bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studies on Hemoglobin E
Authors: NA-NAKORN SUPA , MINNICH VIRGINIA 
Published: October 2019

Abstract
The results of a study of ten members of an unusual family are presented; the mother and four children were found to have homozygous Hgb E disease, the father and three childrens either thalassemia-heterozygous Hgb E or thalassemia-homozygous Hgb E disease. It was impossible to make a definite diagnosis in one boy who might have had any one of the three conditions presented by the rest of the family.
It is not possible from the genetic, clinical and hematologic data to differentiate thalassemia-homozygous Hgb E from thalassemia-heterozygous Hgb E disease in the various members of the family.
The difficulty of differentiating mild thalassemia-heterozygous Hgb E from homozygous Hgb E is presented. Confusion arises in the overlapping of values obtained in the laboratory for the two conditions.
The presence of large numbers of target cells in the peripheral blood is a striking feature in the family. A consideration is made that the abnormality accompanying the Hgb E disease may be a hereditary defect in target cell production which may or may not be a variant of thalassemia.
Suggestive evidence is presented for a minimal hemolytic component in homozygous Hgb E disease manifested by a slightly shortened red cell survival time and a moderate increase in erythrocytic elements in the bone marrow.
Studies of Phagocytic Activity of Lymphocytes
Authors: KOSZEWSKI B. J. , EMERICK C. W. , DICUS D. R. 
Published: October 2019

Abstract
Eight subjects with chronic intractable disease were subjected to intravenous injections of India ink and the peripheral blood was studied for evidence of phagocytosis. Carbon particles were seen not only in the granulocytes and monocytes, but also in lymphocytes. Through these intravital studies, further proof is established for the theory that human lymphocytes are capable of phagocytosis.
In Vitro Effects of X-radiation on White Blood Cells and Blood Platelets
Authors: WAGNER RICHARD , MEYERRIECKS NORMA , BERMAN CARROLL Z. 
Published: October 2019

Abstract
1) Alkaline phosphatase activity of leukocytes is enhanced by radiation with 50,000 r. This disturbance accentuates the inherent aging process of white blood cells and may be explained by changes in the cell envelope.
2) X-radiation diminishes the endogenous oxygen uptake of leukocyte-platelet suspensions by approximately 20 per cent. This response to radiation is demonstrable at exposures of as little as 5,000 r. The decreasing effect is diminished when substrates such as sodium succinate or α-glycerophosphate are added, within a wide range of their concentration. With increasing substrate concentration the decrease due to radiation approaches that of the endogenous respiration and even exceeds it in some of the experiments.
3) In pure blood platelets a similar decreasing x-radiation effect occurs for endogenous respiration as well as succinic dehydrogenase activity; α-glycerophosphate dehydrogenase activity, on the other hand, is enhanced.
4) The oxygen uptake in leukocyte-platelet suspensions due only to leukocytes can be calculated. While the percentage radiation decrease of pure leukocytes is unchanged for endogenous and succinate activity, the decrease for α-glycerophosphate as substrate reaches considerably higher levels (68 per cent compared with 8.2 per cent in leukocyte-platelet suspensions). Thus α-glycerophosphate dehydrogenase activity seems to be most sensitive to x-radiation. It was shown in one of our previous studies that α-glycerophosphate dehydrogenase is one of the most important respiratory enzymes in leukocytes.
5) The glycolytic system in leukocytes remains intact following exposure to radiation with 50,000 r.
Therapeutic Results in Treatment of Hodgkin’s Disease with CB 1348 and R-48
Authors: ROTTINO ANTONIO 
Published: October 2019

Abstract
Forty patients with Hodgkin’s disease were treated with CB 1348 or R-48 or both. These drugs are useful and easy to administer. They have a therapeutic effect upon subjective symptoms and enlarged lymph nodes. The average remission lasts two months, shorter in some cases and longer in other cases. Toxicity is minimal. Hematologic depression occurs late as a rule and is reversible upon discontinuance of the drugs. Both drugs appeared to produce the same effect at about the same rate, and the effect lasted for about the same length of time. R-48 proved effective in some instances where CB 1348 had not been so, and CB 1348 sometimes induced a remission when T. E. M. had failed. In some cases radiation therapy caused recession of nodes when both drugs had been ineffective.
MLL-Rearranged ALL Cells Are Highly Dependent On the Expression of EP300-Interacting Inhibitor of Differentiation 1 (EID1)
Authors: van der Linden Marieke Hendrika , Schneider Pauline , Pieters Rob , Stam Ronald 
Published: October 2019

