bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excess Risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) in a Screened Cohort of Patients with Gaucher Disease (GD)
Authors: Istaiti Majdolen Joleen , Thoren Katie , Revel-Vilk Shoshana , Zimran Ari , Landgren Ola 
Published: December 2024

BACKGROUND
Prior retrospective studies and smaller case series have proposed that patients with Gaucher Disease are more likely to of be diagnosed with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). To our knowledge, we have performed the first systematic screening study to define the prevalence of MGUS in a large cohort of patients with Gaucher Disease.
METHODS
We included consecutive adult (&gt;20 years) Gaucher Disease patients who have been followed at the Gaucher Unit, Shaare Zedek Medical Center, Israel since 2016 and who signed consent for biomarker testing. All assays were performed at the Sylvester Myeloma Institute at the University of Miami. Similar to prior large screening studies, all samples were tested with serum protein electrophoresis (SPEP) and free light-chain (FLC) assays, with reflex immunofixation for positive cases. All analyses were conducted in a blind manner, and results were independently evaluated by two experts. Demographics data, Gaucher Disease genotype, treatment status, and laboratory data, including platelet count, hemoglobin, creatinine, C-reactive protein, immunoglobulin, triglyceride, and glucosylsphingosine (Lyso-Gb1), a downstream metabolic product of glucosylceramide, levels were extracted for the Gaucher Unit database. Variables were evaluated across MGUS subtypes (M-spike MGUS and light-chain MGUS).
RESULTS
The cohort included a total of 411 patients;182 (44%) were males and the median age was 46.5 years (range:20-92). The majority of patients (n=258, 62%) had mild GD genotype and 282 (68.2%) patients had received Gaucher Disease-specific treatment. M-spike MGUS and light-chain MGUS were found in 43 (10.5%) and 83 (20.2%) patients, respectively. In univariate analysis, factors associated with M-spike MGUS were increasing age (OR=1.08, 95% CI: 1.05-1.10), mild genotypes (OR=3.48, 1.49-8.08), and elevated creatinine levels (OR=9.36, 2.2-39.4). Hemoglobin and lyso-Gb1 levels were lower in patients with M-spike MGUS, but this did not reach statistical significance. In multivariate analysis, only older age was associated with excess risk of M-spike MGUS. Similarly, older age was associated with increased risk (OR=1.02, 1.01-1.04) of light-chain MGUS. Gaucher Disease-specific treatment status did not significantly alter the risk of having M-spike or light-chain MGUS.
CONCLUSIONS
In this first systematic screening study of 411 Gaucher Disease patients and with a median age of less than 50 years, the prevalence of M-spike MGUS and light-chain MGUS were 10.5% and 20.2%, respectively, which is significantly higher than rates in the general population. These novel findings are expected to shape future therapeutic strategies and improve patient care, potentially influencing genetic counseling practices in the management of Gaucher Disease.
Blood Cell Homeostasis Is Maintained in the Absence of Resident Mononuclear Phagocytes in Fetal Liver and Bone Marrow in CSF1R Knockout Rats
Authors: Roberts Megan , Carter-Cusack Dylan , Huang Stephen , Maxwell Emma , Summers Kim Z , Irvine Katharine M , Hume David A 
Published: December 2024

Erythrocytes are produced through a highly regulated process that requires an adequate supply of iron to develop properly. The constant production of red blood cells occurs in erythroblastic island (EBI) niches, which exist in the fetal liver during embryonic development and move to the bone marrow. The macrophages within this niche are thought to be essential regulators of erythropoiesis via recycling iron for haemoglobin synthesis and phagocytosing the extruded nuclei generated during terminal erythroid maturation. The proliferation, differentiation and survival of many resident tissue macrophages depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R), including macrophages within haematopoietic tissues. Homozygous loss of function mutation in Csf1r in the rat produces a near complete loss of tissue resident macrophages, which is associated with severe postnatal growth retardation and osteopetrosis.
