bluuebunny/crossref_metadata_2025_split huggingface dataset:
Red Cell Alloimmunization Rate in Patients with Sickle Cell Disease
Authors: Asante Akua , Henrichs Kelly , Blumberg Neil , Love Tanzy 
Published: December 2024

Background: Sickle cell disease(SCD) is a single gene disorder resulting in dysfunctional hemoglobin tetramers that polymerize causing vaso-occlusion (VOC), hemolysis, endothelial damage and inflammation leading to pain and end-organ damage. Red blood cell (RBC) transfusions are vital despite recent advances in treatment. RBC alloimunization complicates treatment with rates of up to 47% limiting availability of compatible RBC units. The etiology of alloimmunization is multifactorial; including donor recipient racial differences, transfusion volume, non-leukoreduced RBCs, infection or VOC during transfusion, age, and pregnancy. Two studies have shown decreased alloimmunization rates in leukemia patients post implementation of universal leukoreduction and ABO identical (ABO-ID) blood product transfusions. The aim of this study is to analyze the impact of ABO-ID policy on alloimmunization rates in the SCD population.
Methods: A retrospective chart review was performed during June 1, 2004 to Dec 31, 2023. 437 patients with SCD were identified. Data was gathered on transfusion history, alloimmunization status, and antibodies identified.
Results: 257 patients were transfused and of that 211 were transfused prior to ABO-ID policy implementation in April 2005 (pre ABO-ID) and 49 after (post ABO-ID). In regard to SCD genotype, 67% were SS, 22% SC, and 11% SBthal. The alloimmunization rate for pre ABO-ID is 30% and post ABO-ID is 4% (p=0.0006). Among the pre ABO-ID group, 182 received ABO-ID transfusions with an alloimmunization rate of 27% compared to a rate of 48% for those transfused with ABO non-identical (ABO non-ID). The post ABO-ID group received significantly less transfusions and were younger compared to those transfused with ABO-ID RBC from the pre ABO-ID group (p&lt;0.05 and p&lt;0.05 respectively).
Conclusion: The alloimmunization rate in patients transfused prior to the ABO-ID policy was higher compared to those transfused after. These results suggest that avoiding the infusion of ABO non-ID antibody, even in small amounts, as with group O RBC transfused to non-O patients, may reduce the rate of alloimmunization in patients with SCD. The increased alloimmunization rate in patients transfused with ABO-ID RBCs prior to ABO-ID policy can be explained by record review limitations due to patients seeking care at outside facilities where transfusion history access was not possible, older age, and higher number of RBC units transfused. This study highlights the need for a better understanding of the risks and pathophysiology of alloimmunization in patients with SCD. Prospective multicenter studies are needed to further evaluate the long term effect of ABO-ID transfusions in this patient population.
Evaluating Clinical Endpoints for C5 Inhibitors
Authors: Ma Mark 
Published: December 2024

Using free C5 levels as surrogate endpoints in complement therapies, especially for marketed Eculizumab and Ravulizumab, is grounded in the drug's specific mechanism of action and the correlation between free C5 levels and clinical outcomes. In studies targeting PNH, trials have shown that Ravulizumab maintains free C5 levels below the established threshold (&lt;0.5 μg/mL).
RLYB116 is an affibody with a high affinity for blocking C5. To determine the free C5 levels from post-dose time points, a free C5 assay was developed on the Gyrolab platform. In the RLYB116 first-in-human (FIH) study, the measured free C5 levels seemingly deviated from the predicted post-dose free C5 levels. This discrepancy was further characterized by spiking varying concentrations of RLYB116 in human serum with endogenous C5. The results indicated that free C5 levels were overestimated when compared to free C5 concentration quantified using the same technology for Ravulizumab studies. Compared to Ravulizumab, the faster Koff for RLYB116-C5 complex likely resulted in the assay capture reagent outcompeting for C5 from the RLYB116, resulting in an apparently higher concentration of unbound C5 (i.e., free C5).
