bluuebunny/crossref_metadata_2025_split huggingface dataset:
AMPK Expressed By Multiple Myeloma Cells Inhibited Metformin-Induced Myeloma Cells Proliferation
Authors: Zi Fuming , He Jingsong , Zhang Enfan , Yang Yang , Huang He , Yi Qing , Cai Zhen 
Published: October 2019

Abstract
Background
Multiple myeloma(MM) is a malignant plasma cells proliferative disease which is characterized by increased blood calcium level, renal insufficiency, anemia, and bone lesions(CRAB). MM is still uncured disease. To further explore the mechanisms of MM was an urgent problem needs to be solved. AMPK is an "energy sensor". Studies had demonstrated that metformin could activate AMPK and exert anti-tumor effect in many tumors. However, a paradoxical phenomenon was found that knockdown AMPK could enhance the anti-tumor effect of metformin. Recent studies had revealed that AMPK maybe a double-edged sword in tumors. Our previous study had discovered that metformin exert anti-myeloma effect without activating AMPK. In this study, we mainly focus on the expression of AMPK in MM cells and to explore whether the expression of AMPK in MM cells could block the anti-myeloma effect of metformin.
Methods
The expression of AMPK in MM cells was detected by Western blotting. Small interfering RNA(siRNA) was used to knockdown the expression of AMPK. Apoptotic cells of MM cells were detected by Annexin V-FITC/PI using flow cytometry analysis. Western blotting was used to elucidate the apoptotic protein of MM cells induced by metformin with or without knockdown AMPK.
Results
Our study revealed that AMPK was obviously expressed by MM cells(Fig.1). Metformin could not activate AMPK signaling pathway. Knockdown AMPK with siRNA could enhance the anti-myeloma effect of metformin(Fig.2 and Fig.3).
Conclusions
Taken together, our data indicated that AMPK was expressed by MM cells. Inhibit AMPK could enhance the anti-myeloma effect of metformin. AMPK maybe a new therapy target.

Disclosures
No relevant conflicts of interest to declare.
SLC30A10 Deficiency: A Novel Cause of Polycythemia and Hepcidin Deficiency
Authors: Bartnikas Thomas Benedict 
Published: October 2019

Like iron, manganese is an essential yet potentially toxic metal. While inherited forms of iron excess were discovered long ago, the first disease of inherited manganese excess was only recently reported in 2012. Mutations in a metal transport protein, SLC30A10, were described in patients with manganese excess, polycythemia, liver failure and Parkinsonism. Manganese excess in these patients is attributed to an essential role for SLC30A10 in hepatobiliary manganese excretion. Polycythemia, liver failure and Parkinsonism are attributed to manganese excess although the underlying mechanisms have yet to be established. To explore the role of SLC30A10 in metal biology and disease, we have generated Slc30a10-deficient mice. Characterization of these mice indicates that murine Slc30a10 deficiency recapitulates the human disease. Given that manganese and iron share some transport pathways, we interrogated iron homeostasis in these mutant mice. Intriguingly, mice display hepcidin deficiency and tissue iron excess. While hepcidin deficiency may explain the tissue iron excess, the cause of hepcidin deficiency is unclear. Based on expression profiling of hypoxia-regulated genes, we propose that hepcidin deficiency reflects aberrant activation of hypoxia signaling by manganese excess in the absence of true hypoxia. Overall, this data suggests novel interactions between iron and manganese with implications for our understanding of the mechanisms by which aberrant metal homeostasis leads to human disease.

Disclosures
No relevant conflicts of interest to declare.
Spliceosome: Physiology and Disease Pathogenesis
Authors: Krainer Adrian 
Published: October 2019

