bluuebunny/crossref_metadata_2025_split huggingface dataset:
TET2 Regulates CD8+ T Cell Differentiation
Authors: Carty Shannon A. , Gohil Mercy , Koretzky Gary A , Jordan Martha S 
Published: October 2019

Abstract
Regulation of DNA methylation is critical for proper T cell differentiation and function. Antigen-specific CD8+ T cells undergo global remodeling of DNA methylation following viral infection, suggesting that DNA methylation may direct antigen-specific T cell responses. TET2 is a member of the Ten-Eleven-Translocation (TET) family, which converts 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC) and subsequent intermediates ultimately leading to DNA demethylation. How TET2 regulates T cell differentiation and function is unknown. Here we demonstrate that TET2 expression is regulated by TCR signaling in primary murine T cells. Furthermore, using a novel flow cytometric assay to measure 5hmC levels on a single cell basis, we find that TCR signaling also regulates TET activity as evidenced by a rapid increase in global 5hmC levels after TCR stimulation that is blunted in TET2-deficient T cells. To determine the role of TET2 in T cell responses, we generated mice deficient in TET2 in the T cell compartment (TET2fl/flCD4Cre+) mice. These mice develop grossly normal thymic and peripheral T cell subsets. Given the regulation of TET2’s expression and activity by TCR stimulation, we used a murine model of acute viral infection, specifically LCMV-Armstrong, to test if TET2 regulates antigen-specific T cell responses in vivo. Following viral challenge, TET2fl/flCD4Cre+ mice have similar antigen-specific CD8+ T cell expansion and effector responses but exhibit significantly enhanced memory CD8+ T cell differentiation compared to control mice. These data demonstrate that TET2 plays a critical role in directing CD8+ T cell differentiation and function. Studies are ongoing to identify specific TET2 regulated genes important in the development of CD8+ T cell memory.

Disclosures
No relevant conflicts of interest to declare.
Metabolic Reprogramming of Acute Myeloid Leukemia Blasts By Bone Marrow Stroma Cells
Authors: Mougiakakos Dimitrios , Jitschin Regina , Braun Martina , Mackensen Andreas 
Published: October 2019

Abstract
Introduction: Acute myeloid leukemia (AML) represents the most common form of acute leukemia in adults. Despite the enormous efforts during the last decades treatment resistance is still observed at a high rate. Previous studies have shown that bone marrow stroma promotes an increased resilience of AML blasts towards chemotherapeutics. Furthermore, current data suggest that alterations of the malignant cells’ metabolism could represent a strong determinant for the disease’s (including AML) course and/or treatment resistance. In fact, a deregulated metabolism could lead to a reduced sensitivity towards therapy and it remains to be elucidated whether this is a mechanism contributing to the blast-protective effects elicited by the bone marrow stroma. Here, we sought out to characterize the impact of stroma cells on the AML blasts’ metabolism.
Methods and Results: The human bone marrow stroma cell-line HS-5 was utilized for establishing the in vitro niche model. We compared in our assays AML cell lines (THP-1, OCI-AML, and KG-1) as well as primary blasts cultured on a HS-5 monolayer or alone. In line with previous observations we could detect an increased proportion of AML cells in the S-phase of the cell cycle upon co-culture with HS-5. When evaluating the cells’ metabolism we observed a shift towards glycolysis despite presence of oxygen, i.e. aerobic glycolysis or the “Warburg”-effect. Basal glycolysis as well as maximal glycolytic capacity upon blocking ATP production in the mitochondrial respiratory chain was increased. Respiration (including basal respiration, coupling efficacy, and maximal respiratory capacity) was not significantly affected. However, mitochondrial biogenesis appeared reduced.
Increased glycolysis was accompanied by an increased up-take of fluorescently labeled glucose as well as an increased expression of glucose transporters. The expression of several glycolytic molecules found to be increased upon HS-5 co-culture. Noticeably, cell-to-cell contact was not a pre-requisite for the metabolic shift. Our data was further corroborated by direct observations from AML patients: AML blasts isolated from the bone marrow exhibited an up-regulated glycolysis as compared to their counterparts from the periphery collected at the same time point.
Conclusion: Taken together, our data indicates a stromal cell-mediated metabolic shift in AML blasts towards aerobic glycolysis. This metabolic phenotype is linked to an unfavorable prognosis and increased chemo resistance. The underlying molecular pathways remain to be elucidated and could represent a promising target for future interventions.

