bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCR2 Expression Promotes Diffuse Large B Lymphoma Cell Survival and Invasion
Authors: Yan-Li Li , Hu Quan-Quan , Wen Zhao-Feng , Li Qian , Zhai Zhi-Min 
Published: November 2021

Abstract
Objective: Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma world wide. It is a phenotypically and genetically heterogeneous disease, accounting for 30-40% of all cases. 50%-70% of patients can be cured by the R-CHOP regimen, but nearly one-third of patients develop relapsed or refractory disease. CC chemokine receptor 2 (CCR2), the high affinity receptor of CC-Chemokine Ligand 2 (CCL2), which is the most representative of the CC chemokine family members, has be regarded to involve in tumor growth, angiogenesis, epithelial mesenchymal transition, metastasis and immune escape etc.. In recent years, the role and mechanism in DLBCL has not been reported yet. Our preliminary study showed that high expression of CCR2 was correlated with clinicopathological characteristics, and an adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) of DLBCL patients. The purpose of this study is to investigate the role of CCR2 expression in DLBCL cells proliferation and migration by in vitro and in vivo.
Methods: CCR2 expression were analyzed in human DLBCL cell lines (SUDHL-2, SUDHL-4, SUDHL-6, OCI-Ly8 and OCI-Ly10) by Western blot (WB). SUDHL-2 and OCI-Ly8 cells were incubated with CCR2 antagonist SC-202525 (Santa Crutz Biotechnology), and control cells were left untreated. The proliferation, migration, apoptosis and signaling pathway were detected by CCK8, transwell, flow cytometry (FC) and WB, respectively in vitro. The engraftment, tumor growth, dissemination and survival time were observed in BALB/c nude mice.
Results: CCR2 were expressed in all human DLBCL cell lines (relative CCR2 expression was higher in SUDHL-2, SUDHL-4 and OCI-Ly8 than in SUDHL-6 and OCI-Ly10 cell lines). Blockade of CCR2 expression signaling with CCR2 antagonist inhibited tumor cell proliferation, migration and anti-apoptosis ability. The signaling involved in the proliferation and migration of DLBCL cells by activating PI3K/Akt signaling pathway, and induced apoptosis through activation of P38MARK signaling pathway. Expression of CCR2 was also associated with increased engraftment, tumor growth and dissemination, and decreased survival time in xenograft mice. Furthermore, administration of CCR2 antagonist decreased tumor growth and dissemination of DLBCL cells, and increased survival time in the xenograft model.
Conclusions: Our study demonstrates that CCR2 plays an important role in the development of DLBCL by stimulating cell proliferation, migration and anti-apoptosis. The inhibition of CCR2 may, therefore, be a potential target for anticancer therapy in DLBCL.

Disclosures
No relevant conflicts of interest to declare.
Enhancing Diversity in Oncology Clinical Trials: Findings of a Case Study in Improving Black Patient Representation in a Multiple Myeloma Trial
Authors: Bhandari Sudip , Lagor Charles , Mueller Judith , Whyte Warren , Heilbroner Samuel 
Published: November 2021

Abstract
Background:
Black patients are underrepresented in multiple myeloma (MM) clinical trials. Despite the promise of Real-World Data (RWD), little research exists on RWD's usage to address this health disparity. In collaboration with a large pharmaceutical partner, we used RWD from commercial datasets (ConcertAI's Electronic Medical Record and claims datasets) aimed at identifying sites with a large Black patient population. We recommended including these sites in a recent clinical trial of Chimeric Antigen Receptor T cell (CAR-T) therapy for MM patients.

