bluuebunny/crossref_metadata_2025_split huggingface dataset:
C/EBPα-p30 confers AML cell susceptibility to the terminal unfolded protein response and resistance to Venetoclax by activating DDIT3 transcription
Authors: Du Mengbao , Wang Mowang , Liu Meng , Fu Shan , Lin Yu , Huo Yankun , Yu Jian , Yu Xiaohong , Wang Chong , Xiao Haowen , Wang Limengmeng 
Published: March 2024

Abstract
Background
Acute myeloid leukemia (AML) with biallelic (CEBPAbi) as well as single mutations located in the bZIP region is associated with a favorable prognosis, but the underlying mechanisms are still unclear. Here, we propose that two isoforms of C/EBPα regulate DNA damage-inducible transcript 3 (DDIT3) transcription in AML cells corporately, leading to altered susceptibility to endoplasmic reticulum (ER) stress and related drugs.

Methods
Human AML cell lines and murine myeloid precursor cell line 32Dcl3 cells were infected with recombinant lentiviruses to knock down CEBPA expression or over-express the two isoforms of C/EBPα. Quantitative real-time PCR and western immunoblotting were employed to determine gene expression levels. Cell apoptosis rates were assessed by flow cytometry. CFU assays were utilized to evaluate the differentiation potential of 32Dcl3 cells. Luciferase reporter analysis, ChIP-seq and ChIP-qPCR were used to validate the transcriptional regulatory ability and affinity of each C/EBPα isoform to specific sites at DDIT3 promoter. Finally, an AML xenograft model was generated to evaluate the in vivo therapeutic effect of agents.

Results
We found a negative correlation between CEBPA expression and DDIT3 levels in AML cells. After knockdown of CEBPA, DDIT3 expression was upregulated, resulting in increased apoptotic rate of AML cells induced by ER stress. Cebpa knockdown in mouse 32Dcl3 cells also led to impaired cell viability due to upregulation of Ddit3, thereby preventing leukemogenesis since their differentiation was blocked. Then we discovered that the two isoforms of C/EBPα regulate DDIT3 transcription in the opposite way. C/EBPα-p30 upregulated DDIT3 transcription when C/EBPα-p42 downregulated it instead. Both isoforms directly bound to the promoter region of DDIT3. However, C/EBPα-p30 has a unique binding site with stronger affinity than C/EBPα-p42. These findings indicated that balance of two isoforms of C/EBPα maintains protein homeostasis and surveil leukemia, and at least partially explained why AML cells with disrupted C/EBPα-p42 and/or overexpressed C/EBPα-p30 exhibit better response to chemotherapy stress. Additionally, we found that a low C/EBPα p42/p30 ratio induces resistance in AML cells to the BCL2 inhibitor venetoclax since BCL2 is a major target of DDIT3. This resistance can be overcome by combining ER stress inducers, such as tunicamycin and sorafenib in vitro and in vivo.

Conclusion
Our results indicate that AML patients with a low C/EBPα p42/p30 ratio (e.g., CEBPAbi) may not benefit from monotherapy with BCL2 inhibitors. However, this issue can be resolved by combining ER stress inducers.
Nursing management of patients dealing with spina bifida: from the prenatal diagnosis to adulthood / nursing intervention for the improvement of the impact of urinary and fecal incontinence on the quality of life of people dealing with spina bifida
Authors: Calabrese Fabiana , Poziello Antonio , Spiezia Gennaro , Rotunno Tiziana , Chervino Ciro , Iannicelli Anna Maria 
Published: March 2024

Abstract
Background
Urinary and fecal incontinence in people dealing with spina bifida, has inevitably an influence on the quality of life. In this analysis, the degree of education on how to manage incontinence and retention is studied, as well as the problems those might create and the consequential degree of autonomy and independence reached into the management of those. The main goal is to increase both nursing assistance and the education of the people dealing with spina bifida.

Methods
A multiple-choice questionnaire with open questions, concerning the bowel and bladder management was structured by all the authors and shared by the Google Docs platform among the members of the ASBI (Associazione Spina Bifida Italia) by the secretariat of the association itself. 125 patients affected by Spina Bifida voluntarily decided to participate and complete the questionnaire. The questionnaire didn’t set any limits as regards the age. For minors, its completion was made under the observation of the caregivers who gave their consent. All the authors participated to administration of the questionnaire to minors.

