bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGFR inhibition augments the therapeutic efficacy of the NAT10 inhibitor Remodelin in Colorectal cancer
Authors: Zheng Yongbin , Song Dan , Guo Ming , Wang Chenhong , Ma Mingzhen , Tao Gongcai , Liu Licui , He Xiaobo , Cao Fengyu , Luo Dan , Zhao Qingchuan , Xia Zhongyuan , An Yanxin 
Published: February 2025

Abstract

Background
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and treatment options for advanced CRC are limited. The regulatory mechanisms of aberrant NAT10-mediated N4-acetylcytidine (ac4C) modifications in cancer progression remains poorly understood. Consequently, an integrated transcriptomic analysis is necessary to fully elucidate the role of NAT10-mediated ac4C modifications in CRC progression.

Methods
NAT10 expression levels were analyzed in CRC samples and compared with those in corresponding normal tissues. The potential mechanisms of NAT10 in CRC were investigated using RNA sequencing, RNA immunoprecipitation sequencing, and acetylated RNA immunoprecipitation sequencing. Additional in vivo and in vitro experiments, including CCK-8 assays, colony formation and mouse xenograft models, were conducted to explore the biological role of NAT10-mediated ac4C modifications. We also evaluated and optimized a potential treatment strategy targeting NAT10.

Results
We found that NAT10 is highly expressed in CRC samples and plays a pro-oncogenic role. NAT10 knockdown led to PI3K-AKT pathway inactivation, thereby inhibiting CRC progression. However, treatment with the NAT10 inhibitor Remodelin induced only a limited and reversible growth arrest in CRC cells. Further epigenetic and transcriptomic analysis revealed that NAT10 enhances the stability of ERRFI1 mRNA by binding to its coding sequence region in an ac4C-dependent manner. NAT10 knockdown decreased ERRFI1 expression, which subsequently activated the EGFR pathway and counteracted the inhibitory effects on CRC. Based on these findings, we demonstrated that dual inhibition of NAT10 and EGFR using Remodelin and the EGFR-specific monoclonal antibody cetuximab resulted in improved therapeutic efficacy compared to either drug alone. Moreover, we observed that 5-Fluorouracil promoted the interaction between NAT10 and UBR5, which increased the ubiquitin-mediated degradation of NAT10, leading to ERRFI1 downregulation and EGFR reactivation. Triple therapy with Remodelin, cetuximab, and 5-Fluorouracil enhanced tumor regression in xenograft mouse models of CRC with wild-type KRAS, NRAS and BRAF.

Conclusions
Our study elucidated the mechanism underlying 5-Fu-induced NAT10 downregulation, revealing that NAT10 inhibition destabilizes ERRFI1 mRNA through ac4C modifications, subsequently resulting in EGFR reactivation. A triple therapy regimen of Remodelin, cetuximab, and 5-Fu showed potential as a treatment strategy for CRC with wild-type KRAS, NRAS and BRAF.
EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8+ T cell dysfunction in neuroblastoma
Authors: Li Di , Li Meng , Zhuo Zhenjian , Guo Huiqin , Zhang Weixin , Xu Yile , Wang Hai-Yun , Liu Jiabin , Xia Huimin , Lin Huiran , Tang Jue , He Jing , Miao Lei 
Published: February 2025

Abstract

Background
Heterogeneous clinical features and prognosis in neuroblastoma (NB) children are frequently dominated by immune elements. Dysfunction and apoptosis in immune cells result from the exposure to continuous tumor-related antigen stimulation and coinhibitory signals. To date, key factors pointing to the restriction of NB-specific CD8+ T cells remain elusive.

Methods
We performed bulk-RNA sequencing and lipidomic analyses of children with mediastinal NB. Bioinformatics analysis and biological validation were applied to uncover the underlying mechanism.

Results
Three subtypes were identified using nonnegative matrix factorization (NMF), among which we highlighted an apoptotic status of infiltrated CD8+ T cells, along with the highest CD52 and EDF1 expression in Cluster3 (C3) subtypes. It was verified that high EDF1 expression in NB cells led to Lactosylceramide (LacCer) accumulation, as well as downstream ganglioside-GD3, which subsequently increased the expression of CD52 and immune checkpoint genes, chemotaxis, and apoptosis-related events in activated CD8+T cells. Mechanistically, EDF1 was recruited as a coactivator to form the NF-κB/RelA/EDF1 complex, which further prevented the promoter region methylation of ST8SIA1, to elevate its transcription.

Conclusion
These findings characterize abundant GD3 in NB cells, which regulated by the EDF1/RelA/ST8SIA1 axis, is responsible for CD8+ T cell dysfunction. Inhibition of EDF1 may reduce suppressive factors and prevent immune escape of NB cells. Modulating NB-associated GD3 levels through metabolic intervention is beneficial for tuning the depth and duration of responses to current NB therapies. The integration of transcriptomic and lipidomic data offers a more comprehensive understanding of the interaction between LacCer metabolites and the immune status in NB.

