ADME/T (absorption, distribution, metabolism, and excretion/toxicity) and PASS (Prediction of Activity Spectra for Substances). GC-MS analysis identified 29 compounds in MESF, consisting primarily of phenols, terpenoids, esters, and other organic compounds. MESF showed moderate cytotoxic activity against brine shrimp and significant thrombolytic and anti-arthritics activities compared with the relative standards. The extract also showed a dose-dependent and significant analgesic and antipyretic activities. Docking studies showed that 1-azuleneethanol, acetate returned the best scores for the tested enzymes. These findings suggested that MESF represents a potent source of thrombolytic, anti-arthritic, analgesic, antipyretic agents with moderate cytotoxic effects.
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Hu, Lan, Yongwan Chun, and Daniel A. Griffith. "A Multilevel Eigenvector Spatial Filtering Model of House Prices: A Case Study of House Sales in Fairfax County, Virginia." ISPRS International Journal of Geo-Information 8, no. 11 (November 10, 2019): 508. http://dx.doi.org/10.3390/ijgi8110508.
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House prices tend to be spatially correlated due to similar physical features shared by neighboring houses and commonalities attributable to their neighborhood environment. A multilevel model is one of the methodologies that has been frequently adopted to address spatial effects in modeling house prices. Empirical studies show its capability in accounting for neighborhood specific spatial autocorrelation (SA) and analyzing potential factors related to house prices at both individual and neighborhood levels. However, a standard multilevel model specification only considers within-neighborhood SA, which refers to similar house prices within a given neighborhood, but neglects between-neighborhood SA, which refers to similar house prices for adjacent neighborhoods that can commonly exist in residential areas. This oversight may lead to unreliable inference results for covariates, and subsequently less accurate house price predictions. This study proposes to extend a multilevel model using Moran eigenvector spatial filtering (MESF) methodology. This proposed model can take into account simultaneously between-neighborhood SA with a set of Moran eigenvectors as well as potential within-neighborhood SA with a random effects term. An empirical analysis of 2016 and 2017 house prices in Fairfax County, Virginia, illustrates the capability of a multilevel MESF model specification in accounting for between-neighborhood SA present in data. A comparison of its model performance and house price prediction outcomes with conventional methodologies also indicates that the multilevel MESF model outperforms standard multilevel and hedonic models. With its simple and flexible feature, a multilevel MESF model can furnish an appealing and useful approach for understanding the underlying spatial distribution of house prices.
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Klabusay, Marti n., Viera Kuhrova, Viera Hrabcakova, Petr Coupek, and Jiri Mayer. "Prognostic Stratification of Patients with Chronic Lymphocytic Leukemia Based on Quantitative Flow Cytometry Evaluation of ZAP-70 Versus Homology of IgVH Plot." Blood 112, no. 11 (November 16, 2008): 2081. http://dx.doi.org/10.1182/blood.v112.11.2081.2081.
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Abstract B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the adult population. It has a heterogeneous behavior and variable prognosis. While some patients experience indolent disease requiring no therapy for many years, others demonstrate a more aggressive type unresponsive to therapy. An accurate prognostic stratification is essential for optimizing the therapeutic strategy. Many prognostic factors are presently known, but their relationships and significance are often not clearly understood. Several markers have been identified, including IgVH mutation status and ZAP-70. Mutation of IgVH (less than 98% homology with the germline sequence) is correlated with better prognosis. Expression of ZAP-70, which is a cytoplasmic ζ-associated tyrosine-kinase essential for T-cell receptor signal transduction, is associated with more rapid disease progression and shorter survival. However, its detection by flow cytometry has many technical difficulties, resulting in high interlaboratory variability. The expression of intracellular ZAP-70 in 217 patients with diagnosis of B-CLL was determined using a new approach: quantitative flow cytometry on CD5+19+ tumor cells. Other laboratory and clinical parameters were evaluated, including gender, age, type and number of therapies, CD38 expression, cytogenetics and mutation status of IgVH. The expressions of ZAP-70 and CD38 were measured in molecules of equivalent soluble fluorochrome (MESF units). The results were correlated with mutation status of IgVH. Patients were divided into two groups by cluster analysis in a plot of IgVH homology versus ZAP-70 MESF (left panel). Overall survival curves for these groups are shown (right panel). It could follow that patients above the diagonal (triangles, group B) in the IgHV versus MESF plot have significantly poorer prognoses (p=0.0001) than do patients below this diagonal (circles, group A). Expression of CD38 above 15000 MESF showed worse prognosis for patients in the group B (p=0.035). Only three of 61 patients with chromosomal aberrations associated with poor prognosis (del11q and del17p) were found in the group A, but all of them had del13q present, as well. The authors introduced a new approach for evaluating ZAP-70 expression in B-CLL cells using quantitative flow cytometry that is easily standardized and not burdened with technical problems. Plotting IgVH homology (%) versus ZAP-70 quantitative expression (MESF) could clearly divide patients according to their prognoses. Figure Figure
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Schwartz, Abe, Adolfas K. Gaigalas, Lili Wang, Gerald E. Marti, Robert F. Vogt, and E. Fernandez-Repollet. "Formalization of the MESF unit of fluorescence intensity." Cytometry 57B, no. 1 (2003): 1–6. http://dx.doi.org/10.1002/cyto.b.10066.
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Klabusay, Martin, Viera Hrabcakova, Petr Coupek, Martin Trbusek, and Michaela Pevna. "Additional value of quantitative expression of ZAP-70 and CD38 for prognostic factors in chronic lymphocytic leukemia." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e19006-e19006. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e19006.
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e19006 Background: Chronic lymphocytic leukemia (CLL) has heterogeneous clinical course. Identification of prognostic markers is important for proper management of disease. Cytogenetics, IgVH mutation status, TP53 functional status, CD38, ZAP-70 and CD49d expression are accepted prognostic factors in CLL. ζ-chain-associated protein kinase 70 (ZAP-70) is associated with disease progression. However, measurement of ZAP-70 and CD38 expression relies on qualitative flow cytometry. Authors tested hypothesis whether quantitative analysis of markers can improve information about prognosis of CLL. Methods: 217 CLL patients were included; diagnosis was made from peripheral blood by morphology and immunophenotyping by flow cytometry with common antibodies. Expressions of intracellular ZAP-70 and surface CD38 were measured using quantitative fluorescence cytometry. Standardized fluorescent microparticles were used to quantify molecules of equivalent soluble fluorochrome (MESF units). Analysis of rearrangement of the IgVH gene was performed according to the European recommendation. Deletions at 11q22-q23 ( ATM), 17p13 ( TP53), 13q34 ( RB1) loci and trisomy of chromosome 12 were detected by I-FISH. Results: Patients’ ages ranged from 33 to 86 years and included all Rai stages. Expression of ZAP-70 ranged from 546 to 5,955 MESF, CD38 from 1,886 to 31,619 MESF. 48% patients embodied mutated and 52% unmutated IgVH status. In cytogenetics, del(13q) was detected in 59%, trisomy 12 in 13%, del(11q) in 21%, and del(p53) in 8% of patients. IgVH (in %) was plotted against ZAP-70 (in MESF) and patients were divided into high (HR) and low risk (LR) groups by cluster analysis based on Kaplan-Meier overall survival curves. Patients in HR group had significantly poorer prognoses (p = 0.0001) than those in LR group. When patients from HR group were clustered according to CD38 expression, very high risk (VHR) group with high CD38 and significantly worse prognosis (p = 0.035) was identified. Conclusions: We have demonstrated that quantitative ZAP-70 and CD38 expressions cannot replace IgVH analysis, but, contrary to that, addition of quantitative data can further specify prognoses of patients with CLL.
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Deutsch, Varda R., Sigi Kay, Marjorie Pick, Yair Herishanu, Ori Rogowsky, Shoshana Baron, Elizabeth Naparstek, and Aaron Polliack. "Quantitation of Zap-70 Expression in B-CLLCells Employing a Novel Flow Cytometry Analysis Method." Blood 104, no. 11 (November 16, 2004): 4785. http://dx.doi.org/10.1182/blood.v104.11.4785.4785.
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Abstract IgVH mutational status and molecular cytogenetics have dramatically improved the ability to predict the prognosis of CLL patients. These tests, however, are highly sophisticated, complex and costly for routine use. ZAP-70, a syk family tyrosine kinase normally expressed in T cells, is a newly described marker which correlates with clinical progression and shorter survival in CLL. A flow cytometry assay to detect ZAP-70 described by Crespo et al (1), appears to be the simplest approach for routine clinical stratification in B-CLL. It is highly informative, and has a strong correlation between the expression of ZAP-70 in CLL cells and clinical outcome. However, in this analysis there are some technical aspects that should be improved to enable it to be standardized as a routine flow cytometry assay. ZAP-70 expression in B-CLL cells is not quantitative but assessed relative to its expression in the T- and NK cells (CD3+, CD56+). This approach can be problematic at times, as ZAP-70 levels in T cells vary in CLL patients as well as in normal controls, probably due to its up regulation following activation. An additional quandary in this assay is that all results are recorded relative to the subjectively delineated T-cell gate. Accordingly, small changes in expression in the T cells can significantly alter the results obtained in some B-CLL samples. In this study we aimed to improve the resolution of the assay by performing a quantitative analysis of ZAP-70 expression within the B-CLL cell population which is uncoupled from T cells. Blood samples were stained by the method described by Crespo et al (1) and ZAP 70 levels in B cell populations in CLL patients (CD19+CD5+) and in healthy volunteers (CD19+) were determined using a standard curve generated by an absolute fluorescent standard of FITC high levels beads with a range of 50–2000 x103 molecules of equivalent soluble fluorochrome (MESF) units per microsphere. Quantitation of expression levels were generated using Quick Cal V2.2 via www.bangslab.com. (Bangs laboratories). Using this analysis system the mean expression levels of ZAP 70 were calculated in healthy B cells (n=11) to be 11,177±1812 MESF units while in CLL (n=36) the mean value was >143,000 MESF units. To determine the reliability of this new method and its clinical relevance we compared our results to data generated using the analysis method of Crespo et al (1). We found a significant correlation between the two methods (r2 = 0.7558). Using ROC curve analysis with maximum sensitivity and specificity, our minimum positive value was found to be 46,700 MESF, with >95% sensitivity at 27,000 MESF and >92% specificity at 67,000 MESF and a Pearson correlation of 0.877 (P<0.0005). We conclude that this assay can provide a more reproducible and reliable analysis of Zap-70 expression in B-CLL, which is easily standardized. This analysis is highly specific as it is quantitative, not subjective and uncoupled from T cell activation in the sample.
