bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post-Transplant Cyclophosphamide or ATG As Gvhd Prophylaxis in Mismatched Unrelated Stem Cell Transplantation? - a Registry Analysis By the EBMT Transplant Complications Working Party
Authors: Penack Olaf , Abouqateb Mouad , Peczynski Christophe , Boreland William , Gulbas Zafer , Gedde-Dahl Tobias , Castilla-Llorente Cristina , Kröger Nicolaus , Eder Matthias , Rambaldi Alessandro , Bonifazi Francesca , Wolfgang Blau Igor , Stelljes Matthias , Dreger Peter , Moiseev Ivan Sergeevich , Schoemans Helene , Koenecke Christian , Peric Zinaida 
Published: December 2023

There is an increased risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when mismatched unrelated donors (MMUD) are used. Prophylaxis with either rabbit anti-thymocyte globulin (rATG, also termed anti-T-lymphocyte globulin) or post-transplantation Cyclophosphamide (PTCy) is often used to reduce the risk of NRM and GVHD. However, it is currently impossible to give general recommendations regarding preference for rATG or PTCy since comparative evidence from larger data sets is lacking.
To better understand the outcome of these GHVD prophylactic regimens, we analyzed outcomes of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies, who underwent peripheral blood alloSCT from 9/10 antigen MMUD between Jan 2018 and June 2021 in the EBMT database. We performed multivariate analyses using Cox cause-specific hazard models, adjusting for known risk factors, and variables that showed significant difference between the two comparison groups.
Overall 2123 patient were included, treatment- and patient characteristics are shown in Table 1. Patients receiving PTCy (n=583) were younger and had undergone alloSCT more recently compared to patients receiving rATG (n=1540). Median follow up was 2.0 years (PTCy) and 2.4 years (rATG). Outcome graphs are shown in figure 1. All outcomes are given starting from AlloSCT (with 95% CI).
NRM (fig 1A) was higher in the rATG arm (2-years NRM: PTCy 18% [14.6-21.6] vs. rATG 24.9% [22.7-27.3]; HR 0.74, p=0.03), Relapse incidence was slightly higher but not significant in the rATG arm (2-years RI: PTCy 22.9% [19.2 - 26.9] vs. rATG 26.2% [23.9 - 28.7]; HR 0.82, p=0.07), Overall survival (fig 1B) was better in the PTCy arm (2-years OS: PTCy 65.7% [61.2 - 69.9] vs. rATG 55.7% [52.9 - 58.3]; HR 0.77, p&lt;0.001), same for Progression free survival (fig 1C) (2-years PFS: PTCy 59.1% [54.4 - 63.5] vs. rATG 48.8% [46.1 - 51.5]; HR 0.78, p=0.001). The incidences of chronic and acute GVHD were not significantly different between the groups; (2-years cGVHD: PTCy 31.7% [27.4 - 36] vs. rATG 30.3% [27.8 - 32.8]; HR 0.95, p=0.67. And 100-days aGVHD grades II-IV: PTCy 29.9% [25.9-34.1] vs. rATG 32.5% [30-34.9]; HR 0.83, p=0.11).
In summary, we found significantly higher survival and lower NRM in recipients of peripheral blood alloSCTs from MMUD receiving PTCy as compared to rATG. The current analysis improves the evidence base for decision making on GVHD prophylaxis in MMUD alloSCT.
Transcriptomic Profile of Peripheral Blood Mononuclear Cells in Sirolimus-Sensitive Acquired Pure Red Cell Aplasia Patients
Authors: Yang Yuan , Hu Qinglin , Yang Chen , Chen Miao , Zhuang Junling , Han Bing 
Published: December 2023