Graphical Abstract
Exosomal mir-126-3p derived from endothelial cells induces ion channel dysfunction by targeting RGS3 signaling in cardiomyocytes: a novel mechanism in Takotsubo cardiomyopathy
Authors: Fan Xuehui , Yang Guoqiang , Wang Yinuo , Shi Haojie , Nitschke Katja , Sattler Katherine , Abumayyaleh Mohammad , Cyganek Lukas , Nuhn Philipp , Worst Thomas , Liao Bin , Dobreva Gergana , Duerschmied Daniel , Zhou Xiaobo , El-Battrawy Ibrahim , Akin Ibrahim 
Published: February 2025

Abstract

Background
Takotsubo cardiomyopathy (TTC) is marked by an acute, transient, and reversible left ventricular systolic dysfunction triggered by stress, with endothelial dysfunction being one of its pathophysiological mechanisms. However, the precise molecular mechanism underlying the interaction between endothelial cells and cardiomyocytes during TTC remains unclear. This study reveals that exosomal miRNAs derived from endothelial cells exposed to catecholamine contribute to ion channel dysfunction in the setting of TTC.

Methods
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with epinephrine (Epi) or exosomes (Exo) from Epi-treated human cardiac microvascular endothelial cells (HCMECs) or Exo derived from HCMECs transfected with miR-126-3p. The immunofluorescence staining, flow cytometry, qPCR, single-cell contraction, intracellular calcium transients, patch-clamp, dual luciferase reporter assay and western blot were performed for the study.

Results
Modeling TTC with high doses of epinephrine (Epi) treatment in hiPSC-CMs shows suppression of depolarization velocity (Vmax), prolongation of action potential duration (APD), and induction of arrhythmic events. Exo derived from HCMECs treated with Epi (Epi-exo) mimicked or enhanced the effects of Epi. Epi exposure led to elevated levels of miR-126-3p in both HCMECs and their exosomes. Exo enriched with miR-126-3p demonstrated similar effects as Epi-exo, establishing the crucial role of miR-126-3p in the mechanism of Epi-exo. Dual luciferase reporter assay coupled with gene mutation techniques identified that miR-126-3p was found to target the regulator of G-protein signaling 3 (RGS3) gene. Western blot and qPCR analyses confirmed that miR-126-3p-mimic reduced RGS3 expression in both HCMECs and hiPSC-CMs, indicating miR-126-3p inhibits RGS3 signaling. Additionally, miR-126-3p levels were significantly higher in the serum of TTC patients compared to healthy controls and patients who had recovered from TTC.

Conclusions
Our study is the first to reveal that exosomal miR-126-3p, originating from endothelial cells, contributes to ion channel dysfunction by regulating RGS3 signaling in cardiomyocytes. These findings provide new perspectives on the pathogenesis of TTC and suggest potential therapeutic targets for treatment.

Graphical Abstract
Targeting ferroptosis: opportunities and challenges of mesenchymal stem cell therapy for type 1 diabetes mellitus
Authors: Dai Le , Wang Qing 
Published: February 2025

Abstract
Type 1 diabetes mellitus (T1DM) is characterized by progressive β-cell death, leading to β-cell loss and insufficient insulin secretion. Mesenchymal stem cells (MSCs) transplantation is currently one of the most promising methods for β-cell replacement therapy. However, recent studies have shown that ferroptosis is not only one of the key mechanisms of β-cell death, but also one of the reasons for extensive cell death within a short period of time after MSCs transplantation. Ferroptosis is a new type of regulated cell death (RCD) characterized by iron-dependent accumulation of lipid peroxides. Due to the weak antioxidant capacity of β-cells, they are susceptible to cytotoxic stimuli such as oxidative stress (OS), and are therefore susceptible to ferroptosis. Transplanted MSCs are also extremely susceptible to perturbations in their microenvironment, especially OS, which can weaken their antioxidant capacity and induce MSCs death through ferroptosis. In the pathophysiological process of T1DM, a large amount of reactive oxygen species (ROS) are produced, causing OS. Therefore, targeting ferroptosis may be a key way to protect β-cells and improve the therapeutic effect of MSCs transplantation. This review reviews the research related to ferroptosis of β-cells and MSCs, and summarizes the currently developed strategies that help inhibit cell ferroptosis. This study aims to help understand the ferroptosis mechanism of β-cell death and MSCs death after transplantation, emphasize the importance of targeting ferroptosis for protecting β-cells and improving the survival and function of transplanted MSCs, and provide a new research direction for stem cells transplantation therapy of T1DM in the future.
Lawsonia intracellularis T3SS effector LI0758, an Rce1 ortholog, activates MAPK and NF-κB signaling in mammalian cells
Authors: Zhong Yuanxiu , Duan Yiyun , Lai Fenju , Zhang Jinhua , Dai Yimin 
Published: February 2025

