bluuebunny/crossref_metadata_2025_split huggingface dataset:
ALL-R: An Anchoring Score to Predict Relapse in Acute Lymphoblastic Leukemia (ALL) Using a Zebrafish Patient-Derived Xenograft Model
Authors: Arner Anja , Blaser Bradley Wayne , Ettinger Andreas , Schmid Bettina , Jeremias Irmela , Binder-Blaser Vera 
Published: December 2024

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Prognosis after initial diagnosis is good; however, patients suffering from relapse have a poor outcome. The tumor microenvironment is recognized as an important factor for disease relapse but little is known about the molecular mechanisms that are involved in this process.
To study microenvironment-mediated mechanisms of relapse development in ALL, we established a larval zebrafish xenotransplantation model that allows the analysis of Leukemic cells (LCs) within an orthotopic niche using time-lapse confocal microscopy.
LCs from ALL patients experiencing early relapse (ER) or no relapse (NR) collected at the time of initial diagnosis were transplanted into zebrafish embryos. LCs homed, engrafted and proliferated within the caudal hematopoietic tissue (CHT), the hematopoietic niche at the larval stage. Migration patterns within the CHT area were quantified over 12-24 hours in a semi-automated workflow. ER-LCs migrated significantly slower compared to NR LCs (12% reduction in frame-to-frame velocity). Maximum distance traveled by ER-LCs within the niche was significantly less (by 13%), compared to NR LCs. In addition, total displacement was significantly decreased by 17 % for ER-LCs, altogether indicating more restricted movement of ER LCs within the niche, and suggesting the presence of important cell-cell interactions. An anchoring score (ALL-R score) was developed to quantify the migration behavior based on velocity, maximum distance traveled, displacement, confinement ratio and straight-line speed. The ALL-R score for ER patients was significantly higher compared to that for NR patients (Mann-Whitney test, p≤0.01).
These findings suggest the application of the ALL-R score as a relapse-prognostic factor in ALL at the time of initial diagnosis.
To understand the molecular basis for these potential interactions, we performed single cell RNA-sequencing on the ER and NR samples used in the study. Gene expression profiling of LCs and monocytes in ER and NR patients revealed: 1) ER LCs were enriched for expression of adhesion molecules such as CXCR4 (log2fc 2.012288; P-value 0.030) compared to NR LCs, 2) predicted cell-cell interactions (using CellChat) were strongest between ER LCs and ER monocytes and 3) MIF-CD74/CXCR4 and CD99-PILRA were the top-scoring ligand-receptor pairs between these groups of cells.
These data suggest that early relapse in ALL may be related to enhanced LC-niche interactions via specific monocyte signaling pathways. Ongoing work is evaluating whether disruption of these pathways might be beneficial to prevent relapse in ALL.
Outcomes of Immune Thrombocytopenia in Patients with Conditions Linked to Higher Autoimmunity Risk: A National Inpatient Sample Analysis (2016-2020)
Authors: Idoate Domench Daniel , Vijay Rao Aniket , Sanjeevi Aditya 
Published: December 2024

Objective: Immune thrombocytopenia (ITP) is an acquired hematological disorder that occurs when the body produces antiplatelet antibodies that bind to circulating platelets, leading to their destruction. This study aims to analyze outcomes of ITP hospitalizations in conditions with increased risk of autoimmunity, using data from the National inpatient sample (NIS) database from 2016 to 2020.
Methods: Data regarding patients demographics, comorbidities and hospital outcomes was obtained from the NIS database 2016-2020, using international classification of diseases (ICD) code, for hospitalizations related to ITP in patients with conditions associated with a higher risk of autoimmunity, including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), Sjogren's Syndrome, Myasthenia Gravis, and Common Variable Immune Deficiency (CVID), as well as in those with Hodgkin Lymphoma, Non-Hodgkin Lymphoma, and Pregnancy. In order to compare the baseline demographics and hospital outcomes, Pearson Chi-square test was used for categorical variables and student T-Test or one-way ANOVA was used for continuous variables, with non-parametric alternatives applied when appropriate. Significance was set at &lt;0.05.
Results: A total of 6,060 patients with ITP and conditions associated with a higher autoimmunity risk were analyzed: SLE (49.50%), RA (18.73%), Sjogren's (8.09%), Myasthenia Gravis (1.24%), CVID (4.04%), Hodgkin Lymphoma (3.05%), Non-Hodgkin Lymphoma (14.60%), and Pregnancy (0.74%). Non-Hodgkin lymphoma had the highest proportion of older patients while SLE and Sjogren were the groups with the highest number of females. SLE was the only group with a higher percentage of African-Americans (41.65%) compared to Whites (31.50%). Regarding outcomes, the highest in-hospital mortality was among Hodgkin Lymphoma (2.70%, p=0.011), while the highest risk of respiratory failure was among non-Hodgkin lymphoma patients (5.08%, p&lt;0.001). The highest number of major bleeding events (30%, p&lt;0.001) and use of IVIG (24.50%, p=0.0009) was among SLE patients. There were no significant differences in the use of PLEX (p = 0,091) between groups. Hospitalization costs and length of stay were significantly higher for Hodgkin Lymphoma ($23,855.80, 4 days, p&lt;0.001), followed by Non-Hodgkin Lymphoma ($19,379.93, 4 days).
Conclusion: This study highlights significant differences in outcomes for ITP patients with conditions that increase the risk for autoimmunity. Lymphoma patients had the highest in-hospital mortality, risk for mechanical ventilation, as well as the highest hospitalization costs and length of stay, while major bleeding was significantly more common among SLE patients. Further research is needed to assess the potential implications of these different conditions and the role they play in ITP outcomes.
Antitumour Effects of Human Antithymocyte Alobulin on Peripheral-T Cell Lymphoma Via Complement-Dependent and -Independent Cytotoxicity in Xenograft Mouse Models
Authors: Gao Beibei , Hu Jiong , Yan Jinsong 
Published: December 2024