Additional experiments were conducted to determine the correlation between hemolysis levels and free C5 levels in samples treated with RLYB116. Experiments included spiking serial concentrations of RLYB116 or Ravulizumab into 100% C5 human serum and then measuring the free C5 and hemolysis levels and, adding serial concentrations of C5 and RLYB116 or Ravulizumab into C5-depleted human serum and measuring the hemolysis levels. Despite a higher measured free C5 value in RLYB116-treated samples, a similar level of hemolysis reduction (&gt;90%) from baseline was observed, indicating complete complement inhibition is achieved in samples treated with RLYB116 or Ravulizumab.
The experimental evidence suggests that the free C5 levels obtained from RLYB116 study were significantly overestimated and it did not reflect the true complement inhibition by RLYB116. Furthermore, based on the totality of data from ex-vivo and clinical results, we conclude that RLYB116 demonstrated comparable or better potency compared to Ravulizumab, with a once weekly/self-administered dose. Additional pharmacodynamic markers, instead of free C5, should be used to support RLYB116 clinical development.
Efficacy and Safety of BeEAM Regimen for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma Patients: A Retrospective, Multicenter Clinical Study
Authors: Hu Renzhi , Liu Jun , Li Qiying , Liu Yao 
Published: December 2024

Objective: To evaluate the efficacy and safety of the BeEAM (Bendamustine + Etoposide + Cytarabine + Melphalan) conditioning regimen for autologous hematopoietic stem cell transplantation (ASCH) in lymphoma patients.
Methods: This study is a retrospective, multicenter clinical study, analyzing the clinical data of 167 lymphoma patients (NHL=152, HL=15) who underwent ASCH after BeEAM conditioning regimen from January 2021 to March 2024 in five tertiary teaching hospitals including the Cancer Hospital affiliated to Chongqing University. The clinical characteristics, transplant-related adverse reactions, hematopoietic reconstitution, efficacy, and survival status of the patients were assessed.
Results: The median age of the patients was 49 years (11-71 years), mainly male (58.0%). Most patients had aggressive B-cell lymphoma, including diffuse large B-cell lymphoma (53.2%), Burkitt's lymphoma (3.0%), as well as mantle cell lymphoma (4.2%), Hodgkin's lymphoma (8.9%), follicular lymphoma (1.2%), and peripheral T-cell lymphoma (16.7%). Among them, 132 patients (78.90%) were in stages III/IV, 111 patients (66.40%) had intermediate-high/ high risk IPI scores, and 60 patients (36.00%) had large tumor masses. Before the intensive therapy, the median number of chemotherapy courses was 2 times (1-9 times), and 78 patients (46.6%) received transplantation after second-line chemotherapy. The median number of CD34+ cells infused after conditioning was 5.14 (2.04-15.68). After transplantation, 8 patients had poor platelet engraftment, and the rest achieved hematopoietic reconstruction. The median time for good engraftment of neutrophils and platelets in peripheral blood post-transplant was 10.42 days (6-30 days) and 11.88 days (5-34 days), respectively.
The median follow-up time of the patients was 15.0 months (7.0, 48 months). During the follow-up period, 71 patients had PD (progressive disease), 31 patients died, the 2-year PFS (progression-free survival) was 56.1%, and the 2-year OS (overall survival) was 84.1%. Among the 167 patients during the conditioning process, 31 patients (18.5%) had infections, 13 patients (7.8%) had severe gastrointestinal reactions, 6 patients (3.6%) had acute kidney injury, and 3 patients (1.8%) had cardiac toxicity.
Conclusion: The BeEAM regimen is effective and well-tolerated for conditioning in autologous hematopoietic stem cell transplantation for lymphoma patients.
Inhibition of p300/CBP Overcomes BTK Inhibitor Resistance in MCL By Counteracting IL-6/JAK/STAT3 Signaling
Authors: Tashiro Yusuke , Shirakawa Kotaro , Arima Hiroshi , Nomura Ryosuke , Horisawa Yoshihito , Emani Stanford , Takeuchi Suguru , Caroline Jelagat , Kazuma Yasuhiro , Matsui Hiroyuki , Matsumoto Tadahiko , Yusa Kosuke , Takaori-Kondo Akifumi 
Published: December 2024

Introduction: Although Bruton's tyrosine kinase inhibitors (BTKi) are effective against relapsed refractory mantle cell lymphoma (MCL), their limited efficacy and resistance remain clinical issues. Previously, we conducted CRISPR/Cas9 screening and found that p300/CBP, lysine acetyltransferases, are the genes responsible for one mechanism of BTKi resistance. A p300/CBP inhibitor A-485 with ibrutinib synergistically induced apoptosis and cell cycle arrest in ibrutinib-resistant MCL cells.
