bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular Components in Whole Blood Contribute to the Development of Thromboembolic Events in Patients with Pancreatic Cancer
Authors: Willems Ruth A.L. , Roest Mark , de Vos-Geelen Judith , de Laat Bas , Ten Cate Hugo 
Published: December 2023

Introduction
Thromboembolic disease is a major complication in patients with pancreatic ductal adenocarcinoma (PDAC), causing morbidity and mortality. One in five patients with newly diagnosed PDAC develops a venous thromboembolism (VTE), which is associated with a decreased overall survival time . Patients with PDAC often have altered blood cell counts, which are further affected by systemic therapy. The high thromboembolic risk in patients with PDAC may be caused by pro-coagulant effects of pancreatic cancer on blood cells. Currently, there are no risk assessment tools or biomarkers available that can identify PDAC patients at highest risk of VTE.
Aims To investigate the impact of PDAC on blood cell dependent coagulation, to characterize the high thrombosis risk in PDAC patients. To predict thromboembolic events in patients with PDAC using blood cell dependent assays, performed in whole blood.
Methods
Patients with locally advanced or metastatic PDAC (n=18) were included in a prospective, observational, case-control study (TROCOPAC study). At inclusion, before the initiation of chemotherapy, blood was collected to study whole blood (WB) coagulation profiles. Thrombin generation (TG) was measured in WB and platelet poor plasma (PPP) of 18 patients with PDAC and 18 healthy individuals matched for age and sex. The capacity of platelets to release granules was measured in a time-dependent manner upon stimulation with a PAR1 receptor agonist in WB. Patients were followed for 6 months upon inclusion. The primary endpoint was the onset of thromboembolic events, both VTE and arterial thromboembolism (ATE).
Results
Patients with PDAC have an increased endogenous thrombin potential (ETP) in whole blood. This difference was not observed in PPP, indicating a procoagulant effect caused by blood cells. Furthermore, patients with PDAC have a prolonged lag time in whole blood, while the lag time in PPP was not different between patients and controls. Platelet and white blood cell counts (WBC) significantly correlated with the WB ETP and peak in patients with PDAC, which was not observed in healthy controls. Of the 18 PDAC patients, 4 developed a VTE (22%) and 1 an ATE (6%). A shorter lag time of WB-TG and an increased maximum capacity of platelets to release granules, at study inclusion, were associated with incident thromboembolic events.
Conclusions
Patients with PDAC have an imbalanced WB-TG profile. The lag time in WB-TG and the granule release capacity of platelets predict an increased incidence of thromboembolic events. Red blood cell and white blood cell abnormalities in PDAC are associated with this disturbance in thrombin generation. Platelets and white blood cells hence appear to be a driving force in the development of thrombosis in patients with PDAC. As such, measuring hemostasis in whole blood would improve the thrombosis risk estimation in PDAC patients.
Comparative Analysis of Patient Characteristics, BTK Treatment, and Treatment Outcomes in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Cross-National Study between the United States and China
Authors: Liu Yin , Chen Yanfei , Xiao Yue , Huang Ruijian , Jiang Feng , Zhou Jifang 
Published: December 2023

Background: Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Real-world data can provide insights into factors influencing BTK inhibitor initiation and switching, enabling a comprehensive understanding of treatment patterns. This study aimed to evaluate these factors in CLL/SLL patients in the United States and Tianjin, China, and compare overall survival outcomes among patients using different BTK inhibitor types.
Methods: We conducted a comparative analysis utilizing real-world data from two sources: the Flatiron Database in the US and Tianjin Regional Healthcare Data in China. Data from both databases were analyzed to identify factors associated with BTK inhibitor initiation and switching in CLL/SLL patients. Additionally, overall survival outcomes were assessed among patients using various types of BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib.
Results: Our analysis revealed key differences in patient characteristics. Median age of US BTK users was 66 years (IQR: 58-73) vs. 61 years (IQR: 59-69) in China. Notably, the US exhibited higher rates of hypertension (40.3% vs. 9.6%), diabetes (12.4% vs, 9.1%) and infections (22.1% vs. 8.1%). BTK treatment utilization differed between the US and China: Ibrutinib 82.3% vs. 81.6%; Zanubrutinib 0.2% vs. 17.2%; and Acalabrutinib 17.5% vs. 0%.
A higher proportion of US BTK users were exposed to immunochemotherapy (50.8% vs. 19.1%). Overall survival rates at 1-year and 3-years from 1 st BTK were comparable (US 95.2% vs. China 96.4%; US 90.2% vs. China 92.3%); and from 2 nd BTK (US 98.6% vs. China 100%, US 96.4% vs. China 100%).
Conclusion: This study contributes to a comprehensive understanding of real-world BTK inhibitor initiation and switching in CLL/SLL patients from the United States and Tianjin, China. Additionally, the 1-year and 3-year OS rates from both 1st and 2nd BTK treatments were generally favorable in both regions, suggesting the effectiveness of BTK therapies in B-cell malignancies. These findings have implications for treatment decision-making and optimizing patient care in CLL/SLL.
IGF2BP1 Promotes Multiple Myeloma with Chromosome 1q Gain Via Increasing CDC5L Expression in an m6A-Dependent Manner
Authors: Xu Jiadai , Liu Peng 
Published: December 2023

