bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of Imatinib-Therapy Failure (IMTF) Score in Children with Chronic Myeloid Leukemia in the Chronic Phase
Authors: Zheng Fangyuan , Yuan Mengyao , Zhang Xiaoshuai , Jiang Qian 
Published: December 2024

Background About 27% children with chronic myeloid leukemia (CML) still experienced imatinib failure. However, there is no appropriate prediction model to accurately predict the outcome at diagnosis.
Objective To validate the predictive performance of the imatinib-therapy failure (IMTF) score and compare the predictive discrimination of IMTF score with ELTS score in newly-diagnosed children with chronic phase CML receiving imatinib-therapy.
Methods Data of children with chronic phase CML diagnosed at &lt; 18 years receiving initial imatinib (260 to 340 mg/m2 daily) from January 2006 to December 2023 were analyzed. Diagnosis, monitoring and treatment response assessment were according to ELN recommendations. The cumulative incidence of therapy response and imatinib-therapy failure by IMTF score and ELTS score was calculated using the Fine-Gray test considering competing events defined as stopping imatinib-therapy, a switch to a 2nd or 3rd generation TKIs, a transplant or death unrelated to CML. FFS, PFS and OS were calculated by Kaplan-Meier method with the log-rank test.
Result s A total of 324 children were included in this study. 196 (61%) were male. Median age at diagnosis was 13 years (IQR, 9-17 years). 298 (92%) patients achieved a CHR by 3 months. With a median follow-up of 77 months (IQR, 51-107 months) for survivor, the incidences of CCyR, MMR, MR4.0 and MR4.5 at 8 years were 96% (94, 98%), 84% (79, 88%), 60% (53, 67%), and 45% (38, 53%); the 8-year probabilities of FFS, PFS and survival were 80% (75, 84%), 92% (88, 95%), 97% (95, 99%), respectively. By IMTF score, 63 (19%), 62 (19%), 103 (32%), 67 (21%), and 29 (9%) children were classified as very low-, low-, intermediate-, high-, and very high-risk groups. Since there was no significant difference between the low- and intermediate-risk groups (p = 0.941), these groups were combined into a integrated low/intermediate risk group. In the very low-, low/intermediate-, high- and very high risk groups, the 8-year cumulative incidences of imatinib-therapy failure were 5% (0,11%), 18% (12, 24%), 30% (18, 41%) and 43% (24, 62%;p &lt; 0.001). There were significant differences in imatinib-therapy failure rate among the very low-, low/intermediate- and high-risk groups (p &lt; 0.001 - 0.036), but not between the high and very high-risk groups (p = 0.184). By ELTS score, the 8-year cumulative incidences of imatinib-therapy failure in the low- (n = 223, 69%), intermediate-(n = 81, 25%) and high risk group (n = 20, 6%) were 14% (9, 19%), 32% (22, 43%) and 36% (14, 58%) (p &lt; 0.001), but no significant difference between the intermediate- and high risk group were observed (p = 0.590). The IMTF score exhibited a higher C-statistic values of 0.680 than the ELTS score (0.644).
Conclusion IMTF score had better predictive discrimination for imatinib-therapy failure in children with CML-CP compared to ELTS score.
Evaluation of Risk Assessment Models for Predicting Venous Thromboembolic Events in Cancer Patients Using Implanted Central Venous Access Devices
Authors: Ma'koseh Mohammad , Farfoura Heba , Abunasser Mahmoud , El-Atrash Maryam , Zayed Anas , Abdel Rahman Zaid , Hamdan-Mansour Renad , Al-Jaghbeer Mohammed J , Abdel-Razeq Hikmat 
Published: December 2024

Introduction
Cancer patients are at an increased risk of venous thromboembolic events (VTEs). Implanted central venous access devices (ICVADs) are commonly used for administering chemotherapy and may further increase the risk of VTEs. Our study aims to evaluate the incidence and predictors of VTEs, utilizing the commonly used VTE risk assessment models (RAMs), in cancer patients receiving chemotherapy through ICVADs.
Methods
Medical records data of adults (≥18 years) who received chemotherapy through ICVADs from January 2022 until December 2023 were retrospectively reviewed. Patients on therapeutic anticoagulation at the time of ICVAD insertion were excluded.
Khorana, COMPASS and ONCOTEV RAMs were calculated as previously described. No routine imaging studies were performed to detect asymptomatic VTEs.