Methods:
We used the following criteria to identify promising sites: (1) high Black patient density, (2) access to a CAR-T accredited parent organization within 100 miles, (3) a hematologist/oncologist who treats MM patients, and (4) a history of treating MM patients with a Proteasome Inhibitor (PI) and Lenalidomide (Len) in the first line of therapy. For (1), sites were ranked using the lower 95% confidence interval for the percent of Black MM patients at the site. For (4), only sites with at least five MM patients who received PI and Len were included.
Our data sources were: ConcertAI's Electronic Medical Record (EMR) and claims datasets to link each patient to a site, and Google maps API to identify the CAR-T center nearest each oncology site. The patients in our data sets were not identifiable, and our research was conducted in compliance with the Health Insurance Portability and Accountability Act.
After having identified and filtered promising sites, we curated individual candidates in the order of Black patient density. The purpose of curation was to validate a final list of sites.
Results:
We identified 17 promising clinical trial sites affiliated with 16 healthcare systems in the mid-west, mid-Atlantic, southeastern, and southwestern regions of the United States (table 1). Our RWD captured an average of 141 MM patients (range: 6-791) who were treated at the 17 sites from 2015-2020. Thirty-nine percent of the patients were Black (range: 13-67%). This percentage was three times the recruitment rate of black patients in MM trials in the US (13%). On average, the sites were 44 miles driving distance (range: 0.8-96 miles) from the closest CAR-T center, had eight hematology/medical oncology specialists on staff (range: 1-17), and had previous interventional trial experience (13 sites had experience with MM trials). All of the identified sites were community-based sites, and none of the sites were previously identified by our pharmaceutical partner.

Conclusions:
We demonstrated that RWD can be leveraged to identify clinical trial sites with a high potential for Black patient recruitment, thereby addressing a known health disparity problem within multiple myeloma (MM) clinical trials.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Magnetic Resonance Imaging Reveals Significantly Increased Cerebral Blood Flow in the Hemoglobin E Mouse Model
Authors: Cui Min-Hui , Branch Craig A , Hirsch Rhoda Elison 
Published: November 2021

Abstract
Hemoglobin E (HbE) is the most common hemoglobin mutation world-wide. EE individuals exhibit a mild anemia as do those with β-thalassemia trait. A paradox arises with the combination of two relatively benign genes in HbE/β-thalassemia (HbE/β-thal) giving rise to highly morbid symptoms, anemia, growth retardation, developmental retardation, thalassemic bone type development, chronic leg ulcers (for a review, S Fucharoen and DJ Weatherall 2012) and often early mortality arising from cardiac failure (N Olivieri, Z Pakbaz et al. 2011). One approach to understanding the characteristics of HbE and this paradox was to generate a transgenic mouse model, expressing solely human HbE. This HbE mouse model exhibits a mild oxidative stress that parallels that observed in human EE individuals (QY Chen, EE Bouhassira et al. 2004, QY Chen, ME Fabry et al. 2012). These transgenic mice also exhibit mild cardiac dysfunction with depressed left ventricular contraction. We present here the first evidence of a significant increase in cerebral blood flow in the full knockout HbE (HbEKO) transgenic mouse model expressing solely human HbE compared to both the HbE+HbF (γ, gamma)-globin transgenic mouse, and the normal background C57 mouse. Cerebral blood flow is assessed non-invasively by MRI imaging. All protocols were approved by the Albert Einstein Institutional Animal Care and Use Committee.
Comparing the HbEKO mouse (without human γ globin) to the C57 normal background mouse, a significant increase of over 20% in thalamus cerebral blood flow at baseline is observed (p=0.008). There is also an approximate 18% reduction in thalamus cerebral blood flow comparing HbE low γ mice to the full HbEKO (no γ) (p=0.011). Concomitant with these observations, no significant difference is observed comparing these low gamma HbE mice to the normal C57 background mouse (p=0.384). The goodness of the data is also seen in the relatively small variation in cerebral blood flow amongst the individual mice in each subset. These findings are of particular relevance to reports of neurologic symptoms, intracerebral hemorrhage, and brain infarct in HbE/β-thal patients (V Wong, YL Yu et al. 1990, S Das, S Dubey et al. 2019).
In conclusion, these results suggest a direct role of HbE RBC initiating altered cerebral blood flow that when further complexed with β-thal could lead to intracerebral hemorrhage and other cerebral pathophysiology. The finding that the HbEKO mice with high HbF are not significantly different in cerebral blood flow from C57 mice may lend further support to therapeutic approaches enhancing the production of HbF in severe hemoglobinopathies, such as in sickle cell anemia, HbE/β-thal, and β-thal individuals.