CSF1R signalling is also implicated in maintaining erythropoiesis in a model of anaemia. We aimed to determine the role of CSF1R-dependent macrophages in steady-state erythropoiesis and iron homeostasis. RNA-Sequencing of fetal liver from late gestation embryos showed no dysregulation of erythropoiesis or iron homeostasis in CSF1R knockout rats, despite loss of macrophage associated genes and reduced staining of the key iron recycling receptor CD163. Reduced CD163 was also observed in the liver and spleen in 3-week-old knockout rats. At three weeks of age, RNA-Sequencing of bone marrow revealed a significant reduction tissue resident macrophage associated genes. Despite the loss of bone marrow, liver and spleen macrophages and altered phenotype of the few remaining macrophages, CSF1R knockout rats have normal haematological parameters and show no indication of iron deficiency or overload. Altogether these results indicate that CSF1R-dependent macrophages are not absolutely required for early-life steady-state erythropoiesis and iron homeostasis in rats. Ongoing studies focus on the mechanism of erythrocyte development, erythrocyte recycling and iron homeostasis in the absence of CSF1R-dependent macrophages.
Patient-Derived Follicular Lymphoma Tumoroids: A Tool to Recapitulate Biological Features of Low and High-Grade Lymphoma
Authors: Gimenez Ruben , Serrat Neus , Castellote-Borrell Miquel , Jiménez-Martínez Victor , Pérez del Río Eduardo , Bachiller Mireia , Araujo-Ayala Ferran , Pérez Raul F , Martínez-Farran Ares , Robles Jose Ángel , Lopez-Guillermo Armando , Campo Elias , Villanueva Josep , Guedan Sonia , Martin-Subero Jose Ignacio , Guasch Judith , Hodson Daniel J , Colomer Dolors , Pérez Galán Patricia 
Published: December 2024

Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, is a paradigm of the contribution of the immune tumor microenvironment (TME) to disease onset, progression, and therapy resistance. To recreate the cellular components, signaling cues, and the physical environment, we have optimized the generation of Patient Derived Lymphoma Tumoroids (PDLT) embedded in collagen I, highly present in the reticular network of the lymphoma lymph node (LN) where FL originates. PDLTs are composed of tumor B cells and autologous T cells. In addition, a supportive follicular dendritic cell line (FDC), or a modified variant expressing specific cytokines and factors (CD40 ligand and interleukin 21) present in FL germinal center (GC) microenvironment (FDC-GC), was integrated. These components rendered a compact tumoroid, rheologically relevant to the lymphoma LN. Our model is capable of sustaining viability for up to 10 days and promote proliferation in the presence of GC cues. Through single-cell RNA sequencing (scRNAseq), we observed that, after culture in PDLTs, both tumor cells and TME maintained a FL-LN gene expression signature. However, coculture with FDCs yielded a profile more closely related to the original biopsy sample, whereas when FDC-GC stimuli were included instead, features of a high-grade FL were recapitulated. In this regard, mass spectrometry analysis of the secretome compartment revealed that high-grade PDLTs are also able to remodel their initial extracellular matrix (ECM) and refine it with newly secreted collagens (I, IV, V and VI), fibronectin, and tenascin C (all of them present in FL-LN), together with vimentin, known to be associated with FL transformation. Finally, we used PDLTs as a preclinical tool for cell therapy. The anti-CD19 CAR-T product ARI-0001 was able to adhere to the tumoroid's surface but shows moderate infiltration and e'icacy, compared to CART activity in Patient- Derived Lymphoma Spheroids lacking ECM. This indicates that ECM may be a crucial player in cell therapy evasion in lymphoma by preventing CAR-T cells from reaching their target cells, which is a common hindrance in solid tumors.
In summary, we have developed a patient-derived model that can recapitulate both indolent and aggressive FL features, providing an in vitro model suitable to study disease biology and personalized therapy testing in the context of structural and cellular elements of the TME, while reducing animal usage.