Objective: Sirolimus is effective for treatment of acquired pure red cell aplasia (aPRCA). Nevertheless, the immunomodulatory effect of sirolimus on peripheral blood mononuclear cells (PBMCs) from aPRCA remains undetermined. This study aims to investigate the immunomodulatory effect of sirolimus using PBMCs transcriptomics of aPRCA patients.
Methods: PBMCs were isolated from treatment-naïve (n = 11) or sirolimus-sensitive aPRCA patients ((n = 11) and then underwent RNA-sequencing.
Results: A total of 4060 genes, including 1639 upregulated genes and 2421 downregulated genes were significantly dysregulated in sirolimus-sensitive aPRCA patients compared with treatment-naïve patients. The top ten dysregulated genes were SYTL5, VSNL1, LINC00707, BTBD17, LINC01954 AL445437.1, IGKV1-8, AC090826.1, PRAME and LINC00520, respectively. Among the identified biological processes significantly enriched by dysregulated genes, B-cell-mediated immunity and circulating immunoglobulin-mediated humoral immune responses are the top two dysregulated immune responses in aPRCA patients with sirolimus treatment. Additionally, TNF, CD40, HLA-DRB1, SERPING1, SERPING1, C1QA, IGLL5 and IGHV3-11 were the key modulator in B-cell-mediated immune or circulating immunoglobulin-mediated humoral immune responses in sirolimus-sensitive aPRCA patients.
Conclusion: We first provided evidence showing the immunomodulatory effect of sirolimus on PBMCs from patients with aPRCA. Sirolimus can modulate the B-cell-mediated immunity and circulating immunoglobulin-mediated humoral immune responses in aPRCA patients.
Serpin-PC in Persons with Severe Hemophilia (PwH): Updated Results from a Multicenter Multi-Part, First-in-Human Study
Authors: Baglin Trevor , Huntington James A. , Koch Annelize , Mocanu Irina , Makhaldiani Levani 
Published: December 2023

Introduction
SerpinPC is an investigational serine protease inhibitor (SERPIN) engineered to specifically inhibit Activated Protein C (APC). The previously presented data from the completed parts of AP-0101 showed that administration of SerpinPC reduced bleeding in persons with severe hemophilia with no observations of unexplained chronic elevation in D-dimer. We will now present all results up to the end of Part 5 by which time we anticipate the median continuous exposure will be more than 3 years.
Methods
AP-0101 is an ongoing first-in-human open-label multicenter study utilizing an adaptive design to investigate the safety, tolerability, pharmacokinetics and efficacy of SerpinPC in subjects with severe hemophilia A and B.
Part 1a was a Single Ascending Dose Study of SerpinPC in 15 healthy male volunteers and 12 males with severe hemophilia.
Part 2 enrolled 23 males with severe hemophilia (19 hemophilia A and 4 hemophilia B), who were not on replacement factor prophylaxis, to receive SerpinPC at 0.3, 0.6 or 1.2 mg/kg, administered as a subcutaneous (SC) injection once every 4 weeks over a 24-week period (6 total doses).
In Part 3, subjects who completed Part 2 received a flat dose of 60 mg of SerpinPC once every 4 weeks for 48 weeks.
Part 4 was a further extension in which subjects who completed Part 3 received 1.2 mg/kg of SerpinPC once every 2 weeks for 24 weeks.
Part 5 was a further extension in which subjects who completed Part 4 continued to receive 1.2 mg/kg of SerpinPC once every 2 weeks for 52 weeks.
Results
Annualized bleed rates, safety and tolerability for Part 5 will be available and a complete summary of all results to the end of Part 5 will be presented, including available pharmacokinetic and anti-drug antibody data.
Venous Thromboembolism Outcomes Among Cancer and Non-Cancer Patients Managed with Patient-Centric Guideline-Driven Protocol
Authors: Cassianni Claire E. , McBane Robert D. , Vlazny Danielle T. , Hodge David O. , Casanegra Ana I. , Houghton Damon E. , Wysokinski Waldemar E. 
Published: December 2023

Purpose/Introduction: Patients with cancer and venous thromboembolism (VTE) have higher complication rates including thrombosis recurrence and bleeding. Real world prospective clinical outcome estimates of VTE management comparing cancer and non-cancer patients are limited. To assess VTE recurrence, major bleeding, and clinically relevant non-major bleeding (CRNMB) in patients with cancer and without cancer, the prospective Mayo Clinic Thrombophilia Clinic Registry was analyzed.
Methods: Upon recruitment, consecutive patients with confirmed acute VTE (03/01/2013 - 04/30/2023) were treated in a standardized, guideline-sanctioned, protocol driven strategy incorporating shared patient-decision making. Patients were divided into groups based on cancer status. After enrollment, patients were actively followed at 3 month intervals, in person whenever feasible, by mailed questionnaire or scripted phone interview to assess vital status, medication compliance, VTE recurrence, major bleeding and CRNMB.
Results: Over the study time-frame, 2,064 patients (53.8% male, 46.2% female) with a cancer and 2,647 patients (54.9% male, 45.1% female) without cancer were enrolled. The most common cancers were gastrointestinal (n=423, 20.5%), pancreatic (n=287, 13.9%), genitourinary (n=198, 9.6%), hematologic (n=171, 8.3%), and lung cancer (n=170, 8.2%). Patients with cancer were older, had lower weight and lower platelet counts compared to non-cancer patients (Table1). Pulmonary embolism (PE, 52.6% vs 43.7%, p&lt;0.001), upper extremity DVT (9.1% vs 6.0%, p&lt;0.001), and splanchnic DVT (11.1% vs 6.9%, p&lt;0.001) were more frequent among cancer patients. In contrast, leg DVT was more frequent among non-cancer patients (65.4% vs.47.2%, p&lt;0.001). While mean duration of anticoagulation was similar between groups, notable differences in 3 month and &gt; 9 month durations were evident as were initial anticoagulant choices (Table 1). Despite a well-organized protocol driven and guideline sanctioned management strategy, patients with active cancer experienced a 2.2-fold higher rate of VTE recurrence (p&lt;0.001) and a 1.8 fold higher rate of major bleeding (p&lt;001) compared to non-cancer patients (Table 2). CRNMB rates did not differ by cancer status.
Conclusions: In this large prospective, guideline-driven and patient-centric registry of VTE management, patients with cancer had significantly higher rate of VTE recurrence and major bleeding, compared to non-cancer patients. These data provide important estimates for power calculations for future randomized trials of VTE treatment.
Efficacy and Safety of Zanubrutinib-Containing Regimens in Patients with Secondary CNS Relapse in Diffuse Large B-Cell Lymphoma
Authors: Bao Li , HU Kai , Ke Xiaoyan , Wang Yutong , Wang Mengzhen , Shi Lei , Sun Kai 
Published: December 2023