Abstract
Abstract 1462
MLL-rearranged acute lymphoblastic leukemia (ALL) remains a difficult to treat type of leukemia, for which alternative and more adequate treatment options are still urgently needed. Various genome-wide transcriptome studies, including ours, have shown that MLL-rearranged ALL patients display highly unique gene expression profiles. In search of new and valid therapeutic targets to which more adequate treatments could be developed, we constantly screen our gene expression profiling data for potential candidates. In the present study we set out to investigate EID1 (EP300-interacting inhibitor of differentiation 1), which we found highly and specifically expressed in MLL-rearranged ALL cells. Validating this observation, quantitative RT-PCR analysis confirmed that EID1 expression was significantly higher in MLL-rearranged ALL cells as compared with other ALL subtypes or healthy bone marrow samples. Next, we performed shRNA-mediated knockdown of EID1 in MLL-rearranged ALL cells, which resulted in a dramatic reduction of viable cells. Subsequently, flow cytometry analyses demonstrated that this rapid reduction of cell viability was due to massive induction of apoptosis as well as an abrupt cell cycle arrest. Consequently, it appeared difficult to study the actual function of EID1 over-expression in MLL-rearranged ALL cells. On the other hand, these features make EID1 an attractive target for therapeutic intervention in MLL-rearranged ALL. Hence, further studies on the function of EID1 in MLL-rearranged ALL and exploring the possibilities to inhibit it are warranted.

Disclosures:
No relevant conflicts of interest to declare.
Bone Mineral Density At Diagnosis Determines Fracture Rate in Children Treated According to the DCOG-ALL9 Protocol
Authors: te Winkel Mariel L , Pieters Rob , Hop Wim C.J. , Roos Jan C. , van der Sluis Inge M. , Bökkerink Jos P.M. , Leeuw Jan A. , Bruin Marrie C. A. , Kollen Wouter J.W. , Veerman Anjo J.P. , de Groot-Kruseman Hester A. , van den Heuvel-Eibrink Marry M. 
Published: October 2019

Abstract
Abstract 1469

Purpose
As survival rates for pediatric acute lymphoblastic leukemia (ALL) have significantly improved, awareness of side effects such as skeletal toxicity becomes increasingly important. As BMD decrease over time might be associated with an increased risk of fractures, we performed repeated measurements of BMD in a large nation-wide study and studied the incidence of fractures in these children treated for ALL.

Methods
Prospectively, serial measurements (at diagnosis, after 32 weeks, after 2 years (at cessation of therapy) and after 3 years (1 year after cessation of therapy)) of bone mineral density of the lumbar spine (BMDLS) were performed in 399 ALL patients using dual energy X-ray absorptiometry (DXA). Using logistic multivariate regression, we evaluated the following putative risk factors for a low BMDLS:age at diagnosis, gender, risk group of ALL treatment, weight and height at diagnosis. Moreover, Kaplan-Meier survival analysis was used to assess the cumulative incidence of fractures in 672 patients treated with the dexamethasone-based DCOG-ALL9 protocol. All reported fractures were symptomatic, and confirmed by X-ray. Cumulative incidences of fractures for different subgroups were compared with the Log-Rank test.

Results
At diagnosis, mean BMDLS of ALL patients was lower than that of healthy peers (mean BMDLS= −1.10 SDS, P< 0.001), and this remained significant lower during and after treatment (8 months: BMDLS = −1.10 SDS, P< 0.001; 24 months: BMDLS = −1,27 SDS, P< 0.001; 36 months: BMDLS = −0.95 SDS, P< 0.001). Multivariate linear regression analysis showed that after correction for weight, height and gender, treatment according to the HR treatment arm and older age at diagnosis had a significant negative effect on the decline of BMDLS during treatment (high-risk group: b = −0.50, P<0.001 and age at diagnosis: b = −0.15, P<0.001). The cumulative incidence of fractures at 3 years was 17.8%. Cumulative incidences of fractures between risk groups and age groups were not significantly different (NHR 18.8% vs. HR 15.7%, P = 0.18 and <10 years 17.7% vs. ≥10 years 17.6%, P = 0.85). Patients who developed fractures had a lower BMDLS during treatment than those without fractures. Treatment-related bone loss was similar in patients without fractures and patients with fractures (respectively: Δ BMDLS = −0.12 SDS vs. Δ BMDLS= −0.36 SDS; interaction group time, P = 0.295).

Conclusion
This large prospective study shows that the low value of BMDLS both at diagnosis and during treatment, rather than the treatment-related decline of BMDLS, determines the markedly increased fracture risk of 17.8%.

