bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mastl Is a New Therapeutic Target for Acute Myeloid Leukemia
Authors: Chen Fangli , Liu Ligen , Chen Huijie , Wu Yicheng , Wang Yuanqin , Fu Zhen , Zhang Tinghua , Jiang Xuewei , Lu Yingting , Zhao Limin , Li Jutang , Yang Li 
Published: December 2024

Recently, the approval of several new generation of targeted therapeutic agents greatly improved the prognosis of Acute myeloid leukemia (AML). Despite of these undeniable progresses, many patients still lack effective therapies. Moreover, resistance to the targeted agents represent major clinical challenges. Therefore, there is an unmet need to discover new therapeutic targets and overcome the resistance. In this study, our strategy is to discover a specific kinase, which can be served as monotherapy and also overcoming resistance to current venetoclax-based therapies.
Through high-throughput screening of a custom kinase inhibitor library of 500 compounds and re-analyzing genome-wide CRISPR/Cas9 screen data sets, we identified Microtubule Associated Serine/Threonine Kinase Like (MASTL) as a potential novel target for AML treatment. Public data and our in house data showed MASTL expression was significantly higher in AML patients than healthy subjects. RNAi and pharmacologic inhibition of MASTL reduced cell viability and colony formation in THP-1 and OCI-AML3 cells. MASTL knock down and MASTL inhibitor significantly reduced tumor growth in THP-1 derived subcutaneous tumor model and prolonged survival in xenograft NCG mouse model. Mechanistically, MASTL knock down induced downregulation of Survivin and upregulation of Puma in THP-1 cells. Transcriptome analysis showed MASTL suppression was associated with several signaling pathways including Rap1, Toll-like receptor, MAPK, TNF signaling pathway. Importantly, MASTL knock down dramatically suppressed the expression of S100A8 and S100A9, which is known to be involved in venetoclax resistance in AML. Both genetic and pharmacologic inhibition of MASTL reversed venetoclax resistance in venetoclax resistant cell lines. The combination of venetoclax and MASTL inhibitor significantly reduced tumor growth than each monotherapy in vivo.
In conclusion, our data suggest that MASTL inhibition is a promising strategy for AML treatment. Moreover, MASTL inhibition potentiates venetoclax response and overcome venetoclax resistance in AML.
Hematopoietic Transcription Factor PU.1 and Enhancer RNA Loup Establish a Feedforward Regulatory Loop Governing Monocyte/Macrophage Biology
Authors: Waliullah A S M , Qiu Kevin , Tran Minh L , Dziegielewska Barbara , Zhang Junyan , Tenen Daniel G. , Goldfarb Adam , Trinh Bon 
Published: December 2024

The ETS transcription factor PU.1, known for its precise expression pattern, plays a crucial role in blood development. Deviations from its normal graded levels in hematopoietic lineages are associated with blood-related neoplasms and malignancies. As a transcription factor, PU.1 binds to purine-rich DNA sequences in enhancers and promoters as well as other transcription factors to regulate gene expression. While noncoding genes are increasingly reported to control fundamental biological processes in both normal and malignant hematopoiesis, most of our understanding of PU.1's role comes from its myeloid coding target genes. Furthermore, the role of PU.1 in enhancer regulation has not been systematically explored, highlighting a critical area for future research.
In this study, we investigated the role of PU.1 in enhancer regulation. To that end, we first compiled a comprehensive catalog of putative and verified enhancers from databases and published sources. We then interrogated this catalog with a genome-wide PU.1 occupancy profile in a myeloid cell line. In doing so, we identified a repertoire of PU.1-bound enhancers in myeloid cells. Given that enhancer-associated noncoding RNAs (eRNAs) are increasingly reported to promote enhancer activities, we focused our attention on this group of noncoding genes. By interrogating the list of PU.1-bound enhancers with the PU.1-mediated transcript profile, we revealed a group of eRNAs regulated by PU.1. Among these noncoding genes, to our surprise, was the eRNA LOUP, which we had previously discovered as an RNA inducer of PU.1. We further demonstrated that PU.1 occupies a genomic region within the LOUP locus that exhibits the epigenetic features of a myeloid-specific superenhancer. In addition to its previously described role in regulating myeloid differentiation and inflammatory signaling, we demonstrated that LOUP regulates the expression of surface markers and cytokines tailored to monocyte/macrophage biology. Furthermore, our data also indicated the role of LOUP in microbial clearance.
Taken together, our findings suggest that LOUP and PU.1 are partner regulatory biomolecules within an enhancer-mediated feedforward regulatory loop that induces the expression of each other, thereby regulating monocytic/macrophage differentiation and functions. We are currently investigating RNA and protein biomolecules that control this feedforward regulatory loop and its role in myeloid neoplasms and malignancies. Our study could provide a fundamental mechanistic understanding of hematopoietic enhancer specificity and lay the groundwork for further translational studies aimed at developing new therapeutic approaches for the treatment of inflammatory diseases and hematopoietic malignancies.
Which Patients Will Benefit More?–the Impact of Different Biological Characteristics of High-Risk Acute Myeloid Leukemia on the Efficacy of Maintenance Treatment with Decitabine after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Liu Jia , Zhu Lidan , Liu Huanfeng , Gao Shichun , Wang Lu , Kong Peiyan , Zhang Xi , Gao Lei 
Published: December 2024