Disclosures
No relevant conflicts of interest to declare.
Amino Acid Accumulation by Human Reticulocytes
Authors: ALLEN DAVID W. 
Published: October 2019

Abstract
1. The concentrations of certain amino acids were measured by ion exchange chromatography in mature red cells, in red cells with a high percentage of reticulocytes, and in the plasma in which these red cells had been suspended. The concentration ratio as a measure of net accumulation of the red cells for amino acids was derived from these data.
2. Adult red cells can accumulate glycine and alanine, but not methionine, valine, isoleucine or leucine.
3. Reticulocytes can accumulate glycine best, then alanine, then methionine, isoleucine, and leucine to approximately the same extent. They were unable to maintain a concentration gradient for valine.
4. In two patients with thalassemia, no abnormality was found in the plasma or red cell levels of citrulline, proline, glycine, alanine, valine, isoleucine, tyrosine, or phenylalanine. In one of the thalassemic patients no abnormality of histidine was found. The amino acid accumulation by thalassemic, or fetal red cells was the same as for normal red cells of comparable reticulocyte percentage.
A Second Example of Blood Group B3
Authors: SUSSMAN LEON N. , PRETSHOLD HANNAH , LACHER MORTIMER J. 
Published: October 2019

Abstract
A second example of an unusual B gene, named B3 by Moullec, has been presented, with a family study. Absorption and elution tests and studies of the saliva of a mother and her daughter established this group as a genetically determined subgroup of B. In our opinion, the substance found in the saliva of these individuals and of so called "aberrant secretors" of groups A2 and A2B may be so specific as to require their specific cell types in order to demonstrate their presence or absence.
STUDIES ON THE PHYSIOLOGY OF THE WHITE BLOOD CELL
Authors: WAGNER RICHARD 
Published: October 2019

Abstract
The technic of determining glycogen in isolated white blood cells was applied to the study of the different types of leukemia and of polycythemia, in order to obtain information on the physiology of the white blood cell. From this study it is concluded that the granulated leukocyte is the only carrier of glycogen in whole blood. The "reducing substances" in lymphocytes and blast cells are not considered as true glycogen.
The glycogen content of wet white blood cells in the rabbit amounts to about 1 per cent. In the human being a range of from 0.17 to 0.67 per cent was calculated. In disease higher percentages occur, in polycythemia up to 1.64 per cent and in glycogen storage disease up to 3.05 per cent.
The glycogen concentration of normal white blood cells is within the same range as that of the striated muscle.
MYELOFIBROSIS ASSOCIATED WITH TUBERCULOSIS
Authors: CRAIL HOWARD W. , ALT HOWARD L. , NADLER WALTER H. 
Published: October 2019

Abstract
Myelofibrosis (fibrotic bone marrow and, usually, an increase in megakaryocytes) is characterized by generalized pains, weakness, loss of weight, enlargement of the liver and spleen and a leuko-erythroblastic anemia.
Four cases of myelofibrosis associated with generalized tuberculosis have been reviewed in detail. Autopsy examination of the 4 cases revealed acute, caseating tuberculosis which was considered to be responsible for the bone marrow and generalized fibrosis observed. A similar type of tuberculosis occurred in 7 of 91 cases of myelofibrosis reveiwed in the literature. The pathogenesis of myelofibrosis associated with tuberculosis is discussed.
In the diagnosis of this syndrome, attention is called to the importance of obtaining a bone marrow biopsy and making a complete bacteriologic and pathologic study of this tissue for tuberculosis.
The 4 tuberculous cases here reported as compared with 5 cases of idiopathic type, are younger, have hyperpyrexia, less splenic but greater lymph node enlargement and run a shorter course before death.
OSMOMETRIC BEHAVIOR OF NORMAL AND ABNORMAL HUMAN ERYTHROCYTES
Authors: GUEST GEORGE M. 
Published: October 2019

