bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct Targets of Epo Receptor-JAK2-pSTAT5 Signalling in Erythropoiesis
Authors: Gillinder Kevin R. , Tuckey Hugh , Bell Charles , Huang Stephen , Ilsley Melissa , Magor Graham , Perkins Andrew C 
Published: November 2019

Abstract
Erythropoietin (EPO) acts through the dimeric erythropoietin receptor (EpoR) to stimulate proliferation, survival and differentiation of colony-forming units-erythroid (CFU-e). We undertook two complimentary approaches to find pSTAT5-depenendent and independent target genes in erythroid cells. We performed RNA-seq of newly transcribed (4sU-labelled) RNA, and ChIP-seq for pSTAT5, 30 minutes after EPO stimulation of J2E cells. This is the first time genome wide pSTAT5 ChIP-seq has been successfully undertaken in hematopoietic cells. We found ~320 robust pSTAT5 occupied sites in the erythroid genome. About 15% of these reside in promoters while the rest reside in intronic enhancers or intergenic regions, some >100kb from the nearest TSS. The majority of peaks contained a central palindromic GAS element, TTCYXRGAA, and there was significant enrichment of GATA and CACCC-box elements, suggesting co-regulation of some EPO-induced genes by GATA1 and KLF1. Using 4sU RNA-seq and CAGE data, we found just 57 genes to be immediately transcribed in response to EPO within 30 minutes while other target genes had delayed responses. We suggest this has biological relevance for feed forward and feedback controls on EPO driven erythropoiesis. Some of the DEGs (e.g. Bcl2l2 and Cish) are known direct targets of pSTAT5, but many are novel and suggest new pathways by which EPO regulates erythropoiesis. These include mRNA splicing, epigenetic regulation via histone methylation, and adaptive changes in the composition of the EpoR. This could provide increased sensitivity of erythroid progenitor cells to anaemic stress; i.e. sensitization of erythroid cells to JAK2-STAT5 signalling. We found a significant overlap between direct STAT5 target genes in erythroid cells, mammary epithelial cells and lymphoid cells, which imply conserved generic effectors of JAK-STAT5 signalling in different cell types. Our results provide new insights into how EPO co-ordinates erythroid cell proliferation, survival and differentiation. Some of these DEGs could be used as biomarkers for monitoring disease activity in polycythaemia vera (PV) and responses to JAK2 inhibitors.

Disclosures
Perkins: Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria.
Use of Multiple Myeloma 70-Gene Prognostic Risk Score As a Continuous Predicitor of Patient Outcome
Authors: van Laar Ryan , Bender Richard A , Zielinski Aga , Leigh Kenton , Barlogie Bart , Morgan Gareth J 
Published: November 2019

Abstract
Background: The 70-gene prognostic risk score (MyPRSR) for patients with multiple myeloma is conventionally used in a binary high/low risk fashion. The ability to more precisely estimate a patients' risk of 5-year relapse or death based on their specific risk score may increase the clinical utility of the assay.
Methods and Results: Logistic regression analysis of the 70-gene score in relation to event free and overall survival data from UAMS TT2/3 series was performed. 274 patients with at least 5 years' follow-up data were included in the analysis. A binary fitted line plot, which fits a model with one continuous predictor with an iterative reweighted least squares algorithm to obtain maximum likelihood estimates of the parameters, was generated for 5-year relapse-free and overall-survival. These plots correspond to the probability of a certain event occurring based on a specific 70-gene score.
The deviance R-square value for the relapse free survival analysis was 12.28% and the odds ratio for the 70-gene score as a continuous predictor was 1.03 (95% CI: 1.02 to 1.05). For overall survival the deviance R-square value was 15.5% and odds ratio 1.07 (95% CI: 1.05 to 1.10).
Conclusion: The 70-gene prognostic risk score is continuously associated with increased risk of 5-year relapse and death. Presentation of a patients' risk score in this format may enable superior risk-based management compared to binary high/low risk stratification. Further work is ongoing to investigate the association between GEP70 and risk of progression from precursor conditions, such as MGUS, to MM requiring treatment.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
van Laar: Signal Genetics, Inc.: Employment. Bender:Signal Genetics, Inc.: Employment. Zielinski:Signal Genetics, Inc.: Employment. Leigh:Signal Genetics, Inc.: Employment. Barlogie:Mount Sinai Hospital: Employment. Morgan:Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding.
Plasma Cell Leukemia in China: Retrospective Analysis of Clinical Characteristics and Prognosis
Authors: Yu Tengteng , Xu Yan , An Gang , Li Zengjun , Hao Mu , Qiu Lugui 
Published: November 2019