Background Relapse is the main cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in high-risk acute myeloid leukemia (HR-AML). Our center and other 11 HSCT centers in China in the early stage to carry out one clinical research on low-dose Decitabine maintenance treatment to prevent relapse of HR-AML after allo-HSCT. Research has found that maintenance treatment with Decitabine can reduce the relapse rate from 38.3% to 15%.Which HR-AML patients will benefit more for maintenance treatment with Decitabine are worth further exploration in clinical practice.
Methods A retrospective analysis was conducted on 296 patients with HR-AML after allo-HSCT who underwent maintenance treatment with Decitabine for more than 6 courses from February 2019 to June 2022 at our center. The impact of different biological characteristics of HR-AML include age, recurrent genetic abnormalities, mutation gene types, and history of pre-leukemia hematological diseases. The main endpoint of the study is the 2-year relapse rate.
Results Among the 296 patients, 52 were over 60 years old and 244 were under 60 years old, indicating that patients under the age of 60 are more likely to benefit from Decitabine maintenance therapy. Common recurrent genetic abnormalities include: 16 cases of t (8,21), 9 cases of inv (16), 9 cases of t (9,11), 6 cases of inv (3), 30 cases of other abnormalities, and 226 cases of no recurrent genetic abnormalities. After maintenance treatment with Decitabine, the 2-year relapse rate of patients with and without recurrent genetic abnormalities were 12.9% and 20.8%(p=0.043), respectively, indicating that maintenance treatment with Decitabine is effective for patients with recurrent genetic abnormalities. Mutated genes are mainly divided into two categories: methylation related gene mutations (151 cases) and other mutations (145 cases). The 2-year relapse rate of patients with methylation related gene mutations and other mutations were 11.2% and 21.4%, respectively (p=0.012), indicating that maintenance treatment with Decitabine is more effective for patients with methylation related gene mutations. According to the history of pre-leukemia hematological diseases, AML was divided into MDS/MPN transformed AML (54 cases) and primary AML (242 cases). The 2-year relapse rates of the two groups were 14.8% and 17.8% (p=0.12), respectively, and there was no significant difference between the two groups.
Conclusion Maintenance treatment with dexamethasone after high-risk AML transplantation is more effective in patients under 60 years old, recurrent genetic abnormalities, and methylation related gene mutations.
Novel Single-Cell RNA Technology Simplifies Measurement of Anti-BCMA CAR-Ts in Patient Samples
Authors: Chen Szu-Ying , Cienciala Martin , Rashid Tasfia , Patino Escobar Bonell , Berne Laura , Georgiev Daniel , Wiita Arun P 
Published: December 2024