Abstract
Pre-mRNA splicing is an essential step for the expression of intron-containing genes, i.e., the majority of genes. Splicing is a high-fidelity process, as required for the correct expression of proteins. However, there is flexibility in the selection of competing splice sites, which gives rise to alternative splicing, a regulated process that greatly increases the diversity of the proteome. Splicing is catalyzed in a stepwise manner by the spliceosome, a macromolecular machine that consists of 5 small RNAs and more than 100 proteins. Key insights about the structure and dynamics of spliceosomal complexes have recently been obtained through cryo-electron microscopy studies. Dysregulated splicing can arise from mutations in the splice sites or regulatory elements of individual genes, from alterations in the levels of regulatory splicing factors (activators and repressors), or from mutations in splicing-factor genes. All of these scenarios can give rise to various cancers, depending on the affected gene and the cellular context. Interestingly, recurrent somatic heterozygous mutations in particular splicing factors involved in branchpoint-sequence and 3'-splice-site recognition have emerged as key drivers of certain myeloid neoplasias. This presentation will review relevant features of the spliceosome machinery, the functional implications for normal and pathological conditions, and the potential for novel therapies.

Disclosures
Krainer: Ionis Pharmaceuticals: Consultancy, Honoraria, Patents & Royalties, Research Funding; Stoke Therapeutics: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Co-founder, Patents & Royalties; Cold Spring Harbor Laboratory: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; H3 Biomedicine: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
Next Generation Sequencing for Blood Group Antigen Profiling
Authors: Lane William 
Published: October 2019

Abstract
There are over 300 serologically defined red blood cell (RBC) antigens and 33 serologically defined platelet antigens, most of which have known genetic changes in 45 RBC or 6 platelet genes that correlate with antigen expression. Exposure to non-self RBC antigens during transfusion or pregnancy can lead to the development of alloantibodies, which on re-exposure can lead to clinically significant and even fatal complications. Therefore, it is vital to know which antigens are present on RBCs. However, traditional serologic phenotyping methods are labor intensive, costly, sometimes unreliable, and reagents are not always available. As such, routine antigen typing is only done for ABO and D antigens.
A large percentage of blood is given for hematologic malignancies that will soon get routine whole genome sequencing (WGS). For a minor added cost this data could be used for RBC antigen prediction. However, there are no published reports of using WGS data to predict RBC antigens. This is likely for several reasons: (1) none of the existing WGS data sets have paired serologic RBC phenotypes, (2) there are no fully annotated and complete databases of genotypes to phenotypes, (3) all of the known alleles are defined using cDNAs numbered relative to the start codon without human genome coordinates, and (4) lack of software capable of automated RBC antigen prediction.
We have created a fully interactive web site of all known blood group genotype to phenotype correlations, fully annotated with relevant information, and mapped to and visually overlaid to their corresponding human reference genome gene sequences, with algorithms to predict antigen phenotypes from inputted sequences. These predictions are part of the General Genome Reports for the 100 patients getting WGS as part of The MedSeq Project. In addition, each patient is undergoing an extensive antigen phenotypic workup using traditional blood bank serology and currently available SNP PCR based assays, which are being used to validate and improve our prediction strategies.
As clinical WGS becomes pervasive we hope that comprehensive blood group prediction will be done on everyone, allowing for easy identification of rare donors and the prevention of alloantibody formation using extended upfront matching of antigens from sequenced recipients and donor.

Disclosures
No relevant conflicts of interest to declare.
Regulation of Hematopoietic Stem Cell Mitochondrial Metabolism
Authors: Ghaffari Saghi 
Published: October 2019

Abstract
Hematopoietic stem cells (HSCs) like most, if not all, adult stem cells are primarily quiescent but have the potential to become highly active on demand. HSC quiescence is maintained by glycolytic metabolism and low levels of reactive oxygen species (ROS), which indicate that mitochondria are relatively inactive in quiescent HSC. However, HSC cycling - and exit of quiescence state - require a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. To improve our understanding of mechanisms that integrate energy metabolism with HSC homeostasis, my laboratory has been focused on the transcription factor FOXO3, which is critical for the maintenance of HSC quiescence and redox state and is implicated in HSC aging. We showed recently that FOXO3 is key to HSC mitochondrial metabolism, independent of its inhibition of ROS or mTOR signaling. Mitochondria divide and fuse constantly in part to segregate and dispose of their damaged counterparts. These processes are influenced by and highly linked to mitochondrial metabolism. We have recently developed imaging approaches to study HSC mitochondrial divisions. Mechanisms by which FOXO3 regulates HSC mitochondria and the impact of impaired FOXO3 on the HSC health and activity, and mitochondrial network will be discussed. Detailed understanding of the mitochondrial metabolism and divisions in HSC and their relationship to nuclear transcription are likely to have broad implications for the state of HSC fitness, regenerative capacity and aging.