Abstract
Normal human erythrocytes suspended in the series of hypotonic salt solutions employed for testing red cell fragility behave like nearly perfect osmometers throughout the series, with their maximum swelling, usually around 175 per cent of their initial volume, sharply defined by their mean surface area. The same principles govern the swelling and hemolysis of some abnormal types of erythrocytes with different characteristics of abnormal fragility or resistance to osmotic hemolysis. The red cells of congenital hemolytic icterus exhibit essentially normal osmotic behavior, but since the spherocytes can swell very little within the limits of their surface area they rupture at higher tonicities, with the maximal swelling in most instances around 150 per cent of their initial volume. Thin cells are capable of greater swelling than normal cells. Moderately hypochromic erythrocytes from patients with mild anemia behaved like perfect osmometers throughout the series, to attain a maximal swelling of around 200 per cent, this value agreeing with predictions based on their mean surface area.
Erythrocytes of patients with thalassemia, sicklemia and pernicious anemia exhibited less than the expected osmometric swelling throughout the series of hypotonic solutions. The cells behaving as imperfect osmometers displayed varying patterns of hemolysis, and of maximal swelling in relation to predicted values. The increased osmotic resistance characteristic of the cells of thalassemia is accounted for by two mechanisms: they swell less than normal cells at each tonicity; and, being thin, they undergo greater swelling (around 220 per cent) before they are hemolyzed.
CORRELATION BETWEEN THE MEAN CORPUSCULAR VOLUME AND RETICULOCYTOSIS IN PHENYLHYDRAZINE ANEMIA IN SWINE
Authors: LAWRASON F. DOUGLAS , ELTZHOLTZ D. C. , SIPE C. R. , SCHORK P. K. 
Published: October 2019

Abstract
1. Six adult swine were given phenylhydrazine hydrochloride orally and intravenously. Hematologic observations, which included periodic bone marrow studies were made before, during, and after the administration of the drug.
2. Five swine responded to the drug in the usual manner with progressive anemia, reticulocytosis, and erythrocytic hyperplasia of the bone marrow. Three animals died between the thirty-ninth and fiftieth day of the experiment after receiving a total dose of 0.30 to 0.35 Gm. per kilogram of body weight. Two swine survived and recovered after receiving a similar dose.
3. One animal died on the fourteenth day of the experiment and exhibited a course which closely resembled that of benzol poisoning. Rapid and progressive granulocytopenia, anemia, and extreme universal hypoplasia of the bone marrow were observed.
4. A direct correlation between the mean corpuscular volume of the red cell and the per cent reticulocytes was found within the limits of 0 to 80 per cent reticulocytosis. With each increment of 10 per cent in the reticulocytes the mean corpuscular volume increased approximately 6.8 cubic microns.
Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes
Authors: Coleman CN , Stoller RG , Drake JC , Chabner BA 
Published: October 2019

Abstract
Deoxycytidine kinase, which phosphorylates deoxycytidine (CdR) and its analog, cytosine arabinoside (ara-C), has been purified 71-fold from human leukemic cells. Biochemical properties of the partially purified enzyme included a molecular weight of 68,000, Kms of 7.8 muM for CdR and 25.6 muM for ara-C, and optimal activity with ATP and GTP as phosphate donors. Ara-C phosphorylation was strongly inhibited by CdR (Ki = 0.17 muM) and dCTP (Ki = 7.3 muM) and was weakly inhibited by ara- CTP (Ki = 0.13 mM). Purification by calcium phosphate gel elution and DEAE chromatography effectively separated this enzyme from cytidine deaminase, which deaminates both CdR and ara-C, and from uridine- cytidine kinase, the enzyme which phosphorylates 5-azacytidine. CdR kinase activity was found to decrease and cytidine deaminase to increase with maturation of normal and leukemic granulocytes. Myeloblasts purified by Ficoll sedimentation revealed an average kinase activity of 15.4 U/mg protein in acute myelocytic leukemia and 12.3 U/mg protein in blastic crisis of chronic myelocytic leukemia (CML). The average ratio of CdR kinase to deaminase activity in crude cell extracts varied from 0.197 in AML and 0.089 in blastic crisis to 0.0004 in normal granulocytes, reflecting the changes which take place with cellular maturation. The absolute levels of kinase and deaminase and the ratio of these two enzymes varied considerably among patients with AML, indicating that quantitative differences may be found in the metabolism of CdR and its analogs in leukemic cells.
Polyclonal hematopoiesis in interferon-induced cytogenetic remissions of chronic myelogenous leukemia
Authors: Claxton D , Deisseroth A , Talpaz M , Reading C , Kantarjian H , Trujillo J , Stass S , Gooch G , Spitzer G 
Published: October 2019