Results
out of 125 participants, 80 were females and 25 males. The questions concerned the level of deambulation (the 35,2% was autonomous, the 30,4% were people who use wheelchairs while the 34,4% is aid-supported), urinary incontinence, with great concern to the self-catheterization technique (the 80,8% claimed to be autonomous in performing self-catheterization, unlike the remaining 19,2%) and the impact of the said incontinence on social life (the 59,2% claimed they do not feel restrained because of their bladder incontinence or retention, unlike the remaining 40,8%). Lastly, we focused on fecal constipation and incontinence (the 57,6% claimed to struggle with incontinence, the 12% claimed they don’t and the 30,4% struggles with both conditions), on the ability of the people dealing with this to intervene to prevent unpleasant situations, in particular by using trans-anal irrigation (the 57,6% doesn’t feel autonomous in performing it).

Conclusion
urinary and fecal incontinence have, of course, an impact on the quality of life of people dealing with spina bifida. Nevertheless, we can observe that it is possible to improve the quality of life of these people, letting them feel confident enough to take part in social activities, through education from an incredibly young age, from 0 up to 25 years old and over, supplied by the medical staff and mostly by the parents (previously educated by the medical staff as well).
Large-scale causal analysis of gut microbiota and six common complications of diabetes: a mendelian randomization study
Authors: Wang Jiachen , Teng Menghao , Feng Ruoyang , Su Xiaochen , Xu Ke , Wang Junxiang , Wang Guoqiang , Zhang Yulong , Xu Peng 
Published: March 2024

Abstract
Background
This study aimed to reveal the association between the gut microbiota (GM) and six diabetic complications: diabetic hypoglycemia; ketoacidosis; nephropathy; neuropathy; retinopathy; and Charcot’s foot.

Methods
GM data were obtained from the MiBioGen consortium and Dutch Microbiome Project while data on the six diabetic complications were obtained from the FinnGen consortium. Two-sample Mendelian randomization (TSMR) was performed to explore the association between GM and the common diabetic complications. Inverse MR analysis was conducted to examine the effect of diabetic complications on the identified GM. Sensitivity tests were conducted to validate the stability of the results. Finally, multivariate MR (MVMR) was performed to determine whether GM had a direct influence on the diabetic complications.

Results
After multiple corrections, the inverse variance weighted (IVW) results predicted 61 suggestive markers between GM and six diabetic complications. In particular, the IVW results revealed that the Bacteroidia class and Bacteroidales order were positively associated with diabetic hypoglycemia while the Verrucomicrobiae class and Verrucomicrobiales order were positively associated with diabetic nephropathy. Based on the replication analysis, these results were identified to be stable. MVMR showed that the results remained stable after accounting for traditional risk factors.

Conclusion
Extensive causal associations were found between GM and diabetic complications, which may provide new insights into the mechanisms of microbiome-mediated complications of diabetes.
Radiological biomarkers reflecting visceral fat distribution help distinguish inflammatory bowel disease subtypes: a multicenter cross-sectional study
Authors: Xiong Ziman , Wu Peili , Zhang Yan , Chen Jun , Shen Yaqi , Kamel Ihab , Wu Bing , Zheng Xianying , Li Zhen 
Published: March 2024

Abstract
Objectives
To achieve automated quantification of visceral adipose tissue (VAT) distribution in CT images and screen out parameters with discriminative value for inflammatory bowel disease (IBD) subtypes.

Methods
This retrospective multicenter study included Crohn’s disease (CD) and ulcerative colitis (UC) patients from three institutions between 2012 and 2021, with patients with acute appendicitis as controls. An automatic VAT segmentation algorithm was developed using abdominal CT scans. The VAT volume, as well as the coefficient of variation (CV) of areas within the lumbar region, was calculated. Binary logistic regression and receiver operating characteristic analysis was performed to evaluate the potential of indicators to distinguish between IBD subtypes.

