bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Importance of WT1 in Leukemia
Authors: Pandey Sony , Moazam Mustafa , Eisermann Kurtis , Hord Jeffrey , Fraizer Gail , Kuerbitz Steven J 
Published: October 2019

Abstract
Abstract 4645
Acute leukemias collectively comprise the most common group of malignancies in the pediatric age group. Increasingly, therapeutic approach and prognosis are influenced by leukemia-specific cytogenetic abnormalities and genetic alterations, thus highlighting the importance of identifying novel prognostic markers. The Wilms’ tumor suppressor gene WT1 is expressed in leukemic blasts and is found to be mutated in approximately 10 percent of leukemia cases. Although it is unclear whether WT1 acts as an oncogene or a tumor suppressor gene in leukemia, it is known to regulate genes involved in cancer progression, including the angiogenic and mitogenic factor, VEGF. Previous studies in kidney and prostate cell lines identified potential WT1 binding sites on the VEGF-A gene promoter and demonstrated that WT1 transcriptionally regulated VEGF expression. Thus, we hypothesized that WT1 transcriptionally regulates VEGF expression in leukemia. To examine WT1 and VEGF expression patterns in pediatric Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML) and non-neoplastic bone marrow samples, we performed quantitative real time PCR. It was observed that WT1 and VEGF expression varied depending upon the type and sub-type of leukemia. Furthermore, to understand the significance of WT1 expression, we over-expressed GFP- WT1 in Molt-4 cells (T-ALL), HL-60 (AML) and K562 cells (CML) and then quantified mRNA levels of VEGF and the potential WT1 target genes CCNA1 and JAG. The results showed that WT1 levels induced variable expression of VEGF, CCNA1 and JAG in these different leukemic cell lines. Elevated expression of WT1 genes harboring mutations of the zinc finger (ZF) DNA binding domain has also been described in a subset of leukemias and has been associated with a poor prognosis. We therefore screened pediatric acute leukemia samples for novel ZF mutations that would abrogate its ability to regulate VEGF and other target genes. Conversely, a well described SNP rs16754 (in exon 7 of the WT1 gene) identified as a good prognostic marker in Cytogenetically Normal AML (CN-AML) was observed in our pediatric population as both homozygous and heterozygous variants of the WT1 gene. Our long term goal is to determine the molecular basis of the prognostic impact associated with variant WT1 expression in pediatric and adult leukemias.

Disclosures:
No relevant conflicts of interest to declare.
Founder Effects of a Recurrent Splicing Mutation IVS9-1G>C of the UNC13D Gene in Korean Patients with Familial Hemophagocytic Lymphohistiocytosis
Authors: Song Joon Sup , Kim Hee Jin , Seo Ja Young , Kim Sun Hee , Lee Ki O , Park In Ae , Lee Mee Jeong , Koo Hong Hoe , Ahn Hyo Seop , Lyu Chuhl Joo , Kim Ji Yoon , Park Eun Sil , Jeon In Sang , Lim Young Tak , Kim Bo Eun , Koh Kyung Nam , Im Ho Joon , Seo Jong Jin 
Published: October 2019

Abstract
Abstract 4730

Background:
Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially fatal disease with an autosomal recessive inheritance. Mutations in the UNF13D gene (FHL3) are the major genetic background of Korean patients with FHL (∼90). In particular, a single splicing mutation, IVS9-1G>C, is recurrent and accounts for the majority of mutant alleles (>50%), suggesting a founder effect. In this regard, the authors investigated the signature of founder effect in Korean patients with FHL3.

Methods:
The study patients were 17 pediatric patients with FHL3 recruited from the Korean Registry of HLH between January 2007 and June 2010. Nine patients had 1 (n=8) or 2 (n=1) mutant alleles of IVS9-1G>C. Haplotypes of the genomic region of UNC13D were reconstructed using the genotype information of short tandem repeat (STR) and single nucleotide polymorphism (SNP) markers in a set of 192 control chromosomes of Korean descent. The haplotypes of the 17 patients were assigned and analyzed with respect to the mutation status.