A Specific Coagulation Factor X Activator for on-Demand Treatment in Hemophilia with Inhibitors
Authors: Liu Wei , Zhou Hu , Huang Ruibin , Du Xin , Zhou ZePing , Zheng Changcheng , Lou Shifeng , Dai Xinyue , Yang Renchi , Zhang Lei 
Published: December 2024

Background
Bemiltenase alfa targeting factor X (FX), purified from Daboia russelii siamensis venom, is developed as a hemostatic agent for hemophilia A or B with inhibitors (HAwI and HBwI).
Methods
This is a prospective, multicenter, open-label, phase Ib/II trial evaluating the safety and efficacy of bemiltenase alfa for on-demand treatment in HAwI and HBwI patients (Clinicaltrials.gov NCT05027230). Adults (18-65 years) male HAwI and HBwI patients were enrolled to achieve multiple doses of bemiltenase alfa in stage 1 (0.10 U/kg dose cohort) and stage 2 (0.10 U/kg cohort and 0.16 U/kg dose cohort). The primary endpoints were safety and hemostatic efficacy. The secondary endpoints were pharmacokinetic (PK) and pharmacodynamic (PD) profiles, alleviation of clinical symptoms of bleeding events, and the dosage of bemiltenase alfa needed to achieve hemostasis.
Results
Between October 2021 and July 2023, 80 patients were assessed for eligibility and 70 were enrolled. The 0.16 U/kg dose group (n=37) achieved an effective hemostasis rate of 96.48% (95% confidence interval: 92.89% to 98.57%) in 199 bleeding events, while the 0.10 U/kg dose group (n=20) showed a comparable rate of 94.07% (88.66% to 97.41%) in 135 bleeding events. The clinical remission rate also showed the same trend. For bleeding events, the 0.16 U/kg cohort required fewer number of injections (1.7±0.9 vs. 2.1±1.1, respectively P&lt;0.001). Four patients in 0.16U/kg cohorts experienced grade one asymptomatic venous thromboembolisms. No drug-related serious adverse events or anti-drug antibodies were observed. PK findings showed that plasma drug concentrations increased with consecutive doses. The PD results indicated bemiltenase alfa can dramatically improve the activated partial thromboplastin time, peak height and endogenous thrombin-generating potential of thrombin generation assay.
Conclusion
Our study indicates that FX as a novel target in treating bleedings showed good efficacy. We also demonstrated for the first time that FX activator from snake venom showed good safety and strong therapeutic effect which supports its potential as a hemostatic treatment for HAwI and HBwI patients.
Generation of FcRH5xCD28 Bispecific Antibodies Synergizing with T-Cell Engagers for Enhanced Multiple Myeloma Treatment
Authors: Majocchi Sara , Moine Valéry , Magistrelli Giovanni , Gueneau Franck , Fischer Nicolas , Shang Limin , Masternak Krzysztof , Ferlin Walter Giovanni 
Published: December 2024

The approval of several bispecific T-cell engagers (TCEs) in recent years has contributed to revolutionizing the treatment of multiple myeloma (MM). However, not all patients benefit from these new treatments and acquired resistance eventually occurs. Consequently, strategies to deepen the extent of the response to TCEs in MM patients are needed.
Here we describe the generation of FcRH5-targeted CD28 bispecific antibodies (bsAbs) designed to co-stimulate T cells specifically in presence of FcRH5-positive MM cells. FcRH5 is a B-cell lineage marker whose extracellular domain (ECD) consists of 9 Ig-like domains (D1 to D9) that is often overexpressed by MM cells. Importantly, MM patients display high levels of soluble FcRH5 (consisting of ECD D1 to D8) and preferential binding of the bsAbs to membrane-bound FcRH5 via domain 9 (D9) is highly desirable to minimize the potential loss of efficacy due to the sink effect. However, the amino acid sequence of D9 shares a high degree of similarity with some of the other FcRH5 ECD domains (intramolecular similarity) and with some of the Ig-like domains present in the ECD of the other FcRH family members (intermolecular similarity). Consequently, the generation of FcRH5-specific antibodies that bind uniquely to membrane-bound FcRH5 is a challenging process.