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Rhein, Peter, Richard Ratei, Rita Mitlohner, Martin Schrappe, Wolf-Dieter Ludwig, and Leonid Karawajew. "CD11b Is a Therapy-Induced Marker for Monitoring Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia." Blood 110, no. 11 (November 16, 2007): 1424. http://dx.doi.org/10.1182/blood.v110.11.1424.1424.
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Abstract Assessment of minimal residual disease (MRD) has become central to the clinical management of patients with acute lymphoblastic leukemia (ALL). Among the methods available for MRD monitoring, flow cytometry (FCM), which relies on the presence of leukemia-associated aberrant immunophenotype, holds great promise for clinical application. However, the major antigens used for FCM-MRD identification (CD10, CD34, CD45, CD20, CD19, TdT) undergo expression changes during therapy. Moreover, the presence of normal hematopoietic progenitors, in particular in the regenerating bone marrow after treatment, negatively impacts the sensitivity and specificity of MRD detection. Recently, we analysed genome-wide gene expression in blasts isolated from peripheral blood of pediatric precursor B-cell (PBC)-ALL patients after one week of therapy (day 8 cells). Expression changes observed in the day 8 cells pointed to several cell surface molecules, whose expression has not been characteristic for B-lineage hematopoiesis. In particular CD11b surface antigen has been frequently up-regulated in the day 8 cells. In the present study, we addressed expression dynamics of CD11b in PBC-ALL at clinically significant MRD timepoints during induction therapy (days 15, 33 and 78; ALL-BFM protocol). To this end, a CD11b specific antibody has been included into a nine-color, single-tube panel (antibodies to CD19, CD20, CD10, CD34, CD45, CD58, CD3, and a nuclear stain Syto16), which has been applied in order to detect residual blasts among 106 cells in bone marrow specimens from patients with PBC-ALL. At day 15, mean expression of CD11b (in MESF units) has been significantly increased if compared with leukemic cells at diagnosis (9600+/−2800 vs 850+/−140; p=0.005). The up-regulation by more than 10-fold has been found in 8 of 24 cases (33%), and has reached, in part, very high levels (eg, 450 MESF vs 49500 MESF at diagnosis and day 15, respectively). This indicates that CD11b expression changes are due to a therapy-induced gene up-regulation rather than to a clonal selection during clinical treatment. At the later timepoints of induction therapy, 7 of 22 patients (day 33) and 2 of 18 patients (day 78) were MRD positive. CD11b expression, if increased at day 15, retained its high values on day 33 (7900+/− 3200 MESF, 6 patients) and on day 78 (15100 MESF, 1 patient). Importantly, in contrast to leukemic cells, their normal CD19+CD10+ counterparts in both, non-leukemic and ALL bone marrow samples, remained CD11b negative. This difference has facilitated a reliable discrimination of normal and leukemic blasts in the MRD positive cases with regenerating bone marrow at day 78. In conclusion, treatment-induced up-regulation of CD11b in PBC-ALL has a promising potential as a novel marker, which may considerably improve specificity of FCM-MRD detection in bone marrow samples with a complex hematopoietic background.
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Gaigalas, A. K., L. L. Wang, A. Schwartz, G. E. Marti, and R. F. Vogt. "Quantitating fluorescence intensity from fluorophore: Assignment of MESF values." Journal of Research of the National Institute of Standards and Technology 110, no. 2 (March 2005): 101. http://dx.doi.org/10.6028/jres.110.010.
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Ramon, Daniel S., Wendy Wagner, Patrick Ching, Connie Chung, Marguerite Buckingham, and Anat R. Tambur. "5-P: Use of MESF for DSA strenght characterization." Human Immunology 68, no. 1 (October 2007): S18. http://dx.doi.org/10.1016/j.humimm.2007.08.028.
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Kebriaei, Partow, Daniel J. DeAngelo, Anjali S. Advani, Susan M. O'Brien, David Marks, Hagop M. Kantarjian, Elias J. Jabbour, et al. "Exploration of Potential Relationships between CD22 and Selected Safety Outcomes in the Inotuzumab Ozogamicin Phase 3 INO-VATE Study." Blood 132, Supplement 1 (November 29, 2018): 4031. http://dx.doi.org/10.1182/blood-2018-99-110552.
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Abstract Introduction: CD22 is widely expressed on leukemic lymphoblasts in patients with B-cell acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin (InO), an anti-CD22 monoclonal antibody conjugated to calicheamicin, has shown significantly higher remission rates than standard of care (SC) chemotherapy in relapsed or refractory B-cell (R/R) ALL, independently of CD22 expression level. Here we report safety outcomes by CD22 expression in patients with R/R ALL receiving InO (vs SC) as salvage therapy in the INO-VATE trial (NCT01564784). Methods: Adults with CD22-positive ALL in 1st or 2nd salvage were randomized to InO (n=164; starting dose 1.8 mg/m2/cycle [0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15 of a 21-28 day cycle for ≤6 cycles]) or SC (n=162; fludarabine/high-dose (HD) cytarabine (Ara-C)/granulocyte colony-stimulating factor, Ara-C plus mitoxantrone, or HD Ara-C).The InO dose was reduced to 1.5 mg/m2 per cycle in patients who achieved complete remission [CR] or CR with incomplete hematologic recover [CRi]. Last patient visit was January 4, 2017. Central flow cytometry was used to assess CD22 expression, which was quantified as % leukemic blasts CD22-positive and as Molecules of Equivalent Soluble Fluorochrome (a quantitative measure of receptor density on leukemic blasts [MESF]). Outcomes were reported in patients by baseline leukemic blast positivity (≥90% vs <90%), and in quartiles of patients (Q1-Q4) defined by CD22 MESF: Q1=lowest CD22 expression, Q4= highest CD22 expression. Results: At baseline, 142 InO patients and 117 SC patients had an evaluable sample for central-lab CD22 analysis. The majority of patients in both arms had high (≥90%) CD22 positivity (InO, 75.4%; SC, 72.6%), with a smaller proportion of patients exhibiting CD22 positivity <90% (InO, 24.6%; SC, 27.4%). The median number of completed cycles in the InO arm for the CD22 expression quartiles was n=2 for Q1, n=3 for Q2, n=2 for Q3, and n=3 for Q4; respective median overall dose was similar across quartiles: 4.2 mg/m2 (range: 1.3-9.2), 4.5 mg/m2 (range: 0.8-9.2), 4.2 mg/m2 (range: 0.8-9.3), and 4.6 mg/m2 (range: 0.8-9.6). In both arms, the most common grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia (InO, 47% vs SC, 44%), thrombocytopenia (InO, 40% vs SC, 58%), febrile neutropenia (InO, 28% vs SC, 55%), leukopenia (InO, 29% vs SC, 34%), and anemia (InO, 24% vs SC, 44%), with similar rates between CD22 MESF expression quartiles (Table 1). Grade ≥3 hepatotoxicity occurred more frequently in the InO arm (17%) vs SC (8%), occurring with similar rates in the CD22 expression quartiles (Table 1). In the InO arm, more patients with ≥90% CD22 positivity received post-treatment SCT (60 [56%] vs 12 [34%] patients with CD22 <90%); 9 (8%) patients with ≥90% CD22 positivity and 2 (6%) patients with <90% also had a pre-treatment SCT. The rate of post-treatment SCT in the CD22 MESF expression quartiles is shown in Table 2. Among patients who proceeded to SCT in the InO arm, where VOD risk was higher, post-transplant VOD occurred in 16 (27%) patients with ≥90% CD22 positivity vs 2 (17%) patients with <90%. When assessing CD22 expression by MESF, the rate of post-transplant VOD was similar across CD22 MESF quartiles (Table 2). Conclusions: The risk of developing TEAEs, including hepatic adverse events, which were more common in the InO vs SC arm, was not associated with intensity of CD22 expression in either the InO or SC arm. Among InO patients with post-treatment SCT, there was no apparent relationship between CD22 expression and the risk of developing VOD, when analyzing CD22 by % positivity or by MESF. Disclosures DeAngelo: BMS: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; Shire: Honoraria; Takeda: Honoraria; Blueprint Medicines: Honoraria, Research Funding; ARIAD: Consultancy, Research Funding; Amgen: Consultancy; Glycomimetics: Research Funding; Incyte: Consultancy, Honoraria. Advani:Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. O'Brien:Sunesis: Consultancy, Research Funding; Acerta: Research Funding; Pfizer: Consultancy, Research Funding; Aptose Biosciences Inc.: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Astellas: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; Kite Pharma: Research Funding; Celgene: Consultancy; Janssen: Consultancy; Vaniam Group LLC: Consultancy; Pharmacyclics: Consultancy, Research Funding; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding. Marks:Novartis: Consultancy; Pfizer: Consultancy; Amgen: Consultancy. Kantarjian:Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria, Research Funding. Wang:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer: Employment, Equity Ownership. Laird:Pfizer: Employment, Equity Ownership. Nick:Pfizer: Employment, Equity Ownership. Stelljes:Amgen: Honoraria; MSD: Consultancy; JAZZ: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria.
