bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes of Peripheral Blood Lymphocyte Subsets and Cytokines in Patients with Multiple Myeloma and Their Clinical Significance
Authors: Fei Li 
Published: November 2020

Objective: Accumulating evidence have indicated that immune response play an essential role in development of multiple myeloma (MM),To evaluate the immune function of patients with MM by detecting the levels of lymphocyte subsets and cytokines, and to analyze the correlation between the immune function and prognosis of patients. Methods: we examined 50 patients with newly diagnosed MM, 20 patients with Relapse / refractory MM and 30 healthy volunteers. the levels of T lymphocyte subsets, activated T cells subtypes, Treg and cytokines in peripheral blood were detected by flow cytometry (FCM).Results: ① compared with healthy control group, CD3 + CD4 + T cells of newly diagnosed MM patients were significantly decreased (P = 0.04), There was no significant difference in CD3+CD8+T and CD4/CD8 of newly diagnosed MM patients with normal controls (P=0.14).The percentage of CD16 + cd56dim NK cells of newly diagnosed MM was significantly lower than that of the normal control group (P = 0.01); There was no significant difference in frequencies of CD3+CD4+T cells, CD4/CD8, CD16+CD56dimNK (P=0.34, P=0.561, P=0.88) between newly treated MM patients and relapsed/refractory MM; HLA-DR-CD8+ activated TS cells of newly diagnosed MM was significantly higher than the normal control group (P = 0.04).② The proportion of CD4 + CD25 + CD127dim T cells(treg) in total CD4 + T cells in of newly diagnosed MM was higher than that in normal control group (P &lt; 0.05). The CD4 + CD25 +CD127dim T cells of MM patients with relapse / refractory MM was higher than that of newly treated patients, but the difference was not statistically significant (P &gt; 0.05). Further analysis showed that CD4 + CD25 + CD127dim T cells in mSMART stratified high-risk group were higher than those in low-risk group (P = 0.03). The number of CD4 + CD25 + CD127dim T cells in patients without PR after 2 courses of PAD was higher than that in patients with≥ PR, but the difference was not statistically significant (P &gt; 0.05). ③ The levels of IL-6, IL-8, TNF - α of newly diagnosed MM were significantly higher than normal control group, and were positively correlated with ISS stage (r=0.61, r=0.67, r=0.59, P均&lt;0.05).④ The levels of IL-6 and IL-8 of newly diagnosed MM with renal injury were significantly higher than those in patients with normal renal function (P &lt; 0.05). Further studies showed that the level of IL-8 was negatively correlated with the proportion of CD16 + CD56dimNK cells (r=-0.65, P&lt;0.05).Conclusion: the abnormal expression of lymphocyte subsets and cytokine levels in MM patients may be related to the tumor load, disease progression and prognosis.

Disclosures
No relevant conflicts of interest to declare.
Low Dose Rituximab Plus High Dose Dexamethasone As First-Line Treatment for Autoimmune Hemolytic Anemia
Authors: Rodríguez-Roque Carlos Saúl , Gomez-De Leon Andres , Morcos-Sandino Michelle , López-Flores Nelson Josafat , Galindo-Calvillo David David , Zertuche-González Elsa Laura , Rodríguez-Zuñiga Anna Cecilia , Gomez-Almaguer David 
Published: November 2020

Introduction
Corticosteroids are the first line therapy for autoimmune hemolytic anemia (AIHA), but are associated with significant adverse events, dependency and frequent relapses. Rituximab is reserved for severe or steroid-resistant disease. Low-dose rituximab is also effective, but its efficacy in the first line has been poorly described. We report our results with this combination.
Methods
Adults older than 16 years newly diagnosed with warm antibody AIHA either primary or secondary were included. Patients systematically received dexamethasone 40 mg for 4 days followed by a 1 mg/kg rapid prednisone taper plus rituximab 100 mg weekly for 4 doses. Our primary outcome was response at day 28 based on the First International Consensus Meeting (complete response: normalization of Hb, no evidence of hemolysis and absence of transfusions; response: increase of Hb by &gt;2g/dl, or normalization of biochemical resolution of hemolysis or absence of transfusion in 7 days), secondary outcome was event-free survival with an event defined as a laboratory or clinical relapse or loss of response.
Results
Sixteen patients were treated with low-dose rituximab during the study period, ten women (62.5%), six men (37.5%). The median age was 34 years (range, 17-78). Three (18.75%) were secondary to lupus erythematosus. The median follow-up was 20 months (range, 0.4-66). Most received 4 doses of rituximab (87.5%). All patients responded at day 28, (100%) 31.2% achieved a complete response (CR). Subsequently, 81.3% achieved CR. Ten (62.5%) were considered steroid-dependent, however, most discontinued treatment without loss of response (75%). The event-free survival was 63.8% to 5 years.
Conclusion
Low-dose rituximab therapy as a first-line in AIHA showed encouraging results as most patients were able to discontinue treatment without relapse.