Background: Multiple myeloma (MM) patients with chromosome 1q gain (1q+) are clinically and biologically heterogeneous. The underlying molecular mechanisms are still under investigation, while identification of targets for effective therapy of this subgroup of MM patients is urgently needed. We aimed to investigate the clinical significance and the regulatory mechanisms of insulin-like growth factor 2 messenger RNA (mRNA) binding proteins 1 (IGF2BP1), a N6-methyladenosine (m6A) reader, in MM patients with 1q+.
Methods: Comprehensive in silico analyses of existed public datasets (MMRF CoMMpass study) and in-house generated high-throughput sequencing datasets (RNA-sequencing, methylated RNA immunoprecipitation sequencing, and crosslinking immunoprecipitation sequencing), along with routine molecular and cellular in vitro assays, as well as in vivo animal model studies, were conducted.
Results: IGF2BP1 displays a high expression level in MM patients with 1q+ and its high expression predicts poor prognosis in these patients. IGF2BP1 overexpression promoted cell proliferation and G1-to-S phase transition of the cell cycle in H929 cells. Combinatory analyses of MeRIP-seq, RNA-seq, CLIP-seq and patients' survival data identified CDC5L as a target of IGF2BP1, which can bind the m6A sites of CDC5L mRNA to upregulate its protein abundance. Higher CDC5L expression also predicted worse prognosis of MM patients with 1q+. Moreover, both knockdown and mutation of CDC5L attenuated the pro-proliferative effect of IGF2BP1. Furthermore, IGF2BP1 inhibitor BTYNB effectively inhibited CDC5L expression in MM cells with 1q+, and suppressed the proliferation of these cells in vitro and in vivo.
Conclusions: IGF2BP1 acts as a post-transcriptional enhancer of CDC5L in an m6A manner to promote the proliferation of MM cells with 1q+. Our work identified a novel IGF2BP1-CDC5L axis and provided new insight in developing targeted therapeutics for MM patients with 1q+.
Deciphering the Epigenetic Landscape in Histiocytic Neoplasms
Authors: Salmon-Divon Mali , Meyuchas Refael , Benhamida Jamal , Shpilberg Ofer , Mazor Roei D. , Yabe Mariko , Petrova-drus Kseniya , Abdel-Wahab Omar , Diamond Eli L. , Hershkovitz-Rokah Oshrat 
Published: December 2023