Results:
Fifteen haplotypes (Ht1-Ht15) were reconstructed based on the genotype data from 5 common SNPs of UNC13D (rs7210574, rs2290770, rs7223416, rs3744007, and rs3744010) in the control group. Haplotype analyses in the control group demonstrated that Ht3 was remarkably more prevalent in the patient group than in the control group (55.0% vs. 31.3%), and all 9 patients with IVS9-1G>C had Ht3. In addition, all patients with IVS9-1G>C except one had the 258 allele of a polymorphic STR marker near UNC13D (DS19S1839).

Conclusions:
The results suggested a founder effect in the recurring mutation IVS9-1G>C of UNC13D in Korean patients. This observation may explain the unusually high proportion of FHL3 in Korea.

Disclosures:
No relevant conflicts of interest to declare.
FLT3-ITD Mutations in AML: Structural and Numerical Variation of Mutations and Identification of Subgroup with Poor Prognosis
Authors: Blau Olga , Berenstein Rimma , Sindram Annette , Thiel Eckhard , Blau Igor Wolfgang 
Published: October 2019

Abstract
Abstract 4868
FLT3-ITD occurs with a frequency of 35%–45% in normal karyotype AML and has an adverse impact on prognosis. FLT3-ITD mutations are very variable in length and position of the tandem duplication. We have analyzed 211 AML patients with a median age of 54 years (range, 17–75). For all patients, intensive double-induction and consolidation therapy were intended. Patients with a matched related (MRD) or unrelated donor (MUD) were allocated to allogeneic stem cell transplantation (alloSCT). To investigate ITD insertion site and length, as well as their clinical impact in AML patients, we have performed sequencing analysis in diagnostic samples from 46 FT3- ITD–mutated patients. In 39 (87%) patients a single sequence was found, 6 patients displayed 2 and more different mutations. The median size of the inserted sequences was 63 nucleotides (range, 21–203 nucleotides). ITD integration sites were categorized according to functional regions of the FLT3 receptor: juxtamembrane domain (JMD), n =29 (JMD switch motif, n=3; JMD zipper motif, n=20; and JMD hinge region, n=6) and beta1-sheet of the tyrosine kinase domain-1 (TKD1), n=17. In the majority of the cases insertion sites were localized in JMD between amino acid (AA) 593 and 609 (n=20; 43%) and in TKD1 between AAs 610 and 615 (n=17; 37%). Integration site was strongly correlated with the ITD size (p=0.001) and with white blood cells (WBC) count (p=0.05). The prognostic significance of FLT3-ITD size is discussed controversial. Several studies reported conflicting results. We have found that CR durations was significant better (p=0.05) in patients with bigger ITD size, and there were no statistical differences in OS and DFS. There was no significant association between the number of mutations and OS or DFS. Presence of the any type of mutations was more common in M5 (16 of 54, 29%, P 0.01). It was associated with normal karyotype (72% vs 43%), p=0,0001; higher white blood cells (WBC) count (98×109/l vs 21×109/l), p=0,0001; higher BM blasts (85% vs 71%, p=0,0001), de novo AML (91% vs 69%), p=0,0001); and inferior OS (p=0,008) and DFS (p=0,01), when we excluded AML M3 patients. The prevalence of ITD allele on the DNA level was heterogeneous. Based on quantitative analysis, the mutant/wild-type (wt) ratio ranged from 0,1 to 11,5. Patients with a mutant/wt ratio above 0,3 had significantly shorter CR duration (p=0,02), OS (p=0,03), and DFS (p=0,01). Taken together, our data confirm that FLT3 mutation represent a common aberration in adult AML and associated with inferior outcome. A high mutant/wt ratio appears to have a major impact on the prognostic relevance.