Disclosures
Gomez-Almaguer: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Tgfβ-Imprinting Decrease CD38 Expression and Lead to Metabolic Reprogramming on Primary NK Cell
Authors: Pereira Marcelo de Souza Fernandes , Sezgin Yasemin , Thakkar Aarohi , Lee Dean Anthony 
Published: November 2020

Transforming growth factor-β (TGF-β) plays an essential role in regulating immune responses through its immunossupressive effect on adaptive and innate immune cells. In addition, we and others have shown that alterations in cell-intrinsic metabolism profiles can significantly impact the function of immune cells. Previously, our group demonstrated that TGFβ-imprinting (TGFβi) decreases NK cell sensitivity to TGFβ through SMAD3 suppression and enhances a pro-inflammatory phenotype with hypersecretion of IFN-γ, TNF-α, and GM-CSF, which appeared to be mediated by an epigenetic mechanism. To evaluate this process, we conducted RNA-seq and ATAC-seq to evaluate the impact of chromosomal remodeling on gene expression. In addition to confirming low SMAD3 transcription, this data showed that TGFβi NK cells have decreased CD38 expression, which we confirmed at the protein level. Since CD38 is an ectoenzyme that regulates nicotinamide adenine dinucleotide (NAD+), a critical component of OXPHOS in both T and NK cells, we examined the effect of TGFβi on NK cell metabolism. TGFβi primary NK cells were generated from peripheral blood of healthy donors as previously described, and using a mitochondrial stress test assay, we observed higher oxygen consumption rates (OCR). However, in the glycolysis stress test assay we observed comparable extracellular acidification rates (ECAR) between Standard expanded and TGFbi NK cells, resulting in higher OCR/ECAR ratios in TGFbi NK cells. Since TGFβ has been shown to induce fragmented mitochondria, and inhibition of mitochondrial fragmentation improved mitochondrial metabolism, we evaluated subcellular structure of TGFβi NK cellsby transmission electron microscopy (TEM). We found no difference in mitochondrial fragmentation between STD and TGFβi NK cells. Together, these results show that TGFβi induces epigenetic reprograming of NK cells that results in increased OXPHOS through CD38 suppression. Moreover, the decreases CD38 expression in TGFβi NK cells could be a promising non-genetic alternative to generating CD38-negative NK cells to avoid fratricide in combination with DARA
Figure

Disclosures
Lee: Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Acute Promyelocytic Leukemia (APL): Seasonal Behavior in Colombia for the Period 2009-2019
Authors: Martínez Cordero Humberto , Ospina Idarraga Juan , Castañeda Contreras Xiomara , Rico Mendoza Alejandro , Idrobo Henry , Martinez Correa Lina , Buitrago Jenifer , Porras Ramírez Alexandra 
Published: November 2020