Background: Histiocytic neoplasms are driven by mutations activating the MAPK/ERK pathway; however, their epigenetic landscape remains poorly understood. MicroRNAs (miRNAs) are epigenetic regulators implicated in cancer development. Moreover, DNA methylation of miRNAs affects hematological malignancies development. Our previous study identified a unique miRNA expression signature in Erdheim-Chester Disease (ECD) patients. To further understand the biological mechanisms of ECD, we investigated the involvement of miRNAs, genes, and their methylation status in ECD, Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD).
Methods: Methylation profiles of 14 LCH, 6 ECD, and 10 RDD patients were determined from histyocitic infiltrated tissues (Illumina EPIC-methylation array). These were compared to controls, suture granulomas (n=4), localized inflammatory reactions characterized by non-neoplastic histiocytic infiltrates. miRNAome data was identified by NanoString analysis and qRT-PCR.
Results: We identified significant alterations in 23,322 methylation sites (FDR&lt;0.05, |Δß|≧20%) between controls and the histiocytosis group, indicating differential epigenetic regulation. ECD and LCH exhibited a shared methylation signature distinct from RDD. Pathway analyses revealed that the differentially methylated genes (DMGs) were involved in inflammatory response, RAS, TNF, and PI3K-mTOR signaling pathways, linked to histiocytic neoplasms. Specifically, we found DMG involvement in regulation and generation of non-coding RNAs. Notably, we observed significant downregulation of the let7-miRNA family, particularly let7b, in ECD and LCH patients. Subsequent analysis revealed hypermethylation of specific CpG islands in the let7b DNA sequence, potentially silencing let7b expression in these diseases. Given the let7-miRNA family's role in regulating the MAPK pathway, this suggests a novel mechanism in the pathogenesis of these neoplasms.
Conclusions: We provide valuable insights into differential methylation patterns in histiocytosis neoplasms, highlighting the involvement of epigenetic modifications in their development and progression. This enhances our understanding of histiocytosis development and may contribute to the identification of novel diagnostic and therapeutic approaches for these patients.
A Retrospective Comparison of Allogenic and Autologous Hematopoietic Stem Cell Transplantation in Patients with T-Cell Lymphoblastic Lymphoma
Authors: Zhu Ying , You Tao , Ai Sicheng , Jin Mao , Cong Mengya , Wu Depei , Huang Haiwen 
Published: December 2023

Background: T-cell lymphoblastic lymphoma (T-LBL) is a rare type of non-Hodgkin's lymphoma accounting for 1%~2% of non-Hodgkin's lymphoma. T-cell lymphoblastic lymphoma is typically found in children and young adults, frequently affecting the mediastinum and bone marrow. It has a poor prognosis and develops quickly. It is anticipated that hematopoietic stem cell transplantation will significantly enhance the prognosis. We conducted a retrospective single center analysis aiming to compare the survival outcomes of autologous and allogeneic hematopoietic stem cell transplantation in patients with T-cell lymphoblastic lymphoma.
Methods: From our center's database, we track down 92 individuals who underwent T-LBL transplantation between August 2011 and June 2022, including 77 individuals who got allogeneic hematopoietic stem cell transplants and 15 patients who underwent autologous hematopoietic stem cell transplants.
Results：For the baseline characteristics of patients,there were significant differences in IPNHLSS staging, bone marrow involvement, IPI score and pre transplant status between Auto-HSCT group and Allo HSCT group.Group allo-HSCT had a higher proportion of bone marrow involvement (57.1% vs. 26.7%,p=0.031), a higher proportion of IPNHLSS staging as IV (57.1% vs. 26.7%,p=0.001) and a lower proportion of CR1 pre transplantations (51.9% vs. 86.7%,p=0.080).
Figure 1 had shown the survival between auto-HSCT group and allo-HSCT group.Among the 15 patients who received auto-HSCT, 2 patients received allogeneic transplantation after relapse, 1 patient died after 3.1 months of survival after secondary transplantation, and 1 patient still survived after secondary transplantation.The 3-year OS rate of auto-HSCT group was 87.7%, while the 3-year OS rate of allo-HSCT group was 65.0%（P=0.086).The 3-year PFS rate of auto-HSCT group was 74.0%, while the 3-year PFS rate of allo-HSCT patients was 73.3%（P=0.95). The 3-year NRM rate of auto-HSCT group was 0%, while the 3-year NRM rate of allo-HSCT group was 9.9%（P=0.127). The 3-year CIR rate of auto-HSCT group was 21.0%, while the 3-year NRM rate of allo-HSCT group was 25.3%（P=0.514).
Conclusion: Hematopoietic stem cell transplantation can significantly improve the prognosis of patients with T-cell lymphoblastic lymphoma. In our study, patients with T-cell lymphoblastic lymphomareceiving autologous hematopoietic stem cell transplantation and those receiving allogeneic hematopoietic stem cell transplantation have distinct baseline data, hence their survival rates also differ.
Effect of Demographic and Environmental Factors on Chronic Lymphocytic Leukemia(CLL) in the State of Colorado
Authors: Zou Yujia , Orfan Nicholas 
Published: December 2023