Disclosures:
No relevant conflicts of interest to declare.
Baseline Metabolic Tumor Volume Is Predictive of Patient Outcome in Diffuse Large B Cell Lymphoma
Authors: Casasnovas Rene-Olivier , Sasanelli Myriam , Berriolo-Riedinger Alina , Morschhauser Franck , Itti Emmanuel , Huglo Damien , Versari Annibale , Coiffier Bertrand , Meignan Michel 
Published: October 2019

Abstract
Abstract 1598
Tumor bulk assessed by maximum tumor diameter was previously found to influence the outcome of young patients with low risk (aaIPI 0–1) DLBCL (Pfreundschuh et al Lancet Oncol, 2011; 12: 1013), but the prognostic impact of bulk and more generally tumor volume in high-risk DLBCL remains to be explored. Conversely, maximum SUV reduction calculated between baseline PET and PET performed after 4 cycles of immunochemotherapy (ΔSUVmax0–4) was recently shown to predict outcome in this population (Casasnovas et al Blood 2011; 118: 37).
In this study, we assessed the metabolic tumor volume (MTV) and the tumor bulk at baseline in 121 patients <60 years with an aaIPI2–3 DLBCL enrolled in the LNH07-3B trial (NCT00498043). We then compared the prognosis value of both parameters to that of ΔSUVmax0–4.
MTV was measured by FDG PET/CT with a semi automatic method using various volume shapes and systematic 41% SUVmax thresholding. Tumor mass with a maximum diameter > 10 cm assessed on CT scan was considered as bulky.
Median follow-up was 28 months. Median baseline MTV was 303 cc (17–1488). Baseline MTV (≥625 cc vs <625cc, on the basis of a ROC analysis) significantly predicts 2-year progression free survival (2y-PFS) (57 % vs 83%; p=0.0032) and 2-year overall survival (2y-OS) (60% vs 90%; p=0.002). By contrast bulk >10 cm was not predictive of outcome.
As previously published ΔSUVmax0–4 (> 70% vs ≤70%) found to predict 2y-PFS (88% vs 40%; p<10-4) and 2y-OS (94% vs 59%; p<10-4). Combining baseline MTV to early response assessed by ΔSUVmax0–4 allows to split the group of good responders patients defined on the basis of ΔSUVmax0–4 >70% after 4 cycles of immunochemotherapy (n=101, 88%) into 2 separated prognosis subsets (2y-PFS: 90% vs. 77%, p<10-4; 2y-OS: 96% vs. 77%, p<10-4). So far MTV could not significantly identify subgroups within the 15 patients with ΔSUVmax≤70% even if patients with higher MTV base line had lower PFS and OS.
In our series baseline MTV was predictive of PFS and OS in high risk DLBCL patients while bulk was not. MTV identified different risk categories of DLBCL patients within DLBCL patients with a good interim response (ΔSUVmax0–4 >70%) and may improve the negative predictive value of interim PET.

Disclosures:
No relevant conflicts of interest to declare.
Pretreatment Serum Level of Osteopontin and Vascular Endothelial Growth Factor Might Have a Prognostic Value in Patients with Diffuse Large B-Cell Lymphoma
Authors: Nacinovic Antica Duletic , Juranovic Tajana , Valkovic Toni , Petranovic Duska , Host Ivan , Fisic Elizabeta , Prolic Andjela , Lucin Ksenija , Stifter Sanja , Jonjic Nives , Labar Boris 
Published: October 2019

Abstract
Abstract 1609

Background:
Angiogenesis is gaining importance in hematological malignancies; it is regulated by a balance of various enhancing and inhibiting angiogenic factors. However, studies related to the prognostic value of angiogenic factors and aggressive Non-Hodgkin lymphomas are limited compared to solid tumors. The aim of this study was to determine pretreatment serum level of vascular endothelial growth factor (VEGF) and osteopontin (OPN) in patients with diffuse large B cell lymphoma (DLBCL) and to investigate whether these factors provide prognostic information.

METHODS:
We measured pretreatment serum levels of VEGF and OPN by Enzyme-Linked Immunosorbent Assay (ELISA) in 67 patients newly diagnosed as diffuse large B-cell lymphoma and in 30 healthy controls. All patients were treated with rituximab-CHOP chemotherapy.