Disclosures
No relevant conflicts of interest to declare.
Inherited Thrombophilias Are Associated with an Increased Risk of COVID-19 Associated Venous Thromboembolism: A Prospective Population-Based Cohort Study
Authors: Stevens Hannah P , Canovas Rodrigo , Peter Karlheinz , Tran Huyen , Kaplan Zane , McFadyen James David 
Published: November 2021

Abstract
Background: COVID-19 is associated with high rates of venous thromboembolism (VTE). The impact of common inherited thrombophilias on the development of COVID-19-associated VTE (COVID-19 VTE) is not well understood.
Objective: To determine if the presence of inherited thrombophilias modifies the risk of COVID-19 VTE or COVID-19 mortality.
Methods: Prospective population-based cohort study evaluating adult participants of the UK Biobank diagnosed with COVID-19 between November 2019 and May 2021. Individuals were of European descent and aged between 45 and 69 at recruitment to UK Biobank. We evaluated six single nucleotide polymorphisms including rs6025 (Factor V Leiden mutation) and rs1799963 (Prothrombin mutation) in addition to two polygenic risk scores (PRS-VTE and PRS-ABO). A genome-wide association study was performed for associations with COVID-19 VTE. COVID-19 VTE was defined using International Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes for VTE following COVID-19 diagnosis. COVID-19 mortality was defined using ICD-10 codes for COVID-19 on the death certificate.
Results: Demographic and clinical characteristics are shown in Table 1. Of the 13 712 COVID-19 positive individuals included in the analysis, the median age was 54 years and 52.5% were female. There were 197 (1.4%) cases of COVID-19 VTE and 890 (6.5%) died due to COVID-19. The rs6025 variant, synonymous with FVL, was associated with a 1.8-fold risk of COVID-19 VTE (95% CI 1.040-2.931) (Table 2). The risk of COVID-VTE was also increased with rs2066865 (OR 1.345; 95% CI 1.074-1.675) and the PRS-VTE (OR 1.262; 95% CI 1.081-1.468) (Table 2). COVID-19 VTE was associated with increased COVID-19 mortality (OR 2.731; 95% CI 1.885-3.901) but this study found no association between the studied inherited thrombophilias and COVID-19 mortality (Table 2). On genome-wide analysis, two novel SNPs, rs4975019 and rs2875853, located on chromosomes 4 and 16 respectively, were associated with an increased occurrence of COVID-19 VTE.
Conclusions: These data demonstrate that several inherited thrombophilias increase the risk of COVID-19 VTE and suggest that two novel SNPs are associated with COVID-19 VTE. These results suggest that certain inherited thrombophilias may assist in characterising a subgroup of COVID-19 patients at higher risk of thrombotic events who require individualised antithrombotic therapy. Future prospective studies are required to evaluate inherited thrombophilias in this patient cohort.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Manipulating MEF2C: Discovering Novel Drugs to Target ETP-ALL
Authors: Meijer Mariska T. , Cordo' Valentina , Hagelaar Rico , Smits Willem K. , Meijerink Jules PP 
Published: November 2021

