bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hemolysis and Free Heme Impact Therapeutic Activity of Anti-CD20 Antibody
Authors: Dimitrov Jordan , Kanyavuz Alexia , Marey-Jarossay Annaelle , Lecerf Maxime 
Published: December 2023

Hemolysis is a process of destruction of erythrocytes that can occur in different hereditary or acquired pathologies. It is accompanied by release of hemoglobin and heme, which both manifest potent pro-oxidative and pro-inflammatory activities. If released in large quantities hemoglobin and heme can directly contribute to systemic inflammation and tissue injury in hemolytic diseases. Moreover, it was demonstrated that heme binds to a significant fraction (ca. 10 %) of human antibodies (Abs) and this binding can result in considerable functional changes. Thus, heme-bound human IgG acquire reactivity towards a large set of unrelated proteins, including autoantigens. In a previous study we observed that 14 % of a repertoire of 117 clinical-stage therapeutic mAbs are able to bind heme and as a result they acquired autoreactivity and polyreactivity. Among these Abs some are specific for CD20 and used in lymphoma therapy (e.g. Rituximab). Importantly, therapeutic mAbs can be administered in patients with ongoing hemolysis. Thus, it is of critical importance to decipher molecular mechanism and functional consequences of interaction of heme with therapeutic mAbs and understand how the therapy of lymphoma can be affected by underling hemolysis and heme release.
The present study has the following objective: to elucidate the effect of heme on the therapeutic activity of anti-CD20 therapy in in vitro and in vivo models of B cell lymphoma. Effect of heme on anti-CD20 therapeutic Abs was assessed by i) binding assays - ELISA, western blot; protein microarrays; absorbance spectroscopy; surface plasmon resonance, and ii) molecular modeling. The impact of heme on functional and therapeutic activity of Rituximab was analyzed by i) site-directed mutagenesis; ii) flow cytometry; iv) in vitro and in vivo models of human B cell lymphoma.
Our data reveled molecular and functional details about the interaction of heme with Rituximab and other anti-CD20 Abs. Thus, we characterized the interaction of Abs with heme, and identified in case of Rituximab the putative binding site for heme that overlapped with antigen binding site. By using a protein array with &gt;9800 human proteins, we identified the target proteins of heme-bound Rituximab. A mouse model of human B cell lymphoma revealed that the therapeutic activity of Rituximab was compromised following exposure to cell free heme under condition of acute intravascular hemolysis. Our study delineates that a fraction of currently used therapeutic mAbs show high sensitivity to heme and their therapeutic activity can be compromised under hemolytic conditions. This finding suggests that therapeutic interventions that reduce free heme and /or intravascular hemolysis should precede therapy with these Abs. Moreover, we identified sequence features of Abs that determine the sensitivity to heme. This finding can help to reduce sensitivity of heme of therapeutic Abs by protein engineering.
CRISPR-Based Gene-Editing Screens Revealed Modulators of Dexamethasone Sensitivity in Multiple Myeloma
Authors: Sobh Amin , Bonilla Emilie , Patel Alisha , Li Jianping , Dalal Mansi , Riva Alberto , Bennett Richard Lynn , Licht Jonathan D. 
Published: December 2023