Introduction: There is a critical clinical need for a technology capable of characterizing cell therapies at time points post infusion. Targeted single cell RNA sequencing (scRNAseq) of anti-BCMA CAR-T cells was performed using a novel encapsulation and barcoding approach from Sampling Human Inc. This proof-of-concept study establishes the performance capability of BCMA antigen functionalized bioparticles for universal anti-BCMA CAR-T detection and mRNA capture directly from complex samples. The platform employs a highly streamlined and instrument free workflow, enabling routine testing of patient samples and providing high-resolution activity data of therapeutic cells in vivo.
Methods: The platform's performance was assessed using a dilution series of PBMCs from a patient receiving anti-BCMA CAR T-cell therapy and a healthy donor. Each sample, consisting of approximately 10,000 cells, was analyzed through an integrated one-step workflow using anti-BCMA CAR encapsulation reagent. Samples were processed directly into barcoded libraries, foregoing separate enrichment or isolation steps, and were sequenced using a standard NGS pipeline. The results were compared to those obtained from a benchmark workflow that employs FACS isolation, followed by analysis with 10X Genomics 3' kits.
Results: The results from the novel approach show strong alignment with existing single cell technologies that employ cell sorting in series with scRNAseq, based on median genes detected (2120 genes per cell) and transcript counts (2589 UMIs per cell). Notably, the platform consistently exhibited a significantly higher mean cell recovery rate (exceeding 70%) and lower false positive rate (&lt;1% CAR-negative cells), permitting analysis on smaller sample sizes. Moreover, the approach demonstrated a decreased percentage of mitochondrial (MT) transcripts, indicating less cellular stress, and lower variability between samples compared to FACS-based methods.
Conclusion: This novel encapsulation and barcoding method from Sampling Human Inc consolidates scRNAseq of anti-BCMA CAR-T cells into a one-step protocol that greatly reduces the time and cost of analysis. The platform significantly increases access to translational scRNAseq data by eliminating isolation and sorting steps to simplify sample preparation at scale. Continued refinement of this platform promises to significantly improve the precision of CAR T-cell typing, with substantial promise for future applications such as precision re-dosing and advanced CAR T-cell engineering.
Clinical Outcomes for Hematopoietic Stem Cell Transplant Recipients with Anemia: An Analysis of the National Inpatient Sample
Authors: Thor Danielle C , Elias Tony , Polineni Vineet , Brik Ben 
Published: December 2024

Background: As hematopoietic stem cell transplant (HSCT) grows in accessibility and utility, it remains imperative to understand outcomes for its recipients. Limited data is available on the comorbid correlations for this steadily increasing patient population. We sought to examine the National Inpatient Sample (NIS) database to describe in-hospital outcomes among patients who received a HSCT and developed anemia.
Methods: Data were extracted from the NIS Database from 2019 and 2020. The NIS was searched for hospitalizations of all patients greater than 18 years old who had previously received a HSCT and were hospitalized thereafter. We then analyzed the outcomes of these patients who developed anemia. Multivariate logistic regression analysis was used to adjust for confounders; SPSS software was used for statistical analysis. The primary outcome was inpatient mortality and secondary outcomes are listed below.
Results: This study included 8,302 patients who had received a HSCT, of which 4888 (58.9%) were found to have anemia. Anemic recipients of a HSCT had slightly higher prevalences of obesity (7.3% versus 7.0%, p&lt;0.001) and smoking (21.1% versus 20.5%, p&lt;0.001), as well as higher prevalences of hypertension (32.4% versus 23.7%, p&lt;0.001) and chronic kidney disease (34.6% versus 21.3%, p&lt;0.001). Multivariate regression demonstrated that anemic recipients of a HSCT had higher inpatient mortality (OR 2.549, CI 2.233-2.910, p&lt;0.001). On secondary analysis, anemic HSCT recipients were found to be more likely to have thrombocytopenia (OR 3.467, CI 3.199-3.757, p&lt;0.001), hypertension (OR 5.141, CI 4.699-5.626, p&lt;0.001), acute kidney failure (OR 3.421, CI 3.187-3.673, p&lt;0.001), all-cause arrhythmias (OR 2.772, CI 2.515-3.056, p&lt;0.001), acute pancreatitis (OR 1.906, CI 1.583-2.294, p&lt;0.001), and pericarditis (OR 3.000, CI 2.478-3.632, p&lt;0.001).
Conclusion: In this nationally-representative, population-based retrospective cohort study, anemic patients who have received a HSCT and were subsequently hospitalized were associated with higher mortality and worse outcomes.
Marriage and Fertility of Patients with Beta Thalassemia Major : A Single Center Experience from Southwest Turkey
Authors: Akgun Cagliyan Gulsum , Izmir Guner Sebnem 
Published: December 2024

