bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mortality Trends in Non-Hodgkin Lymphoma Patients with High Body Mass Index: A Comparative Study of the USA and Europe from the Global Burden of Disease Registry (1991-2021)
Authors: Bhanushali Charmi , Babu Kalaivani , Rajarajan Srinishant , Jayakumar Jayalekshmi , Kasire Sripada Preetham , Roy Arya Mariam 
Published: December 2024

Background:
Several case-control and prospective cohort studies have shown that obesity [body mass index (BMI), ≥30 kg/m²] is associated with elevated risks of non-Hodgkin lymphoma (NHL). This study aims to examine mortality trends and disability-adjusted life years (DALY) associated with high BMI in NHL; globally, in Western Europe, and within the United States (US) over the period of 1991 to 2021.
Methods:
Data from the Global Burden of Disease database, based on the International Classification of Diseases (ICD) version 10, were utilized. ICD code C85.9. was used to extract data for NHL patients. We extracted age-standardized mortality rates (ASMRs) and DALY per 100,000 population (with 95% confidence intervals) separately for both sexes, considering high BMI as a risk factor for NHL in the US, Western Europe, and globally from 1991 to 2021. Trends were analyzed using Joinpoint regression.
Results:
The US has a significantly higher ASMR compared to Western Europe (0.36, 95% CI- 0.12- 0.62 vs. 0.22, 95% CI 0.07- 0.339) and globally (0.36, 95% CI- 0.12- 0.62 vs. 0.15, 95% CI- 0.05- 0.26) for NHL patients with high BMI. Globally, ASMR showed a modest increase of 7.14% (0.14 to 0.15) from 1991 to 2021. In the US, ASMR decreased by 16.28% (0.43 to 0.36), while there was no significant change in Europe. The US also has a significantly higher DALY compared to Europe (8.78, 95% CI- 2.87- 14.92 vs. 5.47, 95% CI- 1.82- 9.53 in 2021) and globally (8.78, 95% CI- 2.87- 14.92 vs. 4, 95% CI- 1.33- 6.90 in 2021). From 1991 to 2021, DALYs witnessed a 13.31% increase globally (3.53 to 4.00), with the US showing a decrease of 26.59% (11.96 to 8.78) and Europe showing a decrease of 7.29% (5.90 to 5.47).
Sex-specific data indicated that globally, male ASMR due to high BMI-related NHL increased by 20% (0.15 to 0.18) and female ASMR by 10.15% (0.12 to 0.13). In the United States, male ASMR decreased by 11.54% (0.52 to 0.46) while female ASMR decreased by 14.69% (0.36 to 0.28). Western Europe saw no significant change in ASMR for males and females over the years. Globally, DALYs increased by 54.50% for males and 55.89% for females over the study period. In the US, DALYs increased by 5.68% in males and decreased by 3.18% in females.
Conclusion:
This study highlights significant regional differences in NHL mortality and DALY burden related to high BMI. The US shows a decreasing trend in ASMR and DALY despite global increases. However, it is to be noted that the US still has higher ASMR and DALY compared to Europe and global average. The significant disparity in ASMR and DALY between the US, Europe, and globally underscores the need for tailored public health strategies to address obesity-related NHL risks.
Efficacy and Safety of Isavuconazole in the Treatment of Invasive Fungal Disease in Patients with Hematological Disorders
Authors: Yang Nan , Pan Pan , Pang Aiming , Jiang Erlie 
Published: December 2024

Introduction:
Invasive fungal infections (IFIs) are a significant contributor to morbidity and mortality in hematological malignancies (HM) patients and stem cell transplant (SCT) recipients. The FDA approved Isavuconazole (ISA) as a primary treatment for invasive aspergillosis and mucormycosis. This study aims to investigate the practical application of Isavuconazole in patients with hematological malignancies (HM) and assess their clinical outcomes and safety profiles.
Patients & methods:
We conducted a retrospective study of patients with probable or possible mold infections who were treated with isavuconazole for a period of at least 10 days between May 2022 and May 2024. A total of 67 patients were included in the study, 20 of whom were receiving chemotherapy, and 47 who had undergone hematopoietic stem cell transplantation (HSCT). Of these, 44 were male and 23 were female, with a median age of 48 years (ranging from 34.5 to 52). Clinical and radiological assessments were carried out at baseline and at 6 and 12 weeks of follow-up.
Results:
The overall success rate was 51% (CR of 30% and PR of 21%) at 6 weeks, 75% (CR of 46% and PR of 28%) at 12 weeks. The 100-day all-cause mortality rate was 19.1%[8.71-28.3%]. Multivariate logistic regression analysis showed that persistent neutropenia, male sex and Invasive Mucormycosis were independently associated with inferior responses to ISA. Isavuconazole was used as monotherapy in 22% of the cases and in combination in 78%. Adverse events potentially related to isavuconazole were reported in three patients (4%), two of whom exhibited elevated creatinine levels, and one patient who exhibited a rash associated with isavuconazole . ISV was employed as the 1st line therapy in 16 (24%) patients and as a subsequent therapy in 51 (76%) patients.
Conclusion:
This study provides encouraging data regarding the efficacy and safety of ISA in HM patients. Neutropenia, male sex, Invasive Mucormycosis are possibly associated with inferior responses to ISA therapy.
A Novel, Universal Targeting Receptor-Adaptor CAR Platform Demonstrates Versatile, Flexible, and Controlled Tumor Inhibition in an Ipsc-Derived T-Cell
Authors: Devaney Andrew , Carton Jill , Hoffman Hunter , Millar Hillary J. , Walker David , Wheeler John , Miller Mike , Dower Chris , Morse Barry , Levitsky Hy , Naso Michael 
Published: December 2024