Results
The study included 772 patients (365 CDs, median age [inter-quartile range] = 31.0. (25.0, 42.0) years, 255 males; 241 UCs, 46.0 (34.0, 55.5) years, 138 males; 166 controls, 40.0 (29.0, 53.0) years, 80 males). CD patients had lower VAT volume (CD = 1584.95 ± 1128.31 cm3, UC = 1855.30 ± 1326.12 cm3, controls = 2470.91 ± 1646.42 cm3) but a higher CV (CD = 29.42 ± 15.54 %, p = 0.006 and p ˂ 0.001) compared to UC and controls (25.69 ± 12.61 % vs. 23.42 ± 15.62 %, p = 0.11). Multivariate analysis showed CV was a significant predictor for CD (odds ratio = 6.05 (1.17, 31.12), p = 0.03). The inclusion of CV improved diagnostic efficiency (AUC = 0.811 (0.774, 0.844) vs. 0.803 (0.766, 0.836), p = 0.08).

Conclusion
CT-based VAT distribution can serve as a potential biomarker for distinguishing IBD subtypes.

Critical relevance statement
Visceral fat distribution features extracted from CT images using an automated segmentation algorithm (1.14 min) show differences between Crohn’s disease and ulcerative colitis and are promising for practical radiological screening.

Key points
• Radiological parameters reflecting visceral fat distribution were extracted for the discrimination of Crohn’s disease (CD) and ulcerative colitis (UC).
• In CD, visceral fat was concentrated in the lower lumbar vertebrae, and the coefficient of variation was a significant predictor (OR = 6.05 (1.17, 31.12), p = 0.03).
• The differences between CD, UC, and controls are promising for practical radiological screening.

Graphical Abstract
Large-scale bioreactor production of extracellular vesicles from mesenchymal stromal cells for treatment of acute radiation syndrome
Authors: Kink John A. , Bellio Michael A. , Forsberg Matthew H. , Lobo Alexandra , Thickens Anna S. , Lewis Bryson M. , Ong Irene M. , Khan Aisha , Capitini Christian M. , Hematti Peiman 
Published: March 2024

Abstract
Background
Hematopoietic acute radiation syndrome (H-ARS) occurring after exposure to ionizing radiation damages bone marrow causing cytopenias, increasing susceptibility to infections and death. We and others have shown that cellular therapies like human mesenchymal stromal cells (MSCs), or monocytes/macrophages educated ex-vivo with extracellular vesicles (EVs) from MSCs were effective in a lethal H-ARS mouse model. However, given the complexity of generating cellular therapies and the potential risks of using allogeneic products, development of an “off-the-shelf” cell-free alternative like EVs may have utility in conditions like H-ARS that require rapid deployment of available therapeutics. The purpose of this study was to determine the feasibility of producing MSC-derived EVs at large scale using a bioreactor and assess critical quality control attributes like identity, sterility, and potency in educating monocytes and promoting survival in a lethal H-ARS mouse model.

Methods
EVs were isolated by ultracentrifugation from unprimed and lipopolysaccharide (LPS)-primed MSCs grown at large scale using a hollow fiber bioreactor and compared to a small scale system using flasks. The physical identity of EVs included a time course assessment of particle diameter, yield, protein content and surface marker profile by flow-cytometry. Comparison of the RNA cargo in EVs was determined by RNA-seq. Capacity of EVs to generate exosome educated monocytes (EEMos) was determined by qPCR and flow cytometry, and potency was assessed in vivo using a lethal ARS model with NSG mice.

Results
Physical identity of EVs at both scales were similar but yields by volume were up to 38-fold more using a large-scale bioreactor system. RNA-seq indicated that flask EVs showed upregulated let-7 family and miR-143 micro-RNAs. EEMos educated with LPS-EVs at each scale were similar, showing increased gene expression of IL-6, IDO, FGF-2, IL-7, IL-10, and IL-15 and immunophenotyping consistent with a PD-L1 high, CD16 low, and CD86 low cell surface expression. Treatment with LPS-EVs manufactured at both scales were effective in the ARS model, improving survival and clinical scores through improved hematopoietic recovery. EVs from unprimed MSCs were less effective than LPS-EVs, with flask EVs providing some improved survival while bioreactor EVs provide no survival benefit.

