bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haematopoietic Stem Cell Transplantation for Hepatitis-Associated Aplastic Anaemia: Clinical Characteristics, Outcomes and Risk Factors
Authors: Jia Li , Liu Yilin , Jiang Erlie , Feng Sizhou 
Published: December 2023

Introduction:
Hepatitis-associated aplastic anaemia (HAAA) is a severe and life-threatening condition that requires effective treatment approaches. Hematopoietic stem cell transplantation (HSCT) has emerged as a promising therapeutic option for HAAA patients. In this retrospective study, we aimed to investigate the clinical characteristics, outcomes, and prognostic factors associated with HSCT in HAAA patients at a prominent Chinese blood disease hospital between 2008 and 2022.
Methods:
A comprehensive review of 35 HAAA patients who underwent HSCT was conducted, and clinical data were analyzed to determine the treatment's efficacy and safety. The patients were primarily categorized into those with severe AA (28.6%) and very severe AA (65.7%), with a predominant male representation (68.6%) and a median onset age of 23 years (range, 9-44). Both haploidentical and matched sibling donors were utilized in comparable proportions.
Results:
The study revealed a promising 5-year overall survival (OS) rate of 74.0% after HSCT, underscoring the effectiveness of this treatment approach in HAAA patients. However, certain factors significantly impacted survival rates and treatment outcomes. Prolonged intervals from diagnosis to HSCT (&gt;=75 days), acute graft-versus-host disease (GVHD), and post-HSCT liver events, such as hepatic GVHD and a three-fold increase in aminotransferase or bilirubin, were found to worsen 5-year OS. Interestingly, higher doses of mononuclear cell count, CD34+, CD3+, CD4+, and CD8+ cells in allografts were associated with poorer OS or graft failure-free survival (GFFS), suggesting that pursuit of higher cell counts in certain cases may be counterproductive.
Furthermore, a close examination of the multivariate models revealed that recipients who received sex-matched grafts experienced better OS, while those with younger male donors had a lower incidence of grade II-IV acute GVHD. Moreover, a higher HLA matching degree (HLA &gt;=7/10) between the recipient and donor emerged as an independent prognostic factor associated with better OS and GFFS.
Conclusion:
This study highlights the safety and efficacy of HSCT as a treatment modality for HAAA patients. Early transplantation, careful donor selection, and efforts to improve post-transplant liver events were identified as crucial factors to optimize treatment outcomes. While the use of certain cells in higher doses may have a negative impact on survival, the importance of achieving a high HLA matching degree cannot be overstated. Moving forward, these findings can serve as valuable insights in guiding the management and treatment decisions for HAAA patients undergoing HSCT. Further research and continuous improvement in transplantation protocols will undoubtedly advance the success rates and long-term prognosis for individuals afflicted with this challenging condition.
CXCR4 Enriched T Regulatory Cells Preferentially Home to Bone Marrow and Decrease Inflammation
Authors: Huang Meixian , Lyu Mi-Ae , Zeng Ke , Sadeghi Tara , Masarova Lucia , Flowers Christopher R. , Parmar Simrit 
Published: December 2023

Background and aim
Adoptive therapy with T regulatory cells (Tregs) is emerging as an important therapeutic strategy for several autoimmune and inflammatory diseases. Optimal homing and payload delivery of these anti-inflammatory cells remain a cornerstone of optimizing their therapeutic efficacy. CXCR4 cell surface expression has been shown to be critical for homing of hematopoietic cells to the bone marrow (BM). Also, CXCR4/CXCL12 axis plays a major role in the pathogenesis of BM inflammatory disorders including myelofibrosis. We hypothesize that enrichment of CXCR4 on the Tregs cell surface will enable their trafficking to BM and ensure a homogenous delivery.