Despite positive outcomes in some hematological oncology patients, several barriers to current autologous CAR T-cell therapies exist that prevent broader clinical success. These include tumor antigen escape, on-target off-tumor toxicities, and limited patient access to treatment. To increase safety and efficacy of CAR T-cell therapies, we are developing a Universal CAR (UCAR) that is activated through a soluble tumor targeting protein that pairs specifically with the UCAR. The UCAR approach enables a single CAR T-cell to target many different antigens through alternative targeting proteins to address antigen escape and tumor heterogeneity. Additionally, greater control of the activity of the cells within a patient is possible since effector activity is regulated through the dosing of the soluble protein. UCAR platforms are particularly interesting for inclusion into allogeneic cell therapy products, as the combination of these technologies enables a fully universal and “off-the-shelf” cell therapy cell line.
Here, we describe the development and functional assessment of the Universal Targeting Receptor-Adaptor Platform (UTRAP), an adaptable, highly specific, and developable system comprised of a novel UCAR and a soluble Bispecific Anti-Idiotype Targeting (BAIT) protein. We demonstrate that T-cells engineered with UTRAP have tunable activity that elicits robust cytotoxicity and tumor control, equivalent to a conventional CAR T-cell in vitro and in vivo. Our results show the flexibility of the antibody-based platform including multi-specific targeting and antigen swapping. Finally, we demonstrate that UTRAP is fully functional in allogeneic iPSC-derived gamma delta T-cells. These results pave the way for UTRAP to be used in any cell type advancing towards a truly universal, off-the-shelf cell therapy product that can adapt to target any tumor type.
A Single-Center, Single-Arm, Phase I Clinical Trial of Anti-BCMA/GPRC5D Bispecific CAR T-Cells in Patients with Refractory and Relapsed Multiple Myeloma with Extramedullary Disease
Authors: Qiu Ling , Ren Shihui , He Ying , Chen Dan , Lai Sihan , Dou Baitao , Li Mengjiao , Shu Rou , Chang Alex H. , Su Yi , Yao Hao , Fan Fangyi 
Published: December 2024

Background: Despite the promising outcomes of chimeric antigen receptor (CAR) T-cell therapy in treating relapsed or refractory multiple myeloma (RRMM), addressing extramedullary disease (EMD) in this context remains a therapeutic challenge. This study aimed to evaluate the safety, efficacy, and activity of anti-BCMA/GPRC5D bispecific CAR T-cells in RRMM patients with EMD.
Methods: A Phase I, single-arm, open-label clinical trial was conducted at the Western Theater Command Hospital of the Chinese People's Liberation Army. Eligible patients were RRMM adults aged 18-75 years with ECOG performance status 0-3 and EMD. Patients received escalating doses of anti-BCMA/GPRC5D bispecific CAR T-cells, starting at 1.0×10⁶ CAR T-cells per kg. The primary endpoints were safety and efficacy, while secondary endpoints encompassed assessment of activity. Safety and activity analyses encompassed all patients who received the CAR T-cell product per protocol. The study protocol was approved by the institutional ethics committee (2024EC1-ky033).
Results: Between July 2023 and May 2024, nine patients with RRMM and EMD were enrolled and underwent leukapheresis. Three patients were subsequently excluded due to rapid disease progression. Six patients received the anti-BCMA/GPRC5D bispecific CAR T-cell infusion. With a median follow-up of 6.5 months (IQR 2-12), the median age was 58 years (IQR 48-67), and the cohort included three males (50%) and three females (50%). Genetic risk factors were present in three patients, undetected in two, and absent in one. The maximum tolerated dose was established as 2.0×10⁶ CAR T-cells per kg. Hematological toxicity, excluding lymphopenia, was the most frequent grade 3 or higher adverse event (100%). Cytokine release syndrome (CRS) occurred in 62.5% of patients, all of which were grade 1 or 2. The overall response rate (ORR) among evaluable patients was 100%, with three patients (50%) achieving complete response (CR), including one with subsequent disease progression. One patient (17%) achieved very good partial response (VGPR), and two (33%) achieved partial response (PR), both of whom subsequently died due to disease progression.
Conclusion: The findings of this Phase I trial suggest that anti-BCMA/GPRC5D bispecific CAR T-cell therapy may represent a promising therapeutic option for patients with refractory and relapsed multiple myeloma complicated by extramedullary disease. Further investigation in larger, controlled trials is warranted to confirm these preliminary observations and refine treatment strategies.
Analysis of Anxiety and Depression Status and Influencing Factors in Multiple Myeloma Patients
Authors: Gao Mengran , Zhang Wei , Fu Rong 
Published: December 2024

