bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Persistent Left Ventricular Regional Wall Motion Abnormalities in Childhood Cancer Survivors after Anthracycline Therapy: Assessment of Global Left Ventricular Myocardial Performance By 3D Speckle-Tracking Echocardiography
Authors: Okuma Hirotsugu , Yagasaki Hiroshi , Shimozawa Katsuyoshi , Mugishima Hideo , Noto Nobutaka 
Published: October 2019

Abstract
Background: Previous studies of childhood cancer survivors demonstrated the existence of transient or persistent left ventricular (LV) regional wall motion abnormalities (WMA) after treatment with anthracyclines, but the differential impact on deformation of persistent regional WMA against global LV myocardial performance is unknown.
Methods: To investigate whether childhood cancer survivors after treatment with anthracyclines with persistent LV regional WMA have a poorer LV myocardial performance compared to those without WMA, 34 long-term childhood cancer survivors (mean age 14.6±4.0 years) with a median cumulative anthracycline dose 234.7mg/m2 (range 80-625mg/m2) who had been off treatment for ≥ 5 years and a preserved LV ejection fraction (EF) (>55%), and 12 healthy control subjects, were studied by using 3D speckle-tracking echocardiography (3D STE). The 34 patients were divided into two groups according to the existence of regional WMA: group 1 (with WMA, n=14), group 2 (without WMA, n=20). 3D STE was performed to assess LV global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), global area strain (GAS), LV torsion, LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LVEF, and LV systolic dyssynchrony index (SDI: % of SD of time to peak of the 16-segment/R-R interval).
Results: Of the 14 patients with WMA, regional WMA was seen at mid-anterior septum in 13 patients (92.8%) and apical septum in 1 patient (7.2%). There was no statistical difference in LVEDV, LVESV, LVEF, GLS, LV torsion or SDI derived from GLS, GCS, GAS among the 3 groups. In contrast, there were significant differences in GRS (p<0.001), GAS (p<0.018), GCS (p<0.025), and SDI derived from GRS (p<0.01) among the 3 groups. Compared with group 2, group 1 had significantly reduced GRS (14.3±6.1% vs. 33.1±10.1%, p=0.003), GCS (-23.5±3.7% vs. -33.9±6.5%, p=0.026), GAS (-34.3±5.1% vs. -45.41±6.6%, p=0.034, respectively), and greater SDI derived from GRS (16.5±5.1% vs. 6.9±2.9%, p<0.01, respectively). Moreover, existence of WMA was correlated with GRS (p<0.0001), SDI derived from GRS (p<0.0001), LVEF (p=0.036), and cumulative dose (p=0.049). Multiple linear regression analysis identified GRS as a significant determinant of the existence of WMA (β=0.751, p=0.001).
Conclusion: Childhood cancer survivors after anthracycline therapy with persistent regional WMA show a poorer LV myocardial performance with mechanical dyssynchrony compared to those without regional WMA, despite a preserved LVEF.

Disclosures
No relevant conflicts of interest to declare.
The Reduction of Erythropoietin Stimulating Agent (ESA) Use Due to the FDA Black Box Warning
Authors: Noxon Virginia , Bennett Charles L , Wu Jun 
Published: October 2019

Abstract
Background: Erythropoietin stimulating agents (ESAs), have been readily used to treat chemotherapy related anemia in cancer patients since 2003. ESAs are a useful substitute for blood transfusions for these patients. However, there were unacknowledged toxicities for ESAs when they were first administered. In March 2007, these toxicities were acknowledged by the FDA when a black box warning was issued for ESAs in these patients. This study aims to observe ESA utilization trends along with VTEs to determine the effect of the black box warning.
Methods: The 2002-2010 merged South Carolina Medicaid- Cancer Registry dataset with Medicaid claims up to 2012 was used to determine the effect of the FDA black box warning. Breast, non-small cell lung and colorectal patients were determined from the cancer registry. Of these, those who had chemotherapy were identified. ESA users were identified from medical and pharmacy claims. The final sample contained those who had their first ESA claim after chemotherapy and who were not dual enrolled in Medicare.
Results: Of the 1,645 cancer patients with chemotherapy, 1,310 (80%) had at least one ESA claim. Total ESA claims by year showed a peak in 2006 at 2,243 claims followed by a decrease to 1,347 in 2007 and 714 in 2006. A month by month breakdown of ESA claims showed the peak in May 2006 at 250 and eventually decreasing to 7 in December 2012. Total VTE events for these patients showed a peak in 2007 at 811 followed by a steep decline to 351 in 2009 and 154 in 2012.
Conclusion: The FDA black box warning may have been effective in reducing ESA utilization. There is also the potential delayed response to the clinical trial data for VTEs and ESA utilization. The meta-analysis in 2008 by Dr. Bennett also seems to have had an impact on reducing ESA utilization and VTE events.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
An Intergenic SNP in the β–globin Gene Cluster Is Associated with Hyperuricemia and Influences Gene Transcription in Vitro
Authors: Kumkhaek Chutima , Shriner Daniel , Doumatey Ayo P. , Rotimi Charles N. , Rodgers Griffin P. 
Published: October 2019