Disclosures:
No relevant conflicts of interest to declare.
Technical Standards and Guidelines for Use of Clinical Genomic Microarray Analysis in Hematopoietic and Other Neoplastic Disorders: A Draft From a Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee
Authors: Slovak Marilyn L , Wolff Daynna J , Li Marilyn M , Lebo Matthew S , Cooley Linda D 
Published: October 2019

Abstract
Abstract 4906
Interrogation of the genome utilizing microarray technologies (copy number array-CGH with or without single-nucleotide polymorphism (SNP) probes) allows detection of genomic gains and losses with unprecedented resolution. Array findings are increasing our knowledge of the genetic basis of hematologic and other malignancies. However, prior to the clinical use of these new analytic tools, laboratories must extensively validate multiple parameters such as their platform(s), software, methods, detection limits, and quality control metrics. The laboratory must demonstrate expertise in the performance of the test and interpretation of the results by testing numerous samples, different sample types, and samples from patients with different types of diseases; these array results should then be compared with the results obtained using the gold standard methods. A working group of the Laboratory Quality Assurance committee of the American College of Medical Genetics (ACMG), a professional organization of board-certified clinical and laboratory geneticists, has drafted technical standards and guidelines for clinical laboratories that intend to offer clinical testing using these technologies.
The ACMG Technical Standards and Guidelines provide support for clinical laboratory geneticists to help them provide quality laboratory genetic services. The guidelines discuss array design, selection and coverage of the genomic microarray platforms, manufacturer's premarket analytical validation recommendations (assay performance characteristics, quality parameters, and software specifications), laboratory validation recommendations for each neoplastic disorder and tissue type (blood, bone marrow, and formalin-fixed paraffin-embedded tissue), quality control metrics and documentation, and methods for confirmation of the copy number aberrations (e.g., conventional cytogenetics, FISH, PCR, MLPA, or a different microarray). Data analysis, interpretation and reporting recommendations relating to clonal diversity, limitations of the assay, and the assessment of the clinical significance of array findings are included. Quality assurance guidelines address laboratory personnel training and certification, proficiency testing, and clinically appropriate turnaround times.
Clinical laboratory medical professionals with appropriate training and certification will correlate clinical and pathological information with array findings for final reporting. The ACMG Laboratory QA committee welcomes input as the draft guidelines are being formulated.

Disclosures:
No relevant conflicts of interest to declare.
Further Observations on the Effect of Cortisone and Thyroxin on the Blood Picture of Hypophysectomized Rats
Authors: MEINEKE HOWARD A. , CRAFTS ROGER C. 
Published: October 2019

Abstract
Adult female rats of the Wistar strain were hypophysectomized and divided into 3 groups, the first of which received no treatment for 100 days, the other 2 groups receiving no treatment for 50 days followed by daily subcutaneous injections of 0.6 mg. of cortisone alone or in combination with 0.005 mg. of thyroxin for another 50 days. Another group of rats served as normal unoperated controls.
Hypophysectomy induced a decrease in the number of nucleated cells in the bone marrow, the erythroid elements being the cells responsible for this decrease; the myeloid elements remained normal in number. These marrow changes were reflected in a decrease in reticulocyte percentage and subsequent anemia, while the total white cell count remained normal.
A combined thyroxin-cortisone therapy induced a decrease in myeloid elements in the bone marrow, which resulted in a decrease in the peripheral white cell count. It increased the number of erythroid elements in the bone marrow to a level above that of the hypophysectomized animals with no treatment but not to normal levels. This is undoubtedly due to a very rapid production and release of these cells, for the reticulocyte count was 72 per cent above normal and the anemia in these animals completely eliminated. Blood volume studies showed that these changes in the peripheral blood were not due to a hemoconcentration.
Cortisone therapy alone induced changes in the myeloid elements in the bone marrow similar to that following the dual therapy, and produced a similar decrease in peripheral white cell count. This therapy did not, however, eliminate the post-hypophysectomy anemia as did the combined therapy. Although erythropoiesis in the marrows appeared stimulated and the reticulocyte percentage was elevated, the total cellular volume in these animals was not elevated.
A combined thyroxin and cortisone therapy will not only prevent post-hypophysectomy anemia, as was found previously, but will eliminate the anemia once it has become established.
Acquired Hypoprothrombinemia
Authors: LEWIS JESSICA H. , FERGUSON JOHN H. , SPAUGH EARLE , FRESH JAMES W. , ZUCKER MARJORIE B. 
Published: October 2019

