bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNMT3B Expression Delays Leukemogenesis,
Authors: Tschanter Petra , Schulze Isabell , Bäumer Nicole , Surmann Beate , Agelopoulos Konstantin , Krug Utz , Berdel Wolfgang E. , Linhart Heinz , Müller-Tidow Carsten 
Published: October 2019

Abstract
Abstract 3446
Acute myeloid leukaemia (AML) is a malignant disease with poor prognosis, which is, among other biological features, characterized by epigenetic changes including alterations in DNA methylation. DNA methyltransferases (DNMT) play an important role in regulation of DNA methylation and mutations of DNMT3A are frequently found in AML. We analyzed the effects of DNMT overexpression on leukemogenesis using an inducible DNMT3B mouse model (Linhart et al., 2007). To analyse the impact of DNMT3B overexpression on leukemia we retrovirally co-transduced lineage-negative bone marrow cells of wildtype and DNMT3Btg mice with a MSCV-cMyc-bcl2 and a MSCV-tTA-GFP containing vector. Under these conditions, doxycycline suppressed DNMT3B expression whereas absence of doxycycline led to overexpression of DNMT3B on the mRNA and protein level. DNMT3B overexpression was not toxic since colony formation in vitro did not differ between DNMT3B expressing and physiologically expressing cells. To analyze leukemogenesis, 5 × 104 sorted GFP-positive cells were transplanted into sublethally irradiated wildtype recipients. Both recipients of transduced wildtype cells and recipients of transduced DNMT3Btg cells developed leukemia with a tendency of delayed leukemogenesis in DNMT3B overexpressing mice. GFP positive leukemic cells were sorted and doxycycline regulated DNMT3B expression was verified by Western blot analysis in vitro. To determine the repopulation capacity of the leukemic cells we performed transplantation of GFP-positive primary leukemia cells into secondary wildtype recipients. Leukemia of both, wildtype and DNMT3B-overexpressing donors was transplantable and lethal. However, DNMT3Btg leukemic cells were severely impaired in leukemia development in secondary recipients. Secondary recipients of leukemic DNMT3Btg cells died significantly later (p= 0.02). Taken together, these findings demonstrate that DNMT3B expression impairs leukemia maintenance. Loss of DNMT activity might contribute to the pool size of leukemia initiating cells.

Disclosures:
Krug: Boehringer Ingelheim: Research Funding.
Re-Evaluation of CD37 As Target for Radioimmunotherapy of Non-Hodgkin Lymphoma,
Authors: Dahle Jostein , Repetto Ada , Mollatt Camilla Sivertsen , Melhus Katrine Brustad , Bruland Øyvind Sverre , Kolstad Arne , Larsen Roy Hartvig 
Published: October 2019

Abstract
Abstract 3732
The monoclonal anti-CD20 antibody rituximab alone or as part of combination therapy, is considered standard therapy for non-Hodgkin's B-cell lymphomas. However, significantly better clinical results have been obtained for beta-emitting anti –CD20 radioimmunoconjugates (RICs) than for rituximab. RICs targeting CD20 may be problematic because of antigenic drift and antigen blocking caused by previous treatments with rituximab. Therefore, novel therapeutic approaches targeting other B cell antigens might be more effective after rituximab treatment failure than a new anti-CD20 treatment. In the present study, we have compared the therapeutic effect of the novel anti-CD37 RIC 177Lu-DOTA-HH1 with the anti-CD20 RIC 177Lu-DOTA-rituximab against Daudi human lymphoma cells in vitro and in vivo. At the same antibody concentration 177Lu-DOTA-HH1 was significantly more effective in inhibiting cell growth in vitro than 177Lu-DOTA-rituximab. SCID mice were intravenously injected with 10 million Daudi cells one week before RIC treatment. A significantly increased survival of mice treated with 177Lu-DOTA-HH1 as compared with 177Lu-DOTA-rituximab treatment was observed. Furthermore, the toxicity of the 177Lu-DOTA-HH1 treatment was significantly lower than for 177Lu-DOTA-rituximab. In addition, we have compared binding properties and biodistribution of HH1 with rituximab. The affinity of HH1 to CD37 was similar to the affinity of rituximab to CD20. The CD37-HH1 complex was internalized 10 times faster than CD20-rituximab. Both antibodies had a relevant biodistribution and low uptake in bone. This work warrants further preclinical and clinical studies with 177Lu-HH1.

