bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Hospital-Acquired Venous Thromboembolism on Surviving Medical Admission: Findings from the Medical Inpatient Thrombosis and Hemostasis Study
Authors: Martin Karlyn A. , Sparks Andrew , Wilkinson Katherine , Packer Ryan , Terrell Deirdra R , Gergi Mansour , Ferraris Augusto , Wood William A. , Repp Allen B , Roetker Nicholas S , Zakai Neil 
Published: December 2024

Introduction
Approximately 200,000 venous thromboembolism (VTE) events occur each year during or within 3 months after medical (non-surgical) hospitalizations in the U.S. The consequences of hospital-acquired VTE (HA-VTE, VTE occurring while hospitalized), such as likelihood of dying during admission, are unknown. The objective of this study was to examine the association between HA-VTE and risk of in-hospital mortality.
Methods
Adults admitted to medical services for at least 1 midnight at one of 5 hospital systems from 2016-2022 were included. Admissions for primary diagnosis of VTE were excluded. Each admission with HA-VTE was matched with up to 4 admissions without HA-VTE based on day of hospitalization, age (± 5 years), sex, race and ethnicity, hospital system, level of care (medical services versus intensive care unit [ICU]), calendar year, and COVID-19 status at admission. The primary outcome was in-hospital mortality. We used conditional logistic regression to estimate the association of HA-VTE with in-hospital mortality, adjusting for the matching factors, anticoagulation level at admission (therapeutic, prophylactic, or none), and the Elixhauser Comorbidity Index. We tested whether the association varied by COVID-19 status.
Results
The matched cohort included 2,061 medical admissions with HA-VTE and 7,908 medical admissions without HA-VTE. In the matched admissions, the mean age was 58 years (SD 16), 57.1% identified as male, 54.5% as White race, 26.6% as Black race, 24.0% were admitted to an ICU, and 10.8% were admitted with COVID-19. The mean Elixhauser Comorbidity Index score was 14.3 (SD 18.4) and 12.2 (SD 17.3) in admissions with and without HA-VTE, respectively. In-hospital mortality occurred in 12.4% of HA-VTE admissions and 5.1% of non-HA-VTE admissions. Compared to non-HA admissions, the adjusted odds ratio (OR) for in-hospital mortality with HA-VTE was 2.71 (95% confidence interval [CI] 2.23, 3.29). The association of HA-VTE with in-hospital mortality was similar for admissions with COVID-19 (OR 2.93; 95% CI 2.33, 3.70) and admissions without COVID-19 (OR 2.18; 95% CI 1.49, 3.18; pinteraction = 0.12).
Conclusions
HA-VTE was associated with a nearly 3-fold increased odds of death during hospitalization in a diverse patient cohort from 5 hospital systems. While increased illness severity may account for some of the increased mortality risk, HA-VTE itself or interventions to treat HA-VTE (anticoagulation) likely contribute. Efforts should be made to understand whether reducing HA-VTE can translate to decreased mortality.
First-in-Human Trial of BCMA-CD19 Compound CAR (cCAR) in Desensitization of Donor-Specific Anti-HLA Antibodies (DSAs) in Haploidentical Stem Cell Transplant Recipients
Authors: Liu Fang , MA Yu , LI Yecheng , Pinz Kevin G. , Wang Xiao , Wada Masayuki , Ma Yupo 
Published: December 2024

Background: DSAs are recipient antibodies targeted against donor class I/II human leukocyte antigens (HLAs). The existence of DSAs before HLA haploidentical hematopoietic stem cell transplantation (haplo-HCT) is known to cause primary graft failure. Currently there is no established method of DSA desensitization. cCAR targets the “root cause” of DSA production, B cells and plasma/long-lived plasma cells, and thus may achieve desensitization through a dual reset of humoral and B cell immune system.
Aims:We present the safety and efficacy of cCAR, which targets antibody- producing “root cause”, B cells and plasma/long-lived plasma cells in our first-in-human clinical trial.
Methods:cCAR is comprised of a complete BCMA CAR fused to a complete CD19 CAR, separated by a self-cleaving P2A peptide. CAR T cells were manufactured in a cGMP facility.
Beginning May 2019 through October 2020, 4 haplo-HCT candidates with high titer of DSA (MFI&gt;5000） were enrolled in this study. All patients received conditioning with fludarabine (30 mg/m2/d) and cyclophosphamide (300 mg/m2/d). CAR T cells were given by dose escalation at 2～4.5×106/kg with a single dose.