Using our proprietary fully human κλ body antibody platform, which relies on a common heavy chain and on two distinct light chains driving specificity and affinity (i.e., one kappa and one lambda), we have identified a panel of cyno cross-reactive, FcRH5 specific (i.e., not binding to other FcRH family members) antibody arms that preferentially bind to membrane-bound FcRH5. Binding experiments using PEAK cells expressing at the cell surface the different FcRH family members or truncated version of the FcRH5 protein confirmed the desired features of the identified antibody arms. These arms were paired to an agonist (but not superagonist) anti-CD28 arm to generate FcRH5-CD28 κλ bodies capable of bridging T cells to MM cells to deliver signal 2. In the absence of signal 1, FcRH5xCD28 κλ bodies showed no sign of T cell activation, potentially limiting peripheral toxicity. FcRH5xCD28 κλ bodies strongly synergized with TCEs such as Teclistamab (BCMAxCD3 bsAb) and Talquetamab (GPRC5DxCD3 bsAb) resulting in enhanced killing of MM cell lines in in vitro T-cell dependent cellular cytotoxicity assays. Of note, in some cases, the bsAbs could even rescue the activity of TCEs (i.e. in settings where the TCEs alone displayed limited or no activity). Importantly, significant activity is retained in the presence of soluble FcRH5 in vitro. Therefore, FcRH5xCD28 bispecific antibodies have the potential to expand the number of patients who benefit from TCE-based therapies, possibly leading to deeper and more durable responses.
Tissue-Resident Double Negative T Cells Mediate Salivary Gland Damage in Chronic Oral Graft-Versus-Host Disease
Authors: Hu Ziyi , Xu Yuxi , He Yuxuan , Xu Qing , Zhou Ya , Wang Qi , Xie Xiaodong , Wang Rui , Wang Xiaoqi , Yang Shijie , Song Qingxiao , Zhang Xi 
Published: December 2024

Chronic graft-versus-host disease (cGVHD) is the most significant long-term complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The oral cavity is frequently affected, second only to the skin, with the majority of cGVHD patients complaining of xerostomia. This condition significantly diminishes patients' quality of life. The manifestations of salivary gland damage in oral cGVHD are similar to classic Sjögren Syndrome, though its pathogenesis remains poorly understood.
Our study examined the pathological features within the salivary glands of cGVHD individuals, identifying periductal infiltration, gland atrophy, and fibrosis. In three murine cGVHD models, categorized as major MHC mismatched, haplo-HSCT and miHA-mismatched GVHD models, immune cell infiltration was mainly comprised of CD8+ T cells and double-negative T cells (DNTs). Notably, these DNTs expressed various cytotoxic molecules (e.g., KLRG1, Granzyme B) and inflammatory cytokines. Furthermore, higher levels of GITR, CXCR6, PD-1, and TIM-3 were observed in DNTs compared to CD8+ T cells, suggesting a TEM/TEMRA-like phenotype with pathogenic roles in cGVHD lesion formation. The DNTs in the major MHC mismatched model exhibited Th1/Tc1 signatures with increased IFN-γ and T-bet expression, while those in the haplo-HSCT model showed Th17/Tc17 signatures with higher IL-17 expression.
We found that the development of DNTs in the salivary gland is thymus independent. Lineage tracing, single-cell RNA, and TCR-CDR3 sequencing in mice showed that GITR+ DNTs originated from Tcf-1+CD8+ T cell progenitors. Moreover, the attraction of these cytotoxic DNTs by GITR ligand (GITRL) expressed on salivary epithelial cells led to glandular damage. Triggering mGITR with anti-mGITR antibodies (DTA-1) promoted the proliferation of DNTs in a CD8+ T cell-dependent GVHD model (C3HSW to B6/SJL)
Our findings reveal that the interplay between salivary epithelial cells and donor-derived DNTs is central to the pathogenesis of salivary gland damage in oral cGVHD. Moreover, these data indicate that the mechanism of salivary gland damage in oral cGVHD differs from that of oral mucosal cGVHD, which is driven by cytotoxic CD8+ T cells.