Disclosures:
Dahle: Nordic Nanovector: Employment. Bruland:Nordic Nanovector: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Larsen:Nordic Nanovector: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
The Toll-Like Receptor-Like Molecule CD180 and Soluble CD14 Transmit Survival Signals in B-Cell Chronic Lymphocytic Leukemia Cells Presumably by Acting As Co-Receptors,
Authors: Seiffert Martina , Schulz Angela , Stilgenbauer Stephan , Lichter Peter 
Published: October 2019

Abstract
Abstract 3883
Survival and proliferation of B-cell chronic lymphocytic leukemia (CLL) cells strongly depend on external factors. When removed from their natural microenvironment CLL cells rapidly undergo spontaneous apoptosis in vitro unless cocultured with stromal cells or non-malignant leukocytes. Recently, we could show that monocytes effectively support long-term survival of CLL cells in vitro. Our results from cytokine antibody arrays and extensive transcriptome analyses of primary CLL cell cocultures suggested a functional role of several soluble factors as well as signaling pathways of innate immunity, like Toll-like receptor-, TREM1- and NRF2-mediated signaling. The most interesting soluble factors are currently quantified in serum samples of the german CLL8 study cohort of CLL patients by cytometric bead arrays. So far, our data show that two of these candidates, CCL2 and soluble CD14, are significantly increased in the serum of CLL patients. In vitro studies using recombinant soluble CD14 demonstrated that CLL cell survival was significantly increased in the presence of this factor. CD14 which is expressed in particular by monocytes and macrophages is an important mediator of innate immunity. Along with TLR-4, CD14 acts as a co-receptor for the detection of bacterial lipopolysaccharide (LPS). Alternatively, LPS can also bind to the toll-like receptor-like molecule CD180, which shows strong homology to TLR-4, but does not harbor an intracellular signaling domain. Since TLR-4 is not expressed in CLL cells, we investigated the potential role of CD180 in CD14-mediated cell survival. Flow cytometry analysis revealed an upregulation of CD180 surface expression in CLL cells under survival-inducing culture conditions. Stimulation of CD180 with a cross-linking antibody resulted in activation of CLL cells measured by increased cell size and upregulation of the activation marker CD86, and significantly increased survival rates of CLL cells. Both CD14- and CD180-mediated survival signals lead to an increase in NF-κB activity and up-regulation of its target gene BCL-2. Depletion of CD180 surface expression in CLL cells abolished the pro-survival effect of soluble CD14, suggesting that this factor mediates its signals via binding to CD180. In summary, our data demonstrate that both, soluble CD14 and the toll-like receptor-like molecule CD180 transmit pro-survival signals in CLL cells, most likely by acting as co-receptors. Currently, we characterize the intracellular signaling machinery which is involved in these processes.

Disclosures:
No relevant conflicts of interest to declare.
Outcome of Patients with Multiple Myeloma (MM) After 1st Relapse Following Front-Line Treatment with Autologous Stem Cell Transplantation (ASCT): Impact of Early Reduced Intensity Allogeneic Transplantation (RICALLO)
Authors: Tabrizi Reza , Vigouroux Stephane , Marit Gerald , Pigneux Arnaud , Melot Cyril , Leguay Thibaut , Bouabdallah Krimo , Dilhuydy Marie-Sarah , Schmitt Anna , Milpied Noel 
Published: October 2019

