bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Treatment Center Characteristics on Early Death Rates in Patients with Newly Diagnosed Acute Promyelocytic Leukemia: Analysis of Data from the SEER Program
Authors: Park Jae H. , Devlin Sean , Lynch Charles , Schwartz Ann , Keegan Theresa , Gonsalves Lou , Hermit Kim , Green Michael , Douer Dan , Tallman Martin S. 
Published: October 2019

Abstract
Background: Acute promyelocytic leukemia (APL) is a unique subtype of AML with a high cure rate of 80-90% when treated with all-trans retinoic acid (ATRA)-based therapy. However, early death at presentation or during induction therapy due to hemorrhage remains the major cause for treatment failure. Using the Surveillance, Epidemiology, and End Results (SEER) data, we have previously reported an early death rate of 17.3% (Park J et al. Blood 2011;118:1248). We hypothesized that the early death may be associated with the expertise and availability of blood products at treatment centers and undertook a retrospective cohort study.
Methods: APL patients diagnosed between 1992 and 2009 were identified using SEER 13 data. Patients with available survival and treatment center information were eligible for the study. Early death was defined as death within one month of diagnosis. The treatment center information was obtained from the American Hospital Association database and included the following characteristics: number of hospital beds (<200, 200-500, >500), presence of intensive care unit (ICU), presence of trauma center (as a surrogate indicator for availability of on-site blood products), and the teaching status (nonteaching, minor, major). Logistic regression was used to compare early death by selected hospital characteristics.
Results: The full-set of pre-specified treatment center information were available from five SEER 13 cancer registries (Iowa, Utah, Detroit, Connecticut, Hawaii); from these registries, we identified 507 eligible patients ofwhom [154 patients (30%)] experienced an early death. Data on bed size, teaching status, ICU presence and trauma center were available in 460, 460, 445 and 434 patients, respectively. Most APL patients were treated at centers with ³200 hospital beds (n=345), dedicated ICU (n=442), trauma center (n=287) and at teaching hospitals (n=349) (see Table 1). Of the treatment center characteristics, analysis revealed that the presence of trauma center was statistically significantly associated with decreased odds of early death (odds ratio: 0.59, 95% CI: 0.39-0.91; p=0.02).
Conclusions: Early death remains as the major cause of treatment failure in APL. To the best of our knowledge, this is the first and largest study reporting an association of treatment center characteristics with survival in APL, and suggests a prompt referral of APL patients to a large treatment center may further improve the outcome of these patients.

Disclosures
Park: Novartis: Consultancy; Baxalta: Consultancy; Juno Therapeutics: Research Funding; Amgen: Consultancy. Douer:Pfizer: Consultancy; Shire: Consultancy, Speakers Bureau; Spectrum: Consultancy; Jazz Pharmaceuticals: Honoraria; Gilled Sciences, Inc: Consultancy.
CCND1 Mutations Increase Protein Stability and Promote Ibrutinib Resistance in Mantle Cell Lymphoma
Authors: Mohanty Atish Ranjan , Sandoval Natalie , Das Manasi , Amin Hesham M. , Marcucci Guido , Pillai Raju , Weisenburger Dennis D , Rosen Steven T. , Pham Lan , Ngo Vu N. 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) represents 6-8% of non-Hodgkin's lymphoma with a median survival of 3-5 years. CyclinD1 (CCND1) chromosomal translocation t(11;14) is the hallmark of this neoplasm, which leads to its deregulated expression. Recent knock down studies of CCND1 in MCL have shown that its role is not only limited to promote cell cycle progression but also for maintaining genomic stability. Knock down of CCND1 results in increased DNA damage in MCL cells and makes them more susceptible to chemotherapy. However, CCND1 is not only prone to frequent translocation but also to somatic mutations. Genomic studies have identified recurring somatic mutations in the coding region of CCND1 in approximately 30% of MCL cases. The hot spot of these mutations is concentrated in exon 1 of CCND1. However, the functional consequence of these mutations is not known. We generated the most common CCND1 mutations (E36K, Y44D or C47S) by site directed mutagenesis and overexpressed these mutants in JEKO-1, UPN-1 or Z-138 MCL cell lines. Here, we show that these single mutations, as compared to the wild type (WT), increased CCND1 protein levels in MCL cell lines and primary tumors. Mechanistically, mutations Y44D or C47S increase the stability of CCND1 protein through attenuation of threonine-286 phosphorylation, which is a prerequisite for export of CCND1 from the nucleus to the cytoplasm, followed by proteolysis through the ubiquitin-proteasome pathway. But the two mutants have stronger affinity to interact with the threonine-286 phosphorylating enzyme glycogen synthase kinase 3 beta ,whereas interaction with cyclin-dependent kinase 4 remains unaffected. Furthermore we observed that these two mutants are preferentially localized in the nucleus compared to WT, as determined by cell fractionation and immunofluorescence assays. In order to understand the relevance of stable CCND1 protein in MCL, we studied the response of WT or mutant CCND1-expressing MCL cell lines to ibrutinib, an FDA- approved Bruton tyrosine kinase inhibitor used for MCL treatment. We observed that forced expression of WT or mutant CCND1 increased the resistance of JEKO-1 cells to ibrutinib. The Y44D mutation sustained the resistance to ibrutinib at supraphysiologic concentrations (5-10 μM). Furthermore, primary MCL tumors with CCND1 mutations expressed a more stable protein and were resistant to ibrutinib than WT cases. These findings uncover new mechanisms for MCL cells to increase CCND1 protein level through somatic mutations, which may provide a survival advantage to the lymphoma cells in developing resistance against the emerging ibrutinib therapy.