The primary endpoint is to evaluate toxicity of cCAR and the second endpoint is to observe the reduction of DSA after cCAR therapy and engraftment post-haplo-HCT.
Results:The median patient age was 35 years (range, 21～48). All were female; 2 with acute myeloid leukemia (AML), 1 with acute lymphocytic leukemia (ALL) and 1 aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH). All donors were from haploidentical family members.
Cytokine release syndrome (CRS) occurred in 3 patients, all grade 1, and resolved within 3～8 days after supportive care or administration of low dose steroids. No neurotoxicity occurred. One patient suffered grade Ⅳ cytopenia which resolved in 2 weeks. No other toxicity occurred.
All patients demonstrated B cell and plasma cell depletion at 4 weeks post-cCAR infusion. The average median fluorescence intensity (MFI) value was 82187 (range, 7820～249840) and 2995 (range, 0～4343) before and after cCAR therapy, respectively.
All patients received a haplo-HCT within 49～135 days and achieved successful engraftment with full chimerism. The median time for neutrophil and platelet engraftment was12 and 13 days, respectively.
Conclusion:Our first-in-human clinical trial of cCAR demonstrated profound efficacy in reducing DSA levels in haplo-HCT candidates. Remarkable depletion of antibody-producing “roots cause”, B cells and plasma/long-lived plasma cells was observed in all patients. Our results suggest cCAR has the potential to benefit patients receiving solid organ transplants or those with other antibody-mediated diseases.
Chromatin Remodeling By GATA1s Alters Megakaryocytic Gene Expression
Authors: de Castro Carini Picardi Morais , Martínez-Cebrián Gerard , Quijada-álamo Miguel , Freed Grace , Lorenzi Lucía , Malinge Sébastien , Wagenblast Elvin , Cuartero Sergi 
Published: December 2024

The GATA1 transcription factor is crucial for the regulation of gene expression during the differentiation of hematopoietic progenitors to erythrocytic and megakaryocytic lineages. Mutations in GATA1 are pervasively found in myeloid leukemia of Down syndrome (ML-DS), a subtype of acute myeloid leukemia that is common in children with Down syndrome. These mutations typically occur in the N-terminal region of the GATA1 gene and lead to the production of a truncated isoform known as GATA1s, which retains the DNA-binding capacity. Expression of the truncated form GATA1s disrupts normal hematopoietic differentiation and leads to the over-production of megakaryocytic progenitors in the fetal liver. In Down syndrome children, this results in a non-lethal blood disorder known as transient abnormal myelopoiesis (TAM), which in many cases progresses to myeloid leukemia.
Our study investigates the impact of the GATA1s isoform on megakaryopoiesis and its underlying molecular mechanisms. We use mouse hematopoietic progenitors and CRISPR-edited human HSPCs and perform transcriptomic and epigenomic analyses to understand how GATA1s differentially controls megakaryocytic gene expression. Our findings indicate that the expression of GATA1s promotes a premature increase of megakaryocyte-specific transcription already in hematopoietic stem cells. The upregulation of megakaryocyte markers is observed in HSCs from both fetal liver and adult bone marrow, though with varying effects across subpopulations. Moreover, the response to megakaryocyte-inducing acute stressors, such as interferon, differs between cells expressing GATA1 and those expressing GATA1s. Despite this early bias, GATA1s-expressing cells show incomplete differentiation into megakaryocytes in culture. ChIP-seq of normal and mutant GATA1 shows that despite both isoforms bind to a majority of shared binding sites, a fraction of these sites is isoform-specific. This is linked to changes in chromatin accessibility, which present different dynamics of gain and loss along megakaryocyte differentiation and which are associated to the number of GATA1 motifs on DNA. Furthermore, Hi-C analysis of global chromatin interactions shows changes in long-range genomic interactions associated to the deregulation of Mk-specific transcripts.
In summary, our work illustrates how GATA1s disrupts normal megakaryopoiesis by inducing early lineage bias and impairing differentiation through remodeling of the chromatin landscape and gene expression. These findings enhance our understanding of GATA1s-related disorders, such as myeloid leukemia of Down syndrome, and may guide future therapeutic strategies.