Various publications have examined the relationship between environmental risk factors and the development of CLL. Factors such as household income, race, altitude and air pollution have been explored. Results have been inconclusive. In this study, we examine these four factors and their possible relationship to the prevalence of CLL.
We accessed the state of Colorado all payer claims database of about 3.6 million people with dates of service from Jan 2017 to June 2020. We calculated age and sex in CLL patients. We used propensity score matching based on age and sex to generate our comparator group on a 1:1 matching scheme. We accessed US EPA 2022 data to get air quality index (AQI) for all zip codes in Colorado and US census data for household income and racial distribution by zip code. We accessed US geological survey data to determine average elevation by zip code. We assess these four factors in relation to CLL and the comparator group.
We found 3622 cases of CLL in the total population. The average age of CLL patients was 69 and the sex distribution was 74% male. After propensity matching, we identified an equal number of non CLL patients as the comparator. In analyzing CLL patients versus the comparators, we found no relationship between average elevation, racial makeup, average household income, or air quality by zip code (P=NS).
In this large statewide population, there was no effect of race distribution, household income, elevation or air quality on the prevalence of CLL.
Deep Learning for Circulating Multiple Myeloma Cell (CMMC) Enumeration with the Cellsearch System
Authors: Biasiolli Luca , Campione Arianna , Ansaloni Pietro , Gentili Nicolò , Miserendino Ramona , Signorini Giulio , Medoro Gianni 
Published: December 2023

Background
Circulating Multiple Myeloma Cell (CMMC) enumeration in blood samples with the CELLSEARCH® system is a minimally invasive assay used to quantify plasma cells in patients with Multiple Myeloma (MM) and in precursor stages MGUS and SMM 1 particularly during disease stages when a bone marrow aspirate is not desirable (Foulk et al. 2017). Currently, CMMC identification is performed by human reviewers through visual assessment, which is a time-consuming procedure that could be affected by subjective interpretations. Modern Deep Learning (DL) methods can provide a solution by automating the process of CMMC identification, thus eliminating subjectivity and producing faster and more reproducible results. The purpose of this study was to train and test an automated algorithm (for research use only) based on DL models for CMMC identification in CELLSEARCH® fluorescent images.
Methods
The DL algorithm was designed to analyze images using a segmentation and a classification network as presented in recent studies (Zeune et al. Nature MI 2020; Coumans et al. ACTC 2021). The DL classification model was trained on 5139 CMMC and 16235 non-CMMC images (training set) of fully anonymized blood samples from the CoMMpass study (NCT01454297 sponsored by the Multiple Myeloma Research Foundation) scanned by CELLTRACKS ANALYZER II® (CTAII). The test set was composed of 75 samples from the CoMMpass study with 1000 images per sample reviewed by an operator (with training and experience of reviewing CTAII images) and processed by the algorithm, for a total of 75000 images. The algorithm was compared with the human reviewer in terms of overall agreement and Cohen's Kappa of the image classification results and of correlation for the CMMC enumeration results per sample.
Results
In the test dataset, out of 75000 images in total the reviewer identified 32403 CMMCs and the algorithm 32842 CMMCs. The DL algorithm and the reviewer provided the same classification for 71711 images, thus showing very high agreement = 95.6% (Cohen's Kappa = 0.91). CMMC counts per sample and linear regression are shown in the figure: slope = 0.95 (95% CI = 0.02), intercept = 26.99 (95% CI = 11.56) and coefficient of determination R 2 = 0.99.
Conclusion
These preliminary results show the potential of applying automated algorithms to CMMC identification with the CELLSEARCH® system in order to remove human subjectivity from the review process, thus maximizing standardization among different research centers.
1) The CMMC assay is run in a CLIA/CAP certified laboratory in the US and is also New York State CLEP approved. In the EU, the CMMC assay is research use only (RUO).
Metabolomics Unveiled the Potential Role of N1-Acetylspermidine As a Biomarker in T-Lymphoblastic Lymphoma/Leukemia Monitoring
Authors: Liu Qinyu , Yang Yunfan , Xu Caigang 
Published: December 2023