VTEs were defined as venous thrombotic events reported after insertion of ICVAD until six months post-removal. Patient characteristics and VTE frequency were compared using Fisher's exact and Mann Whitney U tests. Overall survival (OS) was calculated using the Kaplan Meier method and compared using log-rank test.
Results
A total of 264 patients with a median age of 56 (range: 22-81) years were included in the analysis. The most common cancer types were gastric (n=78, 29.5%), colorectal (n=61, 23.1%), pancreatic (n=51, 19.3%), and breast (n=45, 17%). 148 (56.1%) had metastatic disease.
According to RAMs, 72 (27.3%) had Khorana score &gt;2, 131 (49.6%) had COMPASS score &gt;6, and 42 (15.9%) had ONCOTEV score &gt;1.
During a median follow-up of 11.8 (range: 0.2-29.6) months, VTEs were reported in 51 (19%) of patients, occurring at a median of 3.6 (range: 0.1-20.3) months after ICVAD insertion. 27 (53%) were line related. VTEs were more frequent in patients with history of diabetes (p=0.02), a white blood cell count &gt; 11 X 103/μL at the time of line insertion (p=0.037), and when the time from diagnosis to line insertion was &gt;6 months (p=0.038).
When evaluating the three RAMs for correlation with VTE, there was no significant correlation between VTEs and Khorana (VTE rates: 16% in the low-risk group and 22% in the high-risk group, p=0.075) or COMPASS (VTE rates: 17% in the low-risk group and 21% in the high-risk group, p=0.4) risk groups. However, VTEs were significantly correlated with the ONCOTEV risk (VTE rates: 17% in the low-risk group vs 31% in the high-risk group, p=0.037). The occurrence of VTEs was associated with inferior OS, with 1-year OS rates of 63% vs 75%, (p=0.028).
Conclusion
Cancer patients receiving chemotherapy through ICVAD are at high risk for VTEs. Among the assessed models, ONCOTEV RAM was the most effective to predict VTEs in this group of patients. Further studies are needed to explore the potential role of prophylactic anticoagulation in this context.
ULK1 Regulates the Proliferation and Differentiation of Erythroid Progenitors
Authors: Chen Yijin , Zheng Haiqiong , Luo Qian , Huang Mengmeng , Zhang Meng , Qian Pengxu , Huang He 
Published: December 2024

Erythropoiesis depends on the proliferation and differentiation of erythroid progenitors. However, underlying mechanism of balance of these two processes in erythroid progenitors is largely unknown. Unc-51 like autophagy activating kinase 1 (ULK1) drives the maintenance and differentiation of stem cells, and ULK1 keeps low expression in erythroid progenitors and rapidly increases during differentiation. Therefore, we hypothesize that the proliferation of progenitor cells and their transition to differentiation is regulated by increasing expression of ULK1.
To explore the function of ULK1 in erythroid progenitors, ULK1 was inhibited by inhibitor SBI-0206965 (SBI) or ULK1 shRNA at day 4 (D4) during UCB-derived erythroid differentiation in vitro. Quantifying treated progenitors by colony-forming assay and flow cytometry indicated ULK1 influenced erythroid differentiation at CFU-E cell stages. The results showed that the differentiation of CFU-E cells was depressed, but their proliferation was enhanced when ULK1 was inhibited. Meanwhile, opposite results were observed when over-expressing ULK1 in erythroid progenitors. Moreover, the number of mitochondria, cell cycle, and apoptosis were not impacted by inhibiting ULK1. Further, the proteomics and RNA-sequencing data showed that the expression of AHR signaling-related genes like CYP1B1, CYP1A1, and AHRR were up-regulating by ULK1 inhibition suggesting the activation of AHR. Both AHR antagonist StemReginin 1 and AHR shRNA rescued the effects of ULK1 repressed in erythroid progenitors. We also observed that the number of AHR in the nucleus was increased, though the total expression of AHR was slightly decreased due to ULK1 inhibition, indicating that ULK1 plays a role in regulating AHR activation.
