bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quality of Life after Gene Therapy in Pediatric Patients with Transfusion-Dependent β-Thalassemia and Their Family Caregivers: A Prospective Cohort Study
Authors: Kuang Zhexiang , Wang Anni , Yu Xiao , Xu Jing , Wang Weiwei , Xu Chun , He Xintong , Yuan Weiping , Shi Jun , Xu Li , Xie Wenjun 
Published: December 2024

Objectives To investigate the impact of gene therapy on the health-related quality of life (HRQoL) of pediatric patients with transfusion-dependent β-thalassemia (TDT), and to assess the changes in anxiety and depression levels among their family caregivers during the therapy.
Methods A total of 9 pediatric patients with TDT and their family caregivers were enrolled in this prospective cohort study from July 2020 to July 2023. The Chinese version of the Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) was used to compare changes in children's HRQoL before and 6 months after receiving gene therapy. The Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD) were used to assess the anxiety and depression levels in the family caregivers before and after children's gene therapy.
Results The TDT patient cohort included 3 males and 6 females with a median age of 12 years (range: 5-16 years). The total PedsQL 4.0 score post-gene therapy was significantly higher than the pre-gene therapy score (post: 90.46±11.42, pre: 76.45±10.48, t=-7.79, P&lt;0.001). Scores for both physical function and school performance at 6 months post-gene therapy were also higher than those pre-gene therapy (physical function: t=-7.17, school performance: t=-5.36, both P&lt;0.001). Prior to gene therapy, 3 family caregivers had mild anxiety and 7 had mild to moderate depression. After gene therapy, 1 caregiver had mild anxiety and 1 had mild depression. There was a statistically significant difference in the HAMD score before and after gene therapy (t=3.98, P=0.004), with medians of 9 (range: 4-15) and 4 (range: 2-8), respectively.
Conclusions The HRQoL of pediatric TDT patients improved 6 months after gene therapy, and their family caregivers experienced decreased anxiety and depression. Gene therapy can effectively enhance the health outcomes of both TDT patients and their caregivers.
ARPC2 Targeting Inhibition Progress the Proliferation Suppression of Acute Myeloid Leukemia through PI3K-AKT Pathway
Authors: Chen Chunxiao , Li Fenglin , Lu Ying , Pei Renzhi , Jin Jie , Zhuang Haihui , Li Shuangyue 
Published: December 2024

Background: Acute myeloid leukemia (AML) is a hematologic malignancy originating from the bone marrow, and its high degree of heterogeneity has led to differences in clinical treatment and prognosis. Therefore, there is an urgent need to find new potential biological targets to guide clinical treatment. Actin related protein 2/3 complex subunit 2 (ARPC2) is an actin-binding component involved in the regulation of actin polymerization. Benproperine phosphate and pimozide have been confirmed to be the target inhibitors of ARPC2. However, the role of ARPC2 and the target drugs, benproperine phosphate and pimozide, is poorly known. Therefore, this study intends to explore the expression characteristic and prognosis significance of ARPC2 in AML, as well as to explore the effect by target inhibition of ARPC2 by benproperine phosphate and pimozide in AML .
Methods: Threedataset of AML patients were obtained from TCGA, GTEx and GEO. The relationship between ARPC2 expression and survival of AML patients was analyzed by Kaplan-Meier curves and Cox regression. The main pathways of ARPC2 in AML were analyzed by Gene Set Enrichment Analysis (GSEA) . The toxic effects of benproperine phosphate and pimozide in AML cells were examined by MTS assay. The effects of target inhibition of ARPC2 by benproperine phosphate and pimozide in AML cells were analyzed by Real-time fluorescence quantitative PCR (RT-qPCR) . Cell proliferation was detected by MTS assay, apoptosis was detected by flow cytometry, and the expression of relevant proteins was detected by Western Blot (WB).
Results: Combining TCGA, GTEx and GEO databases, we found that ARPC2 was highly expressed in AML patients (P&lt;0.001). Survival analysis showed that AML patients with high ARPC2 expression had poor prognosis (P&lt;0.05). Univariate and multivariate Cox regression analyses showed that high expression of ARPC2 was an independent poor prognostic factor for AML (P&lt;0.05). GSEA analyses showed that PI3K-AKT pathway, MTORC1 signaling pathway, oxidative phosphorylation and oxidative stress were significantly activated in ARPC2 high expression group. Targeting ARPC2 by benproperine phosphate and pimozide had a significant cytotoxic effect on AML cells with significant concentration and time dependence. Through WB analysis, we found that both benproperine phosphate and pimozide could suppress the apoptosis proteins, such as BCL-2. They could also suppress the PI3K and AKT proteins, which are the key proteins of PI3K/AKT pathway, and this consistent with GSEA analysis.
Conclusion: High expression of ARPC2 is an independent adverse prognostic factor for AML patients. Benproperine phosphate and pimozide can inhibit the proliferation and promote apoptosis of AML cells by targeting ARPC2 through PI3K-AKT pathway, which may provide a new idea for the future targeted therapy of AML.
Targeting p53 Improves Drug Resistance in Mantle Cell Lymphoma By Regulating Mitophagy-Dependent Ferroptosis
Authors: Chen Yingtong , Yang Ping , Zhang Weilong , Wang Jing , Gao Shuang , Yang Yuan , Liu Shuozi , Li Chunyuan , Jing Hongmei 
Published: December 2024