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Coustan-Smith, E., A. Kitanaka, CH Pui, L. McNinch, WE Evans, SC Raimondi, FG Behm, M. Arico, and D. Campana. "Clinical relevance of BCL-2 overexpression in childhood acute lymphoblastic leukemia." Blood 87, no. 3 (February 1, 1996): 1140–46. http://dx.doi.org/10.1182/blood.v87.3.1140.bloodjournal8731140.
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Enforced BCL-2 gene expression in leukemic cell lines suppresses apoptosis and confers resistance to anticancer drugs, but the clinical significance of increased BCL-2 protein levels in acute lymphoblastic leukemia (ALL) is unknown. Among 52 children with newly diagnosed ALL, BCL-2 expression in leukemic lymphoblasts ranged widely, from 4,464 to 59,753 molecules of equivalent soluble fluorochrome per cell (MESF), as determined by flow cytometry. The mean (+/- SD) level of MESF in 43 cases of B-lineage ALL (19,410 +/- 11,834) was higher than that detected in CD10+ B-lymphoid progenitors from normal bone marrow (450 +/- 314; P < .001), and CD19+ peripheral blood B lymphocytes (7,617 +/- 1,731; P = .02). Levels of BCL-2 in T-ALL cases (17,909 +/- 18,691) were also generally higher than those found in normal CD1a+ thymocytes (1,762 +/- 670), or in peripheral blood T lymphocytes (9,687 +/- 3,019). Although higher levels of BCL-2 corresponded to higher leukemic cell recoveries after culture in serum-free medium, they did not correlate with higher cell recoveries after culture on stromal layers, or with in vitro resistance to vincristine, dexamethasone, 6- thioguanine, cytarabine, teniposide, daunorubicin or methotrexate. BCL- 2 protein levels did not correlate with presenting clinical features. Unexpectedly, however, lower-than-median MESF values were significantly associated with the presence of chromosomal translocations (P = .010). Notably, all six cases with the Philadelphia chromosome, a known high- risk feature, had low levels of BCL-2 expression (P = .022). Higher levels of BCL-2 were not associated with poorer responses to therapy among 33 uniformly treated patients, and were not observed in three patients studied at relapse. In conclusion, increased BCL-2 expression in childhood ALL appears to enhance the ability of lymphoblasts to survive without essential trophic factors, and is inversely related to the presence of chromosomal translocations. However, it does not reflect increased disease aggressiveness or resistance to chemotherapy.
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Schwartz, A., L. Wang, E. Early, A. Gaigalas, Y. Z. Zhang, G. E. Marti, and R. F. Vogt. "Quantitating fluorescence intensity from fluorophore: The definition of MESF assignment." Journal of Research of the National Institute of Standards and Technology 107, no. 1 (January 2002): 83. http://dx.doi.org/10.6028/jres.107.009.
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Wang, L. L., A. K. Gaigalas, F. Abbasi, G. E. Marti, R. F. Vogt, and A. Schwartz. "Quantitating fluorescence intensity from fluorophores: Practical use of MESF values." Journal of Research of the National Institute of Standards and Technology 107, no. 4 (July 2002): 339. http://dx.doi.org/10.6028/jres.107.027.
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Gilead, L., O. Bibi, and E. Razin. "Fibroblasts induce heparin synthesis in chondroitin sulfate E containing human bone marrow-derived mast cells." Blood 76, no. 6 (September 15, 1990): 1188–95. http://dx.doi.org/10.1182/blood.v76.6.1188.1188.
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Abstract Human bone marrow-derived mast cells (hBMMCs), differentiated in vitro in suspension culture and under the influence of human peripheral blood mononuclear cells conditioned medium (hCM), were tested for their response to recombinant human interleukin-3 (rhIL-3) and for their behavior in different microenvironments. The hBMMCs were incubated in the presence of rhIL-3 and the changes in their proliferation rate were determined. Recombinant hIL-3 induced a more than sixfold increase in 3H-thymidine uptake into the hBMMC DNA in a dose-dependent manner. Human CM used as a control for proliferation response induced a more than eightfold maximal proliferation rate increase. Rabbit anti-rhIL-3 completely inhibited hBMMC 3H-thymidine uptake induced by rhIL-3 and decreased the hCM-induced proliferation by approximately 50%. These hBMMCs were cocultured with four different mytomicin C-treated cell monolayers and assayed for phenotypic changes. After only 2 days in coculture with either embryonic mouse skin-derived fibroblasts (MESFs) or human skin-derived fibroblasts (HSFs), a marked increase in granule number and density was noted on staining with toluidine blue. Mast cells that initially stained alcian blue+/safranin- at day 0 of coculture became alcian blue+/safranin+ during the coculture period. Human BMMC proteoglycan synthesis shifted from approximately 85% chondroitin sulfate E to approximately 60% heparin within 14 to 19 days of coculture with the MESF monolayer and to approximately 50% heparin within 19 days of coculture with the HSF monolayer. None of the above- mentioned changes were noted in cocultures of hBMMCs with 3T3 cell line fibroblast monolayers or in cocultures with bovine vascular endothelium (BVE) cell monolayers. These results demonstrate microenvironmental effects exerted by the MESF and HSF monolayers on IL-3-dependent hBMMCs similar to those reported in the conversion of murine mast cell phenotype.
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Gilead, L., O. Bibi, and E. Razin. "Fibroblasts induce heparin synthesis in chondroitin sulfate E containing human bone marrow-derived mast cells." Blood 76, no. 6 (September 15, 1990): 1188–95. http://dx.doi.org/10.1182/blood.v76.6.1188.bloodjournal7661188.
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Human bone marrow-derived mast cells (hBMMCs), differentiated in vitro in suspension culture and under the influence of human peripheral blood mononuclear cells conditioned medium (hCM), were tested for their response to recombinant human interleukin-3 (rhIL-3) and for their behavior in different microenvironments. The hBMMCs were incubated in the presence of rhIL-3 and the changes in their proliferation rate were determined. Recombinant hIL-3 induced a more than sixfold increase in 3H-thymidine uptake into the hBMMC DNA in a dose-dependent manner. Human CM used as a control for proliferation response induced a more than eightfold maximal proliferation rate increase. Rabbit anti-rhIL-3 completely inhibited hBMMC 3H-thymidine uptake induced by rhIL-3 and decreased the hCM-induced proliferation by approximately 50%. These hBMMCs were cocultured with four different mytomicin C-treated cell monolayers and assayed for phenotypic changes. After only 2 days in coculture with either embryonic mouse skin-derived fibroblasts (MESFs) or human skin-derived fibroblasts (HSFs), a marked increase in granule number and density was noted on staining with toluidine blue. Mast cells that initially stained alcian blue+/safranin- at day 0 of coculture became alcian blue+/safranin+ during the coculture period. Human BMMC proteoglycan synthesis shifted from approximately 85% chondroitin sulfate E to approximately 60% heparin within 14 to 19 days of coculture with the MESF monolayer and to approximately 50% heparin within 19 days of coculture with the HSF monolayer. None of the above- mentioned changes were noted in cocultures of hBMMCs with 3T3 cell line fibroblast monolayers or in cocultures with bovine vascular endothelium (BVE) cell monolayers. These results demonstrate microenvironmental effects exerted by the MESF and HSF monolayers on IL-3-dependent hBMMCs similar to those reported in the conversion of murine mast cell phenotype.
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Taylor, Ronald P., Andrew W. Pawluczkowycz, Paul V. Beum, Margaret A. Lindorfer, Frank Beurskens, Jan van de Winkel, and Paul Parren. "Complement Activation and Complement-Mediated Killing of B Cells Promoted by Anti-CD20 Monoclonal Antibodies (mAb) Rituximab and Ofatumumab Are Rapid, and Ofatumumab Kills Cells More Rapidly and with Greater Efficacy." Blood 110, no. 11 (November 16, 2007): 2352. http://dx.doi.org/10.1182/blood.v110.11.2352.2352.