Background: Multiple myeloma (MM) is an incurable plasma cell malignancy that accounts for 10% of hematologic malignancies. Despite improved prognosis due to advances in treatment, most patients ultimately develop therapy resistance and relapse. The glucocorticoid dexamethasone is a potent anti-myeloma agent used in combination with proteasome inhibitors and Immunomodulatory drugs (IMIDs) as frontline treatment. Dexamethasone binds to the glucocorticoid receptor (GR), which induces apoptosis by driving an apoptotic transcriptional program. The mechanisms of Dexamethasone resistance in MM remain poorly understood.
Aim: To define cellular processes that modulate dexamethasone sensitivity in MM.
Methods: We performed loss-of-function CRISPR screens in the t(4;14), NSD2 overexpressing, MM cell lines KMS11 and LP1 using the genome-wide Brunello sgRNA library.
Results: The screens identified genes whose loss altered MM cell sensitivity to dexamethasone, most being cell type-specific suggesting heterogeneity in mechanisms influencing dexamethasone cytotoxicity across MM patients. In KMS11 cells, disruption of the IL10/JAK/STAT signaling pathway and glycosaminoglycans/heparan sulfate synthesis pathway increases sensitivity to dexamethasone. By contrast, loss of chromatin remodeling factors including the polycomb group member EPC1 and the SWI/SNF complex components BRD7 and BRD9, altered dexamethasone response exclusively in LP1 cells. Perturbations resulting in dexamethasone resistance in both cell lines include the GR and its co-chaperone PTGES3 in addition to members of the NFKB inhibitor family (NFKBIA, NFKBIB). By contrast, disruption of the druggable GR co-chaperone FKBP5 or the histone deacetylase HDAC8 increased sensitivity to dexamethasone. In addition, the GID/CTLH E3 ubiquitin ligase complex was also identified as a general determinant of dexamethasone resistance in MM cells as disruption of several constituents of this complex resulted in increased dexamethasone sensitivity in both cell lines. The mechanism by which the GID/CTLH complex confers dexamethasone tolerance in MM cells is currently under investigation.
Conclusions: Multiple cellular processes contribute to modulating the cytotoxic effect of dexamethasone in MM. Such processes often regulate expression, stability, or localization of the GR. NFKB signaling and the GID/CTLH E3 ubiquitin ligase activity are key determinants of dexamethasone resistance. Targeting these processes can increase the therapeutic effect of dexamethasone in MM.
Prognostic Factors in Hospitalized Patients with HIV-Associated Burkitt's Lymphoma - Real World Data Analysis
Authors: Pichardo Rayli , Ramo Aula , Abu Omar Yazan , Dabak Vrushali S. 
Published: December 2023

Introduction
Burkitt Lymphoma (BL) is a highly aggressive and rare B-cell non-Hodgkin Lymphoma, characterized by translocation and dysregulation of the MYC gene. BL comes in three distinct forms: endemic, sporadic, and immunodeficiency related, which is most commonly secondary to HIV. Despite improvements in antiretroviral therapy (ART), the reported incidence of BL has remained stable over time. BL is a highly curable disease in patients able to tolerate aggressive therapies. However, little is known about real-world outcomes in United States patients with HIV- related BL. Our study highlights multiple factors associated with inpatient mortality and morbidity.
Methods
The National Inpatient Sample database was queried from October 2015 to December 2020.
Adults aged &gt;= 18 with a primary diagnosis of BL were identified and stratified into those with and without HIV. Complications included were queried using ICD codes most found in the secondary diagnosis variables. Baseline characteristics, inpatient complications, and outcomes were compared using chi-squared and Wilcoxon rank-sum tests. Logistic regression analysis was performed to assess the risk of death before and after adjusting for multiple risk factors.
Results
We found 3,650 admissions with a primary diagnosis of BL, 400 (11%) of whom had HIV. Patients with HIV were younger, 49% were younger than 40 years old as compared to 29% in patients with no HIV. There was a higher percentage of black patients 115 (29%), and most had Medicaid 170 (44%), there was no difference between income, hospital bed size or geographical region. Interestingly, in multivariable analysis, there were no significant differences in length of stay, race, or mortality between patients with and without HIV. The factors associated with mortality in HIV patients included acute renal failure OR 11.4 (1.22 to 107) and Sepsis OR 38.6 (1.62 to 921)
Conclusion
BL is an increasingly important disease in HIV-infected patients given that the incidence remains high despite advances in ART. This nationwide data analysis demonstrates the demographic characteristics of patients with HIV-associated BL in the US and the encouraging findings that outcomes are not significantly different between patients with and without HIV. Yet our study demonstrates the disproportionate distribution of HIV-BL in females and black patients. Further studies are needed to examine gender and racial disparities.
A Real-World Pharmacovigilance Analysis of Chemotherapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia
Authors: Goyal Shriya , Gaddam Shiva Jashwanth , Grewal Udhayvir , Ramadas Poornima 
Published: December 2023