Mechanically, we demonstrated that ULK1 directly interacted with AHR in cytoplasm, and phosphorylates Ser-73 of AHR. Then phosphomimetic (Ser-73 –&gt; Asp, AHRS73D) and loss-of-function (Ser-73 –&gt; Ala, AHRS73A) mutants were generated respectively to study whether Ser-73 of AHR can impact differentiation erythroid progenitors. Compared to AHRWT, AHRS73D promoted the differentiation, while AHRS73A showed the opposite result. Meanwhile, we observed that more AHRS73D were located in the cytoplasm, while more AHRS73A were located in the nucleus. These results were consistent with the observations of ULK1. Together, our data indicate that during the differentiation of erythroid progenitors, increased expression of ULK1 inhibited AHR translocated to the nucleus by phosphorylating Ser-73. On the contrary, low expression of ULK1 benefits AHR translocated to the nucleus, which enhances the proliferation of erythroid progenitors.
Characterizing the Microbiome-Immune Axis in Hematopoietic Stem Cell Recipients
Authors: Becker Sabrina A. , Enssle Julius C. , Wilke Anne C. , Pfundt Sylvia , Zeltner Nico , Jankovic Ana , Wolf Sebastian , Wichelhaus Thomas A. , Kempf Volkard A. J. , Vehreschild Maria J. G. T. , Serve Hubert , Oellerich Thomas , Steffen Björn , Scheich Sebastian 
Published: December 2024

Hematologic diseases such as malignant lymphomas and multiple myelomas are potentially life-threatening diseases, that can be treated with high-dose chemotherapy (HDCT) and subsequent autologous stem cell transplantation (HSCT). However, these therapies lead to severe immunosuppression and an increased risk of infection. Recent studies have demonstrated the importance of gut microbiome diversity for treatment efficacy and preclinical data suggests a direct crosstalk between the microbiome and the immune system of the host. Although it is known that the gut microbiome can impact immune cell subsets, the impact of the microbiome on the immune cell reconstitution in transplant recipients is largely unknown. Therefore, we investigated the effect of the gut microbiome on immune cell reconstitution and outcomes in patients receiving HDCT and autologous HSCT.
We collected paired fecal and blood specimens from patients at five defined time points before and up to 100 days after autologous HSCT. The microbiome diversity and composition were assessed using 16S amplicon sequencing and in a subset metagenomics sequencing. To characterize the immune cell changes, we set up a large flow cytometry panel defining NK, B and T cells including a variety of their subsets e.g. regulatory T cells.
Overall, we analyzed 815 stool samples from 222 patients and 151 matched blood samples from 90 patients. Our data show that microbiome diversity decreases rapidly after autologous stem cell transplantation, hitting a nadir around 14 days post-HSCT, and recovers thereafter up to day 100, similarly in lymphoma and multiple myeloma patients.
To model the microbiome data over time, we utilized multi-omics factor analysis accounting for temporal relationships (MEFISTO) among the samples. Here, the bacterial family of Prevotellaceae was frequently represented among the top variance-explaining latent factors. Immune cell profiling revealed that patients with a high abundance of Prevotellaceae had significantly higher CD4+ lymphocyte counts (p = 0.04) and higher activated CD4+ counts after autologous HSCT. Furthermore, high Prevotellaceae abundance was associated with a significantly increased overall survival (p = 0.02) after autologous HSCT. Notably, the main cause of death in these patients were infections (47 %).
Our findings indicate an association between specific bacterial families and certain immune cell subsets in patients receiving autologous HSCT, that translates into clinical outcome differences. This data opens the rationale for microbiome reshaping studies in stem cell recipients to prevent infectious related deaths.
Lactate Metabolism-Related Genes to Predict the Clinical Outcome and Molecular Characteristics of Multiple Myeloma
Authors: Shu Lingling , Zhu Ziang , Li Yang , Huang Hanying , Chen Xiaoqin , Xia Zhongjun , Liang Yang 
Published: December 2024

Background Metabolic reprogramming is a hallmark of cancer progression and holds great significance for the tumor microenvironment (TME). Lactate, as an abundant metabolite, has been found to play a critical role in the development of cancer and in the immunosuppression of TME. However, the potential role of lactate metabolism-related genes in multiple myeloma (MM) remains unclear.