Characterization of Linvoseltamab's BCMA Binding Epitope and Efficacy Against BCMA Mutations in Relapsed/Refractory Multiple Myeloma
Authors: Lee Ken , Zhou Yi , Franklin Matthew , Ullman Erica , Hermann Aynur , Kroog Glenn S. , Boyapati Anita , Rodriguez Lorenc Karen , Smith Eric , Lin John , Olson William , Sirulnik Leonardo Andres , Olson Kara 
Published: December 2024

Patient outcomes in relapsed/refractory multiple myeloma (RRMM) have improved significantly with the adoption of BCMA targeted CAR-T and CD3 bispecific antibodies (bsAb). However, despite improvements in MM therapies, relapse remains an issue. Recent data from patients who relapsed following treatment with approved BCMAxCD3 bsAbs led to the identification of rare mutations in the extracellular domain of BCMA that can negatively impact the binding and cytotoxic activity of these molecules in vitro (Lee, H., et al, Nat Med. 2024). Linvoseltamab is a fully human BCMAxCD3 bsAb that demonstrated high and durable responses in RRMM. Here we characterize the binding epitope of linvoseltamab and evaluate its binding and activity on cells with identified BCMA mutations.
A 3.4 Å cryo-EM structure of the linvoseltamab Fab fragment bound to the BCMA extracellular domain shows that linvoseltamab features a long heavy chain CDR3, stabilized by a disulfide bond, which plays a major role in binding by inserting into a groove on the surface of BCMA. Linvoseltamab contacts a total of 16 BCMA residues which largely overlap with the reported epitopes of teclistamab and elranatamab (Lee, H., et al, Nat Med. 2024; Josic, M., et al, ASCO 2024). However, linvoseltamab also binds to the very N-terminal end of BCMA, suggesting that it is tilted toward the BCMA N-terminus with a distinct binding orientation.
Binding assays on cells expressing wild-type or mutant BCMA variants demonstrated that, unlike teclistamab and elranatamab, the BCMA R27P mutation had minimal impact on linvoseltamab binding. Additionally, utilizing a Jurkat NFAT-luc reporter assay system which measures BCMAxCD3 specific activation of T-cells, linvoseltamab mediated potent NFAT-luc activation in the presence of cells expressing BCMA-R27P. While the structural analysis showed linvoseltamab contacts BCMA R27, it is located at the edge of the binding interface and thus appears to not be crucial for binding. In addition, BCMA P33 does not contact linvoseltamab, consistent with the observation that the P33S mutation has no effect on linvoseltamab binding or activity. Cell binding and functional reporter bioassay and primary T cell cytotoxicity studies are underway for additional reported BCMA mutations.
This studyidentified a unique binding orientation for linvoseltamab and demonstrated that linvoseltamab retains its binding and functional activity even in the presence of an identified BCMA mutation (R27P) that negatively impacts other BCMAxCD3 bispecific antibodies. This suggests that linvoseltamab may be less susceptible to resistance mechanisms that involve these mutations, resulting in improved patient outcomes.
Optimal Duration of Anticoagulation for Unprovoked Venous Thromboembolism: A Threshold Decision Analysis Model
Authors: Youkhana Kimberley , Greenberg Charles , Djulbegovic Benjamin 
Published: December 2024

Background: The optimal duration of long-term anticoagulation (AC) following an unprovoked venous thrombosis event (VTE) after the initial 3-6 months is unknown. Despite the providers careful consideration of the bleeding risk, probability recurrence off AC, and the patient's values and preferences (VP) about avoiding a recurrent VTE and bleed, the final decision remain subjective. When presented with the same patient, multiple providers may make different recommendations about the duration and intensity of AC. Using threshold decision analysis to model the effects of extended AC treatment we created and tested a model that quantifies the recommendations of the American Society of Hematology (ASH) thrombophilia for long-term AC over 10 years (10 Pr(VTE)).
Methods: We developed a threshold decision model incorporating VTE recurrence risk, AC efficacy, bleeding risks, and patient values and preferences (V&P). Key parameters included:
- VTE risk: 10% in year 1, then 5%/year
- AC efficacy: Relative Risk Reduction (RRR) = 0.85 [0.77 to 0.9]
- Bleeding risk: Low (0.5%/year) and High (1.5%/year)
- Major bleeding on AC: RR 2.17
- Relative value (RV): patient's weighting of VTE vs. bleeding risk
Results: The model calculates a threshold probability (T) at which AC benefits equal bleeding harms. AC is recommended when the probability of VTE without treatment (Pr(VTE)) exceeds the risk of bleeding. In most scenarios, the 10 Pr(VTE) consistently exceeded T, favoring long-term AC. This held true across various RV assumptions (RV=0.5, 1, 2) for both low and high bleeding risk scenarios. The only exception was in the high bleeding risk, worst-case scenario, where patients valuing avoiding bleeding twice as much as VTE (RV=2) might opt against long-term AC.