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Abstract We reacted four different CD20+ cell lines (ARH77, Daudi, Raji, and Z138) with either rituximab, ofatumumab or with no mAb, in 50% normal human serum (NHS) as a complement source. At 10 ug/ml, both mAbs bind to targeted cells quickly (t1/2 < 2 min at 37°C), but there are substantial differences in the rates and efficacy at which rituximab and ofatumumab promote C3b deposition and subsequent complement-mediated cytotoxicity (CMC). After a 3 min incubation of Raji cells with rituximab, 55±3% (n=3, this and all experiments) of the cells were killed and deposited C3b corresponded to 123,000±5,000 molecules of equivalent soluble fluorochrome (MESF); comparable values for cells reacted with ofatumumab were 94±1% dead, and 173,000±19,000 MESF. Even after 12 min only 72±1% of the Raji cells had been killed by rituximab, and C3b deposition mediated respectively by rituximab and ofatumumab was 176,000±10,000 and 300,000±60,000 MESF. A similar experiment with Z138 cells led to the following results for CMC and for C3b deposition after 3 min: rituximab, 41±4% killing and 86,000±7000 MESF; ofatumumab, 83±1% killing and 275,000±25000 MESF. Although ARH77 cells are resistant to rituximab-mediated killing in NHS (26% dead after 60 min, compared to the no mAb background of 22%), these cells are killed rapidly by ofatumumab: 60–80% killing in <15 min. We have reported that infusion of rituximab in patients with chronic lymphocytic leukemia (CLL) can lead to depletion of complement, likely a consequence of substantial complement activation and consumption mediated by the rituximab-CD20 immune complexes on the large numbers of circulating CLL cells. In the absence of effector cells in vitro killing of CD20+ targeted cells by both mAbs shows an absolute requirement for complement. Therefore, we evaluated the effect of target cell concentrations on CMC, to test the hypothesis that killing can be compromised due to exhaustion of complement even if the amount of mAb present is adequate to opsonize the cells. Indeed, whereas CMC of Z138 cells mediated by rituximab and ofatumumab gave 30% and 85% respective killing after one hour for cell concentrations between 1×106 and 1×107 cells/ml, killing was reduced to 15% and 30% when the cell concentrations were raised to 1 ×108 cells/ml. However, we found that killing could be restored simply by providing additional NHS as a complement source, with no requirement for additional mAb. In a similar experiment, Raji cells at 1 ×108 cells/ml were incubated for 15 min in 50% NHS with 10 ug/ml of either mAb; the cells were then diluted 10-fold by the addition of buffer or 50% NHS and incubated for another 15 min. CMC by rituximab corresponded to 26% (addition of buffer) and 45% (addition of NHS); comparable CMC for ofatumumab gave 49% and 82% killing. Translation of these findings to the clinic suggests that at high cell burdens, supplementation of a patient’s serum with a complement source may enhance mAb-mediated killing of CD20+ cells. This concept may be important in certain indications for optimizing the clinical efficacy of ofatumumab, which demonstrates a substantially higher level of complement activation and CMC of targeted cells than rituximab.
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Price, Morgan N., Adam M. Deutschbauer, and Adam P. Arkin. "Four families of folate-independent methionine synthases." PLOS Genetics 17, no. 2 (February 3, 2021): e1009342. http://dx.doi.org/10.1371/journal.pgen.1009342.
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Although most organisms synthesize methionine from homocysteine and methyl folates, some have “core” methionine synthases that lack folate-binding domains and use other methyl donors. In vitro, the characterized core synthases use methylcobalamin as a methyl donor, but in vivo, they probably rely on corrinoid (vitamin B12-binding) proteins. We identified four families of core methionine synthases that are distantly related to each other (under 30% pairwise amino acid identity). From the characterized enzymes, we identified the families MesA, which is found in methanogens, and MesB, which is found in anaerobic bacteria and archaea with the Wood-Ljungdahl pathway. A third uncharacterized family, MesC, is found in anaerobic archaea that have the Wood-Ljungdahl pathway and lack known forms of methionine synthase. We predict that most members of the MesB and MesC families accept methyl groups from the iron-sulfur corrinoid protein of that pathway. The fourth family, MesD, is found only in aerobic bacteria. Using transposon mutants and complementation, we show that MesD does not require 5-methyltetrahydrofolate or cobalamin. Instead, MesD requires an uncharacterized protein family (DUF1852) and oxygen for activity.
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Borowitz, Michael J., Jonathan Shuster, Andrew J. Carroll, Michael Nash, A. Thomas Look, Bruce Camitta, Donald Mahoney, Stephen J. Lauer, and D. Jeanette Pullen. "Prognostic Significance of Fluorescence Intensity of Surface Marker Expression in Childhood B-Precursor Acute Lymphoblastic Leukemia. A Pediatric Oncology Group Study." Blood 89, no. 11 (June 1, 1997): 3960–66. http://dx.doi.org/10.1182/blood.v89.11.3960.
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Abstract This report describes the prognostic significance of the intensity of surface membrane antigen expression in a series of 1,231 children older than 1 year with newly diagnosed B-precursor acute lymphoblastic leukemia (ALL) treated on Pediatric Oncology Group (POG) treatment protocols. All patients had dual-color flow cytometric immunophenotyping performed at a central reference laboratory with a standard panel of monoclonal antibodies. The flow cytometers used in the study were calibrated with a standard fluorescence microparticle that permitted conversion of relative fluorescence channels to standard units of mean equivalents of soluble fluorochrome (MESF). In univariate analysis, fluorescence intensity of CD45 and CD20 was significantly associated with event-free survival (EFS), whereas other markers showed no significant correlation with outcome. Patients whose blasts were greater than the 75th percentile of intensity for CD45 (corresponding to 18,000 MESF units with CD45-FITC, or about 8% of the intensity of normal lymphocytes) fared significantly worse than those with lower-density CD45, and those whose blasts were greater than the 25th percentile of intensity for CD20 (corresponding to 17,900 MESF units with CD20-PE) had a poorer EFS. The intensity of both CD45 and CD20 was independently correlated with outcome. There was no significant correlation between intensity of expression of either antigen and traditional clinical risk factors, ploidy, or t(9; 22) or t(1; 19). All patients with t(4; 11) had CD45 intensity greater than the 75th percentile, but CD45 intensity retained its prognostic significance after adjusting for t(4; 11). In multivariate analysis, both CD45 intensity greater than the 75th percentile and CD20 intensity greater than the 25th percentile were significantly correlated with poor outcome independently of previously reported poor prognostic factors including National Cancer Institute (NCI) risk group, ploidy, trisomies of 4 and 10, and adverse translocations including t(1; 19), t(9; 22), and t(4; 11). We conclude that in childhood B-precursor ALL, the intensity of expression of CD20 and CD45 provides prognostic information not available from simple consideration of antigen expression as positive or negative, and adds to that obtained from traditional clinical and biologic risk factors.
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Mainou-Fowler, T., VA Craig, JA Copplestone, MD Hamon, and AG Prentice. "Interleukin-5 (IL-5) increases spontaneous apoptosis of B-cell chronic lymphocytic leukemia cells in vitro independently of bcl-2 expression and is inhibited by IL-4." Blood 84, no. 7 (October 1, 1994): 2297–304. http://dx.doi.org/10.1182/blood.v84.7.2297.2297.
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Abstract During hematopoiesis, viability factors that suppress apoptosis are required throughout the differentiation process. Some of these factors may also function as growth factors. Interleukin-5 (IL-5) is recognized as a growth factor in hematopoiesis. We examined the involvement of IL- 5 as a viability factor of B-CLL in vitro. In 13 B-CLL cases studied, IL-5 at 20 U/mL increased spontaneous apoptosis by a mean percentage of 53% (range, 20% to 129%) (P < .05) after 2 days in culture. On the third day, the mean percentage increase was 37% (range, 18% to 50%). In all cases, IL-4 protected B-CLL cells against IL-5-induced apoptosis by a mean percentage of 47% (range, 18% to 81%) (P < .001). This protection was specific to IL-4 and it was reduced with anti-IL-4 antibody. In addition, expression of bcl-2 protein in untreated cultures was not significantly different from that of the IL-5-treated cells; mean equivalent of soluble fluorochrome (MESF) was 5.2 (range, 3.0 to 6.8) and 4.9 (range, 3.0 to 6.3), respectively (P > .2). In freshly isolated B-CLL cells, the MESF was 4.5 (range, 2.4 to 6.6). These results show that IL-5 induced apoptosis in B-CLL cells by a pathway that is independent of bcl-2 expression. IL-4 partially protects against this effect.
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Mainou-Fowler, T., VA Craig, JA Copplestone, MD Hamon, and AG Prentice. "Interleukin-5 (IL-5) increases spontaneous apoptosis of B-cell chronic lymphocytic leukemia cells in vitro independently of bcl-2 expression and is inhibited by IL-4." Blood 84, no. 7 (October 1, 1994): 2297–304. http://dx.doi.org/10.1182/blood.v84.7.2297.bloodjournal8472297.
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During hematopoiesis, viability factors that suppress apoptosis are required throughout the differentiation process. Some of these factors may also function as growth factors. Interleukin-5 (IL-5) is recognized as a growth factor in hematopoiesis. We examined the involvement of IL- 5 as a viability factor of B-CLL in vitro. In 13 B-CLL cases studied, IL-5 at 20 U/mL increased spontaneous apoptosis by a mean percentage of 53% (range, 20% to 129%) (P < .05) after 2 days in culture. On the third day, the mean percentage increase was 37% (range, 18% to 50%). In all cases, IL-4 protected B-CLL cells against IL-5-induced apoptosis by a mean percentage of 47% (range, 18% to 81%) (P < .001). This protection was specific to IL-4 and it was reduced with anti-IL-4 antibody. In addition, expression of bcl-2 protein in untreated cultures was not significantly different from that of the IL-5-treated cells; mean equivalent of soluble fluorochrome (MESF) was 5.2 (range, 3.0 to 6.8) and 4.9 (range, 3.0 to 6.3), respectively (P > .2). In freshly isolated B-CLL cells, the MESF was 4.5 (range, 2.4 to 6.6). These results show that IL-5 induced apoptosis in B-CLL cells by a pathway that is independent of bcl-2 expression. IL-4 partially protects against this effect.