Abstract
Hemolysis as a suggested cause of hyperuricemia is based upon the fact that red blood cells contain uric acid. The development of hyperuricemia also generates from an increased synthesis of nucleic acids occurring as part of the erythropoietic response to hemolysis in hemoglobin disorders such as sickle cell anemia, α-thalassemia, and β-thalassemia. In addition, multiple genome-wide association studies (GWAS) have reported significant association between uric acid levels and specific genomic loci. However, the mechanism of hyperuricemia still remains controversial and it is also unknown whether African Americans have higher prevalence of hyperuricemia due to genetic vs environmental risk factors. Here, we used joint admixture mapping and association testing to identify genetic variants associated with serum uric acid levels in African American. Interestingly, we detected 6 SNPs (rs2855125, rs2855126, rs11036415, rs11036496, rs4320977, and rs4348933) in an intergenic region of the β–globin cluster on chromosome 11 are associated with high levels of serum uric acid in populations of African ancestry. Next, we explored the potential regulatory role of intergenic SNPs associated with hyperuricemia using luciferase reporter gene activity assays and electrophoretic mobility shift assays (EMSA). Each SNP-containing DNA fragment was amplified by PCR using human genomic DNA and inserted into a firefly luciferase reporter vector, pGL3-basic vector. 293T or K562 cells were co-transfected with these constructs and a Renilla luciferase vector to control for transfection efficiency. Expression of firefly luciferase driven by each SNP-containing DNA fragment was measured by a dual luciferase reporter assay and normalized by Renilla luciferase expression. SNPs rs2855126, rs11036496 and rs4348933 on chromosome 11 had significantly greater expression levels of firefly luciferase than pGL3-basic-transfected cells in both 293T and K562 cells. Of these, the SNP rs2855126 ancestral C allele (associated with higher serum uric acid levels) showed significantly higher luciferase activity than the derived G allele. Functionally, the luciferase activities from these constructs were determined to be very similar in both cell lines used. Alleles altering expression were further assessed for binding of nuclear extracted proteins by EMSA. We found specific gel shift bands for SNPs rs2855126, rs11036496, and rs4348933, suggesting these SNPs are situated in the binding site of potential transcription factors. These data provide new insights into the potential contribution of imbalanced β-globin gene expression to hyperuricemia.

Disclosures
No relevant conflicts of interest to declare.
The CD21low B Cell Population Is Composed of an Anergic and an Immunostimulatory Germinal Center-like B Cell Subset
Authors: Shimabukuro-Vornhagen Alexander , García Márquez María , Fischer Rieke , Wennhold Kerstin , Iltgen Juliane , Theurich Sebastian , von Bergwelt-Baildon Michael S. 
Published: October 2019