OBJECTIVE
To explore the incidence and influencing factors of anxiety and depression in multiple myeloma patients. METHODS: 509 patients with multiple myeloma in the Department of Hematology, General Hospital of Tianjin Medical University from September 2021 to March 2024 were selected for the study. The Generalized Anxiety Disorder Scale (GAD-7) and Depression Self-assessment Scale (PHQ-9) were used to assess the patients' anxiety and depression, and the Verbal Pain Rating Scale ( VPRS ) and Total Neuropathy Scale Reduced (TNSr) were used to assess the degree of pain and peripheral neuropathy. Clinical data such as patients' personal information, laboratory tests, DS/ISS/RISS staging, treatment line, and efficacy assessment were improved to analyze the incidence and influencing factors of anxiety and depression in patients with multiple myeloma. RESULTS: The incidence of anxiety and depression in patients with multiple myeloma was 22.2% and 31.4%, respectively . Comorbid pain and/or peripheral neuropathy were independent risk factors for the development of anxiety and depression and were significantly associated with the severity of both. CONCLUSION: The incidence of anxiety and depression in patients with multiple myeloma is high, and clinicians should pay attention to the rational intervention of pain and peripheral neurologic symptoms and the early assessment of emotional problems during the peri-therapeutic period of patients!
Rituximab, Lenalidomide, and Zanubrutinib (ZR2) with Sequential CAR-T Cell As First-Line Therapy for High-Risk Large B Cell Lymphoma
Authors: Zhang Mingming , Hu Yongxian , Wei Guoqing , Fu Shan , Feng Jingjing , Hong Ruimin , Chang Alex H. , Huang He 
Published: December 2024

Introduction
CAR-T cell therapy has made a breakthrough in refractory or relapsed large b cell lymphoma (LBCL), but data as a first-line therapy is still scarce. ZUMA-12 study showed significant efficacy of CAR-T cell as first-line therapy for high-risk LBCL. However, some patients have difficulty tolerating chemotherapy prior to CAR-T cell therapy, especially elderly and frail patients. Here we report the results of rituximab, lenalidomide, and zanubrutinib (ZR2) with sequential CAR-T cell as first-line therapy for high-risk LBCL.
Methods
We conducted a single-group trial of first-line therapy in adults with newly diagnosed high-risk LBCL. High risk LBCL included high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 translocations, HGBL not otherwise specified, and DLBCL not otherwise specified with an IPI score of ≥3. Patients received two cycles of ZR2 (rituximab 375 mg/m2 intravenous once on day 1, lenalidomide 25 mg once per day on days 1-21, and zanubrutinib 160 mg twice daily continuously of each 28-day cycle), and those with efficacy assessment of partial response or stable disease received sequential CD19 CAR-T cell therapy. The primary endpoint was complete remission (CR) rate after CAR-T cell therapy. Here we report initial results from this study.
Results
At the cut-off date of 31 June 2024, 23 patients were enrolled. The median age was 68.5 (range 50-84) years old. All the 23 patients finished 2 cycles of ZR2 which was well tolerated. Among them, 18 patients have received sequential CD19 CAR-T cell therapy. During CAR-T cell therapies, only 5 grade 1 cytokine release syndrome was observed, and no grade 2 or higher cytokine release syndrome or Immune effector cell-associated neurotoxicity syndrome was observed. The most common adverse events were hematological, which were thought to be associated with lymphodepleting chemotherapy and recovered in a short time without blood transfusion. After CD19 CAR-T cell therapy, 17/18 (94.4%) patients achieved CR. One patient with stable disease after CAR-T cell therapy received several lines of salvage chemotherapy, and finally achieved CR. After a median follow-up of 24 months, 2 patients experienced disease relapse at 6 and 16 months after CAR-T cell therapy, respectively. Both 2 patients received chemotherapy of RCHOP, and achieved CR again. As of date cut-off, all the 18 patients after CAR-T cell therapy remained in CR. The overall survival rate was 100% and the progression free survival rate at 1 year was 85.7%.
Conclusions
ZR2 with sequential CAR-T cell therapy has enabled chemo-free treatment in newly diagnosed high-risk LBCL. This treatment is characterized by high CR rate, high long-term survival, and low toxicity.
IGF2BP1 Orchestrates Post-Transcriptional Control of Globin Switching through Direct Binding to Globins and Their Regulators
Authors: Coyne Steven , Wu Ting , Vinjamur Divya , Hossain Mir , Bauer Daniel E. 
Published: December 2024