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Rahman, Md Arifur, Ahmed Abu Rus’d, and Md Enamul Haque. "Isolation and Characterization of Antimicrobial Compound from Stem Bark of Traditional Medicinal Plant Sonneratia apetala: Evaluation of their antimicrobial, Cytotoxic and Antioxidant Properties." Bangladesh Journal of Microbiology 38, no. 1 (September 14, 2021): 1–5. http://dx.doi.org/10.3329/bjm.v38i1.55529.
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Sonneratia apetala (S. apetala) (Lythraceae) has been investigated for the isolation and characterization of antimicrobial compounds and evaluation of their biological activities. The chloroform extract of the stem bark and different partitionate of the chloroform extracts i.e. Petroleum ether soluble fraction (PESF), Ethyl acetate soluble fraction(EASF), Methanol soluble fraction(MSF) and aqueous soluble fractions (ASF) were subjected to different chromatographic techniques to isolate secondary metabolites. Successive chromatographic separation and purification yielded a total of two compounds identified and characterized as Taraxerone(1) and 5,8-dihydroxy- 6-methoxy-4,9-dioxo-1,3,4,9-tetrahydronaphthol[2,3-c]furan-1-yl acetate (2) by extensive proton NMR spectrum (1H-NMRspectrum) analysis. The different partitionate like PESF, EASF, MESF and ASF were subjected to screen their antimicrobial properties against some selected Gram positive and Gram negative bacteria and fungi, brine shrimp lethality and antioxidant activities. The maximum zone of inhibition of chloroform extract was found against Pseudomonas sp. (16mm). All fractions showed more activity against Gram negative bacteria then Gram positive bacteria. In the brine shrimp lethality bioassay, among all extracts, the petroleum ether and ethyl acetate soluble fraction showed significant lethality having the LC50 value of 7.72 μg/ml. The antioxidant activity was evaluated in terms of determination of free radical scavenging activity (DPPH assay). Among all the extracts of S. apetala the highest free radical scavenging activity showed by (Methanol soluble fraction) MESF with IC50 value 18.0 μg/ml.
Bangladesh J Microbiol, Volume 38, Number 1, June 2021, pp 1-5
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Afonso, J., C. M. Guedes, A. Teixeira, V. Santos, J. M. T. Azevedo, and S. R. Silva. "Using real-time ultrasound for in vivo assessment of carcass and internal adipose depots of dairy sheep." Journal of Agricultural Science 157, no. 7-8 (October 2019): 650–58. http://dx.doi.org/10.1017/s0021859620000106.
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AbstractFifty-one Churra da Terra Quente ewes (4–7 years old) were used to analyse the potential of real-time ultrasound (RTU) to predict the amount of internal adipose depots, in addition to carcass fat (CF). The prediction models were developed from live weight (LW) and RTU measurements taken at eight different locations. After correlation and multiple linear regression analysis, the prediction models were evaluated by k-fold cross-validation and through the ratio of prediction to deviation (RPD). All prediction models included at least one RTU measurement as an independent variable. Prediction models for the absolute weight of the different adipose depots showed higher accuracy than prediction models for fat content per kg of LW. The former showed to be very good or excellent (2.4 ⩽ RPD ⩽ 3.8) for all adipose depots except mesenteric fat (MesF) and thoracic fat, with the model for MesF still providing useful information (RPD = 1.8). Prediction models for fat content per kg of LW were also very good or excellent for subcutaneous fat, intermuscular fat, CF and body fat (2.6 ⩽ RPD ⩽ 3.2), while the best prediction models for omental fat, kidney knob, channel fat and internal fat still provided useful information. Despite some loss in the accuracy of the estimates obtained, there was a similar pattern in terms of RPD for models developed from LW and RTU measurements taken just at the level of the 11th thoracic vertebra. In vivo RTU measurements showed the potential to monitor changes in ewe internal fat reserves as well as in CF.
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Islam, Md Didarul, Bin Li, Kazi Saiful Islam, Rakibul Ahasan, Md Rimu Mia, and Md Emdadul Haque. "Airbnb rental price modeling based on Latent Dirichlet Allocation and MESF-XGBoost composite model." Machine Learning with Applications 7 (March 2022): 100208. http://dx.doi.org/10.1016/j.mlwa.2021.100208.
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ARRAIZ GOICOCHEA, ALEIDYS S., and VICTOR A. ESTELLER L. "DEL ESQUEMA DE FÁBRICAS DE SOFTWARE A UNA ARQUITECTURA DE REFERENCIA POR MEDIO DE LAS TRANSFORMACIONES DE MODELOS (IMFS & VCD)." Revista Ingeniería Matemáticas y Ciencias de la Información 5, no. 10 (July 10, 2018): 13–31. http://dx.doi.org/10.21017/rimci.2018.v5.n10.a45.
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Mack, David A., Paul V. Beum, Margaret A. Lindorfer, Andrew W. Pawluczkowycz, and Ronald P. Taylor. "The Shaving Reaction Is Facilitated through Trogocytosis: Concerted Transfer of Both Rituximab (RTX) and the Membrane Dye PKH26 from B Lymphocytes to Macrophages Is Demonstrable by Flow Cytometry, Fluorescence Microscopy, and High Resolution Digital Imaging in a Flow Cytometric Environment." Blood 108, no. 11 (November 1, 2006): 2096. http://dx.doi.org/10.1182/blood.v108.11.2096.2096.
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Abstract Opsonization of CD20+ B lymphocytes with the anti-CD20 mAb RTX can promote substantial loss of B cell-bound RTX and CD20 in the presence of acceptor monocytes (Beum et al., J Immunol, 2006). This process of antigenic modulation, or shaving, occurs when patients with chronic lymphocytic leukemia are treated with the standard RTX dose of 375 mg/m2, and represents an escape mechanism for mAb-targeted malignant cells. Shaving in vitro, and likely in vivo, is mediated by mononuclear phagocytic cells: Fc gamma receptors on these cells bind and take up CD20-RTX immune complexes. This process may occur by trogocytosis, in which donor and acceptor cells form immunologic synapses, allowing membrane fragments and cell-surface proteins to be removed from donor cells and transferred to and internalized by acceptor cells. To investigate this hypothesis, Raji cells were stained with the lipophilic fluorescent reporter membrane dye PKH26, and opsonized with RTX or Alexa (Al) 488-conjugated RTX. The cells were incubated with retinoic acid-treated THP-1 cells, a human monocyte/macrophage cell line. THP-1 cells in the mixtures were then stained for CD11b and CD14 for identification. Quantitative analysis of cells by flow cytometry and high resolution digital imaging in a flow cytometric environment (ImageStream, AMNIS Corp.) demonstrated time-dependent transfer of PKH26 from RTX-opsonized Raji cells to THP-1 cells, as illustrated in a representative kinetics experiment in the table. Fluorescence intensity values are given for THP-1 cells after incubation with naïve (control), or RTX-opsonized Raji cells, both of which were PKH26 labeled. Molecules of equivalent soluble fluorochrome (MESF) units or geometric mean fluorescence (GMF) units are used, based on flow cytometry or ImageStream analysis, respectively. PKH26 Fluorescence Intensities Acquired on THP-1 Cells after Incubation with Control or RTX-Opsonized PKH26-Labeled Raji Cells Time of Incubation of Raji and THP-1 Cells, min <1 5 15 45 Control (no RTX on Raji cells) MESF 170 240 260 630 GMF 900 900 1300 3300 Experimental (RTX-opsonized Raji Cells) MESF 700 1200 1700 4300 GMF 3500 6100 8300 19000 Based on the PKH26 signal, a small but readily demonstrable portion of Raji cell membrane is transferred from RTX-opsonized cells to THP-1 cells. Transfer corresponds to only ~5–10% of total PKH26 on Raji cells, which is reasonable as B cells are left intact after shaving. However, we observed >65% transfer of Al488 RTX from B cells to THP-1 cells. Results were confirmed by fluorescence microscopy and by inspection of ImageStream digital images of THP-1 and Raji cells. We believe that transfer of RTX and CD20 from RTX-opsonized B cells to acceptor monocytes/macrophages proceeds via trogocytosis, and plays an important role in the resistance of some B-cell malignancies to RTX therapy. Based on reports of antigenic modulation of targets for other immunotherapeutic mAbs used in cancer treatment, the trogocytic mechanism we document for RTX is likely to underlie antigenic modulation promoted by these mAbs as well.
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Chen, Jenn C., Bruce H. Davis, Nancy C. Bigelow, Carole Ceckowski, JoAnne Robinson, Cynthia Sounart-Miscovich, and Kathrine A. Steel. "Flow cytometric HLA-B27 typing using CD3 gating and molecules of equivalent soluble fluorochrome (MESF) quantitation." Cytometry 26, no. 4 (December 15, 1996): 286–92. http://dx.doi.org/10.1002/(sici)1097-0320(19961215)26:4<286::aid-cyto8>3.0.co;2-a.