Conclusions: Based on current evidence of AC efficacy, bleeding risks, and estimated VTE recurrence rates, long-term AC appears to be the optimal management strategy for most patients with unprovoked VTE. Only in cases of high bleeding risk combined with strong patient preference for avoiding bleeding (RV&gt;2) might discontinuation of AC be considered.
This model provides a framework for personalized decision-making, considering individual patient risks and preferences in determining the optimal duration of AC for unprovoked VTE.
Zanubrutinib Combined with R-CHOP in Patients of Newly Diagnosed DLBCL with p53 Expression: A Single-Arm Prospective Study
Authors: Zhang Liling , Li Qiuhui , Zhu Fang , Wu Gang , Chang Xiaona , Pan Huaxiong , Liu Tao , Liu Xinxiu 
Published: December 2024

Introduction: p53 expression is associated with treatment failure and poor prognosis of diffuse large B-cell lymphoma (DLBCL). Bruton's tyrosine kinase (BTK) is a novel regulator of p53 activity and is involved in the cellular response to DNA damage. BTK inhibitors have shown high efficacy in mantle cell lymphoma and chronic lymphocyte leukemia with p53 alterations, and refractory and relapsed DLBCL. This study explored the efficacy and safety of zanubrutinib, a BTK inhibitor, combined with R-CHOP (ZR-CHOP) in patients of newly diagnosed DLBCL with p53 over-expression.
Methods: Newly diagnosed DLBCL patients with positive p53 protein expression (immunohistochemistry staining ≥50% of cells) were enrolled at the Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from April 2022 to July 2024. ZR-CHOP regimen (zanubrutinib: 160 mg, bid, D1-21; rituximab: 375 mg/m², D1; cyclophosphamide: 750 mg/m², D2; doxorubicin: 50 mg/m², D2; vincristine: 1.4 mg/m², D2; prednisone: 100 mg/d, D2-D6) was administrated every 21 days for a total 6 cycles. Efficacy was evaluated using PET-CT/enhanced CT per Lugano 2014 criteria. The primary endpoint was the complete response rate (CRR), and secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs).
Results: A total of 16 patients were enrolled in the study until July 2024. The median age at diagnosis was 56 years (range 34-67), with 7 patients (43.7%) in Ann Arbor stage III-IV, 2 patients (12.5%) with an ECOG score ≥2, 8 patients (50.0%) with IPI score ≥2, and 5 patients (31.3%) with extranodal involvement. There were 13 cases (81.3%) of double expression of MYC and BCL2, and 15 cases (93.8%) of the non-GCB subtype. By the end of the follow-up period in July 2024, 14 patients were evaluable for efficacy, with an ORR of 100%. 12 patients (85.7%) achieved CR, and 2 patients (14.3%) achieved partial response (PR). With a median follow-up of 11.8 (0.5-20) months, the 1-year PFS and OS rates were 93.8% and 100%, respectively. In terms of safety, common grade 3-4 adverse events included anemia (4 cases), leukopenia (5 cases), neutropenia (4 cases), thrombocytopenia (1 case), and pulmonary infection (2 cases). There were no new safety signals observed.
Conclusions: The ZR-CHOP regimen is highly effective and safe for p53 over-expressed newly diagnosed DLBCL. It shows promise in improving the outcomes of p53-positive DLBCL patients.
Travel Time from Cancer Center Is Associated with Disparities in Non-Hodgkin Lymphoma Diagnosis Among People Living with HIV in Malawi
Authors: Harrington Meagan , Chirwa Amon , Kasonkanji Edwards , Simwinga Lusayo , Mumba Noel , Chikasema Maria , Kumwenda Phaleda , Painschab Matthew S , Fedoriw Yuri D. 
Published: December 2024

Purpose: Kamuzu Central Hospital (KCH) in Lilongwe, Malawi, serves a population of around ten million from the country's Central and Northern regions. As one of just two centers in the country providing pathology and cancer care, the majority of the population is left with the burden of traveling long distances for diagnosis and treatment. HIV-associated non-Hodgkin lymphoma (NHL) is common in sub-Saharan Africa (SSA) due to the high prevalence of HIV in the region. Spatial barriers to care, particularly in relation to travel time, are not well defined in adults with HIV-associated malignancies in Malawi.