In conclusion, targeting the GITR/GITRL signaling pathways emerges as a potential therapeutic strategy for addressing salivary gland dysfunction in oral cGVHD. This finding opens new avenues for more specific and effective treatments for patients suffering from this debilitating condition.
Clinicopathological and Gene Expression Analysis of Hyaline Vascular Castleman Disease
Authors: Nishimura Midori Filiz , Nishimura Yoshito , Iwamoto Yuika , Haratake Tomoka , Ujiie Hideki , Nishikori Asami , Habermann Thomas M. , Dispenzieri Angela , Sato Yasuharu 
Published: December 2024

Introduction:
Hyaline-vascular type unicentric Castleman disease (HV-UCD) is a classic variant of Castleman disease, characterized by localized lymph node hyperplasia. Due to its rarity, there have been few systematic reports summarizing its clinicopathological features globally. Also, its pathogenesis remains unelucidated. The present study aims to provide a detailed clinicopathological and transcriptomic analysis of HV-UCD to enhance the understanding of its underlying mechanisms at a molecular level.
Methods:
We conducted a clinicopathological analysis of 51 HV-UCD cases and performed whole transcriptome analysis on frozen lymph node specimens from four cases. Differentially expressed genes (DEGs) and Gene Ontology (GO) analyses were performed to identify significant pathways and biological processes involved in HV-UCD, with reactive lymphoid hyperplasia as control.
Results:
The mean age of HV-UCD patients was 42.8 years, with no significant gender differences. The most common sites involved were the abdominal cavity (n = 18, 35.3%), mediastinum (n = 11, 21.6%), and retroperitoneum (n = 9, 17.6%), with an average size of the lesions being 4.8 cm. Histologically, 33.3% of cases exhibited “dysplastic follicular dendritic cells (dFDCs)” characterized by multinucleation or large nuclei within and outside follicles, positive for follicular dendritic cells (FDC) markers. DEGs analysis compared to reactive lymphoid hyperplasia revealed significant upregulation of genes related to FDCs and angiogenesis. Notably, the placental growth factor (PGF), a proangiogenic factor and a member of the VEGF family, demonstrated significant overexpression. GO analysis identified significant enrichment of genes involved in angiogenesis, cell adhesion, tissue architecture, and humoral immunity.
Discussion:
This large cohort of HV-UCD cohort provides potentially novel clinicopathological insights. Gene expression analysis demonstrated increased expression of FDC-related genes, suggesting a pivotal role of FDCs in HV-UCD pathogenesis. The differences in the gene profiles related to angiogenesis may contribute to the distinct mechanisms and histological features of HV-UCD and iMCD-TAFRO, where HV-UCD is associated with hyalinization of vascular walls and iMCD-TAFRO is characterized by angiogenesis with endothelial cell swelling.
Conclusion:
The present results suggest the crucial role of FDCs in HV-UCD pathogenesis from the molecular features. Currently, there are no objective diagnostic markers for HV-UCD. Identifying these markers may lead to a clearer understanding of the disease pathophysiology and improve diagnostic accuracy for HV-UCD. Further investigation is warranted to verify the findings.
Clinical and Laboratory Characteristics of Pediatric Patients with ACKR1/Darc-Associated Neutropenia
Authors: Oz-Alcalay Lital , Steinberg-Shemer Orna , Elitzur Sarah , Brik Simon Dafna , Tamary Hannah , Izraeli Shai , Yacobovich Joanne , Gilad Oded 
Published: December 2024

Background: ACKR1/DARC-associated neutropenia (ADAN), resulting from homozygosity for a single nucleotide polymorphism (SNP) in the ACKR1/DARC gene (rs2814778), is a common cause of benign neutropenia that primarily affects individuals of African and Jewish Yemenite descent. We aimed to characterize ADAN in pediatric patients in Israel, given its ethnically diverse population.