Abstract
Background: Plasma cell leukemia (PCL) is an aggressive malignancy characterized by the presence of ≥ 20% plasma cells in the peripheral blood or an absolute plasma cell count >2× 109/L. PCL exists in two forms: primary PCL (PPCL) presents de novo, whereas secondary PCL (SPCL) defined as a leukemic transformation from a previously diagnosed MM.
Materials and methods: We conducted a retrospective analysis in 46 cases with PCL patients enrolled in Blood Diseases Hospital, Chinese Academy of Medical Sciences from June 1997 to June 2016. Survival analysis and treatment response according to the response criteria of IMWG were analyzed to assess the efficacy of Bortezomib or Thalidomide based therapy combined with standard chemotherapy.
Results: Median age of 46 cases was 54.5 years (29-72 years), 28 males and 18 females; primary PCL 20 cases, secondary PCL 26 cases. Among those, 20 cases with kappa type, while 22 λ cases, 4 cases no secretion. Renal dysfunction occurs 51.4% of patients, 69.6% with osteolytic changes. D-S stage: I 1 case, 2 cases of stage II, stage III 43 cases. Complex karyotypes accounted for 45.2%, high frequency of cytogenetic abnormalities occur in IgH / CCND1 rearrangement with 8 cases, 1q21 amplification in 8 cases, RB-1 abnormalities in 6 cases, 4 cases of 17p deletion and 1 IgH / MAF rearrangement . 36 patients were evaluated in treatment responses, the overall reaction (≥MR) was 97.2%; 7 cases acquired complete remission (CR), 14 near complete remission (nCR), 6 very good partial response (VGPR), 8 cases of partial remission (PR), 1 case loss response. 16 cases of Bortezomib based therapy combined with chemotherapy; while 18 patients were treated with thalidomide combined with chemotherapy, 2 cases were conducted with allogeneic stem cell transplantation, 2 patients with chemotherapy underwent autologous stem cell transplantation after standard chemotherapy. Mean Overall survival (OS) was 19 months; primary and secondary PCL median OS was 15 months and 22 months separately (P = 0.098); Thalidomide based regimens and bortezomib-based regimen acquired a median OS 15 months and 30 months (P = 0.083). Median time to progression (TTP) of thalidomide and bortezomib based therapy was 6 months and 25 months (P = 0.03). The overall median TTP was 9 months.
Conclusions: Higher incidence in cytogenetic aberrations was observed in plasma cell leukemia. Combined chemotherapy with bortezomib can improve progression-free survival of patients, but cannot improve overall survival.

Disclosures
No relevant conflicts of interest to declare.
Correlation Analysis Between Serum Lactate Dehydrogenase and Prognosis in Old New Diagnosed Multiple Myeloma Patients
Authors: Yuan Yahui , Gu Yan , Qu Xiaoyan , Shi Qinglin , Bai Hua , Xu Ji , Xu Jiadai , Li Jianyong , Chen Lijuan 
Published: November 2019