Background
Peripheral T-cell lymphomas (PTCL) is a group of non-Hodgkin lymphomas characterised by substantial molecular heterogeneity, rapid progression, poor therapeutic response, and unfavourable outcomes. In recent clinical studies, antithymocyte globulin (ATG)-based allogeneic-haematopoietic stem cell transplantation (allo-HSCT) has markedly improved the prognosis and survival of patients with PTCL. This study aimed to explore whether ATG has toxic effects on PTCL cells and evaluate whether ATG combined with chemotherapy has a synergistic antitumour effect.
Methods
The cytotoxicity and proliferative effects of ATG were tested with the CCK-8 assay and verified using the cell colony formation assay in Hut78, Karpas299, and SU-DHL-1 cell lines. After propidium iodide (PI) staining, the proportion of cells at different cell cycle stages was measured using flow cytometry to determine the impact of ATG on the cell cycle. Transwell assays were performed to examine the effect of ATG on PTCL cell invasion. The apoptotic effects induced by ATG in PTCL cells were evaluated from three aspects, including fluorescein isothiocyante annexin-V/PI detection, mitochondrial membrane potential (∆Ψm) analysis with JC-1, and apoptosis-specific morphological changes. BALB/C-nu/nu mice were used to establish a PTCL cell-induced subcutaneous tumour model to investigate the chemotherapeutic effect of ATG and its synergistic effect with anthracycline.
Results
ATG significantly inhibited PTCL cell growth by suppressing cell proliferation and colony formation. Moreover, ATG treatment decreased cell invasion; however it had no effect on cell cycle arrest in PTCL cells. ATG induced PTCL cell apoptosis, which was partially reversed by pan-caspase inhibitor and caspase 8 inhibitor. Additionally, ATG was able to induce complement-dependent cytotoxicity in PTCL cells. Most importantly, the combination of ATG and doxorubicin exhibited enhanced effectiveness against PTCL cells both in vitro and in vivo, suggesting that ATG can exert a synergistic antitumour effect when administered with doxorubicin.
Conclusion
ATG can exert cytotoxic effects in PTCL cells by activating the caspase-dependent apoptotic pathway and complement-dependent cytotoxicity and can exert a synergistic antitumour effect when combined with traditional anthracyclines in vitro and in vivo. This study provides a scientific basis for the clinical application of ATG for PTCL treatment.
In Vivo CAR Delivery As Supercoiled DNA with Polyasparagine Nanoparticles
Authors: Lee Claudia Y , Zhang Grig , Coker Chris Y , Zheng Sisi 
Published: December 2024