Methods/results/conclusion
Magnetic enrichment of CD25 + cells was performed on umbilical cord blood on day 0, followed by dual enrichment on CXCR4 using CRANE TM (cord blood Tregs, activated and enriched) process on day 3 or 4 (Fig 1A). The enrichment process led to increased number of Tregs expressing CXCR4 on their cell surface (Fig 1B; Treg CXCR4) as well as a CXCR4 hi Treg cells when compared to Treg control (Fig 1C, p&lt;0.0001; n=16). In a Transwell TM system, a higher number of Treg CXCR4 migrated to the bottom well in chemotactic response to SDF1α at 15 minutes as compared to the Treg control cells. Such migration was inhibited by CXCR4 antagonist, AMD3100 (Fig 1D). The migration superiority of Treg CXCR4 was maintained at 30 and 60 min (Fig 1E). In order to understand in vivo transit kinetics, Treg cells were injected into NSG mice and organs were harvested at 12 and 24 hours (Fig 1F). Treg CXCR4 showed preferential homing to BM (Fig 1G), where a higher expression of CXCR4 and CXCL12 than control, was observed (Fig 1H). Other markers including CD62L (homing and suppression), CD39 & CD73 (conversion of ATP to immunosuppressive adenosine), and CXCR5 (Follicular Treg) were also increased in Treg CXCR4 recipients. A decrease in biomarkers including TGFα and TNFβ (inflammation), IL-13 (fibrosis) (Fig 1I) with an increase in GM-CSF (increase Treg potency) (Fig 1J), was observed in Treg CXCR4 recipients with a corresponding decrease in TGFβ family (hematopoietic suppressor) (Fig 1K). We conclude that Treg CXCR4 shows superior homing to BM and is currently being studied in a clinical setting to treat myelofibrosis with suboptimal response to ruxolitinib (NCT05423691).
Oncogenic RAS Signaling Promotes an Immunosuppressive Niche in Acute Lymphoblastic Leukemia
Authors: Ferrao Blanco Mauricio Nicolás , Schweighart Elizabeth , Kester Lennart , Hehir-Kwa Jayne , Belderbos Mirjam E. , den Boer Monique L. , Heidenreich Olaf , Vormoor Josef 
Published: December 2023

Emerging evidence suggests that genomic aberrations in cancer cells may impact the composition of the tumor microenvironment leading to a tumor-specific supporting niche. Previous genomic profiling studies have identified somatic alterations in RAS pathway genes that drive treatment resistance in B-cell acute lymphoblastic leukemia (B-ALL): yet it is unknown whether such genetic events may specifically hijack the leukemic niche.
Here, we analyzed bulk RNA-sequencing data of bone marrow mononuclear cells from 185 pediatric B-ALL patients entering our center and performed mutation calling of RAS pathway genes, namely KRAS, NRAS, BRAF and PTPN11. Transcriptomic analysis revealed attenuated immune responses and decreased T cell activation in samples harboring RAS mutations (n= 62) compared with wild type cases (n= 123). To further explore this finding at single-cell resolution, we sorted bone marrow mononuclear cells from 8 primary B-ALL pediatric patient samples (4 RAS mutant and 4 wild type), enriching on the hematopoietic and non-hematopoietic compartments, followed by single-cell RNA-sequencing using the 10x Genomics platform. Twelve cell populations were identified by the expression of bona fide markers, mapping different immune and stromal cells in the ALL landscape. Specifically, the RAS-mutant microenvironment was defined by dysfunctional CD8+ T-cells, characterized by high expression of TIM-3, TIGIT and LAG-3, as well as regulatory T cells, displaying expression of CTLA-4, ICOS and FOXP3, suggesting a RAS-mediated immunosuppressive mechanism.
In light of these changes, we examined flow cytometry data of bone marrow mononuclear cells collected at diagnosis from our cohort of 185 patient samples. Whereas the overall proportion of lymphoid subsets (T, B and NK cells) was not significantly changed among RAS mutant and wild type groups, we detected a decrease in myeloid subsets (neutrophils, eosinophils, and monocytes) in RAS mutant ALL, which was more prominent in monocytes. Cross comparison of the transcriptional state of monocytes in our single-cell data unravel that monocytes in the RAS mutant niche displayed a non-classical phenotype, characterized with high expression of the immune checkpoint TIM-3, which is a major driver of T cell exhaustion.
Taken together, the bone marrow microenvironment of ALL patients harbouring oncogenic RAS lymphoblasts is defined by dysfunctional immune cell populations. Further studies on the cellular dynamics in the niche will provide the basis for the development of therapeutic opportunities to target the immune micro-environment in RAS mutant ALL.