Abstract
Abstract 4533
The aim of this single center study was to assess the outcome of pts with MM following the first relapse after autologous transplantation, according to whether or not a RICALLO was performed early in 2d response.
Records of the patients were reviewed and the criteria for entering the study were: Symptomatic MM treated frontline with a program including single or double ASCT, relapse at any time following ASCT, response (CR, VGPR or PR) to a second line treatment. RICALLO was proposed to pts with no significant co-morbidities, having a suitable donor (either sibling or 10/10 MUD) and who gave their consent after precise information on the risk of the RICALLO.
One hundred and seven pts treated between 01/2004 and 02/2011 fulfilling the inclusion criteria were identified. The initial treatment for relapse consisted of VD (37 pts), RD (29 pts), TD (36 pts), VTD (4 pts) or autologous SCT (1 pt). 22 pts received a RICALLO (allo group) while in 2d response, a median 7.7 months (2–36) after relapse. The RIC consisted of fludarabine plus either 2Gy ICT or busulfan and ATG (according to ongoing available protocols in the centre). The graft was PBSC from sibling (N: 8) or MUD (N: 14). 85 pts (CT group) received therapies according to ongoing protocols or available standard of cares. Following further relapses, 11 pts received a RICALLO while in ≥ 3d response in the CT group. The main characteristics of the patients in each group: age, MM prognostic factors at diagnosis, type of 1st line therapy (VAD or bortezomib containing regimens), single or double ASCT, time to relapse after ASCT and 2d line treatment were similar between the 2 groups. The response achieved with 2d line treatment was different between 2 groups (CR + VGPR/other: 8/14 and 7/76 in allo and CT group respectively, p= 0.01)
The 3y OS from the time of relapse for the entire cohort was: 47% (CI95%, 41–53). It was of 45% (CI95% 34–56) and of 48% (CI95% 41–55) for the allo group and the CT group respectively (p= ns). The median time from 1st relapse to death was 31 mo in the entire cohort and 20 and 34 mo in the allo group and CT group respectively (p= ns). The causes of death were, relapse in 5 and 33 pts, or treatment toxicity in 8 and 3 pts in the allo group and CT group respectively.
Three 3 y EFS (event = 2d relapse or death) was 16% (CI95%, 11–21) for the whole cohort and 16% (CI95%, 6–26) and 19% (CI95%, 13–25) for the allo group and CT group respectively (p= ns).

Conclusion:
In conclusion, we did not observe any difference in survival or PFS between allo-SCT and CT in patients at first relapse following an auto SCT.

Disclosures:
No relevant conflicts of interest to declare.
Long Term Follow up of Patients with Immune Thrombocytopenia Receiving Rituximab
Authors: Al-Habsi Khalid , Al-Khabori Murtadha K. , Al-Muslahi Muhanna , Pathare Anil , Farsi Khalil Al , Huneini Mohammed Al , Lamki Sulayma Al , Alkindi Salam 
Published: October 2019

Abstract
Abstract 4675

Introduction:
Rituximab has been used in the management of chronic immune thrombocytopenia (ITP) with promising results. The risk of losing response, however, is yet to be determined with long term follow up.

Method:
We retrospectively analyzed 32 consecutive patients (20 females, 12 males) with ITP (including 6 patients with secondary ITP) treated with rituximab in two tertiary care hospitals in Oman between May 2006 and May 2011. Response criteria were based on the International Consensus report (Rodeghiero F et al. Blood 2009).