Disclosures
Pillai: Trillium Therapeutics: Research Funding. Pham:Vyripharm Biopharmaceuticals: Research Funding.
Histone-Modifying Gene Mutations Are Related to Tumor Progression and Response to Histone Deacetylase Inhibitors in Patients with Peripheral T-Cell Lymphoma Not Otherwise Specified
Authors: Ji Mengmeng 
Published: October 2019

Abstract
Objective
Histone modifications are critically involved in pathogenesis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).Histonedeacetylaseinhibitors (HDACIs) exhibited potential anti-lymphoma activity through restoring normal chromatin modification patterns. Here we detected histone-modifying gene mutations in PTCL-NOS and correlated them with tumor progression and therapeutic response to different HDACIs.
Methods
Mutations of important lymphoma-associated histone-modifying genes (MLL2, TET2, CREBBP, EP300, SETD2 and EZH2) were detected by targeted sequencing in tumor samples of 105 newly diagnosed patients with PTCL-NOS and compared with clinical parameters. Moreover, T-lymphoma cell lines bearing representative mutations were treated with four clinically available HDACIs (valproic acid, VPA;suberoylanilidehydroxamic acid, SAHA;Romidepsin,Romi; andChidamide,Chid).
Results
A total of 65 histone-modifying gene mutations were identified in 39 of 105 PTCL patients (Figure 1A). As illustrated in Figure 1B, somatic mutations in MLL2 (encoding H3K4-specific methyltransferase) were most frequently observed (20.0%), followed by mutations of TET2 (13.3%), EP300 and CREBBP (encoding H3K18 acetyltransferase, 7.6% and 6.7%, respectively), and SETD2 (encoding H3K36 methyltransferase, 7.6%). No EZH2 mutation was detected. Clinically, mutation-positive PTCL patients presented with shorteroverall survival than patients without mutations (P=0.0038, Figure 1C).
Based on the crystal structure of each gene (Figure 1D), most mutations were located on SET domain of MLL2 (p.5397-5513), HAT domain of EP300 (p.1287-1663) and SET domain of SETD2 (p.1550-1667), which could lead to loss of H3K18ac, H3K4me3 and H3K36me3 expression, respectively.
Meanwhile, Jurkatcells were treated with VPA, SAHA, Romiand Chidfor 48h and the results showed that all the HDACIs increased the expression of EP300/CREBBP, as compared to the untreated group. Interestingly, VPA and SAHA specifically upregulated SETD2 expression, while Romi and Chid upregulated MLL2 expression (Figure 2A). No obvious change of TET2 expression was found during HDACI treatment. Thereafter,Jurkat cells were transfected with MLL2 mutant (p.V5389M), EP300 mutant (p.H1377R) and SETD2 mutant (p.R1598_). Compared with the WT, mutant reduced the level of H3K18ac, H3K4me3 and H3K36me3 expression, respectively. All the HDACIs restored H3K18 hypo-acetylation induced by EP300 mutant. VPA and SAHA restored H3K36me3 expression inhibited by SETD2 mutant, whileRomi andChid restored H3K4me3 expression inhibited by MLL2 mutant (Figure 2B-2D).
Conclusion
Our study provided the mutational spectrum of histone-modifying genes in PTCL-NOS. HDACIs targeted differently histone H3 acetylation or methylation modulated by the mutations, suggestive their distinct therapeutic efficiency in PTCL-NOS.
Figure. Figure. Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
The Syk Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of EBV-Associated Lymphoma
Authors: Cen Osman , Kannan Karuppiah , Huck Jessica J. , Yu Jie , Zhang Mengkun , Gordon Leo I , Longnecker Richard 
Published: October 2019