Background
Strategies for in vivo reprogramming of immune effector cells have been proposed in the hope to recapitulate the success of ex vivo engineered chimeric antigen receptor t cells (CAR-T) while reducing the manufacturing burden, improving the safety profile and recruiting collaborating immune cell types to expand the appliable indications. Viral and non-viral vectors with tissue tropism selected for in vivo reprogramming applications have been attempted, and the efforts to fully address the off-tissue delivery safety concerns for viral vector and a clinically viable dosing scheme to demonstrate efficacy with the brief durability of mRNA in non-viral vectors continue.
Methods
We deploy CAR encoded in supercoiled DNA formulated with multi-arm polyasparagine nanoparticles (STAR). The physical characteristics, the stability, the molecular dynamics and the biodistribution of the DNA/polyasparagine polyplex were characterized. Anti-murine CD19 CAR expression, its durability and the efficacy as the result of the polyplex transfection were evaluated in vitro and in vivo in blood, livers, lymph nodes, spleen and lungs.
Results
The cationic STAR was found to have half-life of less than 24 hours in PBS, while the expression of the DNA payload sustained over one week. 40ug of DNA delivered by 125ug of STAR was tolerable in mice. The polyplex was found to transfect lymphatic tissue, primarily t-cells, following tail vein injection. The DNA encoding anti-murine CD19 CAR was able to achieve b cell ablation in mouse PBMC and in vivo.
Conclusions
We demonstrated a novel technology platform for in vivo CAR delivery.
Inflammation-Driven NFκB Signaling Represses Ferroportin Transcription in Macrophages Via HDAC 1 and 3
Authors: Marques Oriana , Horvat Natalie , Zechner Laura , Colucci Silvia , Sparla Richard , Zimmermann Stefan , Neufeldt Christopher , Altamura Sandro , Ruiyue Qiu , Müdder Katja , Weiss Guenter , Hentze Matthias , Muckenthaler Martina U. 
Published: December 2024

Anemia of Inflammation is a prevalent co-morbidity in patients with chronic inflammatory disorders.
Inflammation causes hypoferremia and iron-restricted erythropoiesis by limiting Ferroportin (Fpn)-
mediated iron export from macrophages that recycle senescent erythrocytes. Macrophage cell surface
expression of Fpn is reduced by hepcidin-induced degradation and/or by repression of Fpn (Slc40a1)
transcription via cytokine and Toll-like receptor (TLR) stimulation. While the mechanisms
underlying hepcidin-mediated control of Fpn have been extensively studied, those inhibiting Slc40a1
mRNA expression remain unknown. We applied targeted RNA interference and pharmacological screens in
macrophages stimulated with the TLR2/6 ligand FSL1 and identified critical signalling regulators of
Slc40a1 mRNA repression downstream of TLRs and NFкB signaling. Interestingly, the NFкB regulatory
hub is equally relevant for Slc40a1 mRNA repression driven by the TLR4 ligand LPS, the cytokine
TNFβ/LTA and heat-killed bacteria. Mechanistically, macrophage stimulation with heat-killed
Staphylococcus aureus recruits the Histone deacetylases (HDAC) 1 and 3 to the antioxidant response
element (ARE) located in the Slc40a1 promoter. Accordingly, pre-treatment with a pan-HDAC inhibitor
abrogates Slc40a1 mRNA repression in response to inflammatory cues, suggesting that HDACs act
downstream of NFкB to repress Slc40a1 transcription. Consistently, recruitment of HDAC 1 and 3 to
the Slc40a1 ARE following stimulation with heat-killed Staphylococcus aureus is dependent on NFκB
signaling. These results support a model in which the ARE integrates the transcriptional responses
of Slc40a1 triggered by signals from redox, metabolic and inflammatory pathways. This work
identifies the long-sought mechanism of Slc40a1 transcriptional downregulation upon inflammation,
paving the way for therapeutic interventions at this critical juncture.
Molecular Outcome of Chronic Myeloid Leukemia Affected Patients Not in Deep Molecular Response: The “Others” from the Gimema Labnet Network
Authors: Stagno Fabio , Cucci Rosalba , Marsili Giovanni , Castagnetti Fausto , Galimberti Sara , Izzo Barbara , Sorà Federica , Soverini Simona , Messina Monica , Piciocchi Alfonso , Bonifacio Massimiliano , Cilloni Daniela , Iurlo Alessandra , Martinelli Giovanni , Rosti Gianantonio , Fazi Paola , Vignetti Marco , Breccia Massimo , Allegra Alessandro , Pane Fabrizio 
Published: December 2024