Abstract

Lawsonia intracellularis, a Gram-negative obligate intracellular bacterium causing porcine proliferative enteropathy, possesses a type III secretion system (T3SS), yet only a handful of its substrates have been experimentally characterized. In this study, we identify that LI0758 can be secreted by the Yersinia T3SS, which suppresses yeast growth and activates mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathway in mammalian cells. Bioinformatics analyses indicate that LI0758 is an ortholog of Rce1, a eukaryotic CAAX protein endoprotease, sharing a similar subcellular localization on the endoplasmic reticulum (ER). While displaying unique activity in the yeast a-factor reporter system, LI0758 restores Ras2 localization in Rce1Δ mutant strains, implying functional similarity. Our findings underscore LI0758’s pivotal role in activating MAPK pathways and suggest its potential to modulate the localization and function of host CAAX proteins. Further investigation holds promise for elucidating novel bacteria-host interaction mechanisms and fostering the development of innovative therapies against proliferative enteritis.
Predicting ixodid tick distribution in Tamil Nadu domestic mammals using ensemble species distribution models
Authors: Elango Ayyanar , Raju Hari Kishan , Shriram Ananganallur Nagarajan , Kumar Ashwani , Rahi Manju 
Published: February 2025

Abstract

Background
Tick borne diseases are re-emerging around the world, including India. Information about the occurrence of the tick vectors in different geographical locations is essential for controlling the diseases. Tick surveys have not been conducted in many parts of India and information on the current prevalence of tick vectors is not available in all states of India. Many studies have been carried out utilizing modelling methods to predict the distribution of tick species in other countries. The MaxEnt model is widely used for predicting tick species distribution using bioclimatic variables. Lyme disease vectors such as Ixodes sp., Amblyomma sp., and Dermacentor sp. are the most commonly predicted tick species. However, very few studies have been carried out to predict the distribution of tick species in India. Haemaphysalis spinigera, the primary Kyasanur Forest Disease vector, was predicted along the Western Ghats using the MaxEnt model. Rhipicephalus (Boophilus) microplus was predicted across India using the generalized linear model (GLM). Identifying the tick vectors in transmitting the infection through conventional survey and identification methods is cumbersome due to the less number of experienced persons available. Prediction of tick vectors of public health concern, including other tick species in different geographical regions of Tamil Nadu, India, is essential for the prevention and control of tick-borne disease in humans and domestic animals. The present study adopts the package ‘SSDM’ (stacked species distribution models) with R software containing ensemble species distribution models to predict the distribution of tick species using different available environmental and climatic data.

Results
The categorical variables such as land use and land cover (LULC), soil type, elevation, Bio1, Bio10, Bio15, Bio19 and Bio8 contributed more to modelling the distribution of tick species. MaxEnt, GLM, GBM and GAM are suitable models for predicting the tick species distribution in the present study. Among these models, MaxEnt is the most suitable model for predicting tick species distribution in Tamil Nadu, India.

Conclusions
Our results suggest that MaxEnt is a suitable model for predicting the distribution of tick species. Both environmental factors such as LULC, elevation and soil type and bioclimatic factors such as temperature and precipitation contribute significantly to predicting tick species distribution in domestic animals in Tamil Nadu. The SSDM package is very useful and user-friendly graphical user interface for modelling the distribution of tick species. However, the package can be further improved by using higher resolution raster variables in larger areas, which is not currently supported. The predicted elevation range of Ha. spinigera distribution could not be provided due to software limitations.
Screening for coronary artery disease among cancer survivors: rationale and design of the REDEEM-CAD study
Authors: Soh Cheng Hwee , Smith Joel , Shrestha Shristy , Nolan Mark , Wong Joshua , Nerlekar Nitesh , Marwick Thomas H. 
Published: February 2025

Abstract

Background
Cancer survivors are reported to be at a heightened risk of coronary artery disease (CAD) due to shared risk factors, potentially cardiotoxic cancer treatments and premature aging in survivors. Early identification of those who are at greater risk, followed by protective treatment, can prevent CAD progression. However, to date there was a relative paucity of prospective data to optimally guide management of atherosclerotic coronary risk among cancer survivors.