Abstract
Ectopic MEF2C expression due to rearrangements have been recurrently found in patients with human early thymocyte progenitor acute lymphoblastic leukemia (ETP-ALL). ETP-ALL is the most immature subtype of T-ALL and is characterized by the expression of myeloid lineage markers and an ETP-like gene expression profile. In normal haematopoiesis, MEF2C expression occurs at immature stages and in myeloid- and B cell lineages but is absent in early T cell progenitors.
Here, we investigate MEF2C as an oncogene for ETP-ALL. First, we validated our initial observations in an independent T-ALL cohort that ETP-ALL patients highly express MEF2C along with BCL2, HHEX, LMO2 and LYL1 in contrast to other T-ALL subtypes. In addition, we have demonstrated that enforced MEF2C expression in the T-lineage drives a bi-phenotypic CD3 +CD19 + leukemia in mice by inhibiting a T-cell developmental program in favor a B-cell transcriptional program and that resembles human ETP-ALL. This confirms MEF2C as an oncogenic driver of ETP-ALL.
We developed a model system that enabled screening of various drug libraries for compounds that overcome developmental arrest induced by MEF2C-expression, as evidenced by the upregulation of CD3 and TCRγδ. The ETP-ALL-like LOUCY cells express MEF2C as consequence of a del5(q14-qter). Further induction of MEF2C levels (i.e. LOUCY-iMEF2C cells) blocked differentiation of LOUCY cells towards a CD3 +/TCRγδ + phenotype on OP9-DL1 or DLL4-coated plates in contrast to parental LOUCY cells. This model enabled high-throughput screening of drug libraries using a flow cytometry-based assay for drugs that further promote differentiation of LOUCY-MEF2C cells. We identified various epigenetic inhibitors that promoted differentiation of LOUCY-iMEF2C cells. Unlike AML patients, where HDAC4 was shown to play an important role in the activation of MEF2C and the propagation of the leukemia, we found that different HDACs are involved that can block or promote MEF2C function. This suggests that the role of different HDACs in MEF2C regulation is cell-type or disease dependent.
In addition, over-expression of MEF2C raised cellular resistance towards prednisolone treatment. Conversely, inhibition of MEF2C sensitized cells to prednisolone cytotoxicity, even in the presence of MEF2C-overexpression. Together, these data show that MEF2C is an oncogenic driver of ETP-ALL, and ectopic expression of MEF2C negatively affects steroid sensitivity. Specific targeting of only those HDACs that promote MEF2C activity may provide new therapeutic options in ETP-ALL by inhibiting MEF2C function and enhancing steroid sensitivity.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Significance of PD1, PD-L1 Expression , Pathological Subtypes and Metabolic Activity on 18F-FDG PET/CT in Refractory /Relapsing Pediatric Hodgkin Lymphoma
Authors: Khedr Reham , Khorshed Eman , Hassanein Omneya , Abdelrahman Hany , Elwakil Madeeha , Zaghloul Mohamed , Hamoda Asmaa Mohammed 
Published: November 2021

Abstract
Background:
Hodgkin Lymphoma (HL) is a unique disease entity both in its pathology and the young patient population that it primarily affects. Several meta-analyses have demonstrated that high PD-L1 expression levels are correlated with adverse clinical and pathologic features. Objectives: The aim of this study is to evaluate the correlation between the expression of PD-L1 and clinicopathological features, as well as the prognostic significance of PD-L1 expression with regard to interim PET response in relapsing / refractory pediatric HL. Methods: We measured the expression of PD-1/PD-L1 in the baseline diagnostic samples of children with relapsing/ refractory classical HL. The results were correlated with the pathological subtypes as well as the clinical outcome. Results: Of the 88 included patients, 77% had advanced stage HL. PD-1 expression was detected in 50% of cases, whereas PD-L1 (membranous) was expressed by tumor cells in 60% of the cases, and strongly expressed in 16% of cases. Notably, PD-L1 (cytoplasmic) was detected in 55% of the cases. There was a significant differences in the expression levels of PDL-1 between the different pathological subtypes (p = 0.006). OS of patients with PD-L1expression (Cytoplasmic) was 83% vs 91% in patients with absent expression (P=0.001). There was no prognostic significance of PD-L1 expression with regard to PET response (p=0.31). Conclusion: Although PD-L1 expressions did not show statistically significance with well-established prognostic factors, our preliminary data indicate that pathological subtypes and cytoplasmic expression of PD-L1 may have a prognostic implication on survival in pediatric HL.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Research on the Mechanism of SIRT1/AMPK Inducing Resistance to Imatinib in K562 Cells By Inhibiting Srebp to Promote Lipid Metabolism
Authors: Luo Jie , Luo Dongmei , Liang Hanying , Tan Yaxian , Liu Xiaoli , Liu Qifa , Xu Na 
Published: November 2021