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Rigolin, Gian Matteo, Francesco Lanza, and Gianluigi Castoldi. "Photomultiplier voltage setting: Possible important source of variability in molecular equivalents of soluble fluorochrome (MESF) calculation?" Cytometry 20, no. 4 (August 1, 1995): 362–68. http://dx.doi.org/10.1002/cyto.990200413.
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Mendiolina, Jennifer, Patricia Kimble, Marilyn Wetmore, Diane Hartzell, Michael Moritz, and Robert Cirocco. "35-P: Cells Are Not the Same as Antigen Beads: Correlation Between MFI and MESF Values." Human Immunology 71 (September 2010): S43. http://dx.doi.org/10.1016/j.humimm.2010.06.083.
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Brailey, Paul, and Brian Susskind. "Quantitation of fluorescence intensity (FI) on luminex by conversion to molecules of equivalent soluble fluorescence (MESF)." Human Immunology 64, no. 10 (October 2003): S118. http://dx.doi.org/10.1016/j.humimm.2003.08.221.
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Kantarjian, Hagop M., Wendy Stock, Ryan D. Cassaday, Daniel J. DeAngelo, Elias J. Jabbour, Susan M. O'Brien, Matthias Stelljes, et al. "Comparison of CD22 Expression between Baseline, End of Treatment, and Relapse Among Patients Treated with Inotuzumab Ozogamicin Who Responded and Subsequently Relapsed in Two Clinical Trials." Blood 132, Supplement 1 (November 29, 2018): 2699. http://dx.doi.org/10.1182/blood-2018-99-110826.
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Abstract Introduction: Downregulation or loss of B-cell ALL surface antigens (most notably CD19) in patients with acute lymphoblastic leukemia (ALL) targeted by various therapeutic modalities including CART and bi-specific T-cell engagers (BiTEs) has been implicated in acquired resistance to those therapies. Inotuzumab Ozogamicin (InO) is a calicheamicin-conjugated antibody targeting CD22 on ALL blast cells. In the Phase 3 INO-VATE trial, patients with refractory (R/R) ALL who received InO vs standard of care chemotherapy (SC) achieved greater remission, MRD negativity, and improved survival. This study reports CD22 expression levels at baseline, end of treatment (EOT) and relapse in R/R ALL patients who received InO or SC as salvage therapy and subsequently relapsed; the goal of this analysis was to understand if relapse was associated with changes in CD22 expression. Methods: The study population consisted of R/R ALL patients who were treated with InO or SC as part of two clinical trials: Phase 1/2 Study 1010 (NCT01363297; Phase 1, Expansion Phase, + Phase 2 at a dosage of 1.8 mg/m2) and Phase 3 Study 1022 (NCT01564784). This analysis incorporated CD22 expression levels at baseline, at end of treatment, and at relapse. Central laboratory flow cytometry was used to assess CD22 expression, which was quantified as % CD22-positive leukemic blasts and as Molecules of Equivalent Soluble Fluorochrome (MESF), a quantitative measure of CD22 density on leukemic blasts. Outcomes are reported in InO (Study 1022 or 1010) and SC patients who responded to treatment (patients who achieved complete remission/complete remission with incomplete hematologic recovery [CR/CRi]) and subsequently relapsed. CR was defined by <5% marrow blasts and the absence of peripheral blood leukemic blasts; with recovery of hematopoiesis. Results: 25 InO patients (Study 1022, n=19; Study 1010, n=6) and 11 SC patients who responded to treatment and subsequently relapsed were evaluable for central-lab CD22 analysis at baseline. Among InO patients who responded to treatment, the majority had leukemic blasts that were ≥90% CD22-positive at baseline (Study 1022, 66.7%; Study 1010, 66.7%); of the evaluable patients at EOT (Study 1022, n=4; Study 1010, n=0), leukemic blast CD22-positivity was >0-<70%. At relapse, all evaluable InO patients had leukemic blasts with detectable CD22-positivity; with blasts that were predominately <90% CD22 positive (Study 1022, n=6/7; Study 1010, n=5/6 [Table 1]). In contrast, the majority of evaluable subjects who received SC and achieved CR/CRi exhibited CD22 positivity that remained ≥90% at EOT and at relapse When CD22 expression was quantified as MESF, a similar trend was evident (Table 2). In Study 1022, InO patients had a median CD22 MESF of 4085.0 at baseline, which declined to 94.0 at EOT and 418.0 at relapse. In contrast, the median CD22 MESF at EOT and at relapse (3738.0 and 3738.0, respectively) was similar to baseline (4065.0) for SC patients. Conclusions: Among R/R ALL patients who responded to InO treatment and subsequently relapsed, a decrease in CD22 positivity and receptor density was evident from baseline to EOT and relapse, but emergent CD22 negativity was not evident. These results suggest that recurrent disease is associated with decreased CD22 expression, but is not generally attributable to the outgrowth of CD22-negative clones. Disclosures Stock: Jazz Pharmaceuticals: Consultancy. Cassaday:Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Kite Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. DeAngelo:Pfizer Inc: Consultancy, Honoraria; BMS: Consultancy; Glycomimetics: Research Funding; Shire: Honoraria; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Amgen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Takeda: Honoraria; Incyte: Consultancy, Honoraria. Jabbour:Novartis: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. O'Brien:Pharmacyclics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Alexion: Consultancy; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Research Funding; Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy; Acerta: Research Funding; Abbvie: Consultancy; Astellas: Consultancy; Kite Pharma: Research Funding. Stelljes:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria. Wang:Pfizer: Employment, Equity Ownership. Liau:Pfizer: Employment, Equity Ownership. Nguyen:Navigate BioPharma Services, Inc., a Novartis Subsidiary: Employment. Sleight:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer: Employment, Equity Ownership. Neuhof:Pfizer: Employment, Equity Ownership. Laird:Pfizer: Employment, Equity Ownership. Advani:Novartis: Consultancy; Amgen: Research Funding; Glycomimetics: Consultancy; Pfizer: Honoraria, Research Funding.
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Ishida, Hideki, Masashi Inui, Takafumi Yagisawa, Yutaka Yamaguchi, and Kazunari Tanabe. "Quantitative analysis of humoral immunity by flow-cytometric crossmatch using molecules of equivalent soluble fluorochromosome (FCXM-MESF)." Asian Journal of Surgery 43, no. 4 (April 2020): 532–37. http://dx.doi.org/10.1016/j.asjsur.2019.11.005.
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Kaiser, Tiffany E., Brian Susskind, Prabir Roy-chaudhury, Michael Cardi, Lois Arend, Shaoming Huang, Gautham Mogilishetty, Adele Rike, and E. S. Woodle. "Donor specific antibody (DSA) detection by Labscreen beads, based on MESF, correlates with C4d/biopsy proven humoral rejection." Human Immunology 66, no. 8 (August 2005): 94. http://dx.doi.org/10.1016/j.humimm.2005.08.185.
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Rhein, Peter, Richard Ratei, Rita Mitlohner, Giuseppe Basso, Giuseppe Gaipa, Michael N. Dworzak, Martin Stanulla, Martin Schrappe, Wolf-Dieter Ludwig, and Leonid Karawajew. "Integrin Alpha M Chain Expression at Diagnosis Is Inversely Correlated with Cytoreduction Rate and Is Consistently Up-Regulated during Therapy in Acute Lymphoblastic Leukemia (ALL)." Blood 112, no. 11 (November 16, 2008): 2526. http://dx.doi.org/10.1182/blood.v112.11.2526.2526.
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Abstract In childhood ALL, detection and quantification of minimal residual disease (MRD) is of crucial prognostic significance. Gene expression pattern of MRD cells undergoes treatment-related changes which provide insights into the mechanisms of therapy response and resistance. Our recent genome-wide analysis of blasts isolated from peripheral blood (PB) of pediatric patients with B-cell precursor (BCP-) ALL at early stages of induction therapy (day 8) revealed an up-regulation of the gene encoding for integrin alpha M chain (ITGAM, CD11b), and pointed to the involvement of adhesion receptors in the therapy response. In the present study we investigate expression of CD11b at protein level and its clinical relevance in BCP-ALL. At diagnosis, ALL cells heterogeneously express CD11b both in PB (mean 1839+/−515 MESF, 160 pts) and in bone marrow (BM) (655+/−114 MESF, 79 pts). At day 8, increased expression of CD11b has been observed in the majority of PB samples (77 of 100 pts, up-regulation range 1.5- to 74-fold, mean 8.2-fold). In BM, the CD11b expression has been consistently up-regulated at the clinically significant MRD timepoints of induction therapy (days 15, 33 and 78; ALL-BFM 2000 protocol). Moreover, since normal CD19+/CD10+ precursor cells are CD11b negative, the detection of CD11b improved discrimination of normal and leukemic blasts in the MRD positive cases with regenerating BM at day 78. Of particular interest, evaluation of the CD11b expression at diagnosis in context of the early therapy response disclosed its potential clinical relevance. In the bivariate data analysis, expression of CD11b significantly correlated with the blast reduction rate (BRR) and blast count (BC) in PB at day 8 (p=0.007 and 0.001, 103 pts). Similarly, the CD11b expression in BM significantly correlated with the BRR and BC in BM at day 15 (p=0.024 and 0.012, 58 pts). In the multivariate regression analysis, excluding BCR-ABL and MLL-AF4 positive ALL cases and using the additional clinical parameters at diagnosis (age, white blood cell count in PB, DNA index), CD11b expression at diagnosis was the most significant variable contributing to BRR at day 8 (p<0.001, standardized beta coefficient 0.61; 98 pts) and to BRR at day 15 (p<0.001, standardized beta coefficient 0.68; 47 pts). Taken together, our data indicate that the expression of CD11b contributes to the early therapy response and has a promising potential as an MRDspecific marker in BCP-ALL.