Abstract
Epstein-Barr virus (EBV) is associated with the development of several cancers including Burkitt's Lymphoma, Hodgkin Lymphoma, Nasopharyngeal and Gastric Carcinomas. EBV-encoded Latent Membrane Protein 2A (LMP2A), a BCR mimic, is expressed in cancer cells and is essential for transformation, migration and inhibition of differentiation. LMP2A/λ-MYC double transgenic mice develop splenomegaly and lymphoma much faster than mice that express Myc only. LMP2A induces cancer phenotype by recruiting and activating BCR signaling components such as Lyn and Syk kinases to the SH2 motifs found on its N terminal cytoplasmic domain. In this study, we explored inhibition of Syk kinase activity with a novel Syk/FLT-3 inhibitor TAK-659, in lymphomas from these transgenic mice to assess SYK inhibition as a potential therapeutic strategy for EBV-associated malignancies.
The cell lines developed from LMP2A/Myc transgenic mice derived lymphomas showed higher basal pSYK levels than Myc lymphoma cell lines. TAK-659 treatment resulted in early apoptosis within 8hrs in LMP2A/Myc lymphoma cells in comparison to 24 hrs in Myc lymphoma cells. In both pre-tumor and tumor transfer models in vivo, compared with placebo and Myc tumors, LMP2A/MYC mice treated with TAK-659 did not develop splenomegaly and tumor development was totally inhibited in these mice indicating SYK signaling is essential for tumor development in LMP2A/Myc mice. In addition, metastasis of tumor cells into BM was abrogated. TAK-659 killed tumor cells but not host cells in spleen and tumors.
Taken together our data show that TAK-659, even in low nanomolar concentrations, inhibits pSYK and induces apoptosis in LMP2A/Myc tumor cells. It also inhibits splenomegaly and tumor development in our autochthonous and syngeneic tumor transfer models of EBV-associated lymphoma by targeting tumor cells while sparing non-tumor cells. Therefore, TAK-659 may provide an effective therapeutic option for the treatment of EBV-associated malignancies and should be explored further in clinical trials.

Disclosures
Kannan: Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Huck:Takeda Pharmaceuticals International Co, Cambridge, MA: Employment. Yu:Takeda Pharmaceuticals International Co, Cambridge, MA: Employment. Zhang:Takeda Pharmaceuticals International Co, Cambridge, MA: Employment. Gordon:Northwestern University: Patents & Royalties: Patent for gold nanoparticles pending.
The Role of MYC and BCL-2 Double Expression the in DLBCL Patients with Advanced Stage and Elevated LDH Who Received Upfront ASCT after R-CHOP
Authors: Kim Yu Ri , Yoon Sun Och , Kim Soo-Jeong , Cheong June-Won , Lee Hyewon , Chung Haerim , Lee Jung Yeon , Jang Ji Eun , Kim Yundeok , Yang Woo-Ick , Min Yoo-Hong , Kim Jin Seok 
Published: October 2019