Result:
The median age at diagnosis was 25 years (range, 4 – 58). Clinical presentation ranged from mild echymosis to more severe central nervous system bleeding. Patients received a median of one line of therapy before rituximab (range, 1–4), including 3 patients who failed splenectomy. Patients received intravenous rituximab using 375 mg/m2 once weekly for 4 weeks. The median time from diagnosis to receiving rituximab was 21 months (range, 1– 177). Only one patient was positive for Hepatitis C virus, but no hepatitis B or HIV positive in this cohort. Anti nuclear antibody was positive in 34% (10/29) of patients. The median hemoglobin and platelet counts at diagnosis were 12 g/dl (range, 5–16) and 11×109/L (range, 1–60) respectively. The median follow up time after rituximab was 26 months (95% confidence interval: 11–40). The overall cumulative response rate was 59% (partial response of 15% and complete response of 44%). The median time to respond was 30 days (Standard error [SE] 49) with a response rate of 44% at 4 weeks (95% Confidence interval: 29–62%). The multivariable Cox model analysis (variables include: age at diagnosis, gender, number of previous therapies and primary vs. secondary) revealed none of the variables included to be statistically significant. The cumulative rate of loss of response was 32% (6/19) with a median time to lose response of 54 months (SE, 0.03). In patients who lost response, the median time to lose response was 17 months (SE, 14). Of the 6 patients who lost response, 4 received a second course of rituximab and all 4 achieved a full response. No major side effects to rituximab were reported during the follow up.

Conclusion:
Rituximab is an effective and a well tolerated second line therapy for ITP. The response to rituximab can be maintained for a long duration with a high rate of response after retreatment. None of the pretreatment variables studied carried a significant predictive value for response. The study was limited by the small sample size and further larger prospective studies are recommended.

Disclosures:
Off Label Use: Rituximab was used in our study as a second line for the management of chronic immune thrombocytopenia.
Consistent Activation of Flt3 Promotes Hematopoietic Progenitors Toward Dendritic Cell Development in Mouse
Authors: Zhu Xuejun , Yang Zhongfa , Wang Junling , Rosmarin Alan G. 
Published: October 2019

Abstract
Abstract 4789
Dendritic cells (DCs) play key roles in mediating innate and acquired immune responses. DCs have a short half life in peripheral organs and are derived constitutively from bone marrow hematopoietic stem cells (HSCs) and Flt3+ progenitors. Cytokine signaling from Flt3 is crucial for stimulation of DC development. Previous studies demonstrated that injection of Flt3 ligand (Flt3L) in mouse caused a transient, but substantial increase in DC development. The effects of long-term activation of Flt3 signaling with physiological levels of Flt3L, however, have not yet been defined. Transgenic mice with constitutively activated Flt3 signaling were generated by replacing the Flt3 alleles with a mutant version Flt3ITD. Both mature DCs and DC progenitors increased modestly in Flt3ITD mice; both lymphoid and myeloid derived DCs were increased compared with wild type mice. Although the level of DCs in Flt3ITD mice did not reach the high levels in mice injected with Flt3L, the effect of Flt3ITD on DC development was consistent and long-lasting. Thus, activation of Flt3 signaling by different mechanisms led to distinct responses of bone marrow stem and progenitor cells for DC development. Flt3ITD mice provide a unique model to analyze DC differentiation from bone marrow stem and progenitor cells at physiological levels of Flt3L.

Disclosures:
No relevant conflicts of interest to declare.
Dendritic Cells Loaded with Treating Myeloma Cells with Combination of JSI-124 and Bortezomib Can Generate Potent Myeloma-Specific CTLs Through Recovering Dysfunction of Dendritic Cells in Myeloma Patients
Authors: Lee Youn-Kyung , Kim Mi-Hyun , Hong Cheol Yi , Lim Mi-Hyun , Nguyen-Pham Thanh-Nhan , Jin Chun-Ji , Lee Hyun Ju , Yang Deok-Hwan , Jung Sung-Hoon , Ahn Jae-Sook , Bae Soo-Young , Kim Yeo-Kyeoung , Chung Ik-Joo , Hwang Tai Ju , Kim Hyeoung-Joon , Lee Je-Jung 
Published: October 2019