Background
Myelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML) are well-known complications of traditional chemotherapy used to treat different solid and hematological malignancies. It is also reported with some newer drugs (eg. PARP inhibitors). We sought to analyze the real-world data of different chemotherapeutic drugs causing MDS/AML
Methods
From the FDA Adverse Events Report System (FAERS) public dashboard, we obtained the data on all the events reported as MDS and AML. Data was available for the years 1970 - 2023, and the events were analyzed for different drugs.
Results
A total of 24,565 events of MDS and AML were reported to the FAERS database between 1970 and 2023. 11,045 (44.97%) occurred in males, 9,803 (39.91%) in females, and 3,714 (15.12%) events had no sex specified. Most of them were severe AEs, and 11,486 (46.7%) of them were fatal. Among all the different chemotherapeutic drugs, the highest number of reports were related to Cyclophosphamide - 3,735 events (15.20%), followed by Lenalidomide - 3,028 events (12.33%) and Etoposide - 2,017 events (8.21%) (Table 1). When individually analyzed, MDS and AML accounted for 3.1% of all AEs related to Cyclophosphamide, compared to 0.9% for Lenalidomide AEs, and 4.2% for Etoposide AEs (Table 2).
Conclusions
Based on this retrospective analysis, we found that cyclophosphamide was the most common drug associated with MDS/AML reported to the FAERS, followed by Lenalidomide and Etoposide. However, MDS/AML was a more common AE with Etoposide, than with Cyclophosphamide or Lenalidomide. Considering the fatality rates of these events, a comprehensive risk-benefit and possible alternative therapy discussion must be held with the patients prior to treatment planning.
The Prognostic Value of Dynamic Change of NK-Cell Counts in Diffuse Large B-Cell Lymphoma Treated with R-CHOP
Authors: Huan Chen , Zheng Zhongxin , Wei Yongqiang , Guo Xutao , Wei Qi , Feng Ru , Wei Xiaolei 
Published: December 2023

Key words: Diffuse large B-cell lymphoma, Natural killer cell count, prognosis.
Introduction
Natural killer (NK) cell counts at diagnosis have been reported to be associated with poor outcomes, but the dynamic change and prognostic value of NK cell counts after treatment in diffuse large B-cell lymphoma (DLBCL)remain unknown.
NK cell count was test by flow cytometry at diagnosis, interim and the end of treatment. Receiver operating characteristic (ROC) curve was used to determine the best cutoff value for survival analysis. Overall survival (OS) and progression-free survival (PFS) were analyzed by the method of Kaplan-Meier and Cox proportional hazard regression model.
A total of 175 DLBCL patients were analyzed and 45 of them were divided into the low NK cell counts with the cut-off value was 94.5/ul. Patients with low NK cell counts were associated with B symptoms (p &lt; 0.001), high LDH (p=0.002), advanced stage (p &lt; 0.001) and high IPI scores (p=0.001). Survival analysis showed patients with low NK cell counts at diagnosis showed more inferior OS and PFS than those with high NK cell counts (p &lt; 0.001 and p &lt; 0.001). There were 60 patients showed low NK cell counts at the interim, consist of 31patients with low and 29 with high NK cell counts at diagnosis and 65 patients had low NK cell counts at the end of the treatment, consist of 31patients with low and 34 with high NK cell counts at diagnosis. But NK cell count at the interim or end of treatment had no impact on the PFS (p = 0.415 and p = 0.011) and OS (p = 0.537 and p = 0.836) of DLBCL patients. Multivariable analysis revealed that NK cell counts was an independent prognostic factor OS [relative risk (RR);95% confidence interval (CI),0.157-0.984, p = 0.046] and PFS (RR,0.335;95%CI,0.191-0.588, p &lt; 0.001） in all DLBCL patients independent of IPI.
In conclusion, low NK cell counts at diagnosis is a simple and effective adverse prognostic factor in DLBCL patients treated with R-CHOP. However, the NK cell counts at the interim and the end of the treatment showed no impact on outcome.
High IL-10 Expression Is Associated with Poor Prognosis in Primary Gastrointestinal Lymphoma
Authors: Wang Lingli , Ma Lan , Gao Jinjie , Wan Wei , Yang Ping , Zhu Mingxia , Dong Fei , Jing Hongmei 
Published: December 2023