Static and Dynamic Assessment to Identify Ultra-High Risk Multiple Myeloma：Analysis for Patients with Overall Survival No More Than Three Years
Authors: Xu Yan , An Gang , Deng Shuhui , Sui Weiwei , Liu Wei , Huang Wenyang , Wang Tingyu , Yi Shuhua , Zou Dehui , Qiu Lugui 
Published: December 2023

Background: The median overall survival (OS) in multiple myeloma (MM) is rapidly approaching 10 years. However, the prognosis of ultra-high risk MM (UHR-MM) remains very poor, the median overall survival (OS) is no more than 3 years. There is no consensus to define this population till now. Several prognostic factors with significant impact on survival have been discovered over time, with cytogenetic factors as the most potent. Nevertheless, there is little study to investigate the features of these UHR-MM, especially in Asian UHR-MM patients.
Patients and Methods: To understand the characteristic of UHR-MM and help identify these patients as early as possible, we retrospectively analyzed the data of patients whose OS is &lt;3 years from a single Chinese center with static and dynamic assessment. Baseline characteristic and response dynamic were collected.
Results: From 2013.1 to 2019.12, 1270 patients with newly diagnosed MM (NDMM) were enrolled in a single Chinese center. In which, 265 (20.79%) patients deceased in 36 months. 271 survival patients with no more than 3 years follow-up were excluded. Compared with 734 patients survived more than 36 months, median OS were 18.48±10.05 months and 92.70±3.99 months, median progression survival (PFS) were 12.14±4.00 months and 53.66±2.43 months, respectively. These patients are older (median age: 56 vs. 61 years, p&lt;0.0001), with higher percentage of genetic ultra-high risk (including del(17p)≥60%; or ≥2 high-risk cytogenetic abnormalities including TP53 mutation, del(17p)/P53 deletion, t(4;14), t(14;16), t(14;20), 1q21 gain/ amplification), more patients with ISS-III, R-ISS-III, R2-ISS-IV, more patients with primary refractory (including &lt;MR after 2 cycles or &lt;PR after 4 cycles standard first-line therapy) or early relapse (including lost best response within 6 months from the standard first-line therapy), and more patients with primary PCL history. With multivariate analysis, genetic ultra-high risk, primary refractory, early relapse and primary PCL history are independent factors for poorer PFS and OS.
Conclusion: With static and dynamic assessment, we can identify a group of UHR-MM with survival no more than 3 years as early as possible. For these patients, we need more potent therapy model to improve their survival.
Soluble CD163; A Possible New Biomarker in Multiple Myeloma
Authors: Gkioka Annita Ioanna , Gkiokas Alexandros , Alexandropoulos Alexandros , Papadatou Mavra , Koudouna Aspasia , Vasiliki Bartzi , Tryfou Thomai-Marina , Kafasi Nikolitsa , Kyrtsonis Marie-Christine 
Published: December 2023

INTRODUCTION
Tumor associated macrophages (TAM) constitute a major part of the bone marrow microenvironment and play a pivotal role in growth of various hematologic malignancies, such as Multiple Myeloma (MM). Cytokines secreted by TAM, such as hemoglobin scavenger receptor CD163, can be detected in their soluble form (sCD163) and reflect the TAM burden. It was recently published that bone marrow TAMs protect neoplastic plasmacytes from chemotherapy-based apoptosis. In our study, we aimed to investigate the clinical utility of sCD163 in patients with Multiple Myeloma.
PATIENTS AND METHODS
One hundred and nineteen patients were included in the study of whom 80 had symptomatic MM, 30 appeared to have SMM and 8 had MGUS. Clinical and laboratory characteristics were reviewed, after patients' informed consent form. Their median age was 68 yrs (range, 30-89), 53% were men and 47%women; 39%, 27%, and 35% of MM patients were staged ISS1, ISS2 and ISS3 respectively. Serum sCD163 was tested in frozen sera collected at patients' diagnosis and in 30 healthy individuals (HI) . Measurements were performed by ELISA (Duo-Set R&D Quantiquine) according to the manufacturer's instructions. Median value of variables was used as the cut off point. Median time to treatment (TTT) was 0 months (range,0-248) in MM patients and median overall survival (OS) was 67 months (range, 0-248). Statistical analysis was performed with the SPSS v.26 software.