Abstract
Abstract 4926
Signal transducers and activators of transcription 3 (STAT3) is highly activated in multiple myeloma triggered by IL-6. Although DC vaccine can induce antitumor immune response, DCs are faced with dysfunction after loading of tumor antigen. Here we show that the dysfunction of DCs from antigen loading can be recovered by treating JSI-124 and bortezomib on myeloma cells. Treatment of combination JSI-124 and bortezomib induced high expression of heat shock protein 90 (Hsp90) on the surface of dying myeloma cells, DCs loaded these myeloma cells showed low expression of p-STAT3 and reduced IL-10, IL-6 and IL-23 production without any effect on IL-12p70. Also DCs loaded with dying myeloma cells treated by JSI-124 and bortezomib combination could generate the most potent myeloma-specific CTLs targeting to myeloma cells. Our data suggested that treatment of myeloma cells with combination JSI-124 and bortezomib can recover the dying myeloma cells-loaded DC dysfunction through the highly expressed Hsp90 on tumor cells, down-regulated p-STAT3 and inhibitory cytokines, and these DCs can generate to potent myeloma-specific CTLs for obtaining better immunotherapeutic method in multiple myeloma.

Disclosures:
Lee: Vaxcell-Bio therapeutics Co.: Employment. Kim:Vaxcell-Bio therapeutics Co.: Employment. Lim:Vaxcell-Bio therapeutics Co.: Employment. Lee:Vaxcell-Bio therapeutics Co.: Employment.
An Electrophoretic Study of the Abnormal Proteins in Urine, Peripheral Venous and Bone Marrow Sera in Multiple Myeloma
Authors: JIM ROBERT T. S. 
Published: October 2019

Abstract
1. Abnormal and distinct homogeneous globulins of different electrophoretic mobilities have been found in a high percentage of concentrated whole urines from patients with multiple myeloma, occurring either as a single isolated globulin or as the dominant globulin in combination with smaller amounts of albumin and other globulin components. In contrast, the electrophoretic pattern of non-Bence Jones protein observed in a wide variety of diseases is dominated by albumin in association with smaller amounts of various globulin components usually more heterogeneous in nature.
2. The abnormal dominant globulins were found in 21 out of 35 or 60 per cent of the myeloma urines studies, while only 28.5 per cent were positive for Bence Jones protein by the conventional heat test.
3. Electrophoresis of concentrated whole urines in multiple myeloma appears to be a more sensitive technic for the detection of the abnormal urinary protein than the conventional heat test and may be a useful additional diagnostic procedure when the latter reactions cannot be elicited.
4. In patients with multiple myeloma the electrophoretic pattern of the protein in bone marrow serum does not appear to differ significantly from the corresponding protein pattern of peripheral venous serum.
Clinical and Necropsy Findings in Hemoglobin C Disease
Authors: JENSEN WALLACE N. , SCHOEFIELD R. ALAN , AGNER ROY 
Published: October 2019

Abstract
A patient with homozygous hemoglobin C disease was observed during a five month period of time. Estimates of the rates of red cell synthesis were made prior to and during the administration of compound E. The post mortem findings and results of paper electrophoresis of myoglobin are presented.
The Lutheran Blood Groups: A Second Example of Anti-Lub and Three Further Examples of Anti-Lua
Authors: GREENWALT TIBOR J. , SASAKI THOMAS 
Published: October 2019