Abstract
Diffuse large B-cell lymphoma (DLBCL) with MYC and BCL2 protein concurrent expression, double- expressor lymphoma (DEL), by immunohistochemistry (IHC) was related with poor prognosis. To investigate the role of upfront autologous hematopoietic stem cell transplantation (ASCT) in double-expresser lymphoma, we retrospectively evaluated 44 DLBCL patients with advanced stage and elevated LDH who received upfront ASCT. We used the cut off value of BCL2 was 50% and c-MYC was 40%. All patients were treated with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy.
Median age of 44 patients was 52.0 years (range, 23 ~ 64 years). Two-year overall survival (OS) was 83.3% and progression free survival (PFS) was 76.6%. Double-expressor lymphoma (DEL) were detected 14 patients (31.8%). Two-year OS of the patients with DEL was 77.4%, non-DEL was 86.6%. Two-year PFS of the patients with DEL was 77.9% and non-DEL was 80.9%. Eleven (25.0%) patients were germinal center B-cell (GCB) subtype and 33 (75.0%) patients were non-GCB subtype. There was no survival difference between GCB and non-GCB subtype (Figure 1A, 1B). In the patients with GCB subtype, 2 (18.2%) patients were classified to DEL. OS and PFS were not different according to DEL. Among non-GCB subtype, the patients with DEL (n=12) showed the comparable OS and PFS compared to the patient with non-DEL (n=21). Two-year OS of DEL patients was 73.3%, non-DEL was 90.9%. Two-year PFS of DEL patients was 74.1 %, non-DEL was 82.6 (Figure 2A. 2B).
In conclusion, MYC and BCL2 concurrent expression did not show the poor outcome among the high risk DLBCL patients treated with upfront ASCT regardless of molecular classification. It will be need to investigate the role of ASCT in these group of patients.
Figure 1 Kaplan-Meier analysis of overall survival and progression survival in germinal center B-cell subtype versus non-germinal center B-cells subtype Figure 1. Kaplan-Meier analysis of overall survival and progression survival in germinal center B-cell subtype versus non-germinal center B-cells subtype Figure 2 Overall survival and progression survival of patients treated with upfront autologous hematopoietic stem cell transplantation according to the presence of double expression Figure 2. Overall survival and progression survival of patients treated with upfront autologous hematopoietic stem cell transplantation according to the presence of double expression

Disclosures
No relevant conflicts of interest to declare.
Cytochemical Studies of Glycogen Content of Lymphocytes in Lymphocytic Proliferations
Authors: MITUS W. J. , BERGNA L. J. , MEDNICOFF I. B. , DAMESHEK W. 
Published: October 2019

Abstract
The glycogen content of the lymphocytes of 44 cases of various lymphocytic proliferations was studied using a semiquantitative cytochemical technic. The lymphocytes of chronic lymphocytic leukemia and of lymphosarcoma (with one exception) showed greatly increased glycogen content. In acute lymphocytic leukemia and in one case of lymphosarcoma the glycogen content was low. The presence or absence of lymphosarcoma cells in the peripheral blood in cases of lymphosarcoma made no difference in the total score. The difference between the glycogen-positive "lymphosarcoma cell" and the glycogen-negative lymphoblast is apparently due to the greater maturity of the cytoplasm of the lymphosarcoma cell (which results from an asynchronism of nucleocytoplasmic maturation) and immaturity of the cytoplasm of the lymphoblast.
Three cases of benign lymphocytosis with atypical lymphocytes in the peripheral blood gave increased values. One case with atypical lymphocytes had normal values and two cases of lymphocytosis with morphologically normal lymphocytes also had normal values. It is concluded that the increase of glycogen in lymphocytic cells is due to an over-all proliferation of the lymphocytes and is not necessarily related to malignancy per se.
Studies of Megakaryocyte Glycogen. I. A Semiquantitative Method of Measurement: Effect of Phlebotomies in Young Adults
Authors: DANIELL HARRY W. 
Published: October 2019

Abstract
1. The distribution of glycogen and nonglycogen structures in megakaryocytes as demonstrated by the Hotchkiss technic is described.
2. A semiquantitative method for estimating the relative amounts of megakaryocyte glycogen in a bone marrow aspiration has been developed and is described. The result is expressed as the Megakaryocyte Glycogen Score (MGS).
3. The megakaryocyte glycogen scores on 25 aspirations from 14, healthy, young adult volunteers are presented and fall between 20 and 80, except in those subjects with recent acute blood loss or repeated phlebotomies over a period of years.
4. Subjects who have had repeated phlebotomies tend to have higher MGS than subjects without repeated phlebotomies. These higher values of MGS exist in the absence of abnormalities in the reticulocyte count, bone marrow differential count, platelet count, hemoglobin, hematocrit, wbc and differential, and rbc.
5. In one subject with a normal MGS, a 500 cc. phlebotomy was followed in one hour by a decrease in MGS. The MGS had increased above normal by four hours postphlebotomy and was still elevated 25 days after phlebotomy.
6. Implications of these observations are discussed.
Observations on Heinz Bodies in Normal and Splenectomized Rabbits
Authors: ROTHBERG HARVEY , CORALLO LEON A. , CROSBY WILLIAM H. 
Published: October 2019

Abstract
The disappearance from the circulation of Heinz bodies, produced by incubation of blood with phenylhydrazine, was studied in normal and splenectomized rabbits. In the intact animal, red cells damaged by this procedure are removed largely by the spleen. In both intact and splenectomized rabbits, the Heinz bodies are withdrawn from the circulation by removal in toto of the red cells containing them.
Vitamin B12 and Folic Acid Metabolism in Hookworm-Infected Patients
Authors: LAYRISSE MIGUEL , BLUMENFELD NORMA , DUGARTE IRIS , ROCHE MARCEL 
Published: October 2019