RESULTS:
The serum OPN levels were found elevated in untreated DLBCL patients compared to controls: in newly diagnosed patients it ranged from 25 to 238 pg/ml; median 94.2 pg/ml while in the healthy controls it ranged from 13 to 46.5 pg/ml; median 30.0 pg/ml (P=0.00008). There were significant differences in the serum VEGF levels between DLBCL patients and controls (median 480.96 pg/ml vs. 163.8 pg/ml, P=0.001). Serum OPN levels higher than the median level were related to advanced Ann Arbor stage (P=0.026), International Prognostic Index of 2 or higher (P=0.005), ECOG III-V (P=0.004). The complete remission rate after treatment was higher in patients with low OPN serum levels than in those with high OPN serum levels (67.5% versus 32.4%, P=0.002). Elevated serum levels of OPN were strongly associated with shorter overall survival (P=0.007) and event-free survival (P=0.04). In multivariate analysis with International Prognostic Index criteria, OPN remained a significant predictor for overall survival (P=0.033). VEGF level was significantly correlated with age (P=0.01) and serum lactate dehydrogenase level (P=0.02), but not strongly correlated with other potential prognostic factors, and it failed to show prognostic significance.

CONCLUSION:
Our results showed that pretreatment serum level of OPN is significantly related to outcome in DLBCL patients. Ongoing extension study and additional follow-up will provide more information moving forward.

Disclosures:
No relevant conflicts of interest to declare.
Single Nucleotide Polymorphisms in ABCB1 and CBR1 Predict Toxicity to R-CHOP Type Regimens in Patients with Diffuse Non Hodgkin's Lymphoma
Authors: Jordheim Lars-Petter , Ribrag Vincent , Ghesquieres Herve , Pallardy Sophie , Delarue Richard , Tilly Herve , Haioun Corinne , Jardin Fabrice , Salles Gilles , Dumontet Charles 
Published: October 2019

Abstract
Abstract 1616
We analyzed single nucleotide polymorphisms (SNPs) in patients with diffuse large B-cell lymphoma treated in the prospective GELA LNH 2003 studies. Peripheral blood DNA samples collected at diagnosis before chemotherapy were obtained from 760 patients (among a total of 1367 accrued) including 441 randomized to received R-CHOP or modified R-CHOP (LNH 03–7B) and 319 who received R-ACVBP. The median age was 59 years (range 18–93) and there were 441 males and 319 females. 429 were IPI 0–2 (56.4%) and 331 were IPI 3–5 (43.6%). 119 patients had an ECOG performance status >1 (15.7%). B symptoms were present in 261 cases (34.4%). Serum albumin was below 35 g/L in 190 patients (27.7%). 489 patients (66.9%) had complete or unconfirmed complete response after induction therapy and 167 (22%) had partial response. At 5 years the overall survival was 73.9% (95% C.I. 69.7–77.6) and the progression free survival was 64.4% (95% CI 60.1–68.4). A total of 17 SNPs in 13 genes involved in drug metabolism or apopotosis were genotyped by TaqMan SNP Genotyping Assays (Applied Biosystems) on a LC480 (Roche) and correlated with toxicity occurring during treatment. Toxicity was evaluated prospectively using the NCI CTC V3 scale and associations were determined between specific genotypes and grade 3 or 4 toxicities. The studied genes were ABCB1, CAT, CBR1, FGFR4, IL10, NRG1, SLC22A16, SOD2, UGT1A1, CYP3A4, GSTP1, GSTM1 and GSTT1. Among these, 4 SNPs located in ABCB1 and CBR1 were found to be significantly associated with treatment-induced toxicity. The two SNPs localized in the ABCB1 gene were rs2032582 which was correlated with thrombocytopenia (p=0.04) and rs2229109 which was correlated with vomiting (p=0.003) and diarrhoea (p=0.007). The two SNPs localized in the CBR1 gene were rs20572 and rs9024 which were both correlated with anemia, thrombocytopenia and diarrhoea (p=0.02). ABCB1 codes for the drug efflux pump Pgp which has mainly been evaluated for its role in chemoresistance, is also known to be a key regulator of drug elimination and a determinant of pharmacokinetics. CBR1 codes for carbonyl reductase 1 which is involved in the first step of the metabolism of doxorubicin. These results suggest that genotyping of peripheral blood cells could help predict severe toxicity in patients receiving R-CHOP type regimens.