Abstract
Interferon (IFN) therapy of early chronic myelogenous leukemia (CML) frequently produces partial or complete cytogenetic remission of the disease. Patients with complete cytogenetic remission often continue on therapy for several years with bone marrow showing only diploid (normal) metaphases. We studied hematopoiesis in five female patients with major cytogenetic remissions from CML during IFN therapy. Clonality analysis using the BstXI PGK gene polymorphism showed that granulocytes were nonclonal in all patients during cytogenetic remission. BCR region studies showed rearrangement only in the one patient whose remission was incomplete at the time of sampling. Granulopoiesis is nonclonal in IFN-induced remissions of CML and may be derived from normal hematopoietic stem cells.
Primary and secondary cutaneous CD30+lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment
Authors: Bekkenk Marcel W. , Geelen Françoise A. M. J. , Vader Pieter C. van Voorst , Heule F. , Geerts Marie-Louise , van Vloten Willem A. , Meijer Chris J. L. M. , Willemze Rein 
Published: October 2019

Abstract
To evaluate our diagnostic and therapeutic guidelines, clinical and long-term follow-up data of 219 patients with primary or secondary cutaneous CD30+ lymphoproliferative disorders were evaluated. The study group included 118 patients with lymphomatoid papulosis (LyP; group 1), 79 patients with primary cutaneous CD30+ large T-cell lymphoma (LTCL; group 2), 11 patients with CD30+ LTCL and skin and regional lymph node involvement (group 3), and 11 patients with secondary cutaneous CD30+ LTCL (group 4). Patients with LyP often did not receive any specific treatment, whereas most patients with primary cutaneous CD30+ LTCL were treated with radiotherapy or excision. All patients with skin-limited disease from groups 1 and 2 who were treated with multiagent chemotherapy had 1 or more skin relapses. The calculated risk for systemic disease within 10 years of diagnosis was 4% for group 1, 16% for group 2, and 20% for group 3 (after initial therapy). Disease-related 5-year-survival rates were 100% (group 1), 96% (group 2), 91% (group 3), and 24% (group 4), respectively. The results confirm the favorable prognoses of these primary cutaneous CD30+ lymphoproliferative disorders and underscore that LyP and primary cutaneous CD30+ lymphomas are closely related conditions. They also indicate that CD30+ LTCL on the skin and in 1 draining lymph node station has a good prognosis similar to that for primary cutaneous CD30+ LTCL without concurrent lymph node involvement. Multiagent chemotherapy is only indicated for patients with full-blown or developing extracutaneous disease; it is never or rarely indicated for patients with skin-limited CD30+ lymphomas.
Towards a reliable prediction of the aquatic toxicity of dyes
Authors: Umbuzeiro Gisela de A. , Albuquerque Anjaina F. , Vacchi Francine I. , Szymczyk Malgorzata , Sui Xinyi , Aalizadeh Reza , von der Ohe Peter C. , Thomaidis Nikolaos S. , Vinueza Nelson R. , Freeman Harold S. 
Published: October 2019

Abstract

Background
The Max Weaver Dye Library (MWDL) from North Carolina State University is a repository of around 98,000 synthetic dyes. Historically, the uses for these dyes included the coloration of textiles, paper, packaging, cosmetic and household products. However, little is reported about their ecotoxicological properties. It is anticipated that prediction models could be used to help provide this type information. Thus, the purpose of this work was to determine whether a recently developed QSAR (quantitative structure–activity relationships) model, based on ACO-SVM techniques, would be suitable for this purpose.

Results
We selected a representative subset of the MWDL, composed of 15 dyes, for testing under controlled conditions. First, the molecular structure and purity of each dye was confirmed, followed by predictions of their solubility and pKa to set up the appropriate test conditions. Only ten of the 15 dyes showed acute toxicity in Daphnia, with EC50 values ranging from 0.35 to 2.95 mg L−1. These values were then used to determine the ability of the ACO-SVM model to predict the aquatic toxicity. In this regard, we observed a good prediction capacity for the 10 dyes, with 90% of deviations within one order of magnitude. The reasons for this outcome were probably the high quality of the experimental data, the consideration of solubility limitations, as well as the high purity and confirmed chemical structures of the tested dyes. We were not able to verify the ability of the model to predict the toxicity of the remaining 5 dyes, because it was not possible to determine their EC50.

Conclusions
We observed a good prediction capacity for the 10 of the 15 tested dyes of the MWDL, but more dyes should be tested to extend the existing training set with similar dyes, to obtain a reliable prediction model that is applicable to the full MWDL.
The effects of ventilation on left-to-right shunt and regional cerebral oxygen saturation: a self-controlled trial
Authors: Li Peiyi , Zeng Jun , Wei Wei , Lin Jing 
Published: October 2019

Abstract

Background
Increase of pulmonary vascular resistance (PVR) is an efficient method of modulating pulmonary and systemic blood flows (Qp/Qs) for patients with left-to-right (L-R) shunt, and is also closely associated with insufficient oxygen exchange for pulmonary hypoperfusion. So that it might be a preferred regime of maintaining arterial partial pressure of carbon dioxide tension (PaCO2) within an optimal boundary via ventilation management in congenital heart disease (CHD) patients for the inconvenient measure of the PVR and Qp/Qs. However, the appropriate range of PaCO2 and patient-specific mechanical ventilation settings remain controversial for CHD children with L-R shunt.