Methods RNA sequencing data and clinical information of multiple myeloma (MM) were obtained from The Cancer Genome Atlas (TCGA) database. Lactate metabolism-related genes (LMRGs) were sourced from Molecular Signature Database v7.4, and then compared with the candidate genes from TCGA to obtain the final gene set. Prognostic genes were screened using univariate analysis and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. A lactate metabolism-related risk profile was constructed using multivariate Cox regression analysis. The signature was validated by time-dependent ROC curve analysis and Kaplan-Meier analysis. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional analysis were performed to compare high-risk groups with low-risk groups. CCK8 assays were utilized to assess the proliferation ability of MM cells. Transwell assay was employed to detect their migration ability. Intracellular lactate content as well as glucose content was measured to evaluate lactate metabolism levels. Loss or gain-of-function studies were carried out using shRNA knockdown or lentiviral transduction strategies in order to investigate the precise role of LMRGs in MM.
Results We developed a risk signature based on 18 LMRGs. Kaplan-Meier curves confirmed that the high-risk group exhibited a poorer prognosis compared to the low-risk group. Subsequently, a nomogram was constructed to predict the probability of MM survival. Additionally, we conducted GO enrichment analysis and KEGG pathway functional analysis between the high and low-risk groups, which revealed significant associations with immune regulation and energy metabolism. Furthermore, we demonstrated that one of the lactate metabolism-related genes, JAMIP2, could promote myeloma cell proliferation, migration, and lactate metabolism via activating PI3K-Akt signaling pathway.
Conclusion In conclusion, this study identified and constructed LMRGs in MM, which showed high diagnostic accuracy in predicting OS in MM patients and linked to immunity and drug sensitivity. JAMIP2, which was identified as a novel molecule mediating lactate metabolism, promoted MM cell proliferation, migration and lactate metabolism through PI3K-Akt signaling pathway. Future studies are expected to validate the utility of the constructed LMRGs in MM patients.
Analyzing the Rates of Heavy Menstrual Bleeding By Anticoagulant Type in Menstruating Individuals: A Large National Database Study
Authors: Nnawuba Kingsley Chinonyerem , Citla Sridhar Divyaswathi 
Published: December 2024

Background
Menstruating individuals on anticoagulation often underreport heavy menstrual bleeding (HMB), making direct comparisons between drugs challenging. While several studies have noted high HMB rates with anticoagulants, particularly directly acting oral anticoagulants (DOACs), data from large national datasets are lacking. This study aimed to assess and compare the prevalence of HMB among patients on different anticoagulants using a national electronic medical record database. This study aimed to assess and compare the prevalence of HMB among patients on different anticoagulants utilizing a national electronic medical record database.
Methods
Population-level data was collected from TriNETX, LLC, an administrative database containing comprehensive inpatient and outpatient data from 56 tertiary care hospitals in the United States. Data on females aged 15-45 years, from January 1, 2010, to December 30, 2023, who received a new prescription for an anticoagulant (identified by pharmaceutical name and RX Norm code), were analyzed. HMB was defined as the presence of one or more ICD-9 or ICD-10 codes for heavy menstrual bleeding diagnosis within three months after the anticoagulant prescription. Exclusion criteria included prior history of heavy menstrual bleeding, menopause, premature ovarian failure, pregnancy and known bleeding disorders (hemophilia, von Willebrand disease, thrombocytopenia, and qualitative platelet disorders). Data was summarized descriptively, and prevalence rates were calculated. Propensity score matching was completed based on age at the index event and race. The relative risk of HMB was also calculated and compared between the anticoagulants, with a p-value &lt;0.05 considered significant.
Results
A total of 433,872 females on anticoagulant therapy between the ages of 15 to 45 met our inclusion criteria. This included 341,068 patients on Lovenox, 26,075 patients on Warfarin, 26,782 patients on Rivaroxaban, 38,311 patients on Apixaban and 1636 patients on Dabigatran. Patients on Betrixaban and Edoxaban were not analyzed due to their small sample size. Our results showed that prevalence of HMB was lowest among patients on Lovenox compared to warfarin, rivaroxaban, apixaban and dabigatran (p&lt;0.05). Patients on warfarin had the highest prevalence of HMB (6.1%). Among patients on DOACs, those on rivaroxaban had the highest prevalence of HMB (5.6%). Comparative analysis between DOACs showed the following: rivaroxaban vs. apixaban (0.051 vs. 0.048; p=0.003), rivaroxaban vs. dabigatran (0.056 vs. 0.033; p=0.003), and apixaban vs. dabigatran (0.037 vs. 0.033; p=0.533). Further stratified analysis based on race, ethnicity and age is ongoing.
Conclusion:
Our study demonstrates that patients on anticoagulants have a significant risk of HMB, emphasizing the importance of careful patient history and follow-up for HMB assessment. If HMB is present, anticoagulants with lower rates of HMB should be preferred.