Disclosures
No relevant conflicts of interest to declare.
My D88-Dependent Interplay Between Myeloid and Endothelial Cells in the Initiation and Progression of Obesity-Associated Inflammatory Diseases
Authors: Li Xiaoxia 
Published: October 2019

Abstract
Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases.

Disclosures
No relevant conflicts of interest to declare.
Studies on the Etiology of the Elevated Serum Isomerase in Chronic Myelocytic Leukemia
Authors: ISRAELS L. G. , DELORY G. E. , HNATIUK L. , FRIESEN E. 
Published: October 2019

Abstract
1. The phosphohexose isomerase activity of the serum of patients with chronic myelocytic leukemia closely parallels the rise and fall in total granulocyte count.
2. Its separated leukocytes the isomerase activity of the granulocytes was found to be approximately three times that of the lymphocytes.
3. The serum isomerase activity was estimated in dogs with induced leukocytosis and leukopenia. The enzyme activity bore a closer relationship to leukocyte destruction than to leukocyte production.
4. These findings suggest that the elevated serum phosphohexose isomerase activity found in patients with chronic myelocytic leukemia probably originates from disintegrating granulocytes.
Paroxysmal Nocturnal Hemoglobinuria: a Case Report with a Negative Ham Presumptive Test Associated with Serum Properdin Deficiency
Authors: BLAISDELL RICHARD K. , PRIEST ROBERT E. , BEUTLER ERNEST 
Published: October 2019

Abstract
1. A case of paroxysmal nocturnal hemoglobinuria (PNH) has been presented in which the Ham presumptive test for PNH was negative.
2. The basis for this false negative test and the atypical results of the Ham complete acid hemolysis test for PNH appeared to be due to a loss of the in vitro PNH hemolytic activity of the serum associated with a deficiency of properdin.
3. The acidosis accompanying the renal failure in this patient did not appear to accelerate the hemolytic process, for there was no apparent reduction of hemolytic activity in vivo when the acidosis was corrected by the administration of sodium bicarbonate.
4. The autopsy observations suggest that the protracted deposition of massive quantities of iron in the kidneys may play a robe in the not uncommon occurrence of renal disease in PNH.
On the Presence of Hemoglobin in Erythroleukemia Cells
Authors: COWLES JACK , SAIKKONEN JOUKO , THORELL BO 
Published: October 2019

Abstract
The neoplastic cells in acute erythroleukemia of the fowl appear to contain microspectrographically detectable amounts of hemoglobin in their cytoplasms. The acute myeloleukemia cells show no measureable specific absorption at all in the Soret band spectral region. Similar findings were obtained on cells from one case of human erythroleukemia and one of acute lymphatic leukemia.
The Effects of Acute Protein Depletion on the Distribution of Radioiron in Rat Tissues
Authors: BETHARD W. F. , WISSLER R. W. , THOMPSON J. S. , SCHROEDER M. A. , ROBSON M. J. 
Published: October 2019

Abstract
1. The distribution of Fe59 in plasma, bone marrow, erythrocytes, liver, and spleen was determined at specified intervals after single intravenous injections of the radioisotope into normal and protein-deficient rats.
2. In normal rats, injected radioiron followed the usual metabolic pathways; i.e., through bone marrow to erythrocytes, with small, consistent amounts to liver and spleen.
3. In protein-deficient animals normal Fe59 time-concentration relationships were disrupted completely.
4. Less iron was recovered from the tissues of protein-deficient rats than from normal animals.
5. Storage iron in liver and spleen was not conjugated with polysaccharide, even though tissue protein was seriously depleted.
The Pathogenesis of Transferred Chloroleukemia in the Albino Rat
Authors: HARRIS CHARLES , BURKE WILLIAM T. , GRUENSTEIN MARGOT , SHAY HARRY 
Published: October 2019