Abstract
In recent years we have gained an increased understanding of the complexity of B cell biology and function. It has become increasingly recognized that apart from antibody production B cells exert many more function. B cells serve as antigen-presenting cells (APC), they contribute to immunoregulation and represent an important source of cytokines and chemokines. A deeper understanding of the role of B cells in the pathophysiology of human diseases has been hampered by the lack of well-defined functional B cell subsets. We therefore aimed to identify novel human B cell subsets which could serve as biomarkers or targets of therapeutic intervention. Using a transcriptomic approach combined with flowcytometric immune assessment of healthy human subjects and patients we were able to identify several functional B cell subpopulations with relevance to human disease. We were able to define a CD21low CD86pos human B cell subset with strong antigen-presenting capacity which gradually develops from conventional resting B cells under the continuous stimulation via CD40. These cells were phenotypically and functionally distinct from CD21low CD86neg B lymphocytes, which represent anergic B cells. Using calcium flux assays and phospho-specific flow cytometry we were able to show that the CD21low B cell subsets displayed distinct signaling states. Both CD21low B cell subpopulations had an impaired response to B cell receptor stimulation. However, CD21low CD86pos B cells had higher basal calcium levels and basal phosphorylation of BCR-associated signaling molecules such as Syk and Erk. Contrary to CD21low CD86neg B cells, which demonstrated poor antigen-presenting capacity, CD21low CD86pos B cells were potent immunostimulatory antigen-presenting cells. CD21low CD86pos B cells were increased in acute inflammation and autoimmune diseases such as rheumatoid arthritis. CD21low CD86neg B cells, on the other hand, were increased in chronic inflammatory conditions such as chronic HIV infection. The balance between the CD21low B cell subsets varied with the functional state of the B cell compartment in inflammatory conditions and could be used to classify the functional state of the B cell compartment. In summary, we have identified several novel human B cell subsets with distinct functions. Given the large number of B cell-directed drugs which are in clinical development or already approved it seems likely that an increased knowledge of the human B cell subsets will not only provide important insights into the pathology of immune-mediated diseases but will also result in novel therapeutic strategies.

Disclosures
No relevant conflicts of interest to declare.
Regulation of Stimulated and Basal Release of Weibel-Palade Bodies By Syntaxin-3 Containing SNARE-Complexes
Authors: Van Breevoort Dorothee , Wahedi Maryam , Schillemans Maaike , Carter Tom , Huveneers Stephan , van den Biggelaar Maartje , Voorberg J.J. , Bierings Ruben 
Published: October 2019

Abstract
Vascular endothelial cells contain unique rod-shaped secretory granules, called Weibel-Palade bodies (WPBs), which contain a number of haemostatic, angiogenic and inflammatory mediators. Several components that are critical for regulated WPB exocytosis have been identified, including the small GTPase Rab27A and its effector synaptotagmin-like protein 4-a (Slp4-a), but the mechanism remains unclear. We have previously identified syntaxin binding protein 1 (STXBP1) as an endogenous Slp4-a binding partner involved in WPB release, along with the SNARE proteins syntaxin-2 and -3. In this study we investigated the possible role of syntaxin-2 and -3 in WPB exocytosis.
We characterized the subcellular location of these syntaxins in endothelial cells using immunocytochemistry. Syntaxin-2 was primarily associated with the plasma membrane where it localized at VE-caderin-based adherens junctions and at integrin-based adhesions to the extracellular matrix. Interestingly, the t-SNARE syntaxin-3 was primarily associated with WPBs. To further explore its role in WPB biology we mapped the endothelial interaction partners of syntaxin-3 through an unbiased mass spectrometry approach using pull downs of lentivirally-expressed mEGFP-syntaxin-3 with anti-GFP nanobeads. Among its interaction partners are various SNAREs and associated proteins such as syntaxin binding proteins 2 and 5 (STXBP2/5), N-ethylmaleimide-sensitive factor (NSF), SNAP23 and α-SNAP, suggesting we successfully pulled down a SNARE complex and its regulatory machinery that are involved in exocytosis. We further addressed the role of syntaxin-3 in stimulated WPB exocytosis using siRNA-mediated knockdowns and found that depletion of syntaxin-3 led to a significant potentiation of Ca2+- as well as cAMP-mediated VWF secretion. In contrast, we observed a decrease in basal (unstimulated) VWF secretion after silencing of syntaxin-3, which amounts to a significantly increased intracellular VWF content. The potentiation of VWF secretion after depletion of syntaxin-3 was almost completely attributable to an increased WPB pool size; when corrected for increased WPB content the probability of stimulated release of a WPB was unaltered in the absence of syntaxin-3.
Our data position syntaxin-3 as a WPB-linked SNARE-protein that regulates basal secretion of VWF.

Disclosures
No relevant conflicts of interest to declare.
Studies on the Formation of Heinz Bodies. I. Methemoglobin Production and Oxyhemoglobin Destruction
Authors: HARLEY JOHN D. , MAUER ALVIN M. 
Published: October 2019