Despite over a century of work on hemoglobinopathies, a comprehensive understanding of hemoglobin switching and factors regulating hemoglobin expression remains incomplete even as the first CRISPR/Cas9 gene therapy has obtained approvals for the treatment of transfusion-dependent β-thalassemia and sickle cell disease.
We studied factors related to the heterochronically silenced m6A RNA-binding protein IGF2BP1 which has been identified as a positive regulator of fetal hemoglobin expression by directly suppressing BCL11A expression. In contrast to this observation, post-transcriptional control by IGF2BP1 generally acts through improving the translation and mRNA stability of IGF2BP1 target mRNAs in an m6A-dependent manner. To better characterize the IGF2BP1-mediated mechanism responsible for control of fetal hemoglobin expression, we assessed whether BCL11A was required for IGF2BP1-mediated regulation of fetal hemoglobin and discovered a direct BCL11A-independent mechanism. Additionally, we characterize a heretofore poorly understood BCL11A-dependent mechanism for IGF2BP1 in regulating fetal hemoglobin expression.
We developed a luminescent transgenic reporter to disentangle BCL11A-dependent and newly identified BCL11A-independent mechanisms and used this system to discover that IGF2BP1 directly supports the translation of HBG mRNA in a manner requiring intact stop codon-proximal m6A motifs which are absent from the HBB mRNA.
Hemoglobin switching relies on a set of heterochronically regulated transcription factors, miRNAs, and RNA-binding proteins. This work identifies a novel mode of direct post-transcriptional regulation of HBG mRNA by a heterochronically regulated RNA-binding protein, IGF2BP1, that was previously described to regulate HBG indirectly via BCL11A. This work shows that HBG mRNA is bound directly by IGF2BP1 which supports HBG translation. HBB, not normally directly regulated by IGF2BP1, becomes responsive to IGF2BP1 overexpression upon addition of the HBG-derived stop codon-proximal m6A sites to an HBB transgene, a strategy with potential to be exploited for the improved expression of globin transgenes for hemoglobinopathy gene therapy.
Real-World Use and Outcome of Ropeginterferon ALFA-2B in Polycythemia VERA Patients: A Multicenteric Study
Authors: Pugliese Novella , Di Perna Maria , De martino Ugo , Amico Valeria , Annunziata Mario , Martorelli Maria Carmen , Abagnale Davide Pio , Russo Roberta , Ferrentino Maria , Scarpa Alessia , Muriano Francesco , Martinelli Vincenzo , Pane Fabrizio 
Published: December 2024