RESULTS
Median sCD163 was 26618 pg/ml (11831- 35548) in HI, 24366 pg/ml (13166 - 27429) in MGUS, 27665 (18266-39088) pg/ml in SMM, and 27870 (20720-37478) pg/ml in MM patients.Significantly lower levels of CD163 were observed between MGUS and HI (p=0.001) and HI and MM patients (p=0.015). Shorter time to treatment was observed in all MM patients including SMM with sCD163 levels above median (p = 0.034). Patients who became symptomatic after 6 months of diagnosis were studied separately, with levels above the median indicating a shorter time to therapy (p=0.003). Also, a trend of shorter overall survival was observed in all patients (MM, SMM, MGUS) with levels of CD163 above median (p=0.07).
CONCLUSION
Our findings reveal that serum sCD163 levels differed in patients with MGUS, SMM, MM, and HI, and could predict TTT in MM, indicating that cells of the monocyte-macrophage lineage may play a role in disease pathophysiology and progression. sCD163 could eventually prove to be a significant prognostic factor in MM.
Long Noncoding RNA NEAT1 Regulates Acute Graft-Versus-Host Disease By Promoting Macrophage M1 Polarization through JNK Pathway
Authors: Zhang Ran , Huang Zhenli , Wang Li , Cao Weijie , Small Donald , Zhu Ruiqi , Shi Wei , Jiang Zhongxing , Xia Linghui 
Published: December 2023

Introduction
Acute graft-versus-host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The function of macrophages in aGVHD is a hot point in current research. Long noncoding RNA nuclear enriched abundant transcript 1 (lncRNA NEAT1) is closely related to immune-related diseases and affects the function of macrophages. However, the role of LncRNA NEAT1 in aGVHD is unclear in current study.
Methods
Peripheral blood mononuclear cells (PBMCs were collected from the patients with or without aGVHD after allo-HSCT. The expression of lncRNA NEAT1 in PBMCs was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic value of lncRNA NEAT1 in aGVHD was analyzed by receiver operating characteristic curve (ROC) and area under correlation curve (AUC). We transfected RAW264.7 cells and bone marrow-derived macrophages (BMDM) with NEAT1 lentiviral vector or NEAT1 small interfering RNA to change the expression level of NEAT1. The function of NEAT1 and its effect on JNK pathway were analyzed by flow cytometry, qRT-PCR, western blotting and ELISA. Finally, aGVHD mouse model was constructed to evaluate the function of JNK inhibitors in aGVHD.
Results
Compared with non-aGVHD patients, LncRNA NEAT1 was significantly up-regulated in PBMCs of aGVHD patients. ROC and AUC analysis confirmed that the expression level of lncRNA NEAT1 was correlated with the occurrence of aGVHD, which may have certain diagnostic value in aGVHD. We found the expressions of NEAT1 in BMDM and RAW264.7 were remarkably increased after being stimulated with lipopolysaccharide (100ng/ml). The overexpression of lncRNA NEAT1 in RAW264.7 could significantly up-regulate the expression level of iNOS, and induce the differentiation into M1 type. Knockdown of lncRNA NEAT1 in BMDM could significantly down-regulate the gene expressions (iNOS and NLRP3), reduce the protein levels (iNOS, NLRP3 and p-JNK), decrease the proportion of M1 macrophages and inflammatory cytokines secretion (TNF-α and IL-1β), and inhibit the JNK pathway. We found that JNK inhibitor could perform the same function as knocking down lncRNA NEAT1 in BMDM. In addition, JNK inhibitor could improve the survival and pathology, decrease the inflammatory cytokines secretion (TNF-α and IL-1β), and reduce the infiltration of M1 macrophages into the target organs in aGVHD mouse model.
Conclusions
Our results showed that lncRNA NEAT1 may regulate the M1 polarization of macrophages and the secretion of inflammatory cytokines by regulating the JNK pathway. JNK inhibitor may reduce the inflammation in aGVHD mouse models by blocking the function of NEAT1 in macrophages. This study provides a promising therapeutic target for aGVHD.
Pharmacokinetic-Targeting and Dose-Adjustment of I.V. Busulfan for Myeloablative Conditioning in Allogeneic Hematopoietic Cell Transplantation
Authors: Khanolkar Rutvij A. , Kangarloo Shahbal B , Li Na , Khan Faisal , Storek Jan 
Published: December 2023

Introduction: Pharmacokinetically (PK)-targeting intravenous busulfan improves outcomes following allogeneic hematopoietic cell transplantation (HCT). However, the optimal busulfan area under the curve (AUC) likely differs based on the specific conditioning regimen, and the target busulfan exposure is unknown in combination with fludarabine and low-dose total body irradiation (TBI).