Abstract
A study of the changes in hemoglobin of erythrocytes incubated with various test substances has been reported. The concentrations of oxyhemoglobin and methemoglobin in these erythrocytes were measured and the term "intact" hemoglobin was introduced, in order to distinguish these pigments from later degradation products of hemoglobin. Certain agents which are known to cause Heinz body formation and erythrocyte destruction in vivo have been shown to cause methemoglobin formation and "intact" hemoglobin destruction in vitro, and some of these agents were also shown to produce these changes in vivo. The possible significance of these findings in relation to the role of methemoglobin formation in Heinz body production has been discussed.
CONGENITAL HYPOPLASTIC ANEMIA ASSOCIATED WITH MULTIPLE DEVELOPMENTAL DEFECTS (FANCONI SYNDROME)
Authors: ESTREN S. , SUESS JOHN F. , DAMESHEK WILLIAM 
Published: October 2019

Abstract
A sporadic example of Fanconi syndrome (congenital hypoplastic anemia in association with other congenital defects) is reported.
The significance of the simultaneous occurrence of multiple congenital defects in the pathogenesis of congenital hypoplastic anemia is discussed.
THE USE OF PHOTO-ELECTRIC TURBIDOMETRY IN THE DETERMINATION OF RED CELL COUNTS, HEMATOCRITS, AND HEMOGLOBIN
Authors: WHITLOCK J. H. 
Published: October 2019

Abstract
1. Blood turbidometry is recommended as a screening technic for distinguishing between anemic and nonanemic individuals.
2. Blood turbidometry must be supplemented by other technics for an exact diagnosis of the type of anemia. However, with such help it makes its own contribution to the accuracy of the diagnosis.
3. Blood turbidometry alone would seem to be capable of following an anemic individual’s response to therapy once the proper diagnosis is established.
4. Determination of hemoglobin concentration by turbidometry appears as a distinct possibility. However, further investigation is necessary to validate its utility.
5. Evidence is accumulated that the shadow-volume relationship is a constant in several species.
INCONSTANCY AND VARIABILITY OF THE VASCULAR FRAGILITY TEST EVEN IN PURPURIC CONDITIONS
Authors: ROSKAM J. , RENARD CH. , SWALÜE L. 
Published: October 2019

Abstract
Two unusual cases of purpura simplex raise the problem, as yet unsolved, of the pathogenesis of the purpuric eruption. Together with a previous observation of hemorrhagic purpura made by Roskam, they show the inconstancy and variability of the vascular fragility test.
ULCERS OF THE LEG IN MEDITERRANEAN DISEASE
Authors: ESTES J. EARLE , FARBER EUGENE M. , STICKNEY J. M. 
Published: October 2019

Abstract
Ulceration of the skin of the legs may occur in Mediterranean disease. Such ulceration cannot be distinguished grossly from that occurring in sickle cell anemia and congenital hemolytic icterus. The outstanding histologic feature (noted at biopsy of one of these ulcers) is the prominent deposition of iron in the cutis.
THE EFFECT OF QUANTITATIVE AND QUALITATIVE PROTEIN DEFICIENCY ON BLOOD REGENERATION. I. WHITE BLOOD CELLS
Authors: GUGGENHEIM K. , BUECHLER EDITH 
Published: October 2019

Abstract
1. The effect of diets, varying in quantity or quality of protein, on white blood cell regeneration was studied in leukopenic rats, the leukopenia having been induced by a protein-free diet.
2. Diets containing different amounts of casein (3, 6, 9 and 18 per cent, respectively), were fed ad libitum. At the 3 per cent level, a further decrease occurred of white blood cells, whereas the other three diets initiated a regeneration of leukocytes, its degree being more or less in proportion to the casein content.
3. In experiments with diets containing 18 and 30 per cent of casein, the amount of protein eaten and not its level in diet was the decisive factor in the regeneration of leukocytes. The white blood cell regenerating effect of a diet containing an optimal level of protein, may be neutralized when given in restricted amounts.
4. Diets containing nutritionally inferior proteins, fed at 9 per cent level, also impaired normal regeneration of leukocytes. The white blood cell regeneration afforded by the proteins investigated was found to increase in the following order: maize, gelatin, wheat, casein, processed soya, peanut, meat, egg.
5. In white blood cell regeneration promoted by dietary protein, granulocytes were found to react to a greater degree than lymphocytes and monocytes.
Correction of poor platelet transfusion responses with leukocyte-poor HL-A-matched platelet concentrates
Authors: Herzig RH , Herzig GP , Bull MI , Decter JA , Lohrmann HP , Stout FG , Yankee RA , Graw RG Jr 
Published: October 2019