Background：Primary gastrointestinal lymphoma（PGIL）is defined as the primary malignant lymphoma of the gastrointestinal tract. The long-term prognosis and life quality of PGIL patients are influenced due to gastrointestinal complications. Cytokines have a close immunological relationship with lymphocytes, however, the relationship with serum cytokines and PGIL prognosis is still unknown.
Method：We conducted a retrospective analysis of 165 PGIL patients referred to Department of Hematology of Peking university third hospital over a 10-year period between 2012-2022，and serum cytokine detection was performed on 85 patients' peripheral blood. Serum cytokine（IL-2,IL-4,IL-6,IL-9,IL-10,TNF-a）were quantified using flow cytometer. Median follow-up time was 29 months, and 1-year progression-free survival(PFS) of total PGIL patients was 84.1%, and 3-year PFS was 67.9%.The 1-year overall survival（OS）was 90.9%,and 3-year OS was 89.2%.
Results：The median age of PGIL patients was 57-year-old, and 58.8% of them were male. The two most common pathological types were diffuse large B-Cell lymphoma (40.0%) and mucosa-associated lymphoid tissue(30.6%).Our results also showed that IL-4 level was higher in surviving PGIL patients, while IL-10 level was higher in deceased PGIL patients. There was no statistically significant difference in other serum cytokines(IL-2,IL-6,IL-9, TNF-a) between surviving and deceased PGIL patients. Survival analysis showed that the OS of patients in the low IL-10 level group was lower than that in the high IL-10 group（P=0.03）
Conclusion：High IL-10 expression is associated with poor prognosis in primary gastrointestinal lymphoma
Safety and Efficacy of Autologous HSCT in Nine Patients with AIDS-Related Non-Hodgkin Lymphoma
Authors: Liu Jun , Zhou Yixing , Liang Shunsi , Zeng Chensi , Zhang Lingqian , Huang Dehong , Xiao Chunyan , Yang Tao , Li Jieping , Nan Yingyu , Li Qiying , Xiang Ying , Liu Yao 
Published: December 2023

Background：In recent years, with the application of HIV combined with resistance retroviral therapy, the number of AIDS-NHL patients has gradually increased, surpassing Kaposi's sarcoma and becoming the first AIDS-related tumor. The prognosis of AIDS-NHL patients is worse than that of ordinary NHL patients, and more powerful treatment is needed. To analyze the safety and efficacy of 9 AIDS-related non-Hodgkin lymphoma (AIDS-related non-Hodgkin lymphoma, AIDS-NHL) treated with autologous hematopoietic stem cell transplantation (auto-hematopoietic stem cell transplantation, ASCT).
Methods: 9 patients with AIDS-NHL were prospectively treated for their safety and efficacy.
Results: The male to female ratio of 9 AIDS-NHL patients was 8:1, and the median age was 38 years. The pathology types were 4 DLBCL, 2 PBL, 1 BL, 1 HGBL and 1 HL, including 3 patients with refractory relapse (1 each of DLBCL, HGBL and PBL). Except for three patients with refractory relapse, the remaining six patients underwent first-line autologous HSCT. One PBL stage was in stage I low-risk group and the remaining patients were in stage III - IV high-risk group. Before transplantation, one patient was progressive, one patient was in partial remission, and the other patients achieved complete remission after chemotherapy. All patients underwent autologous HSC mobilization using PEG-G-CSF, with all CD34 + cell numbers&gt; 210 ^ 6 / Kg. Transplantation pretreatment was performed with the BeEAM protocol, with a median time to granulocyte engraftment of 11 days and a median time to platelet engraftment of 14 days, with no transplant-related death. Two patients who did not achieve CR before transplantation all died due to disease progression within 3 months after transplantation, and the remaining patients remained in complete disease remission through follow-up until February 28,2023.
Conclusion: AIDS-NHL patients are aggressive and have a poor prognosis, and active treatment is needed to improve their long-term survival. Our center prospectively performed autologous HSCT in nine patients with AIDS-NHL, and the results showed that the time of granulocyte and platelet engraftment was consistent with that of ordinary NHL patients, with no transplant-related death and was well tolerated. Failure to achieve complete remission before transplantation may be one of the adverse factors for the early death of patients.
The Addition of Lenalidomide to R-CHOP Is Effective for Prevention of CNS Relapse in High-Risk Patients with Diffuse Large B-Cell Lymphoma
Authors: Wei Xiaolei , Guo Xutao , Wei Qi , Xiong Dan , Zhang Peng , Zhang Zewen , Wei Yongqiang , Feng Ru 
Published: December 2023