Abstract
【Abstract】 Objective Multiple myeloma (MM) is a kind of plasma cell malignancy tumor with larger heterogeneity. Patient's survival varies greatly. This study retrospectively analyzed serum lactate dehydrogenase (LDH) in 107 cases of elderly MM patients, to discuss its correlation with other clinical indicators of MM and the prognostic significance. Methods 107 cases of elderly MM patients were selected from our hospital from July 2008 to January 2016 as the research objects, all of whom were above 60 years and were newly diagnosed. OLIPAS AU5400 fully automatic biochemical analyzer was used to assay serum LDH concentration, and prognosis analysis was carried out combined with patients' clinical data. On this basis, 73 cases of MM patients were given R-ISS staging. Results At primary diagnosis, about 9.4% patients had increased LDH (10/107), with the median follow-up time of 15 (1-88.5) months. Median overall survival (OS) was 52.5±6.9 months in normal LDH group, while 15.5±5.2 (months) in elevated LDH group, and there were statistically significant differences (p<0.001); Median progression free survival (PFS) was 24.0±3.5 months in normal LDH group, while 12.0±10.5 monthsin elevated LDH group, and there were statistically significant differences (p=0.008). Multiple factors analysis showed that LDH was an independent prognosis factor of elderly MM. Median OS of patients was 44 and 72 months (p=0.820) with stage II and stage III of ISS staging, while median PFS was 23 and 22 months (p=0.963); Median OS of patients was 44 and 22.5 months (p=0.308) with stage II and stage III of R-ISS staging, while median PFS was 24 and 14 months (p=0.105). Conclusions LDH is one of the important indicators for prognostic judgment of elderly MM patients. R-ISS staging based on LDH level is superior to the ISS staging system in prognostic judgment.

Disclosures
No relevant conflicts of interest to declare.
On the Redox Profile of B- Cell Terminal Differentiation and Multiple Myeloma: New Insights and Therapeutic Opportunities
Authors: Hassen Wafa , Kassambara Alboukadel , Jourdan Michel , Boireau Stephanie , Seckinger Anja , Hose Dirk , Kang Yubin , Klein Bernard , Moreaux Jerome 
Published: November 2019

Abstract
Redox homeostasis is fundamental for normal cellular functioning and is maintained by the net physiologic balance between production and removal of ROS. Redox signaling has been shown to coordinate the global signal transduction pattern critical for the control of key cellular processes including differentiation and tumorogenesis. In the present study, we review the systematic expression of ROS-producing and antioxidant genes and we draw up a full redox portrait of B cells all the way throughout B- cells expansion and differentiation and in malignant plasma cells. Our data firmly established that B-cells terminal differentiation entails drastic reshaping of the redox profile and underscore the stark transcriptional divide between B cells and plasma cells compartments with a major contribution of the Thioredoxin-Glutathione system in latter one. Furthermore, we advanced significant evidence that the most aggressive Multiple Myeloma cells (MMCs) witness increased expression of ROS producing genes and actively upregulated multiple antioxidant systems, which likely afforded high cytoprotective capacities and compromise chemotherapy efficacy. More importantly, we describe a transcriptional redox signature that enables the demarcation of good versus bad prognosis of MM patients and hold promise for robust molecular signature that could predict responsiveness. Finally, our data pinpointed the Thioredoxin-Glutathione system as actionable targets to circumvent drug resistance. Using Human Myeloma cell lines and primary cultures of MMCs, we validated Thioredoxin-Glutathione system as new critical, key functional node in the oncogenic network of MMCs whose depletion kill tumor cells and improve the response rate. We provided herein a preclinical data, which warrants further clinical investigation for the potential use of redox-modulators as a novel MM treatment strategy.

Disclosures
No relevant conflicts of interest to declare.
Low Pre-Transplant Vitamin D Levels Predict an Inferior Survival in Patients with Multiple Myeloma Undergoing an Autologous Stem Cell Transplant
Authors: Rakhee Vaidya , Ahlers Shane , Rodriguez Cesar , Lamar Zanetta S. , Hurd David D 
Published: November 2019