Background: Drug resistance in mantle cell lymphoma (MCL) represents a critical challenge in clinical practice. Our preliminary findings indicated a high p53 mutation rate in drug-resistant MCL patients, accompanied by diminished expression of mitophagy-related markers PINK1 and Parkin, and elevated level of the ferroptosis-related marker GPX4 in these resistant cases. This study aimed to explore the regulatory relationship between p53, mitophagy, and ferroptosis in MCL.
Methods: The expression ofPINK1, Parkin and GPX4 was detected in MCL patients and MCL cell lines (Jeko, Mino, Rec1, Z138 and JVM2 cells).The correlation between p53 expression and the expression of PINK1, Parkin, and GPX4 in MCL patients was analyzed via GEO database. MCL cell lines were treated with APR-246, an agent targeting mutant p53, and then cell proliferation, gene expression and ROS level were determined by CCK-8, qPCR and flow cytometry. The regulatory mechanism between p53 and PINK1 was revealed by CUT&Tag technology.
Results: Compared with chemotherapy sensitive MCL patients, chemotherapy resistant MCL patients have lower expression of mitophagy-related genes PINK1 and Parkin, and higher expression of ferroptosis-related gene GPX4. Low expression of Parkin and high expression of GPX4 were associated with poor prognosis in MCL patients. Besides, p53 expression was positively correlated with PINK1 expression and negatively correlated with GPX4 expression in GSE93291 database. In p53-mutant MCL cells (Mino and Rec1), the expression of PINK1 and Parkin was lower than that of p53-deficient MCL cells (Jeko) and p53-wild type MCL cells (Z138 and JVM2), while the expression of GPX4 and SLC7A11 was higher than that of p53-deficient and p53-wild type MCL cells. APR-246 showed significant inhibitory effect on cell proliferation of p53-mutant MCL cells, while its inhibitory effect was not strong on p53-deficient and p53-wild type cells. After APR-246 intervention, the expression of PINK1 and Parkin was significantly increased, the expression of GPX4 and SLC7A11 was significantly decreased, and ROS accumulation was observed in p53-mutant cells. However, these phenomena were not occurred in p53-deficient and p53-wild type cells. CUT&Tag assay revealed mechanistically that PINK1 was transcriptionally activated by p53.
Conclusions: Our study elucidates the specific mechanism by which targeting mutant p53 could improve drug resistance in MCL by regulating mitophagy-dependent ferroptosis, and provides a new therapeutic strategy for chemotherapy resistant MCL patients.
Senescence Gene Senex May Regulate Apoptosis Signaling Pathway, Stem Cell Signaling Activation and Tumor Microenvironment to Promote Tumorigenicity and Invasiveness of Burkitt Lymphoma Cell
Authors: Zhai Zhimin , Li Qian , Tao Qianshan , Ren Xiyang , Guo Jinjing , Wang Huiping 
Published: December 2024