Conclusions
LPS-EVs as an effective treatment for H-ARS can be produced using a scale-up development manufacturing process, representing an attractive off-the-shelf, cell-free therapy.
Pre-clinical evaluation of the efficacy and safety of human induced pluripotent stem cell-derived cardiomyocyte patch
Authors: Miyagawa Shigeru , Kawamura Takuji , Ito Emiko , Takeda Maki , Iseoka Hiroko , Yokoyama Junya , Harada Akima , Mochizuki-Oda Noriko , Imanishi-Ochi Yukiko , Li Junjun , Sasai Masao , Kitaoka Fumiyo , Nomura Masaki , Amano Naoki , Takahashi Tomoko , Dohi Hiromi , Morii Eiichi , Sawa Yoshiki 
Published: March 2024

Abstract
Background
Cell- or tissue-based regenerative therapy is an attractive approach to treat heart failure. A tissue patch that can safely and effectively repair damaged heart muscle would greatly improve outcomes for patients with heart failure. In this study, we conducted a preclinical proof-of-concept analysis of the efficacy and safety of clinical-grade human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches.

Methods
A clinical-grade hiPSC line was established using peripheral blood mononuclear cells from a healthy volunteer that was homozygous for human leukocyte antigens. The hiPSCs were differentiated into cardiomyocytes. The obtained hiPSC-CMs were cultured on temperature-responsive culture dishes for patch fabrication. The cellular characteristics, safety, and efficacy of hiPSCs, hiPSC-CMs, and hiPSC-CM patches were analyzed.

Results
The hiPSC-CMs expressed cardiomyocyte-specific genes and proteins, and electrophysiological analyses revealed that hiPSC-CMs exhibit similar properties to human primary myocardial cells. In vitro and in vivo safety studies indicated that tumorigenic cells were absent. Moreover, whole-genome and exome sequencing revealed no genomic mutations. General toxicity tests also showed no adverse events posttransplantation. A porcine model of myocardial infarction demonstrated significantly improved cardiac function and angiogenesis in response to cytokine secretion from hiPSC-CM patches. No lethal arrhythmias were observed.

Conclusions
hiPSC-CM patches are promising for future translational research and may have clinical application potential for the treatment of heart failure.
Staphylococcus aureus and biofilms: transmission, threats, and promising strategies in animal husbandry
Authors: Song Mengda , Tang Qi , Ding Yakun , Tan Peng , Zhang Yucheng , Wang Tao , Zhou Chenlong , Xu Shenrui , Lyu Mengwei , Bai Yueyu , Ma Xi 
Published: March 2024

AbstractStaphylococcus aureus (S. aureus) is a common pathogenic bacterium in animal husbandry that can cause diseases such as mastitis, skin infections, arthritis, and other ailments. The formation of biofilms threatens and exacerbates S. aureus infection by allowing the bacteria to adhere to pathological areas and livestock product surfaces, thus triggering animal health crises and safety issues with livestock products. To solve this problem, in this review, we provide a brief overview of the harm caused by S. aureus and its biofilms on livestock and animal byproducts (meat and dairy products). We also describe the ways in which S. aureus spreads in animals and the threats it poses to the livestock industry. The processes and molecular mechanisms involved in biofilm formation are then explained. Finally, we discuss strategies for the removal and eradication of S. aureus and biofilms in animal husbandry, including the use of antimicrobial peptides, plant extracts, nanoparticles, phages, and antibodies. These strategies to reduce the spread of S. aureus in animal husbandry help maintain livestock health and improve productivity to ensure the ecologically sustainable development of animal husbandry and the safety of livestock products.
I feel blue– teacher, can you help me? A study on the effect of digital literacies on language learners’ technostress, on-line engagement, autonomy, and academic success
Authors: Feng Xiuxia , Liu Huying 
Published: March 2024