Abstract
The pathogenesis of transferred chloroleukemia in the rat was studied and the following results were derived. This type of leukemia colonized in an orderly manner, after intraperitoneal inoculation of leukemic cells, first in the retroperitoneal fat, then almost simultaneously in liver, spleen, lungs, and bone marrow. Only after the leucocyte pool was saturated with leukemic cells did the peripheral blood show an increase in both abnormal and normal components.
Studies on Glutathione Stability in Erythrocytes of Cases with Past History of Favism or Sulfa-Drug-Induced Hemolysis
Authors: SZEINBERG A. , ASHER Y. , SHEBA CHAIM 
Published: October 2019

Abstract
1. The glutathione stability test of Beutler has been performed on blood samples from cases with past history of hemolytic anemia due to Vicia faba or sulfa drugs and some members of their families.
2. In all the affected cases the level of reduced glutathione (GSH) in erythrocytes fell below 30 mg./100 cc. RBC after two hours incubation with acetylphenylhydrazine (APH). Four out of 13 relatives examined showed the same results.
3. Out of 117 control cases only five showed similar results. All the five cases were Jews of Sefardic origin.
4. Indications have been found that by addition of glucose to the blood samples tested by the above method more clear-cut results could be obtained.
5. The decrease of the reduced glutathione level in the abnormal cells incubated with acetylphenylhydrazine could not be prevented by addition of glucose.
6. The decrease of reduced glutathione level in normal and abnormal cells incubated at 37 C. for 24 hours without acetylphenylhydrazine was prevented by addition of glucose. No such protective action of glucose on GSH in hemolysates had been found.
The Effect of a Riboflavin Antagonist Upon Leukocytes of Normal and Shay Myeloid Chloroleukemic Rats
Authors: MUSSER ELIZABETH A. , HEINLE ROBERT W. 
Published: October 2019

Abstract
1. Administration of a riboflavin antagonist to nonleukemic Wistar rats resulted in granulocytosis without lymphopenia.
2. The analog did not have any beneficial effect on the course of myeloid chloroleukemia in Wistar rats. There was a tendency for the leukemic rats receiving the analog to have larger numbers of abnormal granulocytes than blank-injected controls, although the differences were not statistically significant.
3. Administration of TEPA resulted in rapid and prolonged remission of the myeloid chloroleukemia, as noted by others.
Myelomatosis with the "a2-Type" Serum Protein Pattern
Authors: OWEN J. A. , RIDER W. D. 
Published: October 2019

Abstract
1. A case of myelomatosis with "a2-type" myeloma protein in the serum is described.
2. Previously reported cases of myelomatosis with this rare type of serum protein pattern have been reviewed.
3. It is concluded from the limited data available that the clinical features of cases with the "a2-type" serum protein pattern and the prognosis are, in general, not different from those of patients with other protein abnormalities.
Observations on the Anemia of Cryptogenetic Splenomegaly II. Expansion of the Plasma Volume
Authors: MCFADZEAN A. J. S. , TODD DAVID , TSANG K. C. 
Published: October 2019

Abstract
In cryptogenetic splenomegaly, although there is consistently a significant reduction in hemoglobin concentration and in the red cell count, the total red cell volume may be reduced, normal or increased.
Following splenectomy the total red cell volume is either within normal limits or is increased, yet significant anemia persists.
Before splenectomy a significant increase in plasma volume is consistently present. Following splenectomy the plasma volume falls, but it remains significantly greater than normal. It would appear that the greater the plasma volume before splenectomy the greater is the fall following splenectomy. This fall in plasma volume is not a prompt response to splenectomy, for the fall which occurs one month after splenectomy is equalled or exceeded by that occurring in the succeeding four months.
It is concluded that an expanded plasma volume before splenectomy contributes with the hemolysis previously reported to the development of the anemia encountered in cryptogenetic splenomegaly. Expansion of the plasma volume at least contributes to the anemia which persists following splenectomy.
Starch Block Electrophoretic Studies of Human Hemoglobin Solutions II. Results in Cord Blood, Thalassemia and other Hematologic Disorders: Comparison with Tiselius Electrophoresis
Authors: JOSEPHSON AARON M. , MASRI M. S. , SINGER LILY , DWORKIN DAVID , SINGER KARL 
Published: October 2019