Introduction:
Infertility and hypogonadotropic hypogonadism are still a significant problem due to iron overload in patients with beta thalassemia major (BTM). In our study, we aim to evaluate the marriage and fertility status of the patients with BTM.
Material and Method:
Adult patients living in Denizli with BTM were included in the study. All of the patients were receiving iron chelator therapy and transfusion regularly. In routine follow up all patients were consulted to the endocrinology. The files of the patients were examined retrospectively. We recorded all datas from the files as age, gender, marriage, divorce or have a child.
Results:
In our study, 82 adult patients with BTM were included. The median age was 26 (Min:18, max:45 years). 43.9% (n:36) of the patients were male and 56.1% (n:46) were female. The median ferritin level was 1352 (304-5464). 47.5% (n:39) of the patients had undergone splenectomy. The rate of hypogonadism was 40.2 % (n:33), hypothyroidism was 17% (n:14), hypoparathyroidism was 8.5% (n:7) and diabetes mellitus was 9.7% (n:8) in the patients.The marriage rate was 25.6% (n:21, 10 men, 11 women). The mean age of marriage was 26 years (18-32 years). The duration of mean marriage duration was 3.4 years (3 months - 6 years). There were no couples with both partners with BTM. 1 marriage was between a couple with BTM and sickle cell anemia. The number of divorced patients with BTM was 2.4% (n:2). There was no significant difference between in terms of ferritin levels between married and single patients. We found that the rate of marriage rate was higher in cases without hypogonadism and it was statistically significant (p&lt;0.001). Only 2 patients of married had hypogonadism (2/21). There was no spontaneous miscarriage in the patients. The number of patients who had a child was 12.1% (n: 10, 4 men and 6 women). The mean of the children was 1.4. The patients having 2 or more children was 4.8% (n: 4).
Discussion: In our country, all couples are scanned for the presence of BTM routinely. Although the tests are easy and accessible, births of babies with BTM are still reported today. Whereas, if the patients with BTM are managed correctly and iron load is reduced, they can marry, start a family and have a healthy child. Unfurtunately, patients with BTM still have not only metabolic problems but also social problems.
Clinical Outcomes for Hematopoietic Stem Cell Transplant Recipients with Hyperlipidemia: An Analysis of the National Inpatient Sample
Authors: Elias Tony , Thor Danielle C , Polineni Vineet , Brik Ben 
Published: December 2024

Background: As hematopoietic stem cell transplant (HSCT) grows in accessibility and utility, it remains imperative to understand outcomes for its recipients. Limited data is available on the comorbid correlations for this steadily increasing patient population. We sought to examine the National Inpatient Sample (NIS) database to describe in-hospital outcomes among patients with known hyperlipidemia who received a HSCT.
Methods: Data were extracted from the NIS Database from 2019 and 2020. The NIS was searched for hospitalizations of all patients greater than 18 years old who had previously received a HSCT and were hospitalized thereafter. We then analyzed the outcomes of these patients with hyperlipidemia. Multivariate logistic regression analysis was used to adjust for confounders; SPSS software was used for statistical analysis. The primary outcome was inpatient mortality and secondary outcomes are listed below.
Results: This study included 8,302 patients who had received a HSCT, of which 2641 (31.8%) were found to have hyperlipidemia. These HSCT recipients had a higher prevalence of obesity (9.8% versus 7.0%, p&lt;0.001), hypertension (38.2% versus 23.7%, p&lt;0.001), smoking (26.8% versus 20.5%, p&lt;0.001), and chronic kidney disease (29.7% versus 21.3%, p&lt;0.001). Multivariate regression demonstrated that recipients of a HSCT with hyperlipidemia had higher inpatient mortality (OR 1.329, CI 1.251-1.413, p&lt;0.001). On secondary analysis, HSCT recipients with hyperlipidemia were found to be more likely to have non-alcoholic fatty liver disease (OR 1.607, CI 1.414-1.826, p&lt;0.001), anemia (OR 1.485, CI 1.456-1.514, p&lt;0.001), thrombocytopenia (OR 1.457, CI 1.407-1.508, p&lt;0.001), hypertension (OR 2.057, CI 1.965-2.152, p&lt;0.001), acute kidney failure (OR 1.550, CI 1.499-1.604, p&lt;0.001), all-cause arrhythmias (OR 1.689, CI 1.590-1.795, p&lt;0.001), pericarditis (OR 1.419, CI 1.300-1.549, p&lt;0.001), sepsis (OR 1.439, CI 1.400-1.479), coagulopathies (OR 1.379, CI 1.299-1.463, p&lt;0.001), chronic pulmonary disease (OR 1.805, CI 1.700-1.916, p&lt;0.001), severe liver disease (OR 1.429, CI 1.335-1.530, p&lt;0.001), and acute heart failure (OR 1.905, CI 1.811-2.003, p&lt;0.001).
Conclusion: In this nationally-representative, population-based retrospective cohort study, patients with hyperlipidemia who have received a HSCT and were subsequently hospitalized were associated with higher mortality and worse outcomes.
The Long-Term Effect of L-Glutamine Administration in Sickle Cell Disease Related Liver Damage
Authors: Katoch Omika , Pradhan-Sundd Tirthadipa 
Published: December 2024