Background: In the era of immune-targeted therapy represented by rituximab, despite improved remission and survival rates in patients with diffuse large B-cell lymphoma (DLBCL), central nervous system (CNS) relapse, occurring in some DLBCL patients after achieving remission, remains a clinical challenge. Zanubrutinib is one of a new generation of BTK inhibitors that have higher blood-brain barrier permeability compared to other BTK inhibitors.
Research Design and Methods: We performed a multicenter retrospective study to evaluate the efficacy and safety of Zanubrutinib-containing regimens for salvage treatment in 28 relapsed DLBCL patients with CNS involvement treated in 6 centers from January 2020 to December 2021.
Results: The IPI score and CNS-IPI score did not have good enough predictive significance for lack of consistency of the median time from the initial diagnosis to CNS recurrence. Of the 28 patients, 16 had targeted next-generation sequencing (NGS) data. NGS test was performed on their tissue samples that were obtained at initial diagnosis and/or at the timepoint of CNS relapse in DLBCL. 8 at the time of initial diagnosis and 10 at the time of recurrence, with 2 of them having undergone NGS sequencing at both initial diagnosis and recurrence. Median study follow-up from CNS relapse was 8.55 months, all patients were evaluated for response with 20/28 (71.4 %) showing a response: 11 CR, 9 PR, and 4 SD, 4 PD. The median PFS is 6.6 months, and the median OS has not yet been reached. Notably, MYD88, CD79B, or TP53 mutations tested at diagnosis in these patients were associated with significantly more favorable treatment response, while patients with a dual rearrangement of MYC and BCL2 and/or BCL6 genes did not get a treatment response to Zanubrutinib-containing regimens. It has well-tolerated toxicity with few adverse events requiring treatment discontinuation or dose reduction.
Conclusion: Zanubrutinib-containing regimens extended PFS and OS in relapsed DLBCL patients with CNS involvement.
The Iron Chaperone Poly C Binding Protein 1 Regulates Iron Efflux through Intestinal Ferroportin in Mice
Authors: Wang Yubo , Protchenko Olga , Huber Kari , Shakoury-Elizeh Minoo , Philpott Caroline 
Published: December 2023