Methods: To elucidate the synergistic mechanism, we conducted RNA sequencing using an ibrutinib-resistant MCL cell line, Granta519, and compared the transcriptomic profiles of Granta519, treated with ibrutinib, A-485, or both.
Results: Genes related to the G2M checkpoint were upregulated when treated with the combination therapy. Pathway enrichment analysis revealed that the combination therapy downregulated pathways including Myc targets, TNF-α signaling via NF-κB, E2F targets, mTORC1 signaling, and IL-2/STAT5 signaling activation. Moreover, we observed that addition of A-485 restored the efficiency of ibrutinib to suppress downstream BCR signaling in Granta519 cells. We also detected IL6/JAK/STAT3 signaling activation by ibrutinib monotherapy, and the addition of A-485 significantly counteracted IL6/JAK/STAT3 signaling activation, suggesting that IL6/JAK/STAT3 signaling contributes to ibrutinib resistance.
Pathway analysis showed that Myc was the most suppressed target by the combination therapy, reducing Myc mRNA levels by 90%. Using the MTS assay, we confirmed that Myc overexpression impaired the therapeutic effect of A-485 and significantly reduced the synergistic therapeutic effect of the combination therapy. This impairment suggests that the combination therapy achieves therapeutic effects by attenuating Myc function. We next focused on IL6/JAK/STAT3 signaling and tested ruxolitinib to inhibit JAK1/2. Interestingly, the IC50 value of ruxolitinib was lower in ibrutinib-resistant cells than ibrutinib-sensitive cells. To confirm that A-485 suppresses IL6/JAK/STAT3 signaling, we also confirmed that A-485 inhibited the nuclear translocation of STAT3 and the acetylation of STAT3 by Western blotting.
Conclusion: p300/CBP inhibition overcomes BTKi resistance in MCL through IL-6/JAK/STAT3 signaling inhibition and attenuation of Myc transcription. Thus, p300/CBP inhibition could be a novel strategy for treating BTKi-resistant MCL.
A Case of Proliferative Glomerulonephritis with Monoclonal Kappa-Light Chain Deposits Treated with Daratumumab Combination Therapy
Authors: Du Jun , Wang Jue , Lv JunTing , Xiao Dan , Liu Jia , Zhong Lu 
Published: December 2024

Introduction: Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a chronic glomerular disease caused by monoclonal gammopathy. Daratumumab has been proved effective in the treatment of plasma cell myeloma while its effect for PGNMID has rarely been reported.
Methods: A Daratumumab combination therapy (D-VCd regimen, specifically are Daratumumab + Dexamethasone + Bortezomib + Cyclophosphamide) was adopted to treat a patient diagnosed with PGNMID with glomerular deposits mainly composed of κ-light chain ( κ-light chain restricted PGNMID).
Results: The utility of D-VCd regimen showed a favorable effect in this patient. After the fixed course, his clinical symptom, laboratory parameters, neoplastic plasma cells clonity all restored to normal range, and no obvious disease progression was observed throughout the treatment. Following the treatment, 24H microalbuminuria, 24H urine total protein levels restored from 6142.35 and 9114.7mg/24h to 117 and 212mg/24h, respectively. Urinal IgG titers transformed from 129mg/L to 6.3mg/L. Urinary κ and λ -light light-chain decreased from 49.6 and 31.7mg/L to 7 and 3.9mg/L, respectively. All the while serum creatinine fluctuated within the normal range.
Conclusion: This case underscores the utility of Daratumumab in treatment of PGNMID, and it's inferred that Daratumumab has clinical effects in the disease primarily through targeting tumor clonity. However, data on the use of Daratumumab in clinical trials of PGNMIDs is currently so limited that that more experiments are needed to support the inference.