Abstract
Introduction
Nearly 40% of patients with newly diagnosed multiple myeloma are vitamin D deficient (Br J Haematol. 2008;142(3):492-4). Low vitamin D levels are associated with a higher ISS (International staging system) stage, higher creatinine, and higher serum C-reactive protein levels at diagnosis (Am J Hematol. 2009;84(7):397-400). Along with its key role in bone metabolism, vitamin D promotes differentiation, inhibits proliferation and is pro-apoptotic at the cellular level. In our retrospective study, we assessed the prognostic effect of pre-transplant vitamin D levels in patients with multiple myeloma (MM) undergoing their first autologous stem cell transplant (ASCT).
Methods
All patients who underwent an ASCT for MM since 2010 were identified from the Wake Forest University Comprehensive Cancer Center registry. 25-hydroxy vitamin D levels checked within 90 prior to ASCT were recorded, along with key clinical variables as noted in table 1. Receiver operating characteristic (ROC) analysis was employed to define best discriminant levels for predicting mortality. Survival was calculated from the date of transplant to the date of death or last follow up. The JMP (SAS Institute) statistical package was used for all calculations.
Results
A total of 176 patients received ASCT for MM from 2010 to 2015, of whom 158 (90%) had pre-transplant vitamin D levels checked within 90 days of ASCT and were included in the analysis. Most patients (140/158, 89%) underwent ASCT within one year of MM diagnosis. ROC analysis identified a 25-OH vitamin D level of ≤ 23 ng/mL (AUC 0.57) as best discriminant level for predicting mortality. Using this cut-off, vitamin D deficiency was identified in 60% (94/158) patients. Low vitamin D levels were significantly associated with younger age at MM diagnosis and ASCT (P =0.001). There were no other significant differences in the baseline characteristics of patients with low versus normal vitamin D levels (Table 1). Survival from the time of transplant was inferior in vitamin D deficient patients compared to those with normal levels (HR 2.55, 95% CI 1.08-7.03; P= 0.03). Median survival in vitamin D deficient patients was 25 months versus 32 months in those with normal vitamin D levels (P= 0.03). Multivariable analysis in the context of ISS and ASBMT disease risk confirmed the independent prognostic relevance of vitamin D levels (P= 0.01).
Conclusion
Low pre-transplant vitamin D levels are associated with an inferior survival in patients with multiple myeloma who undergo an ASCT. Further studies are needed to determine whether repleting vitamin D in vitamin D deficient patients improves outcomes.
Prognostic impact of pre-transplant vitamin D levels in MM patients undergoing an autologous stem cell transplant
Table 1 Table 1. Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Bone Marrow CD4+ and CD8+ Lymphocyte Infiltration Patterns Define Overall- and Progression Free Survival in Multiple Myeloma and May Predict IMiD Response: an Analysis from the Austrian Myeloma Registry
Authors: Willenbacher Ella , Brunner-Veber Andrea , Weger Roman , Willenbacher Wolfgang 
Published: November 2019

Abstract
Introduction:
In Multiple Myeloma immune dysregulation with quantitative and qualitative changes in T-cell subpopulations is thought to result in a reduced anti-tumour immune response promoting disease progression.
Methods:
A retrospective cohort of 45 myeloma patients was analyzed for the extent of tumor infiltrating CD4+ and CD8+ lymphocytes by means of immunohistochemistry using sophisticated automated evaluation software.
Results:
Here, for the first time we analyzed trephine biopsies of myeloma patients and we report a significant association of different patterns of immune cell infiltrations with OS and PFS suggesting that these patients might particularly benefit from immune modulating therapeutic strategies:
CD4+ T-cells below a cutoff of 0.28% lymphocytes/total nucleated cells were associated with a significantly longer overall survival, while CD8+ T-cells above the cutoff of 6.51% predicted a longer progression free survival. Treatment with immunomodulatory drugs resulted in a significantly better overall- and progression free survival for patients with adverse local immunological features compared to those treated with proteasome inhibitors or non-novel agents.
We suggest that immune dysregulation in myeloma significantly influences overall- and progression free survival. We will now validate this immuno algorithm of lymphocyte infiltration patterns as a predictive biomarker of IMiD responsiveness in the framework of a large randomized phase III trial. If confirmed they might be used as a putative biomarker to guide rational therapy allocation in the future.