CD163+ Macrophages Orchestrate Tumor Immunity By Spatially Fortifying Follicular Lymphoma Against CD8+ T Cells Attack during Early Progression
Authors: Lin Zhijuan , Yu Xingxing , Hong Yan , Liu Long , Li Zhifeng , Zha Jie , Xu Bing 
Published: December 2024

B ack ground: The tumor immune microenvironment (TIME) plays a pivotal role in the development and progression of follicular lymphoma (FL). However, the evolution of TIME during progression of disease within 24 months (POD24) remains poorly understood.
Methods: We employed imaging mass cytometry with a panel of 36 meta-tagged antibodies to examine the immune architecture of lymph nodes from 13 FL patients, both at diagnosis and during POD24.
Results: Our analysis revealed a decrease in immune infiltration from the peri-follicular regions towards the follicular centers in FL. Notably, there was an increase in CD163+ macrophages within the follicles, accompanied by an upregulation of PD-1 ligands during POD24. Spatial analysis showed that FL cells tend to evade immune attacks not merely through spatial separation from CD8+ T cells but by proactively recruiting immunosuppressive cells prior to encountering these T cells. Furthermore, during POD24, more CD8+ T cells in proximity to FL cells were found interacting with macrophages rather than regulatory T cells (Tregs). There was also an observed increase in the cooperation between macrophages and Tregs, which collectively worked to subdue cytotoxic T cell activity, thereby creating a more immunosuppressed environment.
Conclusions: FL cells exhibit more aggressive evasion tactics and exist within a more immunosuppressive microenvironment during POD24. These findings suggest that immunotherapeutic strategies targeting PD-1, macrophages, and CTLA-4 may hold promise for improving outcomes in FL patients experiencing early progression.
Pro-Inflammatory Monocytes As Key Effector Cells in Peripheral Circulatory Inflammatory Storms Driven By IFN-γ and IL-6 Pathways in Imcd
Authors: Yin Xuejiao , Liu Yi , Tong Hongyan , You Liangshun 
Published: December 2024

Objective: Dysfunctional cytokine-driven inflammatory storms in patients with idiopathic multicentric Castleman disease (iMCD) are a recurring issue affecting both symptoms and mortality, yet a thorough understanding of the involved immune cells remains incomplete. A comprehensive and detailed peripheral immune landscape is crucial for effectively treating iMCD.
Design: We employed single-cell RNA sequencing of 150936 cells from a cohort of 19 individuals, including 15 iMCD patients with mild or severe disease, as well as 4 healthy controls. For validation, we also enrolled a second cohort of 108 newly diagnosed iMCD patients with available IFN-γ data from 2015 to 2024.
Results: The activation and mobilization pervasive across all immune cells subtype during flares contribute to widespread systemic inflammatory storm in iMCD. Peripheral memory B C2 cells were the main source of plasma B and activated B cells in iMCD. Additionally, this cell subpopulation is where IL-6 mRNA is predominantly found in peripheral blood mononuclear cells (PBMCs). PADI/CCL/IL7R monocytes may be the primary effector cells in peripheral circulatory inflammatory storms. These cells exhibit the highest inflammatory scores, show the greatest activation of IL-6 signaling pathways, and overproduce VEGF-A, thereby being classified as pro-inflammatory monocytes. Furthermore, pro-inflammatory monocytes stimulated the overproduction of IL6 through promoting memory B C2 cell proliferation and transitions via BAFF signaling pathway, thus forming a vicious cycle that constantly stimulates the generation and expansion of inflammatory storms. In the cell-cell communication analysis, we identified IFN-II as a crucial signaling pathway, uniquely enriched in iMCD, with the highest relative strength index in both count and weight signaling patterns. Ligand-receptor analysis showed IFNG was mainly expressed in KLCRC2 NK, GZMK NK, NKT, and CD8TEX cells, whereas IFNGR1 and IFNGR2 were mainly expressed in pro-inflammatory monocytes. Besides, the level of IFNG expression was observed to correlate with iMCD severity. In the second iMCD cohort used for validation, IFN-γ levels were positively correlated with disease severity but negatively correlated with treatment response and progression-free survival (PFS).
Conclusion: This study provided an important resource for in-depth understanding the pathogenesis of iMCD and identify additional therapeutic strategies.