Abstract
Matching donor-recipient pairs for HL-A antigens provides a logical starting point for selecting donors for recipients with extensive prior transfusion histories. However, during the course of continued exposure to even HL-A-matched platelet concentrates, further sensitization occurs, as indicated by progressively poorer post-transfusion increments and transfusion reactions. There is evidence that such sensitization may be due to non-HL-A antigens. Finally, it is postulated that the poor post-transfusion platelet increments obtained when standard platelet concentrates are used result from the leukoagglutinin antigen-antibody reaction involving the platelet as an “innocent bystander.” The standard platelet concentrate can be purified by a simple method of centrifugation (178 g times 3 min), removing about 96% of the contaminating white blood cells with concomitant loss of about 21% of the platelets. The use of these leukocyte-poor platelet concentrates can restore compatible transfusion increments in highly alloimmunized thrombocytopenic recipients. The luekocyte-poor concentrates can diminish undesirable transfusion reactions following imcompatible platelet transfusions.
Fluorescent labeling of human platelets
Authors: Horne WC , Guilmette KM , Simons ER 
Published: October 2019

Abstract
Noncovalently bound fluorescent probes have been used to study changes in the platelet which may occur during platelet aggregation. Platelets were exposed to either N-phenyl-naphthylamine (NPN) or 8-anilino-1- naphthalene-sulfonic acid (ANS). Both dyes were bound by the platelet, and platelet aggregation by collagen or thrombin was unaffected by the presence of the label. No change in fluorescence intensity or wavelength of maximum intensity was observed during platelet aggregation.
Selection of benign primitive hematopoietic progenitors in chronic myelogenous leukemia on the basis of HLA-DR antigen expression
Authors: Verfaillie CM , Miller WJ , Boylan K , McGlave PB 
Published: October 2019

Abstract
Chronic myelogenous leukemia (CML) is a lethal malignancy of the human hematopoietic stem cell. Here we report that coexistent benign, primitive hematopoietic progenitors can be distinguished from their malignant counterparts in CML bone marrow by differences in cell surface antigen expression. Selection of bone marrow cells expressing the CD34 antigen but lacking the HLA-DR antigen results in recovery of small lymphocyte-like blasts, which initiate and sustain production of myeloid clonogenic progeny in vitro. Secondary clonogenic cells derived at week 1, 5, and 8 from long-term bone marrow cultures (LTBMCs) initiated with primitive progenitors, which lack HLA-DR antigens, exhibit neither the Philadelphia chromosome (Ph1) nor the corresponding bcr/abl mRNA characteristic of CML. In contrast, clonogenic cells recovered at week 1, 5, and 8 from LTBMCs initiated with the CML HLA- DR+ population contain Ph1 and express bcr/abl mRNA. This observation indicates that it may be possible to select a population of viable, exclusively benign hematopoietic stem cells from CML bone marrow capable of repopulating the hematopoietic compartment following autologous bone marrow transplantation.
Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation
Authors: Wingard JR , Plotnick LP , Freemer CS , Zahurak M , Piantadosi S , Miller DF , Vriesendorp HM , Yeager AM , Santos GW 
Published: October 2019

Abstract
Growth was assessed during the first and second years following bone marrow transplantation (BMT) in 47 children treated by either busulfan plus cyclophosphamide (BU/CY) (n = 24) or cyclophosphamide plus fractionated total body irradiation (CY/TBI) (n = 23). Before transplant, the median height was only 0.2 SD below age- and sex- adjusted means (range, -2.5 to +3.0). Height was greater than 2.0 SD below normal in only three patients (6%). The pretransplant heights were comparable in the BU/CY and CY/TBI groups (-0.1 v -0.6 SD, P = .35). Following transplant, median 1- and 2-year heights were 0.7 and 0.9 SD below normal, respectively. Growth rates were 2.2 SD and 1.4 SD below normal during the first and second years, respectively. Growth rates were greater than 2.0 SD below normal in 24 of 47 (51%) at 1 year and in 12 of 31 (39%) at 2 years after transplant. Growth rates in patients treated with BU/CY were comparable to those treated with CY/TBI during both years: -2.5 versus -1.7 SD during the first year (P = .19, Wilcoxon), and -1.5 versus -1.1 SD during the second year (P = .61). Growth rates during the second year correlated with growth rates during the first year (r = .36, P = .046). Growth rates during the first year were lower in patients who had been given prior cranial irradiation, those who were near pubertal age at the time of transplant, and those who were transplanted for a disease other than acute lymphoblastic leukemia (ALL). During the second year, poor rates of growth were associated only with the use of corticosteroids after transplant.