Abstract
The results of starch block electrophoresis of normal adult hemoglobin in the various disease states has been reported. The slow-moving fraction, A2, is elevated in all patients so far studied with thalassemia. Some patients with Addisonian pernicious anemia also show an increase in this fraction.
Cord blood contains very little A2.
The A2 fraction has no correlation with the severity of the disease.
The A2 fraction found on starch seems to be identical with the small, fast-moving component noted in the Tiselius apparatus at acid pH.
Iron deficiency anemia of the acquired type tends to have a lower amount of A2 than normal, with an increase to average normal values after therapy.
Sickle Cell Disease in India
Authors: SHUKLA R. N. , SOLANKI B. R. , PARANDE A. S. 
Published: October 2019

Abstract
Five cases of sickle cell disease are reported with complete clinical, hematologic and genetic studies. Four were cases of sickle cell anemia and one had sickle cell thalassemia. The importance of the presence of a focus of sickling in this area has been discussed.
Hereditary Methemoglobinemia in Alaskan Eskimos and Indians
Authors: SCOTT E. M. , HOSKINS DALE D. 
Published: October 2019

Abstract
Methemoglobinemia is unusually frequent in Alaskan Eskimos and Indians in whom 15 confirmed cases in a population of about 20,000 are known. It appears to be due to the absence of a factor in red cells which mediates the reduction of methemoglobin by reduced pyridine nucleotides. This anomaly is probably inherited as a recessive trait.
The amount of methemoglobin present at any one time in these persons is variable, depending on some environmental influence. The evidence suggests that this environmental influence is the dietary intake of ascorbic acid.
The Response of Eosinophils to Total-Body X-Radiation of the Monkey
Authors: ELDRED EARL 
Published: October 2019

Abstract
1. Circulating levels of eosinophils in the monkey have been followed before and after total-body exposure to a near median-lethal dose of x-radiation.
2. Eosinophils are moderately decreased during the first three days and strongly depressed in the second and third weeks. During the fourth week these cells rapidly reappear, and an absolute and relative eosinophilia ensues which is maximal at the fifth to seventh week.
Refractory Megaloblastic Anemia Associated with Excretion of Orotic Acid
Authors: HUGULEY CHARLES M. , BAIN JAMES A. , RIVERS SHIRLEY L. , SCOGGINS ROBERT B. 
Published: October 2019

Abstract
A case is presented of a child who had a megaloblastic anemia which was not responsive to vitamin B12 nor to folic acid. The erythrocytes were hypochromic and microcytic, but there was no response to iron or to pyridoxine. Neither parent and no siblings had evidence of thallassemia. The autopsy did not reveal evidence of Di Guglielmo’s disease.
A striking feature was the excretion of large amounts of orotic acid in the urine.
Improvement followed administration of adrenal steroid hormones without reversal of the megaloblastic marrow nor striking reduction in orotic acid excretion.
A seemingly complete hematologic remission and a remarkable reduction in orotic acid excretion followed the administration of a crude mixture containing uridylic acid and cytidylic acid while steroid hormones were continued. Before further studies could be made the child died of severe varicella.
Life Span of Thrombocytes and Erythrocytes in Normal and Thrombocytopenic Calves
Authors: MIZUNO N. S. , PERMAN V. , BATES F. W. , SAUTTER J. H. , SCHULTZE M. O. 
Published: October 2019

Abstract
1. Bovine thrombocytes and erythrocytes became labeled with P32 following an intramuscular injection of DFP.32
2. The life span of bovine thrombocytes calculated from survival curves of DFP32-labeled thrombocytes was about 10 days.
3. The life span of bovine erythrocytes calculated from the linear portion of the survival curve was about 110 to 120 days.
4. There was no significant difference between the life span of the thrombocytes and erythrocytes from normal calves and those from calves with thrombocytopenia induced by the feeding of trichloroethylene-extracted soybean oil meal.