Background: The SENEX gene, encoding the protein ARHGAP18, is thought to be involved in the development of various diseases. Previous studies have shown that the SENEX gene may trigger tumor cell senescence and is highly expressed in relapsed and refractory lymphoma. However, the mechanism of action of the SENEX gene in Burkitt's lymphoma remains unclear.
Methods: We verified the effect of SENEX gene-induced cellular senescence on RAJI cell through a series of functional experiments, including senescence-associated-β-galactosidase(SA-β-Gal) staining, cell proliferation, apoptosis and Transwell assays. The effects of SENEX gene-triggered senescence on the expression levels of senescence-related proteins, EMT-related proteins and WNT/β-catenin signaling pathway star proteins were detected by Western blot experiments. In addition, we established an immunodefic ient mice model of subcutaneous xenografts to observe the effects of SENEX gene-triggered tumor cell senescencehe biological characteristics and survival of lymphoma in vivo.
Results:Chemotherapy-induced SIPS significantly improves the SENEX gene and senescence-associated proteins, promoting resistance to apoptosis and leading to drug resistance. Through in vitro experiments, we found that SENEX gene-mediated SIPS affects the levels of senescence-associated proteins, enhances tumor cell apoptosis resistance, and increases tumor invasiveness via epithelial-mesenchymal transition (EMT) and the WNT/β-catenin pathway. In vivo experiments revealed that both chemotherapy-induced and SENEX gene-mediated SIPS promote malignant growth of mouse xenografts and reduce survival time. The mechanisms involve resistance to apoptosis through cellular senescence, tumor invasion and metastasis promotion via the WNT/β-catenin signaling pathway, and tumor progression through alterations in the tumor microenvironment.
Conclusion: Our study reveals that the SENEX gene can regulate the apoptosis signaling pathway, stem cell signaling activation and reprogram the tumor microenvironment to promote tumorigenicity and invasiveness of Burkitt's lymphoma cells both in vitro and in vivo. The SENEX gene may be a potential therapeutic target for Burkitt's lymphoma.
Molecular Characteristics of Bone Marrow Mesenchymal Cells in Ph+ Acute Lymphoblastic Leukemia and Their Protective Effects on Leukemia Cells
Authors: Mi Yingchang , Fang Qiuyun , Hao Qishan 
Published: December 2024

Objective: The study aimed to compare the biological characteristics of bone marrow mesenchymal cells (MSCs) in patients with Ph-positive acute lymphoblastic leukemia (Ph+ ALL) with different disease states, to identify the differences in cyto-protective effects of MSCs with different disease states on leukemia cells and explore the possible mechanisms.
Methods: Bone marrow samples were collected from patients with Ph+ B-ALL and healthy donors, cultured to obtain primary MSCs, passaged and identified. The proliferation ability of MSCs in vitro and the impact on the migration ability of Ph+ ALL cell line SUP-B15 in each group were tested. MSCs from different groups were co-cultured with SUP-B15, and apoptosis of SUP-B15 cells after treated with drugs (imatinib, dasatinib, dexamethasone) was detected. Transcriptome sequencing was performed on MSC cells from different disease states. RT-PCR method was used to detect the expression level of target gene in MSCs.
Results: (1) Donor (DR) MSCs proliferated more strongly than ALL - MSCs in vitro (P &lt; 0.01). Proliferation ability in vitro of MSCs from relapsed and refractory (RR-MSCs) ALL patients was stronger than that of MSCs from complete remission group (CR-MSCs) and MSCs in newly diagnosed ALL group (ND-MSCs) (P &lt;0.05, P &lt;0.05).
(2) After treatment with the drugs, proportion of apoptosis in SUP-B15 cells was significantly reduced in co-culture group. The protective ability of DR-MSCs and ND-MSCs were more marked than CR-MSCs (P &lt; 0.001, P &lt; 0.05, P &lt; 0.01, P &lt; 0.0001; P &lt; 0.05, P &lt; 0.05, P &lt; 0.05, P &lt; 0.001).(3) GO enrichment analysis of transcriptome sequencing results showed that BMP4 was significantly up-regulated in ND-MSCs compared with DR-MSCs (FC=3.311, P. adj=0.024). The expression levels of BMP4 in ND-MSCs and RR-MSCs were higher than those in DR- MSCs (P&lt;0.05, P&lt;0.01); RR-MSCs showed higher expression levels of BMP4 than CR-MSCs (P&lt;0.05); CR-MSCs showed lower expression levels of BMP6 than ND-MSCs (P&lt;0.05), CR- MSCs BMP6 expression was also lower in ND-CR matched MSCs than ND- MSCs (P&lt;0.05).
Conclusion: Ph + ALL-MSCs showed weaker proliferative ability than DR-MSCs in vitro. MSCs derived from different disease states showed different protective effect of SUP-B15 cells from apoptosis (the protective effect of DR-MSCs and ND-MSCs are stronger than CR-MSCs). This protection was associated with the expression of genes involved in the BMP/SMADs signaling pathway.
Thrombopoietin Receptor Agonist Added to Standard Immunosuppressive Therapy for Hepatitis-Associated Aplastic Anemia
Authors: Wang Min , Ge Meili , Fang Liwei , Jing Liping , Mi Yingchang , Zhang Fengkui , Zheng Yizhou , Shi Jun 
Published: December 2024