Abstract
Background Leukemia stem cells (LSC) have the characteristics of independent of BCR-ABL kinase activity and metabolic reprogramming to support self-renewal. They are the root cause of the occurrence of chronic myeloid leukemia (CML), mediating TKI resistance and leading to clonal evolution. LSC self-renewal depends on the activity of SIRT1, the enhanced of SIRT1 induces LSC mitochondrial metabolic reprogramming. Studies have shown that SIRT1 and abnormally activated lipid metabolism are important reasons for inducing CML resistance to imatinib.
Objective Study the mechanism of SIRT1 regulating lipid metabolism and intervention strategies under imatinib therapy.
Method Liquid chromatography coupled with mass spectrometry (LC-MS) were used to analysis the lipid metabolism in imatinib-resistant CML cell line K562-R under low-glucose conditions. RT-qPCR and Western blot were used to detect the key enzymes related to lipid metabolism, and the SIRT1 inhibitor TV-6 was given to study the regulation mechanism of SIRT1 on lipid metabolism.
Result Firstly, we found that the glycolysis/gluconeogenesis pathway and fatty acid metabolism were abnormal in K562-R cells by metabolomics, compared with normal culture conditions, the expression of SIRT1 and AMPK were significantly increased, the expression of fatty acid synthesis-related genes (SREBP, FASN, ACC, SCD1) was significantly reduced, and the fatty acid β oxidation rate-limiting enzyme CPT-1 is significantly increased inK562-R cells under low-glucose conditions. Therefore, in the low-glucose environment, the expression of the above genes was reversed after the application of the SIRT1 inhibitor TV-6.
Conclusion K562-R imatinib-resistant cells can down-regulate the expression of SREBP through up-regulated SIRT1/AMPK pathway under low-glucose conditions, thereby inhibiting the expression of transcription factors involved in lipogenesis, reducing fatty acid synthesis, and providing the imatinib-resistant cells with the energy which required for proliferation.
Keyword Chronic myeloid leukemia; Metabolomics; Lipid metabolism; SIRT1/AMPK

Disclosures
No relevant conflicts of interest to declare.
The MYC/MIZ1 Complexes Are Required for Germinal Center B Cell Lymphomagenesis
Authors: Gunawan Arief Suryono , Toboso-Navasa Amparo , Chakravarty Probir , Clear Andrew James , Calaminici Maria , Calado Dinis Pedro 
Published: November 2021

Abstract
We previously showed that the formation of protein complexes between MYC and its partner MIZ1 (MYC-interacting zinc finger 1) is critically required for germinal center (GC) B cell expansion (Toboso-Navasa et. al., JEM 2020). MYC and MIZ1 are transcriptional activators; however, they can form a transcriptional repressor complex that represses MIZ1 target genes. High expression of MYC is commonly found in aggressive B cell lymphoma, most notably in Burkitt Lymphoma (BL) and in a fraction of Diffuse B cell lymphomas (DLBCLs). In DLBCL, MYC positivity is associated with poorer prognosis, especially when co-expressed with BCL2, and increased proliferative capacity. However, it remains unclear whether the requirement for MYC-MIZ1 complexes for cell expansion is retained in lymphoma, similar to what we observed in GC B cells.
We first investigated MIZ1 expression in primary samples of B cell lymphoma sub-types and found it to be ubiquitous in BL (100% of cases; 14/14), whereas virtually absent in low-grade Follicular Lymphoma (7% of cases, 4/58). Roughly 42% of DLBCL cases (36/85; ) co-expressed MYC and MIZ1 and that was associated with increased cell proliferation assessed by Ki67. To investigate the role of MYC-MIZ1 complexes in lymphomagenesis, we generated compound mutant mice overexpressing in GC B cells wild-type MYC or a MYC mutant that cannot interact with MIZ1 (MYC VD) in combination with PI3K. MYC VD cannot repress MIZ1 target genes but displays normal interaction with MAX and transcriptional activation. As shown previously (Sander et. al., Cancer Cell 2012) MYC synergised with PI3K for BL development; however, overexpression of MYC VD plus PI3K had significantly delayed disease development and developed instead plasma cell hyperplasia. Analysis of pre-tumoral cells by single cell RNAseq revealed massive expansion of a unique GC B cell cluster only in mice carrying MYC and PI3K and this cluster had the highest suppression of MYC-MIZ1 target genes among all GC B cell clusters.
Taken together, this data indicates that the fraction of cells in which MYC and MIZ1 are co-expressed represents a "sweet spot" for B cell lymphomagenesis; and that the transcriptional repressive complex formed by MYC and MIZ1 is crucial for GC B lymphomagenesis.

Disclosures
Toboso-Navasa: Benevolent AI: Current Employment. Calado: Myricx Pharma: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties: Cancer Treatments. WO patent WO 2020/128475 A1 (2020).