Abstract
1. An example of the blood group antibody, anti-Lub, was found in a patient who had a mild hemolytic transfusion reaction. It was shown to possess the characteristics of an immune antibody and to be able to distinguish between a single dose and a double dose of the Lub gene.
2. Three new examples of the antibody, anti-Lua, are presented. All of them were found in normal blood donors and have properties which indicate that they are naturally occurring antibodies.
Dr. R. R. Race and Dr. R. Sanger confirmed the presence of anti-Lub in Mrs. S.’s serum, and studied other members of her family and the three anti-Lua sera. We are grateful to them for many favors and their kind encouragement.
We are obligated to Miss Marie Cutbush for making available the LuaLua cells from Mrs. R. and her sister, and for a supply of anti-Lub serum.
Thanks are due to Dr. A. E. Mourant who furnished our original supply of anti-Lua serum and to Dr. Philip Levine for the anti-Tja and anti-Vel sera.
We are indebted to Dr. J. M. Fine of Milwaukee for permission to study Mrs. S. and to the patient and her family for their cooperation.
The sera from 18,613 blood donors were studied by Betty McCarthy, Rosemary Polka, Pearl Lemke, Agnes Molnar, Jeannette Flagstadt and Betty Hutter.
Leukocyte Changes During Acute Cross-Circulation Experiments Between Leukemic and Normal or Irradiated Rats
Authors: HOLLINGSWORTH J. W. , FINCH S. C. , CHALTAS MARY 
Published: October 2019

Abstract
1. Normnal and irradiated rats underwent periods of cross-circulation with Shay granulocytic chloroleukemic rats.
2. The leukemic white blood cells disappeared rapidly from the arterial blood of the irradiated rat at a rate approximately identical with that of the removal of cross-transfused normal leukocytes.
3. Many leukemic cells remained in the arterial blood of normal recipent rats during the 90 miniute observation time after cross-circulation.
4. It was postulated that leukocytes transfused its rats by this method remain viable. In the irradiated leukopenic recipient, the rapid arterial blood removal rate of transfused cells may represent distribution in a depleted total body leukocyte "pool." Similarly, distribution may occur more slowly in normal animals with normally saturated tissue stores of leukocytes.
5. There was no indication that a large dose of total body irradiation increased the capacity of the reticulo-endothelial system to remove transfused leukocytes from circulation.
Radioactive Vitamin B12 Absorption Studies: Results of Direct Measurement of Radioactivity in the Blood
Authors: DOSCHERHOLMEN ALFRED , HAGEN PAUL S. , LIU MARGARET 
Published: October 2019

Abstract
A new method for the determination of the absorption of vitamin B12 has been described using measurement of radioactivity in the blood or plasma after the ingestion of physiologic test doses of Co60 labeled vitamin B12.
Although doses of 1.0 µc. (0.92 µg. vitamin B12) gave higher counts, equally reliable results were obtained with 0.5 µc. (0.46 µg. vitamin B12). The radioactivity was found in the plasma portion of the blood.
With this method it was possible to differentiate between all of nine patients with pernicious anemia and 36 control subjects.
In non-pernicious anemia subjects and in pernicious anemia patients given intrinsic factor, there was a relatively delayed rise in the blood or plasma radioactivity until a peak was reached in the 8 to 12 hour interval after the ingestion of the test dose. This absorption curve was quite different from the early rise observed by others after massive oral doses of vitamin B12, indicating a different mode of absorption.
Following the peak blood concentration the radioactivity gradually declined and small amounts usually persisted for as long as one week, quite different from the rapid disappearance after parenteral administration previously reported.
This method appears valuable in the diagnosis of pernicious anemia and other vitamin B12 malabsorptive states, in the evaluation of intrinsic factor activity, and in studies of various aspects of the metabolism of vitamin B12.
Studies on Thrombopoiesis
Authors: IZAK G. , NELKEN D. , GUREVITCH J. , HERZOG MISS A. 
Published: October 2019

Abstract
Thrombocyte production from megakaryocytes of healthy humans, dogs, guinea pigs and mice was observed continuously for one to six days in tissue culture.
Approximately 70 per cent of the explanted megakaryocytes broke down to give rise to numerous platelets, while the remaining 30 per cent of the cells remained unchanged.
The newly formed thrombocytes were separated from the rest of the bone marrow tissue, counted and their serotonin absorbing capacity determined.
There was invariably a gradual increase in both the number of thrombocytes and in their serotonin absorbing capacity during the one to six days of observation.
The results obtained were similar in human megakaryocytes and in those of experimental animals.