Background: Hepatitis-associated aplastic anemia (HAAA) is a rare variant of severe aplastic anemia (SAA) characterized with a syndrome of bone marrow failure that traditionally occurs within 6 months of an acute attack of hepatitis. HAAA is potentially lethal if left untreated. Management includes immunosuppression with antithymocyte globulin and cyclosporine and allogeneic hematopoietic stem cell transplantation. Addition of thrombopoietin receptor agonist (TPO-RA) improves both the overall response rate and complete response rate of SAA patients. Here, we tried to investigate the effect and adverse events of TPO-RA added to standard immunosuppressive therapy for HAAA.
Methods: A total of 17 HAAA patients who received ATG, cyclosporine and TPO-RA as first-line treatment between April 2019 and January 2024 were enrolled. 6 patients were SAA and 11 patients were very severe aplastic anemia (VSAA) according to the criteria of the International Aplastic Anemia Study Group. All TPO-RAs were added within 1 months after ATG initiation at dose of their standard administration respectively.
Results: Of all the patients, 8 received avatrombopag (2 with SAA and 6 with VSAA), 5 received eltrombopag (1 with SAA and 4 with VSAA), and 4 received hatrombopag (3 with SAA and 1 with VSAA). The median neutrophil count was 0.23 (range 0.01-0.78) ×109/L, median reticulocyte count was 11 (range 1-40) ×109/L, and median platelet count was 5 (range 1-12) ×109/L. All patients achieved the end-point of 3 months and 16 patients achieved the end-point of 6 months. The rate of complete response was 11.8% and rate of overall response was 52.9% at 3 months. The rate of complete response at 6 months was 41.2% and rate of overall response was 70.6%. The overall response rate of patients treated with avatrombopag, eltrombopag and hatrombopag were 37.5% vs 40% vs 100%, and 62.5% vs 60% vs 100% at 3, 6 months after IST, respectively. The overall response rate at 3 months and 6 months were both higher than historical results of standard IST (ATG and cyclosporine, 34.1% at 3 months and 56.1% at 6 months). All TPO-RAs were safe, and there was no drug-related liver dysfunction. No patient discontinued TPO-RA due to adverse events.
Conclusions: In conclusion, the addition of TPO-RA to IST was safe and associated with higher overall response rate among patients with HAAA.
Engineering Next-Generation CAR T Cells Via Genetic Screens
Authors: Datlinger Paul , Pankevich Eugenia , Arnold Cosmas D , Pranckevicius Nicole , Lin Jenny , Romanovskaia Daria , Schäfer Moritz , Orts Anne-Christine , Nemc Amelie , Biesaga Paulina , Chan Michelle , Neuwirth Theresa , Ladstaetter Sabrina , Piras Francesco , Li Wentao , Krausgruber Thomas , Bock Christoph 
Published: December 2024

The successes of genetically engineered chimeric antigen receptor (CAR) T cells in B cell
leukemia and lymphomas have revolutionized the field of immunotherapy. However, durable
remission is only achieved in a subset of patients, and poor treatment efficacy has been
reported for solid tumors. These limitations often result from intrinsic dysfunctions of T cells,
such as poor proliferation, compromised effector function, or T cell exhaustion.
CRISPR-based functional genetic screens assess the impact of genetic modifications at the
genome-wide level and could greatly accelerate the design of improved T cell-based
therapies. We developed a new technology, CRISPR applied by mRNA electroporation and
lentivirus, to enable efficient genome editing and high-throughput screening in CAR T cells.
The simultaneous delivery of the CAR and a CRISPR guide RNA (gDNA) enabled single-
gene perturbation as well as genetic screens with libraries of target genes in CAR T cells
directed against various antigens. Our mRNA-based protocol for the delivery of CRISPR
modifiers extends the available tool kit for genome engineering in primary human T cells
from loss-of-function mutations to precise base editing and CRISPR activation.
We performed genome-scale fitness-based CRISPR screens in human T and CAR T cells. We
uncovered gene regulators specific to TCR-driven and CAR-driven proliferation. Moreover,
our screens robustly identified canonical immunotherapy targets such as CTLA4, along with
genes that have not been characterized in T cells. We have thus demonstrated the high
scalability and efficiency of our technology and created a comprehensive map of genetic
perturbations tuning CAR T cell performance.
Our platform is compatible with CROP-seq technology for single-cell CRISPR screens and
with pooled in vivo screening of CAR T cells in a mouse leukemia model. Thus, the
technology enables unbiased immunotherapy target discovery, and can be applied for high-
throughput characterization of functional regulators in primary human cells.
Association between Waist Circumference, Body Mass Index, High-Density Lipoprotein Cholesterol Level, and Risk of Chronic Myeloid Leukemia
Authors: Kim Ka Young , Han Kyung Do , Yoon Jae-Ho , Lee Sung-Eun 
Published: December 2024