Methods: This study included 1019 adult HCT recipients that received myeloablative conditioning including fludarabine, busulfan, anti-thymocyte globulin, and low-dose (4cGy) TBI. Busulfan was administered as a total dose of ~3.2mg/kg given equally from days -5 to -2 pre-transplant. Total AUC was estimated using measurements of serial serum samples. Multivariate Cox and Fine-Gray regression were used for comparison of AUC subgroups. The primary outcomes of interest were relapse-free survival (RFS) and overall survival (OS).
Results: Median AUC was 62.3 mg∙hr/L (range: 39.4-128.0 mg∙hr/L). Total AUC exposure of 49.3-57.5 mg∙hr/L was associated with greater RFS (67% vs. 47%, HR=1.82, P=0.014) and OS (71% vs. 46%, HR=1.99, P=0.008) compared to patients with higher AUCs of 57.5-73.9 mg∙hr/L. Although very low (&lt;49.3 mg∙hr/L) or very high (&gt;73.9 mg∙hr/L) AUCs trended towards worse RFS and OS compared to 49.3-57.5 mg∙hr/L, this analysis was limited by the small number of patients with extreme AUCs and did not reach statistical significance. Except potentially for patients with a high/very high HCT disease risk index, 49.3-57.5 mg∙hr/L appeared to be the optimal AUC regardless of patient sex, age, or primary disease.
Conclusion: Within the evaluated AUC range, 49.3-57.5 mg∙h/L appeared to be associated with the most favourable survival. Pharmacokinetic-targeting to this range may improve outcomes.
PRT2527, a Novel Highly Selective Cyclin-Dependent Kinase 9 (CDK9) Inhibitor, Has Potent Antitumor Activity in Combination with BTK and BCL2 Inhibition in Various Lymphoid Malignancies
Authors: Fultang Norman , Schwab Ashley M , McAneny-Droz Sophia , Heiser Diane , Scherle Peggy A , Bhagwat Neha 
Published: December 2023

CDK9 is a master regulator of transcription that modulates transcription elongation via phosphorylation of RNA polymerase II. Short-term inhibition of CDK9 depletes short-lived transcripts and labile proteins such as MCL1, BFL1 and MYC to promote cancer cell death.
We previously described PRT2527, a novel, potent, highly selective CDK9 inhibitor with anti-leukemic activity in various preclinical models. PRT2527 is currently under evaluation in a Phase I clinical trial in patients with relapsed/refractory hematologic malignancies (NCT05159518).
Here we demonstrate PRT2527 potently inhibits cancer growth and induces cell death in various models of Diffuse Large B Cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL), through depletion of MCL1, BFL1 and MYC. We also show that combination of PRT2527 with BTK inhibitors (BTKi) or BCL2 inhibitors (BCL2i) leads to more robust and durable responses in multiple pre-clinical models. In these studies, the combination of PRT2527 with BTKi or BCL2i was well tolerated.
Mechanistically, we show that in cell lines, BTK inhibition upregulates BMF, an endogenous inhibitor of BCL2 and BCL-xL, driving cells towards MCL1 and BFL1 dependency. Concurrent depletion of MCL1 and BFL1 with PRT2527 led to complete inhibition of Bcl-2- family mediated survival signaling, potently inducing cell death. In a similar fashion, Venetoclax-driven BCL2 inhibition also potentiated the anti-tumor activity of PRT2527. Consistent with our findings in vitro, we confirmed potent combinatorial inhibition of tumor growth by PRT2527, administered once weekly, and BTKi or BCL2i, administered daily, in CDX and PDX in vivo models of DLBCL and MCL. We observed reduced BFL1 and MCL1 as well as increased BMF in tumors of mice treated with BTKi and PRT2527 suggesting complete Bcl-2 family inhibition. We also demonstrated enhanced induction of apoptosis by PRT2527 in primary CLL patient samples simultaneously treated with BTKi or BCL2i.
Additionally, we demonstrated that PRT2527 potently inhibits growth in Ibrutinib-resistant MCL cell lines. Further work characterizing PRT2527 as monotherapy and in combination with BTKi and BCL2i in in vivo models of BTKi-resistant MCL and CLL is currently ongoing.
Altogether these data provide a rationale for evaluating PRT2527 in combination with BTK and BCL2 inhibitors for the treatment of patients with relapsed/refractory hematologic malignancies.