Methods: We included all patients with HIV-associated NHL from the KCH Lymphoma Study, a prospective observational cohort, from June 2013 to June 2023 (n=117). The location of study patients' residence was mapped using QGIS with further descriptive and survivorship analyses, including demographic and clinical characteristics, conducted in R. AccessMod 5 was used to produce models of travel time to KCH, using assumptions from previous literature.
Results: The diagnoses included in this analysis were diffuse large B cell lymphoma (DLBCL) (n=79), Burkitt lymphoma (n=22), plasmablastic lymphoma (n=13), and primary effusion lymphoma (n=3). Estimated travel time to clinic varied significantly (range: 20-618 minutes). 48% of patients were from Lilongwe district which makes up only 10% of the population of the catchment area. We noted a significant negative relationship between mean travel time to KCH and reported incidence of HIV-associated malignancies (correlation= -0.015; p=0.009). Travel time varied significantly when disaggregated by HIV status, with HIV+ART- individuals tending to be resident closer to the cancer center than HIV- or HIV+ART+ patients (p=0.005). In addition to disparities in diagnosis, HIV-associated NHL patients had worse progression-free survival as travel time to clinic increased (p=0.02), which remained significant after controlling for known prognostic markers including stage, performance status, and lactate dehydrogenase.
Conclusion: Cancer care in Malawi is centralized, leading to diagnostic and treatment disparities. NHL patients who live further from KCH tend to face more challenges accessing diagnosis and treatment, particularly if they have comorbidities, such as HIV. Interestingly, the HIV+ ART- group tended to come from closer to KCH than other groups, implying that patients with curable lymphomas in more remote parts of the country are likely dying before they can be diagnosed and treated. Implementation science approaches are urgently needed to close the gap on both diagnostic and treatment disparities.
Identification of Ikaros As Novel Interaction Partner of Cyclin D1/CDK4 in MCL
Authors: Sun Xiaoyang , de Bra Stephan , Schmitz Tatjana , Tholen Stefan , Andrieux Geoffroy , Martens Uta Sabine Sabine , Boerries Melanie , Schilling Oliver , Duyster Justus , Miething Cornelius 
Published: December 2024

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by cyclin D1 (CycD1) overexpression. CycD1 physiologically works as a cell cycle regulator in conjunction with CDK4/6, inducing cell cycle progression in G1/S phase. The role of CycD1 in oncogenesis is manyfold, including promoting proliferation, regulating DNA damage response and controlling migration and invasiveness, but many of the interacting proteins and the functional mechanisms underlying their interaction remain unexplored. We therefore aimed to systematically screen for novel CycD1-interacting proteins in MCL using proximity-dependent biotin identification (BioID).
Using an MCL mouse model based on the cooperation of CycD1 and c-myc, we established lymphoma lines from mice expressing CycD1 linked to a bacterial biotin ligase BioID2. The approach enables covalent biotinylation of proteins closely interacting with CycD1 after the addition of biotin. After optimization of the labeling procedure, CycD1-interacting proteins in the MCL cell line were tagged and enriched by streptavidin pull-down, followed by mass spectrometry analysis. The association of CycD1 with candidate proteins was verified by co-immunoprecipitation (Co-IP) and immunofluorescence co-localization and investigated functionally by shRNA knockdown and inhibitor treatment.
Among other candidates, we found the transcription factor Ikaros (Ikzf1) to be specifically interacting with CycD1. The interaction in a complex consisting of CycD1, CDK4, and Ikaros was verified by Co-IP in human MCL (hMCL) cells, and CycD1 and Ikaros were found to co-localize in the cell nuclei of hMCL cells. Knockdown of Ikaros and treatment with the Ikaros degrader lenalidomide and also the novel degrader CFT7455 induced apoptosis, G1-phase arrest and decreased CycD1 expression, indicating a direct effect of Ikaros on CycD1 levels. In ongoing experiments, we observed that CDK4 inhibition may affect the phosphorylation of specific amino acids in Ikaros, altering the nuclear localization and transcriptional activity of Ikaros.
In summary, we identified Ikaros as a novel interaction partner of CycD1/CDK4 in MCL. Our results indicate that Ikaros can transcriptionally regulate and stabilize CycD1, and in turn, CycD1-CDK4 may phosphorylate Ikaros and affect Ikaros transcriptional activity. This feedback loop may play an important role in the pathogenesis of MCL and could serve as a novel potential therapeutic target in MCL.