Case Series of Myeloid Sarcoma from a Tertiary Center
Authors: Rahman Iris , Kim Salem , Latif Hira , Smith Hedy 
Published: December 2024

Introduction: Myeloid sarcoma (MS) represents a rare neoplasm derived from myeloid precursor cells, typically manifesting as an extramedullary tumor mass. While frequently associated with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS), it can also manifest independently as a solitary lesion. This phenomenon underscores the heterogeneous clinical presentations of myeloid sarcoma, necessitating thorough diagnostic evaluation and tailored management strategies. Management strategies are primarily guided by protocols established for AML, although MS exhibits considerable clinical variability and is associated with a generally unfavorable prognosis (Aldapt et al., 2022, Blood). Herein, we report six cases of myeloid sarcoma diagnosed at a tertiary care facility over the preceding decade.
Clinical Cases: The average age at presentation was 42 years old with average baseline hemoglobin 8.84, WBC 11.49 (range: 0.2 to 35.5), LDH 445. The average time to treatment was 32 days. 5 cases were associated with a diagnoses of MDS or AML while one case had no associated diagnosis.
Case 1 presented with gingival MS in the context of AML, achieving disease remission after multiple rounds of chemotherapy. Case 2, diagnosed with CML, was found to have a gastric mass on CT, which was later diagnosed as MS with AML transformation. Case 3, known for MDS, presented with bleeding and was diagnosed with MS involving an axillary lymph node. Case 4 presented with finger ulceration, diagnosed with MS and concurrent AML necessitating finger amputation and ongoing treatment. Case 5 presented with a rapidly growing eye mass, diagnosed with MS that metastasized and subsequently developed AML. Case 6 presented with neck and chest pain, diagnosed with solitary mediastinal myeloid sarcoma, experiencing persistent disease activity despite treatment.
The overall prognosis was poor, compounded by treatment complications and mass effect. Treatment approaches varied; two patients underwent surgical interventions due to mass-related complications. Immunohistochemical profiles differed across biopsies, with genetic testing for targeted therapies conducted only in the most recent patient (Case 4).
Conclusion: This case series aims to explore the diverse presentations and progression of myeloid sarcoma (MS). Extramedullary masses can vary in location and may present asymptomatically. MS should be considered in patients with a history of myeloid disorders or new masses. Delays in diagnosis and treatment are common as patients often seek care from multiple providers despite the disease's rapid progression. While management guidelines primarily align with those for AML, integrating surgical oncology guidelines could improve outcomes, especially in cases of isolated MS where mass-related complications and disease progression are concerns.
GATA2-TGF-b1-TAL1 Axis Is Essential for Human NK Cell Development and Function
Authors: Wang Dandan , Zhang Fangfei , Yang Chao , George Anjali , Veltri Anthony , Thakar Monica , Verbsky James , Myers Kasiani , Kee Barbara L. , Rao Sridhar , Bresnick Emery H. , Malarkannan Subramaniam 
Published: December 2024

Introduction: Natural killer (NK) cells are the major innate cytotoxic lymphocytes that mediate rapid and robust effector responses against tumors and pathogens without prior sensitization. However, the transcriptional mechanisms involved in human NK cell development and functions are yet to be fully defined. The transcription factor (TF) GATA2 is essential for regulating the survival, proliferation, and differentiation of hematopoietic stem cells (HSCs) and NK cell development. GATA2 forms a chromatin-bound heptad complex with other TFs (TAL1, FLI1, RUNX1, LYL1, LMO2, and ERG) to regulate hundreds of target genes in HSCs, which are lineage and stage-specific. GATA2 promotes the transition of HSCs into common lymphoid progenitors (CLPs) and its mutation results in the reduction of CD56Bright NK cells with or without reduced CD56Dim NK cells. Variants, including T354M in the second DNA-binding zinc finger domain, impair human NK cell development and function. A member of the heptad complex is TAL1, a class II basic helix-loop-helix (bHLH) TF that plays an essential role in controlling hematopoiesis along with GATA2. TGF-b1 functions as a checkpoint to maintain NK cell immaturity at the CD56Bright stage. However, it is unknown how TGF-b1 transcriptionally regulates human NK cell development and whether there are any links between GATA2, TGF-b1, and TAL1.