Abstract
Hypoprothrombinemia was encountered in 105 patients including cases of vitamin K deficiency, liver disease, newborns, Dicumarol-type drug therapy and a few miscellaneous disorders. The findings stress the association of acquired hypoprothrombinemia with deficiencies proconvertin and PTC and suggest that these three proteins are formed in the liver and that vitamin K is essential to their production.
An Unusual Syndrome of Hemolytic Anemia, Thrombocytopenic Purpura and Renal Disease
Authors: SHUMWAY CLARE N. , MILLER GERALD 
Published: October 2019

Abstract
This paper describes a recurrent illness which occurred in a child and consisted of hemolytic anemia, thrombocytopenia, and a renal disease clinically resembling acute glomerulonephritis. The hemolytic process was characterized by unusual red cell morphology together with evidence of an extracorpuscular hemolytic mechanism. Acute respiratory infections appeared to be related to exacerbations of the disease. Splenectomy failed to prevent recurrence of the hematologic abnormalities, and cortisone did not appear to influence the course of one typical episode of illness.
It is the authors’ opinion that this syndrome represents a form of "hypersensitivity" and may be related to the syndrome of thrombotic thrombocytopenic purpura.
Leukocytic Alkaline Phosphatase
Authors: KENNY JOHN J. , MOLONEY WILLIAM C. 
Published: October 2019

Abstract
1. Evidence of a marked difference in alkaline phosphatase activity in the leukocytes of normal subjects and individuals with chronic myelogenous leukemia has been provided by observations on the behavior of the enzyme following prolonged incubation and during pyogenic infection.
2. Therapy with radiation and radiomimetic drugs in chronic myelogenous leukemia and myeloid metaplasia resulted in a marked fall in leukocyte count but no change was observed in the relative population of alkaline phosphatase positive and negative cells.
3. In our laboratory histochemical and biochemical values for leukocyte alkaline phosphatase have been similar to those reported in the literature for typical cases of chronic myelogenous leukemia and most leukemoid reactions. However, in certain cases parodoxical findings have been noted in which histochemical and biochemical studies were inconsistent with the pathologic diagnosis.
4. The inadequacies of purely morphologic criteria in these atypical cases were noted and the desirability of the further development of cytochemical methods has been pointed out.
Erythrokinetics. IV. The Plasma Iron Turnover as a Measure of Erythropoiesis
Authors: BOTHWELL THOMAS H. , HURTADO ARNOLD V. , DONOHUE DENNIS M. , FINCH CLEMENT A. 
Published: October 2019

Abstract
Experimental and clinical studies have been performed to define more clearly the significance of the plasma iron turnover.
It has been shown that the plasma iron turnover is not affected by the rate of red cell destruction and to only a limited extent by increased body stores. It does, however, reflect the degree of erythroid marrow activity and is a sensitive indicator for measuring changes in such activity.
A series of 85 studies in normal subjects and in patients with various hematologic disorders were carried out to define the range of response with anemia and to assess the clinical value of the plasma iron turnover as an index of erythropoiesis. In states of marrow hyperfunction it is increased from 3 to 6 times normal and may be depressed to approximately half normal with marrow hypofunction. The plasma iron turnover is increased with marrow dyspoiesis. This increase is a measure of total erythropoiesis and does not indicate the production of viable red cells.
A Case of Congenital Afibrinogenemia
Authors: FERNANDO P. B. , DHARMASENA B. D. 
Published: October 2019

Abstract
1. A case of congenital afibrinogenemia of a Sinhalese boy of 22 years is reported.
2. The main features of the reported cases are reviewed.
3. The principal features of this case are total absence of fibrinogen in the blood, complete non-coagulability of blood, history of several episodes of hemorrhage dating from infancy, low erythrocyte sedimentation rate, cosanguinity of the parents and the occurrence of spontaneous hemoperitoneum from which he recovered after operation.
4. Treatment consists of blood or fibrinogen transfusion.
Attempted Passive Transfer of Thrombotic Thrombocytopenic Purpura
Authors: BRITTINGHAM T. E. , CHAPLIN HUGH 
Published: October 2019

Abstract
Transfusion of 300 ml. of plasma from a patient with thrombotic thrombocytopenic purpura produced no hematologic change in a healthy recipient; 10 months after the infusion there has been no evidence of transmission of any disease.
Studies on Abnormal Hemoglobins
Authors: SINGER KARL , JOSEPHSON AARON M. , SINGER LILY , HELLER PAUL , ZIMMERMAN HYMAN J. 
Published: October 2019