Introduction: Sickle Cell Disease (SCD) is an autosomal recessive genetic disorder in the β-globin gene resulting from a point mutation at its sixth position where hydrophilic glutamic acid substitute with hydrophobic valine that results in mutated sickled hemoglobin. This mutation, which occurs in both copies of the gene, promotes hemolysis, vaso-occlusion, and sterile inflammation. SCD patients experiences serious health complications including multi organ failure including liver failure. Currently, there are no effective treatment available for SCD related liver problems.
Methods: In the present study, we have studied the long-term effect (for up to eight weeks) of L- glutamine administration (10-12 mg/mL) via drinking water on liver pathophysiology using quantitative liver intravital microscopy, advanced imaging, and biochemical analysis in humanized SCD mice.
Results: We found that oral L-glutamine administration significantly reduced the accumulation of iron, heme, and hemoglobin in liver of SCD mice but had no effect on ameliorating liver vaso-occlusion and liver fibrosis. We also found the reduced expression of Kupffer cells after L-glutamine administration which may led to the failure of the resolution of fibrosis and hepatic cell death. Moreover, the balance between proinflammatory vs anti-inflammatory macrophages were impaired in SCD mice liver post L-glutamine treatment. We also found activation of hepatic stellate cell markers including α-SMA, collagenase 1 and 2 post L-glutamine treatment in SCD mice liver.
Conclusion: Our current study highlights the long-term effects of L-glutamine in SCD mouse liver. Interestingly, despite a considerable decrease in hepatic heme-hemoglobin-iron accumulation, chronic liver injury did not ameliorate post-L-glutamine treatment suggesting the need to investigate the long-term effects of L-glutamine therapy on vaso-occlusion, Kupffer cell expression, hepatic cell death, and liver fibrosis in SCD patients.
Global, Regional, and National Burden of Hodgkin Lymphoma from 1990 to 2021: Estimates from the 2021 Global Burden of Disease Study
Authors: Wang Mengyao , Hu Qian , LI He , Liao Yi , Niu Ting 
Published: December 2024

Background: Hodgkin lymphoma (HL) is an uncommon B cell lymphoma.This article aimed to assess the global, regional, and national burden of HL from 1990 to 2021, by gender, age, and social-demographic index (SDI) and to to estimate the trends of HL globally from 1990 to 2021.
Methods: Data on HL, including incidence, mortality, and disability adjusted life-years (DALY), from 1990 to 2021 were obtained from the 2021 Global Burden of Disease study. The trends of HL burden were estimated using age-standardized rate (ASR) and estimated annual percentage change (EAPC).
Results: HL incidences increased by 19.23%, from 54671 in 1990 to 65182 in 2021 while the age-standardized incidence rate (ASIR) declined from 1.12 to 0.79 (EAPC= -1.1; 95% CI, from -1.16 to -1.05 ). Regarding SDI level analysis, the ASIR in all SDI regions demontrated a slight decrease. Incidence showed a bimodal distribution with peak values in patients aged 20-29 years and patients aged 75 years or higher. The number of death cases and DALYs remained stable. The age-standardized death rate (ASDR) decreased by 2.07% (95% CI, from − 2.01% to − 2.14%) per year. And the annual age-standardized DALY rate decreased by 1.88% (95% CI, from − 1.83% to − 1.94%). ASDR and age-standardized DALY rate showed a clear gradient across different SDI levels, with higher SDI regions showing lower age-standardized DALY rate and ASDR compared to lower SDI regions.The incidence, death and DALYs, whether in numbers or ASR, in male subjects was higher than that in female subjects. But the disparity in these indicators between the genders is gradually narrowing over time.
Conclusion: Globally, incidence of HL was stable, while mortality and DALY rate of HL had been decreasing from 1990 to 2021. Despite the reduction in mortality and DALYs across all SDI regions, an observed phenomenon existed, which was high SDI region exhibited the highest incidence but the lowest mortality and DALYs, whereas Low SDI region showed the lowest incidence but the highest mortality and DALYs. This result indicated that advanced diagnostic and therapeutic approaches can effectively improve HL prognosis, reducing both mortality and disability. And more attention should be paid to establish specific strategies in low SDI region to reduce death and DALYs.