Results: We discovered that primary human NK cells express high levels of TAL1, and its target genes, including multiple GTPase of immunity-associated protein (GIMAP) family members, which were significantly upregulated in NK cells from patients with ten GATA2 pathogenic variants and GATA2 variant-expressing cells. GATA2 repressed TAL1 transcription, whereas GATA2T354M failed to repress TAL1. In contrast, GATA2T354M substantially reduced the expression of TGFB1 and known TGF-b1 target genes in human NK cells. Mechanistically, GATA2 regulated the TGFB1 promoter, and ATAC-seq and CUT&Tag assays using human primary NK cells revealed the TGFB1 promoter exists as accessible chromatin, GATA2 occupied the promoter. Occupancy was associated with elevated levels of H3K4me3, an active promoter mark. Thus, GATA2-mediated regulation of TGFB1 at an early commitment stage permits an orderly and successful transition of early NK cell developmental stages. Exogenous TGF-b1 augmented TAL1 degradation, suggesting that decreased TGF-b1 with a concomitant increase in TAL1 formed the mechanistic basis for defective NK cell development in patients with the GATA2T354M variant. The interplay between GATA2, TGF-b1, and TAL1 provides an important missing link required for early human NK cell development.
Conclusion: We identified a GATA2-TAL1-TGF-b1 axis that is essential for human NK cell development and maturation. Dissecting the underlying mechanisms unveiled a new dimension in NK cell biology and pathology.
Assessing Venous Thromboembolism Risk in Patients with Multiple Myeloma: A Nationwide Population-Based Study in Taiwan
Authors: Liu Chia-Jen , Tsai Chun-Kuang , Hsu Te-Lin , Wang Hao-Yuan 
Published: December 2024

Background . Venous thromboembolism (VTE) represents a significant disease- and treatment-related complication in multiple myeloma (MM). The studies of VTE in Asian myeloma patients are limited due to the low incidence of VTE in the Asian population. We conducted a comprehensive nationwide population-based study to elucidate the incidence and risk factors of VTE among MM patients in Taiwan.
Material and methods. We consecutively enrolled all patients newly diagnosed with MM in Taiwan from 2000 to 2021. The patients aged less than 18 or those without baseline data were excluded. The primary endpoint was the occurrence of VTE, including deep venous thrombosis and pulmonary embolism. Hazard ratios (HRs) for VTE risk in MM patients relative to an age- and sex-matched cohort were computed using Cox proportional regression analysis. Therapeutic agents were integrated into the Cox models as time-dependent covariates to mitigate immortal time bias. Multivariable Cox proportional hazards models were employed to identify independent predictors of VTE.
Results. This study encompassed 10,865 patients with MM and the same matched individuals, with a median age of 68 years (interquartile range 60-77). Among the MM patients, 57.0% were male. The most common comorbidities were dyslipidemia (76.3%), hypertension (67.5%), chronic kidney disease (45.2%), coronary artery disease (CAD; 44.0%), and chronic obstructive pulmonary disease (COPD; 39.3%). One hundred sixty-four VTE events developed among the MM patients, with a follow-up of 31,078.0 person-years. The VTE incidence was 14.5 times higher in the MM cohort than in the matched cohort (5.3 vs. 0.4 cases per 1,000 person-years; p &lt; 0.001). Univariate analysis identified several significant predictors of VTE, including CAD (HR 1.81), COPD (HR 1.37), cerebrovascular accident (HR 1.60), heart failure (HF; HR 1.47), hypertension (HR 1.85), prior VTE (HR 24.29), age ≥ 65 years (HR 1.54), male gender (HR 0.75), and immunomodulatory drug (IMiD) therapy (HR 1.70). The multivariable Cox proportional hazards models highlighted CAD (adjusted HR 1.43; 95% CI 1.01-2.01, p = 0.042), prior VTE (adjusted HR 21.12; 95% CI 11.30-39.47, p &lt; 0.001), and IMiD therapy (adjusted HR 1.68; 95% CI 1.19-2.37, p = 0.003) as independent risk factors for VTE in MM patients. Further analysis of IMiD therapy revealed adjusted HRs of 1.53 (95% CI 1.09-2.17; p = 0.015) for thalidomide and 2.05 (95% CI 1.34-3.13; p = 0.001) for lenalidomide.
Conclusion. This study substantiates the elevated risk of VTE in MM patients compared to an age- and sex-matched cohort. CAD, prior VTE, and immunomodulatory drug treatment are linked to an increased VTE risk in this population. These findings underscore the importance of implementing targeted preventive strategies for this high-risk group.