Iron is an essential nutrient required by all cells but used primarily for red blood cell production. Because humans have no effective mechanism for ridding the body of excess iron, the absorption of dietary iron must be precisely regulated. The critical site of regulation is the transfer of iron from the absorptive enterocyte to the portal circulation via the sole iron efflux transporter, ferroportin (FPN). Here we report that poly(rC)-binding protein 1 (PCBP1), the major cytosolic iron chaperone, is necessary for the regulation of iron flux through FPN in the intestine of mice. PCBP1 binds iron-glutathione complexes in the cytosol of cells and delivers the iron to ferritin, the iron storage protein, to iron centers in enzymes, and to iron-sulfur cluster chaperones. PCBP1 also limits the chemical reactivity of iron, thereby limiting iron-catalyzed oxidative damage in cells.
To explore the role of PCBP1 in dietary iron absorption, we developed mice with an inducible, enterocyte-specific deletion of PCBP1. Mice lacking PCBP1 in the intestinal epithelium exhibit low levels of enterocyte iron, poor retention of dietary iron in enterocyte ferritin, and excess efflux of iron through FPN. Kinetic studies of iron transport using a stable isotope ( 57Fe) coupled with a mini-hepcidin that blocks FPN activity demonstrated that PCBP1 deletion had no effect of intestinal iron uptake but caused high rates of iron efflux through FPN. Surprisingly, excess iron efflux occurred despite lower levels of FPN protein in enterocytes and upregulation of the iron regulatory hormone hepcidin. PCBP1 deletion and the resulting unregulated dietary iron absorption led to poor growth, severe anemia on a low iron diet and liver oxidative stress with iron loading on a high iron diet.
To investigate the roles of PCBP1 more precisely in enterocytes, we developed 3-D organoid cultures from intestinal epithelium which functionally expressed the major iron trafficking proteins: divalent metal transporter 1, PCBP1, ferritin, transferrin receptor 1 and FPN. Ex vivo culture of wild-type and PCBP1-depleted enteroids demonstrated normal patterns of FPN expression and hepcidin-mediated turnover. However, fluorescence measurements of kinetically labile iron pools in enteroids competent or blocked for FPN iron efflux indicated that PCBP1 dramatically altered efflux activity. PCBP1 functioned as a cytosolic buffer for iron, binding and retaining iron and thereby keeping “free” iron at very low levels. This low concentration of free iron limited its availability for FPN-mediated efflux and allowed hepcidin-mediated changes in FPN levels to regulate the amount of iron exported from the enterocyte. Thus, by binding enterocyte iron, PCBP1 reduces the concentration of unchaperoned, “free” iron to a low level. This low level of cytosolic free iron is necessary for hepcidin-mediated regulation of FPN activity.
Spectrum and Clinical Features of Gene Mutations in Chinese Follicular Lymphoma
Authors: Li Chunyuan , Yin Jingjing , Yuan Yue , Yang Ping , Liu Hui , Jing Hongmei 
Published: December 2023

Background: Follicular lymphoma (FL) is the most common indolent lymphoma with variable biologic presentation and heterogeneous clinical outcomes, and some of patients experiences early progression and have inferior survival outcomes. Next-generation sequencing (NGS) identified recurrently mutated genes in FL. While few studies on gene mutations in Chinese FL patients have been identified in the real world, this present study aimed to characterize the genomic landscape and provide insights into the biomarkers of high-risk FL populations.
Methods: 590 FL patients were reviewed, and 100 patients with sufficient samples were enrolled in our cohort. We performed targeted sequencing of 521 lymphoma-related genes based on NGS in this study.
Results: A total of 207 genetic alterations were detected in 99/100 patients. T NFRSF14, CARD11, and NOTCH3 mutations were common in FL1-2 patients compared to FL3a patients (p = 0.025, 0.0036, and 0.0047, respectively). SOCS1 mutations were more common in patients with Ki-67 index &gt; 30% (p =0.324), and PRDM1 mutations were more common in patients who experienced progression of disease within 24 months (POD24) (33.3% vs. 0%, p =0.008). We observed a trend that patients with a high mutation load (with ≥ 6 mutated genes) showed decreased PFS compared with patients with &lt; 6 mutated genes (p=0.068). For patients who received R-CHOP-like regimens, the multivariate COX proportional hazard modeling identified TP53, TNFAIP3, and SOCS1 mutations as independent risk factors of PFS (HR 6.76, 95% CI 1.81 to 25.18, p =0.004; HR 3.68, 95% CI 1.06 to 12.82, p =0.041; HR 5.07, 95% CI 1.81 to 21.73, p =0.029). TP53 and TNFAIP3 were significant independent predictors of PFS when testing with either FLIPI (p=0.029) or FLIPI2 (p=0.023) in multivariable analysis.
Conclusion: Our study depicted genomic characterization of real-world Chinses FL patients and demonstrated TP53, TNFAIP3 and SOCS1 mutations can help identify high-risk patients.
Survival Outcomes of Patients with Diffuse Large B-Cell Lymphoma Who Received Autologous Stem Cell Transplantation in Germany - Real World Evidence from an Administrative Database
Authors: Borchmann Peter , Heger Jan-Michel , Mahlich Joerg , Papadimitrious Micheal , Riou Sybille , Werner Barbara 
Published: December 2023