Methods
Thirty-one pediatric patients with L-R shunt, 1–6 yr of age, were included in this observation study. Patients were ventilated with tidal volume (VT) of 10, 8 and 6 ml/kg in sequence, and 15 min stabilization period for individual VT. The velocity time integral (VTI) of L-R shunt, pulmonary artery (PA) and descending aorta (DA) were measured with transesophageal echocardiography (TEE) after an initial 15 min stabilization period for each VT, with arterial blood gas analysis. Near-infrared spectroscopy sensor were positioned on the surface of the bilateral temporal artery to monitor the change in regional cerebral oxygen saturation (rScO2).

Results
PaCO2 was 31.51 ± 0.65 mmHg at VT 10 ml/kg vs. 37.15 ± 0.75 mmHg at VT 8 ml/kg (P < 0.03), with 44.24 ± 0.99 mmHg at VT 6 ml/kg significantly higher than 37.15 ± 0.75 mmHg at VT 8 ml/kg. However, PaO2 at a VT of 6 ml/kg was lower than that at a VT of 10 ml/kg (P = 0.05). Meanwhile, 72% (22/31) patients had PaCO2 in the range of 40-50 mmHg at VT 6 ml/kg. VTI of L-R shunt and PA at VT 6 ml/kg were lower than that at VT of 8 and 10 ml/kg (P < 0.05). rScO2 at a VT of 6 ml/kg was higher than that at a VT of 8 and 10 ml/kg (P < 0.05), with a significantly correlation between rScO2 and PaCO2 (r = 0.53). VTI of PA in patients with defect diameter > 10 mm was higher that that in patients with defect diameter ≤ 10 mm.

Conclusions
Maintaining PaCO2 in the boundary of 40-50 mmHg with VT 6 ml/kg might be a feasible ventilation regime to achieve better oxygenation for patients with L-R shunt. Continue raising PaCO2 should be careful.

Trail registration
Clinical Trial Registry of China (http://www.chictr.org.cn) identifier: ChiCTR-OOC-17011338, prospectively registered on May 9, 2017.
Clozapine and desmethylclozapine: correlation with neutrophils and leucocytes counting in Mexican patients with schizophrenia
Authors: Vaquero-Baez Mayela , Díaz-Ruíz Araceli , Tristán-López Luis , Aviña-Cervantes Carlos , Torner Carlos , Ramírez-Bermúdez Jesús , Montes Sergio , Ríos Camilo 
Published: October 2019

Abstract

Purpose
The aim of present study is to measure plasma clozapine (CLZ) and N-desmethyl clozapine (DMC) as biomarkers to correlate drug concentrations with the appearance of preclinical adverse hematic effects.

Methods
A high-performance liquid chromatographic method, using a diode-array (ultraviolet) detector, was validated to obtain reliable concentrations of CLZ and DMC, its main metabolite, in plasma of 41 schizophrenic patients taking CLZ. Blood neutrophils and leucocytes counting were concurrently assessed as a proxy to subclinical adverse reactions.

Results
The analytical method employed was linear, reproducible, and stable to measure concentrations of CLZ between 30 and 1000 ng/mL, while 12.5–560 ng/mL of the metabolite. The method allowed us to correlate CLZ plasma concentrations, the time taking CLZ and CLZ dose as determinants of neutrophils’ counting with a R2 = 0.447, using a multiple regression analysis model. Likewise, the correlation of leucocyte counting vs CLZ plasma levels and CLZ time, showed a R2 = 0.461. DMC correlated significantly with both neutrophils and leucocytes counting, but was excluded from the regression when CLZ concentration was included in the model. Finally, no other hematological adverse reactions were recorded. One patient presented a cardiovascular complication. The negative correlation between clozapine and neutrophil count observed in patients, suggest that CLZ itself, but not DMC, could be related to hematologic side-effects.

Conclusion
The findings of this study, demonstrate for the first time, that plasma levels of CLZ and time taking the drug are independent determinants of blood neutrophils and leucocytes, so the monitoring of plasma CLZ may be useful in the clinic practice to determine safe dosing of the drug.