Introduction: CML is now managed as a chronic disease requiring both long-term treatment and close molecular monitoring in most patients. Evidence suggests that in a substantial number of patients (pts) who achieved a stable deep molecular response (DMR) TKI treatment can be safely discontinued. Therefore, treatment-free remission (TFR) is increasingly regarded as a feasible treatment goal in about 20% to 40% CML pts. Nevertheless, a proportion of pts with chronic-phase CML treated with TKIs still remain in stable major molecular remission (MR3) or less (MR2 only), do not achieve a DMR and therefore require long-term TKI therapy.
Patients and Methods: Hence, we focused our clinical attention on those CML pts not candidates for a TFR path, having achieved within 6 months, and further maintained, a stable MR3 or less (MR2) by investigating the large LabNet CML database, a network founded by GIMEMA in 2014. This network standardized and harmonized the molecular methodology among 51 laboratories distributed all over Italy for the diagnosis and the molecular residual disease monitoring.
Results: Out of 9,699 pts, 585 met study endpoints and achieved a MR2/MR3 within 6 months with a minimum follow up of 24 months. CML pts received frontline therapy as follows: 219 with IM, 133 with DAS and 233 with NIL. Within 24 months, 375 pts achieved a DMR (MR4, MR4,5), whereas 187 showed a stable MR2/MR3 response and 23 had some molecular fluctuations less than MR2. With the successive follow up &gt; 24 months, 123 out of 187 (66%) achieved a DMR, 59/187 (32%) remained in stable molecular response and 5/187 (2.7%) lost the response. No difference was observed in achieving molecular responses by the three different TKIs. Among the MR2/MR3 cohort the median time to therapy switch was 37 months. Moreover, median observation time (OT) was 5.5 yrs for the total study group (585), 5.5 yrs for the DMR group (375), 5.4 yrs for the stable MR2/MR3 (187) and 4.8 yrs for the MR2 ones (23).
Conclusion: A MR2/MR3 stable response achieved within 24 months seems predictive of a good molecular outcome since 66% of these pts obtained a DMR in the successive follow up of 24 months of. Molecular fluctuations less than MR2, although in pts with a previous obtained MR3, might represent a reliable warning sign.
Global Trends of Burden of Chronic Myeloid Leukemia Based on Socio-Demographic Index (SDI): A Comparative Epidemiological Study
Authors: Chaulagain Prashant , Poudel Ashmita , Aryal Saurav , Sainatham Chiranjeevi , Lutfi Forat 
Published: December 2024

Background:
The clinical outcome for patients with chronic myeloid leukemia (CML) has changed dramatically in the past two decades, especially after the rise of Tyrosine Kinase Inhibitors. Conversely, the outcome has been worse for countries with lower socioeconomic statuses. Comprehensive epidemiological research is warranted to evaluate the global burden of CML based on SDI.
Method:
Our team used data from the Global Burden of disease (GBD) 2021 database. The analysis was done using the Institute of Health metrics and evaluation (IHME) GBDx data tool. GBD estimated the burden of diseases, injuries, and risk factors for 204 countries and territories and selected subnational locations. Incidence, death, disability-adjusted life-years (DALYs), and its corresponding age-standardized rate between 1990 to 2021 were used to describe the distribution of CML burden according to age, sex, social-demographic index (SDI).
Results:
The incidence of CML globally in 2021 was 35830 .87(95%, 27938.95-42,581.45) as compared to 39481.75(95%, 33292.61- 45117.18) in 1990. The Estimated total percentage change in incidence has decreased in High SDI and High Middle SDI countries; however, it has increased in Middle, Low Middle, and Low SDI countries.
There were 29220.42 (95%, 23525.47-34250.55) deaths in 1990, distributed as 4% in Low SDI, 14% in Low Middle SDI, 21% in Middle SDI, 23% in high middle SDI and 38% in High SDI countries. Similarly, there were 23159.13(95%, 17502.80-28477.39) deaths due to CML in 2021. Deaths were distributed as 7% in Low SDI, 23% in Low Middle SDI, 28% in Middle SBI, 18% in High Middle SDI and 24% in High SDI Countries. The absolute change in the percentage of deaths decreased globally by -0.21 (-0.01 to -0.34). The absolute change in the percentage of death decreased in High SDI and high middle SDI countries and increased in Middle SDI, Low middle SDI, and Low SDI countries.
The Absolute Percentage Change in DALY in 2020 compared to 1990 decreased -0.36(95%, -0.14 to -0.50) globally. All categories of countries based on SDI had decreased DALY except Low SDI countries, which had an increased absolute change in DALY of 0.17.
Similar results were obtained when data was stratified by age and sex.
Conclusion
The disease burden of CML has decreased globally, especially in countries with higher SBI, in the past three decades. The increase in incidence and death rates was mainly observed in lower SDI countries. Increasing resources and aid to lower SDI countries can help to decrease the global burden of CML.
DLBCL in Older Adults: Is Age Just a Number in LMIC?
Authors: Ali Natasha , Iftikhar Raheel , Khan Zeeshan Ahmed , Ahmed Usman , Mahmood Humera , Aziz Zeba 
Published: December 2024