AbstractThis phenomenological study explored the experiences of language learners in the digital age, specifically investigating the intersection of digital literacy, technostress, online engagement, autonomy, and academic success. Twenty participants, selected through purposive sampling, shared Chinese as their native language and were between 18 and 20 years old, with five participants being female. Employing interviews and document analysis, the study aimed to understand the subjective meanings, emotions, and perceptions associated with these phenomena. The findings revealed the multifaceted nature of technostress, the crucial role of digital literacy in shaping online engagement and autonomy, and the nuanced impact on academic success. These qualitative insights contribute to a deeper understanding of the complex relationships in the digital language learning landscape. The study has implications for educators, materials developers, syllabus designers, and policy-makers, providing practical insights to enhance language learning experiences in the digital era. Future research may further explore specific dimensions uncovered in this study to adapt educational practices to the evolving digital terrain.
STAT3–mediated up-regulation of DAB2 via SRC-YAP1 signaling axis promotes Helicobacter pylori-driven gastric tumorigenesis
Authors: Duan Yantao , Kong Pengfei , Huang Mingzhu , Yan Yonghao , Dou Yi , Huang Binhao , Guo Jing , Kang Wei , Zhu Caixia , Wang Yuyan , Zhou Donglei , Cai Qiliang , Xu Dazhi 
Published: March 2024

Abstract
Background
Helicobacter pylori (H pylori) infection is the primary cause of gastric cancer (GC). The role of Disabled-2 (DAB2) in GC remains largely unclear. This study aimed to investigate the role of DAB2 in H pylori-mediated gastric tumorigenesis.

Methods
We screened various datasets of GC to analyze DAB2 expression and cell signaling pathways. DAB2 expression was assessed in human GC tissue microarrays. H pylori infection in vivo and in vitro models were further explored. Immunostaining, immunofluorescence, chromatin immunoprecipitation, co-immunoprecipitation, Western blot, quantitative polymerase chain reaction, and luciferase reporter assays were performed in the current study.

Results
The bioinformatic analysis verified that DAB2 was 1 of the 8 genes contributed to tumorigenesis and associated with poor prognosis in GC. The median overall survival and disease-free survival rates in DAB2high group were significantly less than those in DAB2low group. These findings demonstrated that H pylori transcriptionally activated DAB2 expression via signal transducer and activator of transcription 3 (STAT3)-dependent pathway. By bioinformatics analysis and knockdown or overexpression of DAB2, we found that DAB2 upregulated Yes-associated protein 1 (YAP1) transcriptional activity. Mechanistically, DAB2 served as a scaffold protein for integrin beta 3 (ITGB3) and SRC proto-oncogene non-receptor tyrosine kinase (SRC), facilitated the phosphorylation of SRC, promoted the small GTPase ras homolog family member A (RHOA) activation and phosphorylation of YAP1, and ultimately enhanced the YAP1 transcriptional activity.

Conclusions
Altogether, these findings indicated that DAB2 is a key mediator in STAT3–regulated translation of YAP1 and plays crucial roles in H pylori-mediated GC development. DAB2 might serve as a novel therapeutic target for GC.
p53 biology and reactivation for improved therapy in MDS and AML
Authors: Zawacka Joanna E. 
Published: March 2024

AbstractMyelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) originate from preleukemic hematopoietic conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS) and have variable outcomes despite the successful implementation of targeted therapies. The prognosis differs depending on the molecular subgroup. In patients with TP53 mutations, the most inferior outcomes across independent studies were observed. Myeloid malignancies with TP53 mutations have complex cytogenetics and extensive structural variants. These factors contribute to worse responses to induction therapy, demethylating agents, or venetoclax-based treatments. Survival of patients with biallelic TP53 gene mutations is often less than one year but this depends on the type of treatment applied. It is still controversial whether the allelic state of mutant TP53 impacts the outcomes in patients with AML and high-risk MDS. Further studies are needed to justify estimating TP53 LOH status for better risk assessment. Yet, TP53-mutated MDS, MDS/AML and AML are now classified separately in the International Consensus Classification (ICC). In the clinical setting, the wild-type p53 protein is reactivated pharmacologically by targeting p53/MDM2/MDM4 interactions and mutant p53 reactivation is achieved by refolding the DNA binding domain to wild-type-like conformation or via targeted degradation of the mutated protein. This review discusses our current understanding of p53 biology in MDS and AML and the promises and failures of wild-type and mutant p53 reactivation in the clinical trial setting.