Abstract
Studies on the metabolism of B12 and folic acid were performed in patients with heavy hookworm infection and severe iron deficiency anemia, and in patients with light infection, noninfected patients and normal subjects.
Patients with heavy hookworm infection showed a marked decrease of the serum B12 as compared with normal subjects. Eight of 21 cases studied showed values of serum B12 below 100 µµg./ml.
Twelve of 13 patients with severe hookworm infection showed impairment of the pteroylglutamic acid intestinal absorption; however, none of them exhibited megaloblastic proliferation in the bone marrow. They all recovered with iron therapy alone. The patients with light infection and the noninfected patients with iron deficiency anemia did not demonstrate significant differences from the normal subjects studied.
The Pelger-Huët Anomaly in Three Families and Its Use in Determining the Disappearance of Transfused Neutrophils from the Peripheral Blood
Authors: ROSSE WENDELL F. , GURNEY CLIFFORD W. 
Published: October 2019

Abstract
1. Thirteen cases of Pelger-Huët anomaly occurring in three families are presented and discussed. The second recorded case of the anomaly in Negroes is included; the occurrence of familial hereditary elliptocytosis in this same family and the possible relationship to the Pelger-Huët anomaly are discussed.
2. Certain less well-known facts about Pelger-Huët anomaly are considered in relation to the cases presented.
3. The survival time of transfused neutrophils in the peripheral blood was investigated using the anomaly as a tagging device. Most of the cells were found to be absent from the peripheral blood stream in 6 to 8 hours, and none was found after 49.5 hours.
The Effect of Anemic Anoxia on the Cellular Development of Nucleated Red Cells
Authors: ERSLEV ALLAN J. , Ruiz Elva 
Published: October 2019

Abstract
The action of an anoxic stimulus on red cell production was studied in rabbits bled 20 ml./Kg., kept anemic for 20 hours and then reinfused with the previously removed blood. This 20-hour period of anemic anoxia was followed by a characteristic reticulocyte response, a response which was modified by nitrogen mustard or colchicine administered immediately after the 20-hour period of anemia, but was not influenced by anoxia or hyperoxia in the postanemic period. When mitotic division was arrested by colchicine during the 20-hour period of anemic anoxia, the onset of the reticulocyte response, though delayed by 1 to 2 days, was otherwise of characteristic magnitude.
These observations indicate that (1) the anoxic stimulus operates in the bone marrow by accelerating the differentiation of stem cells into pronormoblasts, and that thereafter (2) the maturation and multiplication of differentiated nucleated red cells proceed at fixed rates independent of the anoxic stimulus.
Normal Functions of the Spleen Relative to Red Blood Cells: A Review
Authors: CROSBY WILLIAM H. 
Published: October 2019

Abstract
During all the stages of a red cell’s life the normal spleen exerts a normal function. Eight of these functions have been considered: (1) erythropoiesis; (2) an effect upon red cell production; (3) an effect upon maturation of the red cell surface; (4) the reservoir function; (5) the "culling function"; (6) iron turnover and storage; (7) the "pitting function"; (8) destruction of old red cells.
Preserved Platelets: Their Preparation, Storage and Clinical Use
Authors: TULLIS JAMES L. , SURGENOR DOUGLAS M. , BAUDANZA PHILIPPA 
Published: October 2019

Abstract
A method is described for the isolation and preservation of human blood platelets. Their use in a platelet bank after storage of up to two years is described. The practical advantages to the recipient include small administration volume, freedom from pyrogenicity and immediate availability in the event of thrombocytopenic bleeding. The advantages of this technic to the hospitals include a saving of time, a saving of blood and the elimination of the frantic efforts of blood bank and laboratory personnel to produce large numbers of fresh platelet concentrates at the time of platelet needs.
The remarkable stability of preserved platelets is believed largely due to the method developed for their isolation from blood, wherein the cells are separated from the coagulation proteins with which they normally interact, prior to enzymatic degradation. The importance of a controlled atmosphere of CO2 for retention of clot retraction is presented. The in vitro and in vivo activities of the preserved cells are discussed. A hypothesis is suggested for the autocatalytic stimulation of new platelet production through temporary correction of a thromboplastic deficit by the transfusion of preserved platelets.