Procedure: We assessed children with isolated neutropenia treated during 2018-2023 at one pediatric center, for the ACKR1/DARC polymorphism, using Sanger sequencing or targeted next-generation sequencing.
Results: Of 115 patients evaluated, 55 (47.8%) were diagnosed with ADAN; of these, 27 (49%) were in the severe range (neutrophil count 0-0.5X109/L). The allele distribution revealed 40.0% of Muslim Arab and 58.2% of Jewish origin. The diverse geographical range included Yemenite, Ethiopian, Mediterranean, Asian, and European ancestry. Fifty-one percent had a family history of neutropenia. The median age at the first neutropenia detection was 1.1 years; nearly 90% were identified during routine blood counts. The median absolute neutrophil count at diagnosis was 0.5X109/L (interquartile range 0.3). Patients did not show an increased susceptibility to infections either before or during the median follow-up period of 2.5 years (interquartile range 1.54) after the diagnosis of ADAN. In 42 patients (75.0%), neutrophil counts increased during febrile illnesses.
Conclusions: We identified ADAN in individuals of variable ethnicities, almost half with severe neutropenia. We recommend testing for ADAN in all children with isolated neutropenia without severe infections. This suggests that homozygosity for the ACKR1/DARC rs2814778 SNP eliminates the need for further investigation, follow-up, or treatment in this clinical scenario.
Reduction of Lactate Production By Phospholipase C Inhibition in Cold Stored Platelets
Authors: Oh Thomas T , Talackine Jennifer R , Lee Ji H , Barrera Gema D , Meledeo Michael A , Xiang Lusha 
Published: December 2024

Introduction: Anaerobic glycolysis and resultant lactic acid accumulation have been shown to impair platelet function during cold storage. The goal of current study is to understand the contribution of phospholipase C (PLC) activity to glucose utilization in cold stored platelets.
Methods: Healthy human platelets were stored in 35% plasma and 65% platelet additive solution (PAS) at 4oC for 15 days after PLC inhibitor (U73122 in 1% dimethyl sulfoxide (DMSO)). Mini aliquot storage bags (BCSI) were used to store platelets in PAS. An iSTAT blood analyzer (Abbott Point of Care) using CG4+ and CHEM8 analysis cartridges measured levels of glucose and lactate values on days 1 - 15 of storage. Five groups were included: control, DMSO vehicle, and three doses of U73122: 10, 20, and 50 µM.
Results: The mean basal level (BL) of lactic acid in the PAS was 0.31 ± 0.01 mM in control and DMSO vehicle groups on the storage day 1 and increased on day 15 of storage to 1.67 ± 0.14 mM in control (5.4-fold increase) and 1.83 ± 0.18 mM in vehicle (6-fold increase). However, lactic acid level only slightly increased to 0.96 ± 0.06 mM, 0.62 ± 0.07 mM, and 0.51 ± 0.05 mM in 10, 20, and 50 µM U73122 groups, respectively, after storage for 15 days. The BL glucose in PAS was 29 ± 0.92 mg/dl in control and DMSO vehicle groups, decreasing to 12.75 ± 2.44 mg/dl (control) and 12.14 ± 2.14 mg/dl (vehicle) after 15 days. Only mild decreases in glucose were observed 15 days after U73122 treatments (24.4 ± 1.47 mg/dl, 24.4 ± 1.94 mg/dl, and 25.2 ± 1.3 mg/dl in 10, 20, and 50 µM, respectively).
Conclusion: The dose-dependent decrease in glucose usage and lactate production with PLC inhibitor U73122 indicate that anaerobic glycolysis is being inhibited in these cold-stored platelets. This suggests that PLC may be a potential therapeutic target to alleviate acidosis and platelet storage lesions.
DoD disclaimer: The views expressed in this abstract are those of the author(s) and do not reflect the official policy or position of the U.S. Army Medical Department, Department of the Army, DoD, or the U.S. Government.