Advances in the treatment of chronic myeloid leukemia (CML) have resulted in increased prevalence. However, a more comprehensive understanding of its pathogenesis and epidemiology is necessary. Recent studies suggested the association between altered lipid metabolism and carcinogenesis, prompting an investigation of the relationship between metabolic disorders and incidence of CML. Thus, we conducted a study to examine the association between waist circumference, body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), and the incidence of CML.
Using data from the Korean National Health Insurance Service from 2009 to 2017, a competing risks regression was conducted to examine the hazard ratios of CML in 3,879,560 individuals aged 20 years and above.
During a mean of 10.13±1.24 years of follow-up, there were a total of 848 cases of CML, including 539 male and 309 female patients.
1) Individuals in the group with a waist circumference equal to or greater than 100cm had the greatest risk of CML (adjusted hazard ratio [aHR], 95% CI = 1.593, 1.058-2.398), compared to those with a waist circumference from 80 to less than 85cm.
2) Those with a BMI less than 18.5 showed the lowest incidence of CML ([aHR], 95% CI = 0.509, 0.278-0.931) in comparison to the reference population with a BMI between 18.5 and 22.9.
3) Individuals in the highest quartile of HDL-C had the lowest risk of CML ([aHR], 95% CI = 0.795, 0.657-0.961) compared to those in the lowest HDL-C quartile.
A large waist circumference was significantly associated with increased risk of CML, whereas a low BMI and high HDL-C were associated with a reduced risk of CML. This suggests that a large waist circumference may be an independent risk factor of CML, whereas a low BMI and high HDL-C may be association with a protective effect against CML.
Predicting Vaso-Occlusion in Sickle Cell Disease By Microfluidics and Modeling
Authors: Ji Catherine , Chen Yi-Hua , Peng Zhangli 
Published: December 2024

Sickle cell disease (SCD) affects approximately 100,000 Americans and occurs in 1 out of every 365 African-American births. One of the most debilitating symptoms of SCD is pain crisis caused by sickled red blood cells clotting microvasculature, which is termed vaso-occlusion. There are currently no methods to monitor or predict pain crises. This study aims to design a method by applying a microfluidic device and modeling system to predict vaso-occlusion events in SCD.
The study was designed to incorporate experimental and modeling approaches to predict the clotting of the microvasculature. The microfluidic device monitors and records the passage of healthy and sickled red blood cells through pores that mimic the smallest human microvasculature. Blood samples were obtained from the sickle cell patients. Using this approach, the migration of normal and sickled red blood cells through the pores of the microfluidic device was monitored, and the passage time was recorded.
The recorded data was integrated with a mathematical model of the passage of sickle cells through microvasculature to predict the clotting under various conditions. Specifically, the images of blood smear from the blood samples were used to calculate the statistical distributions of different types of sickle cells and construct computational model. The cells were modeled using a multiscale cell model based on the finite element method coupled with a boundary integral model of the surrounding flows. Pressures at the physiological conditions in various microvasculatures were applied to push the cells to pass through the pores. The altered cell shape and mechanical properties of different types of sickle cells were incorporated into the multiscale model to distinct them from normal red blood cells. After calibrating the passage time against measurements in the microfluidic experiments, the probability of vaso-occlusions was predicted based on the measured statistical distributions of sickle cells and dimensions of microvasculatures.
We found that sickled red blood cells could pass through the pores in the microfluidics. However, the dynamic and quantity of the migration were significantly compromised. This is closely related to the percentages of different types of sickled red cells, reflecting the severity of patients' disease. Through the changes in the size of the microvasculatures, the possibility of clotting of various vasculature in the body can be predicted using this model with patient-specific blood smear images. In this respect, we analyzed 72 blood smears from 24 patients with sickle cell disease. The percentage of the sickle cells out of total red blood cells were quantified in each smear using a computational approach. Indeed, the frequency of sickled red cells is positively correlated with the frequency of vaso-occlusion events in these patients. We conclude that this novel design of the vaso-occlusion prediction system could be useful in predicting the clotting and pain crisis of SCD patients.