Abstract
A family study is reported in which the simultaneous presence of C-thalassemia and S-thalassemia disease is noted. Marked interaction of the genes for the abnormal hemoglobins and for thalassemia is evident.
The value of the accessory hemoglobins for the diagnosis of thalassemia minor is discussed.
The Hb S + F pattern can no longer be assumed to be diagnostic of sickle cell anemia. Evaluation of all hematologic data and the family background of the patient may be necessary to rule out the presence of the thalassemia gene.
A discussion of the genetics of the double heterozygous states for thalassemia and an abnormal hemoglobin is presented.
Quantitative Plasma Amino Acid Values in Leukemic Blood
Authors: KELLEY JOHN J. , WAISMAN HARRY A. 
Published: October 2019

Abstract
1. Quantitative methods for analysis of free amino acids in plasma have been performed on blood from normal and leukemic individuals.
2. An increase in the glutamic acid phenylalanine and "leucine" levels was found in the blood plasma of patients with acute leukemia.
3. Both the chronic myelogenous and the chronic lymphatic leukemia patients had high levels of glutamic acid, phenylalanine, alanine and proline.
4. Lower than normal levels of asparagine and threonine were found in the plasma of patients with acute leukemia.
Studies in Leukemia
Authors: SCHOOLMAN HAROLD M. , SPURRIER WILMA , SCHWARTZ STEVEN O. , SZANTO PAUL B. , YATES LEROY 
Published: October 2019

Abstract
1. A 33 week old Swiss female mouse that had been caged with AKR males exhibited a "spontaneous" lymphoblastoma resembling the spontaneous disease in the AKR strain.
2. Tumor cell suspensions of this animal did not grow when inoculated into AKR mice.
3. Tumor cell suspensions grew progressively in both Swiss and DBA mice, producing a leukemia.
4. Cell-free filtrates of leukemic Swiss or DBA mouse brain induced leukemia in 48 of 106 adult Swiss mice inoculated intracerebrally and 39 of 55 animals inoculated intraperitoneally. The leukemia appeared in the majority of the animals within one to three weeks from the time of inoculation.
5. Cell-free filtrates of the leukemic tumor failed to induce leukemia under the conditions of the experiment.
Serum Vitamin B12 in Leukemias and Malignant Lymphomas
Authors: RACHMILEWITZ M. , IZAK G. , HOCHMAN A. , ARONOVITCH J. , GROSSOWICZ N. 
Published: October 2019

Abstract
High serum vitamin B12 levels were found in chronic myeloid leukemia and in acute leukemia with myeloid differentiation. Following x-ray therapy and repeated blood transfusions, a drop of serum vitamin B12 was found.
In chronic lymphatic leukemia, undifferentiated stem cell leukemia, Hodgkin’s disease, and multiple myeloma, the serum vitamin B12 concentrations were normal.
In polycythemia with marked leukocytosis the serum B12 was normal.
In myelosclerosis high B12 values may be found.
The serum vitamin B12 in chronic myeloid leukemia is in a bound form and the binding capacity for added B12 is increased.
Serum vitamin B12 determination may be of some value in differentiating various types of leukemia and other myelo-proliferative disorders.
The Nature of the Hemorrhagic Disorder Accompanying Hemolytic Transfusion Reactions in Man
Authors: KREVANS JULIUS R. , JACKSON DUDLEY P. , CONLEY C. LOCKARD , HARTMANN ROBERT C. 
Published: October 2019

Abstract
A hemorrhagic diathesis has been observed in 2 patients who received 500 ml. of incompatible whole blood. In both, hypofibrinogenemia, hypoprothrombinemia and thrombocytopenia were observed and there was no evidence of increased fibrinolytic activity. In one, accelerin activity was reduced and there was transient evidence of a low-titered circulating anticoagulant.
The most likely explanation for the observed changes is intravascular coagulation in the recipient, presumably initiated by the thromboplastin-like activity of the hemolyzed red blood cells.