Central nervous system (CNS) relapse is an uncommon but devastating event in patients in diffuse large B-cell lymphoma (DLBCL). Although several prophylaxis attempts including intrathecal methotrexate and intravenous high-dose methotrexate were conducted to reduce the CNS relapse rate, the optimal management remained uncertain. Herein, we performed an open-label, multicenter trial to explore the efficacy and safety of the combination of lenalidomide and R-CHOP (R2-CHOP) for preventing the CNS relapse in the high-risk diffuse large B cell lymphoma.
Eligible patients were aged 18-80 years, newly diagnosed DLBCL and high risk for CNS recurrence: CNS-IPI:4-6 or involvement of testicular, kidneys or adrenal glands. Lenalidomide orally 25 mg per day was administered on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 regimen. All patients received aspirin 100mg per day prophylaxis throughout. The primary endpoint was 2-year central nervous system relapse rates. The secondary endpoint were 2-year overall survival, progression-free survival, and treatment-emergent adverse events. This trial is registered with ClinicalTrials.gov, number NCT04544059.
A total of 56 DLBCL patients with high-risk for CNS relapse were included in this study. The median age of the patients in this study was 57 years old (range 26-77） and 47.8% patients were female. 88.9% patients had a CNS-IPI score ≥4 and the left patients may be involved with testicular, kidneys or adrenal glands. With a median follow up of 20 months,45patients finished planned cycles of R2-CHOP treatment and only 2（4.4%） patient developed CNS relapse. The 2-year progression-free survival and overall survival were 77.8% and 79.7%, respectively.
In summary, lenalidomide with R-CHOP is effective for prevention of CNS relapse in high-risk patients with diffuse large B-cell lymphoma.
Keywords:
Diffuse large B-cell lymphoma, central nervous system relapse, lenalidomide.
Risk Factors for Positive Posttransplantation Measurable Residual Disease in Patients with Acute Lymphoblastic Leukemia
Authors: Wang Yuewen , Fu Guomei , Xu Lanping , Wang Yu , Cheng Yi-Fei , Zhang Yuanyuan , Zhang Xiaohui , Liu Yanrong , Liu Kaiyan , Huang Xiao-Jun , Chang Ying-Jun 
Published: December 2023

Background: The level of MRD before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-HSCT MRD. However, no work has been devoted to the risk factors for positive post-HSCT MRD in patients with ALL. This study evaluated the risk factors for post-HSCT MRD positivity in patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic HSCT (allo-HSCT).
Methods: A total of 1683 ALL patients were enrolled. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis.
Results: Both in total patients and in T-ALL or B-ALL, pediatric or adult, HLA-matched sibling donor transplantation or haploidentical HSCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity ( P &lt; 0.001 for all). Disease status was also a risk factor for post-HSCT MRD positivity in all patients and in the B-ALL, pediatric, or haploidentical SCT subgroups ( P =0.003; P=0.035; P =0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively ( P&lt;0.001). Multivariate analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as LFS and OS.
Conclusion: Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic HSCT.