Objective: For adult patients with T lymphoblastic leukemia/lymphoma (T-ALL/LBL), current methods for therapeutic response monitoring based on bone marrow examinations lack convenience. A biomarker in blood with high sensitivity can make daily monitoring easier. Our team attempted to identify easily obtained and highly sensitive T-ALL/LBL tumor biomarkers through metabolomics, and meanwhile explore potential metabolic therapeutic targets.
Methods: We performed non-targeted metabolomic analysis on archived plasma samples from 30 newly diagnosed T-ALL/LBL patients and matched controls from 2015-2018. Based on these results, we expanded the sample size to 50 patient and matched control plasmas for targeted metabolomic validation, and explored potential mechanisms using public databases.
Results: A total of 90 differential compounds were detected in non-targeted analysis. Orthogonal partial least squares discriminant analysis showed that the metabolic patterns of the patients and the controls were significantly different (R2=0.915, Q2=0.723, pR2=0.010, PQ2=0.010). KEGG pathway enrichment showed that the detected differential compounds were involved in 41 known metabolic pathways, and the methionine metabolism pathway was highly ranked. Random forest analysis verified significant differentiation between cases and controls based on metabolic differences (ROC curve AUC=0.928, p&lt;0.001), with acetylspermidine contributing most significantly. Targeted validation in the expanded cohort showed decreased methionine, increased methylthioadenosine, and significantly increased N1-acetylspermidine in patient plasma. All these three metabolites could be localized in methionine and related polyamine metabolism pathways, with N1-acetylspermidine upregulation particularly pronounced (fold change=3.590, p&lt;0.001). Plasma N1-acetylspermidine alone could effectively differentiate patients from controls (ROC curve AUC=0.888, p&lt;0.001). Public database records (GSE109231) suggested that upregulated spermidine synthase may explain this alteration in N1-acetylspermidine.
Conclusion: N1-Acetylspermidine showed promising potential as a tumor biomarker for T-ALL/LBL therapeutic monitoring, while methionine and polyamine metabolism abnormalities may constitute new T-ALL/LBL metabolic therapeutic targets.
Atrial Arrhythmia in Sickle Cell Anemia: A Missing Piece to Prevent Cerebrovascular Complications?
Authors: d'Humières Thomas , Sadraoui Zineb , Savale Laurent , Boyer Laurent , De Luna Gonzalo , Habibi Anoosha , Messonier Laurent , Calvet David , Lellouche Nicolas , Derumeaux Geneviève , Bartolucci Pablo 
Published: December 2023

Background: Although Sickle Cell anemia (SCA) patients carries an increased risk of stroke and an important left atrial (LA) remodeling, the reality of atrial arrythmia (AA) has never been prospectively assessed.
Purpose: The aim of this study was to identify the prevalence and predictors of atrial arrhythmia in SCA patients among Drepacoeur registry.
Methods: From January 2019 to November 2022, consecutive adult patients with SCA were referred to the physiology department to specifically analyze cardiac function and were prospectively included. They underwent a 24-hour electrocardiogram monitoring (ECG-Holter), transthoracic echocardiography, and laboratory tests on the same day. The primary end point was the occurrence of AA, defined by the presence of excessive supraventricular ectopic activity (ESVEA) on ECG-holter (i.e. &gt;720 premature atrial contractions [PACs] or any run ≥ 20 PACs), recent history of paroxysmal atrial fibrillation (AFib), of persistant AFib.
Results: Overall, 130 patients were included. Mean age was 45±12 years, 48% were male. AA was observed in 34 (26%) patients (17 with more than 720 PACs/day, 6 with at least a run ≥ 20 PACs, 11 with recent history of paroxysmal AFib and 5 with persistant AFib). Ageing (52±9 vs. 42±12 years, P=0,004), LA dilation (LAV i, 71±24 vs. 52±14 ml/m², P&lt;0.001) and history of stroke without underlying cerebral vasculopathy (23% vs. 7%, P=0.04) were independently associated with AA. Age and LAV i correlated with PAC load on ECG-holter (R=0,56, P&lt;0,001 and R=0,33, P&lt;0.001 respectively). Interestingly n age over 47 years or a LAV i &gt;55ml/m² could predict AA with a positive prective value of 33% and a negative one of 92%.
Conclusion: Atrial arrythmia is common in adult SCA patients and is associated with ageing, LA remodeling and considerably increases the risk of ischemic stroke. This study provides tools for early detection of AA and prevent cardiac and cerebrovascular dramatic complications in this highly vulnerable population.