Background
Acute promyelocytic leukemia (APL) is a malignant hematologic disease with a high cure rate, but unfortunately it produces several serious complications at the onset of the disease that explain the high early mortality. Based on clinical experience and the papers that precede this document, it has been observed that the incidence of this type of hematological cancer tends to increase at certain times of the year. The present study aims to determine the possible variations in the time intervals of the prevalence of promyelocytic leukemia in Colombia in the decade 2009 to 2019, in order to identify the behavior of the event, seasonality and cyclicality.
Methods
With data from the individual records of service provision (RIPS) of the official Colombian health system, the prevalence of APL in Colombia from 2009 to 2019 was identified. A filter was made by people attended, main diagnosis, C924 - promyelocytic leukemia acute, by year, semester and month. The analysis was performed with RStudio, R version 4.0.2 (2020-06-22); The fpp2 library was used, the analysis of the monthly and quarterly time series was carried out, the decomposition of the time series was carried out, trying through this process to evaluate the seasonal indices through additive and multiplicative types.
Results
During the entire period 2009 to 2019, 2,986 APL diagnoses were found throughout the national territory of Colombia. A progressive increase in prevalence was determined in the period studied (Graph 1). Cycles of increasing cases were observed every 10 months in the period 2009 to 2015 and in the cycle from 2016 to 2019 there was a prolongation of the cycle every 17 months, which strongly suggested that APL has cyclical behavior. Quarterly seasonality was identified by the multiplicative method with increases and decreases that behave in a similar way throughout the period studied (Graph 2).
Conclusion
APL is a highly curable disease that requires adequate support at the onset of the disease to avoid early mortality. The data from this study allow us to conclude that for the period 2009 to 2019 there is a seasonal behavior of this malignant hemopathy. The possibility of predicting during which months of the year the incidence of the disease will increase can serve to properly plan the health services in charge of treating this disease. Additional studies are required to determine what is the cause of the cyclical and seasonal behavior of this APL

Disclosures
Idrobo: Amgen:Honoraria, Speakers Bureau;Takeda:Honoraria, Speakers Bureau;Janssen:Honoraria, Speakers Bureau;Tecnofarma:Honoraria, Speakers Bureau;Abbvie:Honoraria, Speakers Bureau.
Bendamustine-Bortezomib-Dexamethasone (BVD) in Heavily Pretreated Multiple Myeloma: Old/New in NOVEL Agents' Era
Authors: Cerchione Claudio , Catalano Lucio , Nappi Davide , Rocco Stefano , Palmieri Salvatore , Pareto Anna Emanuele , Musuraca Gerardo , Lucchesi Alessandro , Pane Fabrizio , Ferrara Felicetto , Martinelli Giovanni 
Published: November 2020

Introduction
Bendamustine is an old bi-functional alkylating agent which has proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM).
Aims
Thus, aiming to provide further insights in this field, also in novel agents'era, we present here a retrospective, real-life analysis of patients with relapsed/refractory MM (rrMM), who had received salvage therapy with bendamustine in combination with bortezomib and dexamethasone (BVD).
Methods.
81 patients (44 M/37 F), with rrMM, median age at diagnosis 59.4 years (r. 36-82), median age at start of treatment 63.6 years (r.37-86) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (B 90 mg/sqm days 1,2; V 1.3 mg/sqm days 1,4,8,11, D 20 mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression.
All patients had previously received bortezomib-based and IMIDs-based treatments, and 32% (26/81) had also received radiotherapy. 69% (56/81) had undergone single or double autologous and three (2%) allogeneic stem cell transplant. All patients were relapsed and refractory to last therapies received before BVD.
Results
Bendamustine was well tolerated, with grade 3-4 transfusion-dependent anemia in 56% (46/81) of patients, and 43% (35/81) grade 3-4 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs.
According to IMWG, ORR was 63% (51/81: 7 CR, 18 VGPR, 15 PR, 11 MR) with 11 PD and 19 patients in SD, which can be considered as an impressive result in this subset of rrMM patients. In particular, for 11 patients, BVD was, after having achieved at least a PR, a bridge to second auSCT, and for two patients a bridge to alloSCT. Eight patients have surprisingly achieved a notable PR after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide).
Median time to response was 1.3 months (r.1-3), median OS from diagnosis was 67.3 months (r.6-151), median OS from start of Bendamustine was 9.6 months (r.2-36).
Conclusions
The triplet Bendamustine-Bortezomib-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, and, in particular cases, it could be considered as a bridge to a second autologous or allogenic SCT, also after failure of novel agents.