Disclosures:
Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Sanofi-Aventis: Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.
The Internal Ribosome Entry Site-Medaited Expression of VEGF Rescues HS Sultan Tumor Cells From Mammalian Target of Rapamycin (mTOR)-Inhibitors Induced Apoptosis in Vivo
Authors: Frost Patrick , Gera Joseph , Lichtenstein Alan K. 
Published: October 2019

Abstract
Abstract 1659
An important molecular target of mTOR inhibitors in cancer therapy is VEGF expression and neo-angiogenesis. In prior studies, we demonstrated that, although rapalog mTOR inhibitors only induce G1 arrest in B-cell tumor lines, their administration in vivo in xenograft models resulted in tumor cell apoptosis that correlated with inhibition of neo-angiogenesis and VEGF expression within the tumor bed. Other in vitro studies have shown that IRES-dependent translation of myc and D-cyclins can provide a fail-safe mechanism for expression when mTOR inhibitors prevent cap-dependent translation and may act as a resistance mechanism to induction of G1 arrest in vitro. We, thus, tested if VEGF IRES activity could likewise regulate induction of anti-tumor effects and apoptosis in vivo. To test if VEGF IRES activity can regulate anti-tumor responses in vivo, we utilized the HS-Sultan B cell lymphoma line that is PTEN null. Its heightened AKT activity disarms the VEGF IRES, preventing this fail-safe mechanism and sensitizing to mTOR inhibitors. We ectopically expressed a version of the VEGF ORF in these cells fused to the p27 IRES (p27-VEGF), an IRES which is insensitive to AKT and effective in PTEN-null tumors. p27-VEGF transfected tumor cells were used as subcutaneous challenges in immunodeficient mice and results of mTOR inhibitor treatment compared to control mice challenged with tumor cells transfected with the VEGF ORF but without an AKT-resistant IRES. The anti-tumor responses were enumerated by assessing tumor size and tumor apoptosis, neo-angiogenesis and VEGF expression assessed by immunohistochemistry, ELISA, and Western blot analysis of tumor lysate. Ectopic expression of VEGF fused to the p27 IRES specifically enhanced VEGF expression and neo-angiogenesis in tumors of mice treated with the rapalog temsirolimus or active site mTOR inhibitor pp242 and significantly reduced tumor cell apoptosis and anti-tumor responses. The results confirm the critical role of VEGF expression in tumors during treatment with mTOR inhibitors and, furthermore, underscore the importance of IRES activity as a resistance mechanism to such targeted therapy.

Disclosures:
No relevant conflicts of interest to declare.
PRKD2 Serine-Threonine Kinase, an Essential Effector of Gabp Transcription Factor, Is Required for Development of Chronic Myelogenous Leukemia
Authors: Yang Zhong-Fa , Zhang Haojian , Ma Leyuan , Peng Cong , Chen Yaoyu , Green Michael , Li Shaoguang , Rosmarin Alan G. 
Published: October 2019

Abstract
Abstract 1672
Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm (MPN) caused by transformation of hematopoietic stem cells (HSCs) by the BCR-ABL oncogene. CML is associated with excessive proliferation of HSCs and massive expansion of the myeloid cell pool. GABP is an ets-related transcription factor that controls critical genes in myeloid and lymphoid development, and has been implicated in control of HSC growth. GABP is an obligate multimeric transcription factor that includes the DNA-binding ets component, GABPα, along with various GABPβ partner proteins. We conditionally deleted Gabpa in mouse bone marrow and found that Gabpa cells have a profound growth disadvantage due to cell cycle arrest in HSCs. In a mouse model of CML, animals transplanted with BCR-ABL-infected bone marrow developed massive myeloid cell expansion and died with a MPN. Induced deletion of Gabpa prevented development of CML, yet mice continued to produce mature BCR-ABL-expressing granulocytes for months without apparent illness. BCR-ABL+ cells were transplantable into secondary recipients without development of CML, and contributed to all hematopoietic lineages, thereby confirming expression of BCR-ABL by long-term HSCs. We used a bioinformatic approach to analyze GABP-bound genes that are upregulated in both human and mouse LSCs compared to normal HSCs. Among 115 GABP-bound, CML-associated genes, we identified Protein Kinase D2 (PRKD2) as a candidate effector of GABP. PRKD2 is a diacyl glycerol- and Protein Kinase C-activated serine-threonine kinase that has been implicated in cancer, but has not previously been associated with HSC functions or CML. Deletion of Gabpa markedly reduced PRKD2 expression in normal HSCs and progenitor cells. In vitro growth of BCR-ABL+ bone marrow cells was prevented by Gabpa deletion, but growth was partially rescued by forced expression of PRKD2. Knockdown and pharmacologic inhibition of PRKD2 blocked cell cycle entry of BCR-ABL+ cells. We conclude that Gabp is required for HSC cell cycle entry and for development of CML, and that these effects of GABP are mediated, in part, by PRKD2. These findings suggest that PRKD2 kinase may serve as a novel therapeutic target in leukemia.

Disclosures:
No relevant conflicts of interest to declare.