Ropeginterferon alfa-2b (Ropeg) emerges as a novel, long-lasting mono-pegylated IFN approved in Italy for treating polycythemia vera (PV) in adult patients without symptomatic splenomegaly and reimbursed for PV patient intolerant to hydroxyurea (HU), women of childbearing potential, and individuals with a history of skin cancer (SC).
Ropeg proved effective and safe in phase 3 trials, but more data is needed to understand its real-world use.
The study collected clinical data to assess the safety and efficacy of Ropeg in PV patients across five hematological centers in Campania. Ropeg was administered as per the data sheet, complete hematological response (CHR) was evaluated according to ELN criteria. Additionally, HCT, PLT, WBC and molecular responses were analyzed separately.
A total of 47 PV patients were enrolled, with a median age at Ropeg start of 60 years (range 28-90), and 70% (33/47) were male.
Thirty patients switched from prior HU after a median time of 11.8 months (range 1-299), due to intolerance. Three patients also transitioned from ruxolitinib, and one from peg-IFN. Ropeg was used as first-line therapy for 3 women of childbearing age, 2 patients with prior SK, and 8 male patients who were intolerant to phlebotomies and declined HU. The median time from PV diagnosis and Ropeg initiation was 45 months (range 1-345). In the year prior to starting Ropeg, the median number of phlebotomies was 2 (range 1-5). The median time on Ropeg was 12 months (range 1-21), with the median starting dose being 125 mcg every two weeks (range 50-150). At 12 months CHR rate was 64.7% for the 17 evaluable patients, HCT response was 82.4%. Ten patients (21.2%) required additional phlebotomy sessions during the treatment. At the same time point PLT and WBC responses were 82.4% and 100%, respectively and all but one had JAK2V617F allele burden reduction. CHR rate, HCT, PLT and WBC response increased over treatment as well as the median Ropeg dose that at 12 months was 200 mcg (range 100-250).
Three patients had grade 1 liver function test increases, which resolved after dose reduction, and one patient developed autoimmune thyroiditis without discontinuing treatment. After three months, four patients discontinued Ropeg for the following reasons: suspected Ropeg-related depression, gastrointestinal bleeding, worsening splenomegaly, autoimmune disease; one patient died from an unrelated cause.
Our findings indicate that Ropeg is generally well-tolerated and shows improvements in hematologic parameters. Although some response rates may vary, the overall trend is positive, with several measures reaching complete or near-complete response over time.
Immunomodulatory Effects of MEK Inhibition in Multiple Myeloma
Authors: Acharya Chaitanya , Jayasinghe Reyka G. , Hamilton Mark , Gnjatic Sacha , Kim-Schulze Seunghee , Cho Hearn Jay , Kumar Shaji , Mulligan George 
Published: December 2024

Introduction
As part of the Multiple Myeloma Research Foundation (MMRF) MyDRUG umbrella clinical trial, we compared immune cell transcriptomic and proteomic signatures of multiple myeloma bone marrow samples from patients assessed by single-cell RNA sequencing (scRNA-seq) and mass cytometry (CyTOF). The goal of our study is to evaluate the effects of cobimetinib on the immune repertoire over the treatment course at single-cell resolution.
Methods
Bone marrow samples were collected from patients prior to therapy with cobimetinib (baseline/BL), after 2 cycles of cobimetinib therapy (EOC2), after 2 cycles of combination cobimetinib with IPd (EOC4) and at the end of treatment or at disease progression (EOT). All samples were processed into CD138+ myeloma cell and CD138- “immune cell” fractions for single-cell analysis. In this study, the CD138- “immune cell” fractions were transcriptionally profiled by single-cell RNA-sequencing (scRNA) at up to four time points.
Results
Transcriptome profiles of approximately 50,000 cells were analyzed across 22 samples from 9 patients with tumor MAPK Pathway mutations including: BRAF (p.K483Q, p.V600E, n=2); KRAS (p.Q61H, p.G12V, p.G12R, n=3); NRAS (p.Q61H, p.Q61R, p.Q61K, n=4). A subset of paired samples were subject to CyTOF with two immune related panels to supplement the single-cell transcriptomic findings. Focusing on one immune panel, 4 samples were profiled at baseline and end of cycle 2 while two samples were profiled only at baseline capturing over 600,000 cells spanning both timepoints. Our immune focused CyTOF panel contained 41 markers including T and NK cell markers (CD4,CD8A,CD3, GZMB, CD56), Myeloid lineage markers (CD14), B/Plasma markers (CD19, CD20, SLAMF7, CD38) among others. The largest populations captured by CyTOF included 260,000 neutrophils, 139,000 monocytes, 130,000 CD4/CD8 T cells, 43,000 NK cells, 40,000 dendritic cells and 22,000 B/plasmablasts/myeloma cells. Exhaustion markers, including LAG3 and TIGIT, are increased in CD8 and CD4 T cells after MEK inhibition, while PD1 is downregulated. PD-L1 is upregulated in both T cell compartments (CD4/CD8), monocytes and in residual myeloma cells profiled by both CyTOF and scRNA-seq. Both the IFNG and STAT1 pathways are concurrently upregulated post MEK inhibition in transcriptionally distinct CD8 T cell subsets profiled by scRNA-seq, suggesting a mechanism influencing PD-L1 expression.
Conclusions
These data indicate IFNG pathway activation by CD8+ T cells post MEK inhibition promotes PD-L1 expression on residual myeloma cells, suggesting the PD-L1 and IFNG signaling axes is activated in relapsed refractory myeloma patients after MEKi treatment. Here we present immunophenotypic and transcriptional profiling of longitudinal samples pre/post-MEK inhibition with multiple myeloma patients which can inform precision guided treatment options.