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with increasing incidence. Autologous stem cell transplantation (ASCT) is a treatment option for patients who relapse or progress after up-front chemoimmunotherapy if they suitable for ASCT. However, patients may not qualify for this treatment because of age and/or comorbidity or because they are non-responder to second-line chemoimmunotherapy. Limited real-world data of the ASCT patient population is available for Germany. Therefore, this retrospective database analysis was conducted to describe real-world survival outcomes of patients with DLBCL who received ASCT in Germany.
Patients and Methods: Using a large claims database of the German statutory health insurance with 6.7 million enrollees between 2010 and 2019, we identified patients who were newly diagnosed with DLBCL, had no other cancer co-morbidity, and received ASCT (index date). Pre-defined treatment lines were used to identify the utilization of ASCT. Unadjusted overall survival (OS) from index was plotted by means of the Kaplan-Meier estimator for the overall population and for those patients who had/had not a subsequent treatment line after ASCT. Furthermore, we performed a Cox proportional hazard survival regression with the following co-variates: age, sex, Charlson Comorbidity Index (CCI), time from start of first line treatment to ASCT, and presence of subsequent treatment after ASCT.
Results: 112patients received ASCT. Among them, 39.3% received subsequent treatment after ASCT. Time to ASCT was on average 11.7 months for the entire cohort. Median OS estimated by Kaplan-Meier was 83.4 months for the entire cohort and 27.8 months for patients who received subsequent treatment. Median OS was not estimated for the group without subsequent treatment, for whom the Kaplan-Meier curve reached a plateau at just under 90%, assuming a potential cure. Finally, the only variable significantly reducing the OS was the presence of subsequent treatment after ASCT in a time-dependent model.
Conclusion: Given the high survival outcomes, ASCT is a valuable treatment option for relapsed/refractory DLBCL. However, only a small subset of patients is fit enough to benefit from this treatment and patients who fail ASCT have a poor prognosis. Therefore, novel therapeutic approaches are required to address these unmet medical needs.
Epigenetic Control of B Cell Autoimmunity By Jmjd1c
Authors: Zhang Yongguang , Yu Mei , Zheng Yongwei , Chen Yuhong , Izaguirre-Carbonell Jesus , Zhu Nan , Wen Renren , Wang Demin 
Published: December 2023

Emerging evidence underscores the importance of e pigenetic modifications in controlling B-cell development and function. While Jmjd1c, a member of the l ysine - specific histone demethylase 3 subfamily, is known to regulate the self-renewal of normal hematopoietic stem cells and leukemia stem cells, its impact on B cell biology is unknown. To explore Jmjd1c's role in B cells, we developed B-cell-specific Jmjd1c-deficient mice through crossbreeding Jmjd1c “floxed” mice with B cell-specific Mb1-Cre mice. The absence of Jmjd1c did not impact B-cell development, but it did lead to significant alterations in basal B cell antibody production. Specifically, we observed skewed isotypes from IgG2c and IgG3 to IgG1 and IgG2b. Additionally, Jmjd1c deficiency affected antigen-specific immune responses upon T-dependent and T-independent antigen challenges, implying a crucial role of Jmjd1c in B cell function. Furthermore, auto-antibody array assays revealed increased self-reactive antibody production in Jmjd1c-deficient animals, indicating the role of Jmjd1c in regulating self-reactive B cells. At a cellular level, Jmjd1c-deficient B cells showed elevated expression of CD86, a canonical marker of B cell activation. Moreover, these B cells exhibited increased BCR-induced cell proliferation, suggesting hyperactivity to antigens, including self-antigens. Notably, Jmjd1c deficiency induced systemic autoimmune disorder in a BM12-induced systemic lupus erythematosus (SLE) animal model, resulting in amplified auto-antibody production and CD86 expression.
To investigate the underlying molecular mechanisms, RNA sequencing analysis demonstrated upregulation of B cell receptor signaling related genes, NF-κB pathway signature genes, and cell cycle-related genes in Jmjd1c-deficient B cells upon anti-IgM stimulation, consistent with their hyperresponsiveness. Of particular interest, we observed upregulation of genes encoding the 26S proteasome complex, a pivotal regulator of diverse cellular processes including NF-κB pathway activation and self-antigen presentation. To explore the epigenetic aspect of these genes, we employed CUT&Tag sequencing and found that Jmjd1c deficiency correlated with increased levels of H3K36me1, a marker of active chromatin and gene transcription. Moreover, the H3K36me1 levels of B cell receptor signaling related genes, NF-κB pathway signature genes, and cell cycle-related genes were significantly augmented in Jmjd1c-deficient B cells upon anti-IgM stimulation. Notably, 26S proteasome subunit genes that were upregulated in Jmjd1c-deficient B cells exhibited higher H3K36me1 modification at the promoter regions.
Collectively, our study provides valuable insights into the epigenetic control of B cell autoimmunity through the regulation of H3K36 mono-methylation by Jmjd1c. This mechanism plays a critical role in B cell activation and function, including the regulation of key genes such as those encoding the 26S proteasome complex.