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Doubek, Michael, Yvona Brychtova, Anna Panovska, Jakub Trizuljak, Ludmila Sebejova, Olga Stehlikova, Jana Chovancova, et al. "Ofatumumab Added To Dexamethasone In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia. Results From a Phase II Study Of The Czech Leukemia Study Group For Life." Blood 122, no. 21 (November 15, 2013): 2877. http://dx.doi.org/10.1182/blood.v122.21.2877.2877.
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Abstract The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue despite remarkable improvements in prognostication and therapy. One emerging treatment option for relapsed/refractory CLL is the use of high-dose corticosteroids. High-dose methylprednisolone or dexamethasone combined with rituximab are active in relapsed/refractory CLL, but serious infections are frequent and progression-free survival (PFS) is short. The purpose of this clinical trial was to determine the efficacy and toxicity of ofatumumab-dexamethason (O-dex) combination in relapsed or refractory CLL population. The trial was an open-label, multi-center, non-randomized, phase II study. The O-dex regimen consisted of intravenous ofatumumab (Cycle 1: 300mg on day 1, 2000mg on days 8, 15, 22; Cycles 2-6: 1000mg on days 1, 8, 15, 22) and oral dexamethasone (40mg on days 1-4 and 15-18; Cycles 1-6). Premedication consisted of glucocorticoid, paracetamol, and antihistamine before each ofatumumab infusion. All patients received allopurinol, omeprazol, co-trimoxazole, and fluconazole for prophylaxis of tumor lysis syndrome and infections. The O-dex regimen was given for a minimum of 3 cycles, until best response, or a maximum of 6 cycles. Between July 2010 and December 2012, 32 patients (pts.) were recruited at 3 centers. Basic patient characteristics at the start of O-dex therapy were as follows: median age 66 years (range, 50-77); 24 males, 8 females; median CIRS score 7 (0-15); median previous treatment lines 3 (1-10); 30 (94%) pts. were pretreated with fludarabine and 12 (38%) with alemtuzumab; Rai III/IV stage was present in 20 (63%) pts.; 6 (19%) pts. had bulky lymphadenopathy; IgVH genes were unmutated in 30 (94%) pts.; del 11q was present in 6 (19%) and p53 defects (del 17p and/or TP53 mutation) in 8 (25%) pts. The median number of O-dex cycles administered was 6 (1-6). Twenty two (69%) pts. completed at least 3 cycles of therapy. The remaining 9 patients were prematurely discontinued due to CTCAE grade 3/4 infections (7 pts.), disease progression (1 pt.), or uncontrollable diabetes mellitus (1 pt.). Overall responses/complete remissions (ORR/CR) were achieved in 22/5 pts. (69/16%). One patient achieved minimal residual disease negativity (measured by 4-color flow cytometry) at the end of therapy. Median PFS was 10 months. In patients with p53 defects, ORR/CR were achieved in 5/2 pts. (63/25%). The Median PFS was 10.5 months for this subgroup. Median overall survival (OS) has not yet been reached. During therapy, CTCAE grade 3/4 toxicity consisted of bacterial infections (25%), ofatumumab infusion-related side-effects (9%), neutropenia (9%), hyperglycemia (6%), and anemia (3%). No reactivation of herpetic viral infection was observed during the course of therapy. Nine patients died during the follow-up as a result of disease progression (6 pts.), infections (2 pts.), or complications after allogeneic stem cell transplantation (1 relapsed pt.). The median CD20 antigen density in CLL cells was 4766 (881-18515) MESF (molecules of equivalent soluble fluorochrome) units at baseline. At the end of therapy, CD20 density had significantly decreased (median 821 MESF; 443-2637); nevertheless, it was high once more at relapse (median 6619 MESF; 628-21359). In vitro testing of malignant pts. cells sensitivity to dexamethasone and ofatumumab did not show synergistic or additive effect of these compounds in majority of patients. Also, in vitro testing did not clearly predict the outcome of O-dex therapy. Conclusions The O-dex regimen shows relatively high ORR and CR, with promising findings for PFS and OS (including pts. harboring p53 defects), as compared to published data on rituximab plus dexamethasone regimen or ofatumumab in monotherapy. The infectious toxicity in 1/4 of pts. represents the most frequent side effect for this regimen. The study was registered at www.clinicaltrials.gov (NCT01310101). Disclosures: Doubek: GlaxoSmithKline: Research Funding. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding.
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Girouard, Timothy C., Donna M. Fitzpatrick, and Susan L. Saidman. "19-P: Conversion of Luminex data to MESF units using quantiplex beads does not result in more consistent quantitation." Human Immunology 69 (October 2008): S17. http://dx.doi.org/10.1016/j.humimm.2008.08.038.
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Koo, Hyeongmo, Soyoung Lee, Jiyeong Lee, and Daeheon Cho. "Spatio-Temporal Variability of the Impact of Population Mobility on Local Business Sales in Response to COVID-19 in Seoul, Korea." ISPRS International Journal of Geo-Information 11, no. 10 (October 20, 2022): 532. http://dx.doi.org/10.3390/ijgi11100532.
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Social distancing is an effective method for controlling the COVID-19 pandemic by decreasing population mobility, but it has also negatively affected local business sales. This paper explores the spatio-temporal impact of population mobility on local business sales in response to COVID-19 in Seoul, South Korea. First, this study examined the temporal variability by analyzing statistical interaction terms in linear regression models. Second, the spatio-temporal variability was captured using Moran eigenvector spatial filtering (MESF)-based spatially varying coefficients (SVC) models with additional statistical interaction terms. Population mobility and local business sales were estimated from public transportation ridership and restaurant sales, respectively, which were both obtained from spatial big datasets. The analysis results show the existence of various relationships between changes in the population mobility and local business sales according to the corresponding period and region. This study confirms the usability of spatial big datasets and spatio-temporal varying coefficients models for COVID-19 studies and provides support for policy-makers in response to infectious disease.
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Vázquez, Diego, Carmen López-Vázquez, José Olveira, Isabel Bandín, and Carlos Dopazo. "Quantitative Flow Cytometry to Measure Viral Production Using Infectious Pancreatic Necrosis Virus as a Model: A Preliminary Study." Applied Sciences 8, no. 10 (September 26, 2018): 1734. http://dx.doi.org/10.3390/app8101734.
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In recent decades, flow cytometry (FCM) has become an important tool in virology, due to its applications in viral replication and viral-cell interactions, as well as its capacity to quantify proteins (qFCM). In the present study, we have designed and evaluated a qFCM procedure for the in vitro analysis and quantification of fish viral proteins, using the infectious pancreatic necrosis virus (IPNV) as a model. We have also tested its use for viral titration and adapted the MARIS (method for analysing RNA following intracellular sorting) method for simultaneous quantification of viral RNA expression in infected cells. The procedure has proved to be repeatable and reproducible to an acceptable level, although to ensure reproducibility, the repetition of standard curves is inevitable. Regarding its use for viral quantification, a direct relationship (by a second-degree polynomial regression) between viral titres and Molecules of Equivalent Soluble Fluorochrome (MESF) was observed. Finally, the results support the use of this technology, not only for virus quantification, but also to study viral replication from a quantitative approach.
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Fronza, Cátia de Azevedo, Aline Lorandi, and Patricia Beatriz Lemes. "Dados de escrita em séries iniciais: ortografia, fonologia e textualidade." Trabalhos em Linguística Aplicada 45, no. 2 (December 2006): 187–204. http://dx.doi.org/10.1590/s0103-18132006000200003.
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Neste artigo, apresentam-se dados sobre a pesquisa Produção de textos nas séries iniciais: evidências fonológicas e de textualidade, que obteve um corpus formado por 1649 textos de 227 crianças de 2ª, 3ª e 4ª séries de escolas da rede privada de ensino (Fronza, 2004a, 2004b e 2004c). Nos textos, foram identificadas palavras cuja escrita diferenciava-se das convenções ortográficas. As diferenças foram classificadas a partir de uma adaptação de Cagliari (1997), obtendo-se um levantamento de alterações ortográficas ou convencionais e de alterações fonológicas (cf. Varella e Cesaro, 2004), tendo sido considerados seus contextos referentes à posição que ocupam na estrutura da sílaba e da palavra. Após a identificação das alterações e das indicações de progressos significativos a cada coleta e de uma série para outra, com a diminuição de palavras alteradas, o estudo centrou-se nas ocorrências fonológicas, representadas pela MES (Modificação na Estrutura Segmental, cf. Cagliari, 1997). Nos casos de MES, são consideradas as alterações de MESE (MES de Escrita), indicando casos em que há mudança de significado da escrita para a leitura e de MESF (MES de Fala), que se refere às ocorrências da escrita muito semelhantes às faladas por crianças de 2 a 4 anos. Diante desses textos, com uma produção variada e rica, fez-se um estudo sobre a relação entre as alterações de MES e as indicações de textualidade, verificando em que medida tais alterações prejudicaram os textos quanto à coesão, à coerência e à informatividade (Beaugrande e Dressler, 1997). As reflexões e constatações desses estudos oferecem contribuições diretas para a compreensão da forma como as crianças representam graficamente o sistema fonológico da língua, o qual já é de domínio da maioria delas na modalidade oral, a fim de promover um acompanhamento positivo na superação das dificuldades fonológicas, entendendo que as dificuldades ortográficas se estendem pelos anos de escolarização.