Disclosures
Lucchesi: Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria.
Cardiovascular Toxicities of Tyrosine Kinase Inhibitor in CML
Authors: Master Samip R , Mansour Richard Preston 
Published: November 2020

Background: Cardiovascular (CV) toxicity is a known toxicity of tyrosine kinase inhibitors (TKI) used for chronic myeloid leukemia (CML). Imatinib, dasatinib, nilotinib and bosutinib are all approved for first line treatment for CML. We did a retrospective analysis on adverse effects (AE) of TKIs that has been made available to public by the FDA.
Methods: The FDA has made the data on AEs of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the CV AEs of various TKIs for the years 2017-2019.
Results: The percentage of CV AE compared to total AEs reported for Imatinib, Dasatinib, Bosutinib , Nilotinib and Ponatinib were 7.2%, 10.5%, 15.8%, 23.4% and 23.5% respectively. The percentage of CV AE leading to death for Imatinib, Dasatinib, Bosutinib , Nilotinib and Ponatinib were 8.3%, 9.1%, 9.1%, 13.7 % and 18.6% respectively.
Conclusions: Out of the reported cases of AEs to TKIs approved for front line CML, nilotinib appears to have more CV AE compared to imatinib, dasatinib and bolutinib. Imatinib appears to have least CV AE out of the total AEs reported

Disclosures
No relevant conflicts of interest to declare.
Liver X Receptor (LXR) Is a Novel and Reversible Regulator of Trauma-Induced Coagulopathy
Authors: Einersen Peter , Mitra Sanchayita , Selby Reid , Moore Ernest E. , Kelher Marguerite , Fragoso Miguel , Schiller Daran , Swope Megan , Nunns Geoffrey , Vigneshwar Navin , Chandler James , Ghasabayan Arsen , Desisto John , Sanford Bridget , Dzieciatkowska Monika , Johnson Linda , Cohen Mitchell J. , D'Alessandro Angelo , Peltz Erik , Banerjee Anirban , Hansen Kirk , Silliman Christopher C. , Jones Kenneth 
Published: November 2020

Trauma-induced coagulopathy (TIC) manifests as a bimodal disruption of normal fibrinolysis, where at the two extremes, fibrinolytic shutdown (TICFS) places the patient at increased risk for thromboembolism and post-injury multiple organ failure, and systemic hyperfibrinolysis (TICHF) results in excessive bleeding. Plasma proteomic profiles for 65 trauma patients were used to identify changes in the patient's plasma protein profile stratifying them by risk for TIC. A strong correlation was seen between total plasma protein concentration of individual patients and the concentration of coagulation proteins within that patient, suggesting that trauma-induced coagulation may be affected through a mechanism that controls the efflux of many coagulation proteins into the plasma (Figure 1). Pathway analysis, in addition to elucidating changes in the coagulation cascade, identified several proteins that are known to be regulated by the Liver X receptor/Retinoid X receptor (LXR/RXR), suggesting that LXR/RXR-mediated activity may regulate TIC (p=9.03E-26). Validation experiments in a rat model revealed that fibrinolytic response to an LXR antagonist and/or agonist can be observed in less than 60 minutes (Figure 2). Additionally, we show through reciprocal rescue of fibrinolysis that the TIC phenotypes (TICHF and TICFS) are one continuum and are ultimately co-reversible, where the reduced LXR signaling that causes sequestration of blood factors in the liver leading to excess bleeding or induced LXR signaling that causes excess efflux leading to thrombosis can be reversed through administration of the LXR agonist or antagonist, respectively. Thus, as modulation of LXR shows co-reversibility and rapid response, induction/inhibition of the LXR pathway provides a direct and novel therapeutic intervention in severely injured patients at risk for TIC.

Disclosures
No relevant conflicts of interest to declare.
Establishment ofin VitroDrug Sensitivity Screening Assay for Chronic Lymphocytic Leukemia (CLL) Primary Patient Samples
Authors: Vishwakarma Bandana Ajay , Wesa Amy 
Published: November 2020