Disclosures
Willenbacher: Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Willenbacher:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commision: Research Funding.
Overexpression of Raf Kinase Inhibitor Protein (RKIP) in Multiple Myeloma and Its Molecular Signature
Authors: Shvartsur Anna , Garban Hermes , Bonavida Benjamin 
Published: November 2019

Abstract
Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS) that can evolve to asymptomatic pre-MM and later to symptomatic MM. MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets. The metastatic suppressor/anti-resistance factor Raf-1 kinase inhibitor protein (RKIP) inhibits the Raf/MEK/ERK1/2 and NF-κB pathways and sensitizes resistant tumors to drug-induced apoptosis. Whereby all tumors examined exhibited low levels of RKIP, in contrast, our prior findings demonstrated that RKIP is overexpressed (primarily in its inactive phosphorylated form) in MM cell lines and patients-derived tumor tissues (Baritaki et. al, FIDT 2:1-13, 2011). We examined transcriptomic datasets on Oncomine platform (Life Technologies) for the expression of RKIP and several-associated gene products in both pre-MM and MM. Several gene products were found to be overexpressed such as RKIP, Bcl-2, and DR5 and underexpressed such as Bcl-6 and TNFR2 in both pre-MM and MM. A differentially expressed pro-apoptotic genes were observed in pre-MM versus expression of anti-apoptotic genes in MM. Based on these analyses on mRNA levels and on protein levels in published studies of the above differentially expressed genes, we have found a molecular signature each for pre-MM and MM. Once the molecular signatures are validated experimentally, they will be useful for a more precise diagnosis/prognosis of the disease stages and will also identify novel molecular therapeutic targets.

Disclosures
No relevant conflicts of interest to declare.
Bortezomib-Melphalan-Prednisone (VMP) Versus MP As Initial Treatment for Patients Older Than 75 Years with Newly Diagnosed Multiple Myeloma
Authors: Kim Min Kyoung , Kim Kihyun , Yoon Dok Hyun , Suh Cheolwon , Lee Jae Hoon , Jung Sung-Hoon , Lee Je-Jung , Kim Hyo Jung , Kim Jin Seok , Lee Jeong-Ok , Eom Hyeon Seok , Lee Won Sik , Mun Yeung-Chul , Do Young Rok , Kang Hye Jin 
Published: November 2019

Abstract
Although bortezomib-melphalan-prednisone (VMP) therapy is a well-established standard treatment for patients with multiple myeloma (MM) who are ineligible for high-dose therapy, it is not clear whether very elderly patients should be treated with VMP, considering the toxicities. The purpose of this case-control study was to compare the efficacy of VMP versus melphalan-prednisone or cyclophosphamide-prednisone (MP/CP) as initial therapy for very elderly patients.
We retrospectively studied 202 patients aged 75 years or older with newly diagnosed multiple myeloma between March 2007 and February 2015. One-hundred twenty two patients received VMP and eighty patients received MP/CP regimen were enrolled from 13 institutions throughout Korea.
Patient characteristics were comparable in these two groups. Overall response rate was 69.7% in VMP patients and 47.5% in MP/CP patients (P=0.002). Complete response rate was 24.6% in VMP patients and 10% in MP/CP patients (P=0.005). After a median follow-up for survivors of 28.4 months, progression-free survival was significantly different between the two groups (median 21.0 vs. 11.9 months in VMP and MP/CP group, respectively, P=0.037). Overall survival was also significantly different between the two groups (median 34.6 vs. 27.8 months in VMP and MP/CP group, respectively, P= 0.023). Hematologic grade 3-4 toxicities were more common with VMP (anemia: 29.1% vs 15.3%, P=0.077; thrombocytopenia: 39.3% vs. 15.3%, P < 0.001). Grade 2-4 diarrhea (22.5% vs. 2.8%, P = 0.001), vomiting (13.7% vs. 1.4%, P = 0.011), and peripheral sensory neuropathy (35.3% vs. 4.2%, P <0.001) were also more common with VMP.
Despite the presence of age-related comorbidities, VMP therapy was associated with modest toxicity, a better response rate and prolonged survival, supporting the use of this effective combination as frontline therapy for very elderly patients with MM.

Disclosures
Lee: Amgen: Membership on an entity's Board of Directors or advisory committees. Kim:Celltrion, Inc.: Research Funding.