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Jacoby, Meagan A., Rigoberto de Jesus, Jin Shao, Daniel Koboldt, and Matthew J. Walter. "Dysfunctional DNA Double-Strand Break Repair Is Present in a Subset of Primary t-AML/t-MDS Myeloblasts." Blood 118, no. 21 (November 18, 2011): 2415. http://dx.doi.org/10.1182/blood.v118.21.2415.2415.
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Abstract Abstract 2415 The chromosomal aberrations found in treatment-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/t-MDS) cells suggest that disease initiation and progression may result from the inappropriate response to double-strand DNA breaks (DSBs) induced by prior exposure to radiation or chemotherapy. We hypothesized that dysregulation of DSB repair by homology-directed repair (HDR) or nonhomologous end joining (NHEJ) in t-AML/t-MDS may result from acquired mutations in HDR/NHEJ pathway genes. To test this possibility, we used next-generation sequencing technology to identify somatic genetic variants in 21 canonical HDR and 9 NHEJ DNA repair genes, as well as a subset of 7 DNA damage response genes using tumor DNA and paired normal DNA obtained from 25 t-AML/t-MDS patients. We identified 6 patients with somatic changes in 3 of these genes (RAD51L3, EME1, TP53). As dysfunctional DSB repair from epigenetic or post-translational modifications in DSB repair pathway genes or abnormalities in other DNA repair pathway genes would be missed using this approach, in parallel we performed functional studies of DSB repair using primary bone marrow cells from 16 of these t-AML/t-MDS patients and CD34+ cells from 5 normal donors. We evaluated DSB by measuring phosphorylated histone H2AX (pH2AX), a well established marker for DSB, in myeloblasts (CD45 dim, low side scatter) and lymphocytes (a surrogate for normal cells) in these samples. Baseline measurements of primary cells, coupled with a time course to measure pH2AX induction and decay after 2 Gy of irradiation (IR) were used to assess the basal DSB burden and response to acute damage, respectively. pH2AX levels were measured by flow cytometry and the geometric mean of the fluorescence intensity was converted to mean equivalent soluble fluorophore (MESF) through the use of standard beads included in each experiment. We found that 4 of 16 t-AML/t-MDS patients had myeloblasts that displayed baseline and post-damage pH2AX levels similar to normal CD34+ controls, while 12/16 patients had abnormal pH2AX levels which fell into one of three major patterns. 1) The first subset had myeloblasts in which baseline pH2AX levels were elevated compared to normal donor CD34+ (average MESF 23,107 vs 11,490, respectively; p<=0.002) suggesting an increased basal DSB burden in these cells. Furthermore, the myeloblasts showed impaired pH2AX induction (measured at 30 min. post IR) compared to CD34+ controls (1.53 vs 2.97 fold increase in pH2AX over baseline, p<=0.002), suggesting a defect in detecting DSB. This phenotype was unique to patients harboring trisomy 8 and was tumor specific, as their lymphocytes displayed baseline and post-induction pH2AX levels similar to lymphocytes from normal controls. No somatic (tumor) sequencing variants were present in the interrogated genes, raising the possibility that trisomy 8 could be driving an abnormal DNA damage response. 2) A second subset of patients had impaired pH2AX induction compared to normal donor CD34+ cells (1.44 vs 2.97 fold increase in pH2AX over baseline, p<=0.01), again suggesting a defect in detecting DSBs. These patients also lacked somatic changes in HDR/NHEJ pathway genes. 3) The final subset of patients had delayed resolution of pH2AX levels compared to CD34+ controls post IR either at 4 hours (average MESF 39,260 vs 25,480, p<0.05) or delayed resolution over the entire 24 hour period compared to controls (p<0.001). These data are consistent with a DSB repair defect and similar to our data showing cells lacking BRCA2, a gene central to the HDR pathway, have elevated pH2AX levels at 4–24 hours post DSB induction compared to BRCA2 sufficient cells (p=0.01). One of these patients had an acquired mutation in the HDR gene RAD51L3. We are currently determining the sensitivity of primary t-AML/t-MDS cells with abnormalities in pH2AX levels to a combination of DSB inducing chemotherapy and PARP inhibition, which is synthetically lethal in the setting of HDR defects. We show cell lines lacking RAD51L3 are more sensitive to PARP inhibition compared to isogenic controls (surviving fraction (SF)50 5 nM vs 20,000 nM). In total, this study confirms that DNA repair genes are mutated in t-AML/t-MDS, suggests that dysfunctional DSB repair is present in t-AML/t-MDS myeloblasts, and provides a rationale to test whether the abnormal DNA damage response can be exploited therapeutically using a synthetic lethal approach in this disease. Disclosures: No relevant conflicts of interest to declare.
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Wexner, Steve, and Christopher White. "Mesh in a mess?" Colorectal Disease 20, no. 3 (March 2018): 177–78. http://dx.doi.org/10.1111/codi.14000.
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Chien, Patrick. "The mess of mesh." BJOG: An International Journal of Obstetrics & Gynaecology 127, no. 1 (December 11, 2019): 1–2. http://dx.doi.org/10.1111/1471-0528.16008.
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Berenbrink, M., Y. R. Weaver, and A. R. Cossins. "Defining the volume dependence of multiple K flux pathways of trout red blood cells." American Journal of Physiology-Cell Physiology 272, no. 4 (April 1, 1997): C1099—C1111. http://dx.doi.org/10.1152/ajpcell.1997.272.4.c1099.
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The volume sensitivity of different K flux pathways has been determined in trout red blood cells subjected to volume perturbation. Gentle hyposmotic swelling induced a K influx in a Cl-containing saline but not in NO3- or methanesulfonate (MeSF)-containing salines, consistent with the activation of a Cl-dependent flux. Extreme hyposmotic swelling led to larger K fluxes in all salines but with reduced anion discrimination of the Cl-dependent flux. In contrast to these graded responses, isosmotic swelling using ammonium chloride or beta-adrenergic stimulation activated only Cl-dependent fluxes in an all-or-none fashion. The relationship between the hyposmotically and isosmotically induced pathways was studied by coactivation using either ammonium chloride or isoproterenol with anisosmotic treatment. Cells in ammonium chloride-containing hyposmotic salines showed no additive K flux over that induced by hyposmotic treatment alone, indicating that the isosmotically induced Cl-dependent flux was identical to the hyposmotically induced Cl-dependent flux. However, cells coactivated by hyposmotic and beta-adrenergic treatment showed a small Cl-dependent flux in addition to that induced by hyposmotic treatment alone. This small third component was unaffected by anisosmotic treatment. We conclude that the major Cl-dependent and Cl-independent K flux pathways are distinct and separate and that the former has an anion dependence that varies with cell volume and a volume sensitivity that varies with ionic strength.
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Petros, Peter. "Re: The mess of mesh." BJOG: An International Journal of Obstetrics & Gynaecology 127, no. 5 (February 8, 2020): 650–51. http://dx.doi.org/10.1111/1471-0528.16103.
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Đogo-Mračević, Svetlana, Slađana Arnautović, Aleksandar Lolić, Danica Perušković, and Tamara Bakić. "Determination of nitrite and heavy metals content in meat and its products." Hrana i ishrana 58, no. 2 (2017): 24–29. http://dx.doi.org/10.5937/hraish1702024q.
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Ljutić, Daniel, Jelka Pleadin, Sanja Kolarić Kravar, Lidija Dergestin Bačun, Tina Lešić, Greta Krešić, and Mladenka Malenica. "Kvaliteta mljevenog mesa s područja grada Zagreba." Meso 21, no. 6 (2019): 586–93. http://dx.doi.org/10.31727/m.21.6.1.
Full textAbstract:
Cilj ovog rada bio je ispitati kvalitetu mljevenog mesa dostupnog na području grada Zagreba te ocijeniti sukladnost ovih proizvoda s obzirom na zahtjeve propisane za mljeveno meso Uredbom (EU) br. 1169/2011 o informiranju potrošača o hrani. U istraživanju su korišteni pretpakirani uzorci mljevenog mesa (n = 42) nabavljeni u maloprodajnoj mreži s područja grada Zagreba, podijeljeni u tri kategorije ovisno o vrsti mljevenog mesa: goveđe mljeveno meso (n = 12), svinjsko mljeveno meso (n = 13) te miješano svinjsko i goveđe mljeveno meso (n = 17). Parametri kvalitete mljevenog mesa ispitani su primjenom standardnih akreditiranih metoda: udio kolagena (HRN ISO 3496:1999), udio ukupnih bjelančevina (HRN ISO 937:1999) i udio ukupnih masti (HRN ISO 1443:1999). Analizom dobivenih rezultata utvrđeno je da ukupno devet uzoraka (21%) nije udovoljavalo zahtjevima propisanim Uredbom po pitanju omjera kolagena i bjelančevina ili udjela masti, odnosno da ti proizvodi nisu imali vjerodostojne informacije na deklaracijama odnosno nazive vrste mljevenog mesa. Utvrđene nepravilnosti upućuju na nužnost sustavnih kontrola kvalitete mljevenog mesa dostupnog na tržištu.