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. CLL is characterized by proliferation and accumulation of monoclonal, small, mature CD5+ B-cells in peripheral blood, bone marrow and secondary lymphoid organs. The current treatment regimens have improved overall survival but CLL patients will eventually experience relapse. The disease is still incurable making it a necessity to discover and screen for new drugs. Patient derived CLL specimens undergo spontaneous apoptosis when grown in culture and is a major limitation to screening for new therapeutic drugs.
We have established anin vitroculture conditions which supports growth and proliferation of patient derived primary CLL cells. Champions has a bank of primary CLL patient samples across different Rai stage, genetic mutations and relapsed and refractory cases. Using the optimizedin vitroculture conditions, we tested three CLL human primary samples (models) for proliferation . All three models proliferated 1.5 to to 2-fold in the optimized media in 6 days, as measured using CellTiter-Glo®. We also examined the phenotypic changes in the cells after growing them in the established media. Flow cytometric analysis showed that the CLL cells mostly retained the primary phenotypic characteristic CD5+CD10-Cd19+CD20+ even after being in the culture for 6 days.
Next, we screened for sensitivity of primary CLL patient samples (N=10) against known standard of care (SOC) drugs venetoclax, ibrutinib, idelasib, chlorambucil and cytarabine. Primary patient samples derived from peripheral blood mononuclear cells (PBMC) were cultured in 96 well plates in the enriched media and treated with respective drugs over a concentration range over 5 logs. Drug sensitivity was assessed using CellTiter-Glo® luminescent cell viability assay on day 3. Ourin vitroassay indicated that some, but not all patient samples were sensitive to approved standard of care drugs. A relapsed bendamustine pre-treated patient sample was sensitive to all the SOC drugs tested. In addition to drug response, whole exome sequencing and RNAseq are being conducted on these samples, to compare mutational analyses with drug responsiveness. With clinically annotated patient-derived CLL samples, WES and RNAseq plus drug response to standard of care provides a comprehensiveex vivoplatform for the preclinical testing of drug candidates, which may not only provide information on agent efficacy, but that can permit potential biomarker mining and exploration of patient selection criteria for investigational new agents in CLL.

Disclosures
No relevant conflicts of interest to declare.
Sialylated Glycans Regulate MUC13 and the Proto-Oncogenes Pim-1 and Myc to Control Hematopoietic Stem and Progenitor Cell Numbers
Authors: Rivadeneyra Leonardo , Lee-Sundlov Melissa M. , Glabere Simon , Ashwood Heather , Burns Robert , Hoffmeister Karin M. 
Published: November 2020

The enzyme β-1-4 galactosyltransferase 1 (β4GalT1) plays a critical role in thrombopoiesis by modulating sialo-glycan (sialyl N-acetyl-lactosamine or LacNAc) content and function of the β1 integrin on megakaryocytes (MKs) (Nat. Commun. 2020;11(1):356). Recent data, however, point to a more complex role for β4GalT1 in hematopoiesis, as the promoter region of its conserved gene, B4galt1, is rich in enhancer sequences for transcription factors associated with cell identity and pro-oncogenic regulatory programs.
Here, we investigated the homeostasis of hematopoietic stem and progenitor cells (HSPCs) in B4galt1-/- mice. We demonstrate that lack of Sialylated LacNAc synthesis perturbs HSPCs beyond the homing deficiency associated with lack of homing sialo-glycan motifs. Flow cytometry analysis showed that B4galt1-/- mouse bone marrows have increased numbers of Long-Term HSCs (LT-HSCs, defined as LineageNeg/Sca-1Pos/c-KitPos/CD150Pos/CD48Neg). The increase in HSC numbers led us to investigate their phenotypic and functional features further. While quiescence markers in B4galt1-/- LT-HSCs were indistinguishable relative to controls, LT-HSCs expressed more of the platelet marker CD41 on their surface, supporting a highly expanded CD41+ subset of LT-HSCs. Platelet-bias of LT-HSCs has been associated with inflammation and aging. However, our data do not support an increased cytokine inflammatory profile in the bone marrow.
Instead, single-cell RNA sequencing (scRNA seq) of sorted β4galt1-/- LineageNeg/Sca-1Pos/c-KitPos (LSK) cells showed a significantly increased expression of the proto-oncogene Pim-1, its target, Myc, and the heavily O-glycosylated transmembrane receptor mucin 13 (MUC13), compared to control cells. Analysis of LT-HSC glycan expression using lectin microarray showed the expected decrease in N-glycosylation associated with B4galt1 deficiency, but also an increase in O-glycans, consistent with overexpression of MUC13, expression of which was enriched compared to other surface mucins. The data show that B4galt1 deletion leads to overexpression of the proto-oncogenes Pim-1, Myc, and MUC13 in HSPCs. The data suggest that MUC13-associated O-glycans and glyco-synthetic genes are potential therapeutic targets for hematologic malignancies since mucins have anti-inflammatory functions and alterations in mucin expression are with inflammation and cancer.

Disclosures
No relevant conflicts of interest to declare.