Background and objective: Diffuse Large B-cell Lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma in adults. Limited data is available from low middle income countries (LMIC) in patients aged more than 60 years, with DLBCL. Our objective was to determine the presentation, comorbidities, socioeconomic status (SES), treatment received and outcomes of elderly patients with DLBCL.
Subjects and methods: We conducted a multi-centre, retrospective study from 2015 till 2023 and included all adult patients diagnosed with DLBCL. Patients aged more than 60 years were included in the analysis. The variables assessed were age, gender, ECOG status, SES, presenting signs and symptoms, and treatment received. Kaplan Meier curve was plotted for all patients. T-test was used to calculate comparative means and difference in overall survival (p value &lt;0.05). SPSS version 29 was used to perform the analysis.
Results: A total of 652 cases of DLBCL were identified during the study period of which 154 (24%) patients were more than 60 years of age. The median age was 67 years. Male: female ratio was 1.3:1. Approximately 71% of our patients had ECOG performance scores between 2 and 3 and median IPI score of 3. The most common presenting symptoms were fever, weight loss and night sweats and 83% presented with advanced disease. Rituximab+CHOP (RCHOP) regimen was administered to 51% of patients. Relapse of disease was present in 24% who eventually received salvage treatment with either rituximab, ifosfamide, carboplatin, and etoposide (R-ICE), gemcitabine, cisplatin, methylprednisolone (GemP) or dexamethasone, high-dose cytarabine and cisplatin (DHAP). Approximately 65% of patients who received either first line or salvage chemotherapy were not fit enough to undergo consolidation with autologous transplant after achieving remission. In the limited resource group, 55% of patients had a median disease-free survival (DFS) of 0.4 years. In patients with enhanced resources (40%) the DFS was 1.3 years (p value 0.001). The overall survival (OS) was 0.5 years and 1.5 years in limited and enhanced resources group respectively (p value 0.002). Poor survival outcomes were related to multiple comorbidities, inability to give full dose chemotherapy and recurrent infections.
Conclusion: In 80% of the patients the most common presenting symptoms were fever, weight loss and night sweats. RCHOP was administered in approximately 50%. The DFS and OS were decreased in our cohort as compared to international literature. The OS and DFS was better in patients with enhanced as compared to limited resources group. However comorbidities, recurrent infections and poor performance status also contributed to decreased survival. The results suggest that age along with availability of resources play a vital role in management of DLBCL in LMICs.
Systematic Annotation of Secretory Pathway Genes As a Discovery Tool for New Therapeutic Targets in AL Amyloidosis
Authors: Saunders Brendan , Quetglas Carlos , Fasshauer Dirk , Elsasser Suzanne , Bianchi Giada 
Published: December 2024

Background: FLC secretion drives pathogenesis in AL amyloidosis yet molecular mechanisms underlying the protein network supporting FLC secretion are uncharacterised and therapeutic strategies targeting them do not exist. Recently, The Protesotasis Consortium (Elsasser et al.) published a comprehensive annotation of the Human Proteostasis Network; however, genes involved in the vesicular transport system from transgolgi to cell membrane (terminal secretory pathway) were not included. We were interested in systematically annotating these genes to support therapeutic discoveries in AL amyloidosis and other secretory disorders.
Methods: Genes involved in the plasma cell secretory pathway were identified by two criteria: ‘entity-based’ and ‘domain-based’. ‘Entity-based’ inclusion involved genes previously annotated in literature to be involved in the secretory pathway. ‘Domain-based’ inclusion encompassed genes containing structural domains and motifs enriched in the secretory pathway. Twelve motifs were identified: AAA, Arf, C2/Mun, SNARE, NSR, Proppin, Ras, Rhomboid, Rint, SM, SNAP, ZW10; from which novel genes were incorporated.
Results: Using the approach above, we compiled a list of 1262 putative genes involved in the secretory pathway. Entity-based inclusions encompassed 1,087 genes while domain inclusion supplemented 175 genes. We organized these genes based on subcellular localization and function. We detailed 8 localization categories and 13 function categories. We constructed a map combining these 2 variables to obtain a tentative model of the terminal secretory pathway.
Conclusion: This is the first systematic effort to compile a comprehensive, task-oriented annotation of the terminal secretory pathway with the overarching goal to support basic and translational research efforts. Seen through the lens of AL amyloidosis research, this tool will be useful to develop novel treatments targeting light chain secretion to improve outcome for patients.