Methods
The REDEEM-CAD (Risk-guidEd DisEasE Management plan to prevent CAD in patients with previous cancer) study is a prospective cohort study conducted in Victoria and Tasmania, Australia aiming to evaluate the efficacy of a comprehensive CAD screening strategy. Cancer survivors aged ≥ 40 years with cancer treatment ≥ 5 years prior are eligible for the study. Consented participants will be stratified into low, intermediate or high risk of major atherosclerotic adverse events based on clinical assessment and biochemistry tests. Subsequently, those within the intermediate risk will be referred for coronary artery calcium (CAC) scoring, with computed tomography coronary angiography (CTCA) completed where CAC > 0 and < 400. Participants with high risk or CAC > 400 will be informed about strategies (including lipid-lowering therapy) to manage asymptomatic CAD. Those with low clinical risk or CAC = 0 will conclude their participation while those with CTCA imaged at baseline will be referred for a follow-up CTCA 2-year post-baseline. The primary endpoint is to identify the prevalence of CAD, identified via CAC scoring, among cancer survivors classified as intermediate risk. Secondary endpoint includes the absolute change in total coronary plaque volume over 24 months among those imaged at baseline and follow-up.

Summary
The REDEEM-CAD study will be the first study to systematically evaluate risk of CAD in cancer survivors, and subsequent responsiveness to coronary risk reduction. This will offer valuable insights into the efficacy of the CAD screening strategies among cancer survivors and the impact of treatment on managing plaque progression.

Trial registration
NCT05366153.
Context modulates evidence accumulation in split-second handball penalty decisions
Authors: Weinberg Henrietta , Müller Florian , Cañal-Bruland Rouwen 
Published: February 2025

Abstract
Due to severe time constraints, goalkeepers regularly face the challenging task to make decisions within just a few hundred milliseconds. A key finding of anticipation research is that experts outperform novices by using advanced cues which can be derived from either kinematic or contextual information. Yet, how context modulates decision-making in split-second decisions remains to be determined. Here, we aimed at examining the influence of contextual information on real-time evidence accumulation in split-second decision-making using handball penalty decisions. In Exp. 1 we validated the applicability of hierarchical drift–diffusion modeling (HDDM) for the chosen split-second handball penalty scenario. Following validation, Exp. 2 directly addressed the main aim, namely, to examine how contextual information affects the HDDM parameters drift rate, as the rate of evidence accumulation, and non-decision time, which encompasses perceptual and motor processes. Participants predicted shot direction in temporally occluded videos of handball penalties, with probability (i.e., contextual) information regarding the shot direction being manipulated in half of the trials. Results showed that contextual information systematically affected the drift rate, indicating faster evidence accumulation when context information predicts the subsequent action. Vice versa, incongruent context information resulted in slower evidence accumulation. By contrast, non-decision time was only affected by the mere presence of contextual information (i.e., longer with context information). Our study is the first to show that contextual information modulates evidence accumulation on extremely short timescales in highly time-constrained penalty decisions.
A high offset stem design does not increase stem migration under full weight bearing in cementless total hip arthroplasty: a model-based RSA study
Authors: Reiner Tobias , Sonntag Robert , Kretzer Jan Philippe , Clarius Michael , Jakubowitz Eike , Weiss Stefan , Kinkel Stefan , Walker Tilman , Gotterbarm Tobias , Nees Timo Albert 
Published: February 2025

Abstract

Background
High-offset stems in cementless primary total hip arthroplasty (THA) have been potentially associated with early aseptic femoral loosening. This study aimed to evaluate the primary and secondary stability of a cementless high-offset femoral component under full weight-bearing conditions using model-based RSA, comparing it with a standard offset stem in patients undergoing THA.

Methods
In this prospective, observational, single-center study, 42 patients with end-stage hip osteoarthritis underwent cementless primary THA using either a standard (SL-PLUS Standard) or a high-offset (SL-PLUS Lateral) cementless stem. Radiostereometric analysis (RSA) was employed to monitor stem migration at six weeks and three, six, twelve, and twenty-four months. Clinical outcomes were assessed using the modified Harris Hip Score (HHS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).

Results
There were no significant differences in mean stem subsidence between the groups at any follow-up interval, indicating comparable primary and secondary stability. After minimal initial subsidence (SL-PLUS Standard: up to −0.54 mm; SL-PLUS Lateral: up to −0.73 mm), no further progressive migration was observed. A significant difference in stem anteversion was noted between the groups at six months (P = 0.021) and two years (P = 0.001). The SL-PLUS Lateral group had significantly better WOMAC scores at the two-year follow-up (P = 0.027).

Conclusions
This RSA study demonstrated similar migration patterns for the high-offset and standard-offset cementless stems within the first two years after operation. Both groups exhibited initial subsidence followed by high secondary stability. Based on the results of this study, the SL-PLUS Lateral is a safe alternative for patients with high femoral offset undergoing cementless THA.
Challenges in the application of Maslow’s hierarchy of needs for children living in Gaza amid ongoing conflict started in October 2023
Authors: Qutishat Mohammed 
Published: February 2025

Abstract

Background
The ongoing conflict in Gaza, which escalated on October 7th, 2023, has significantly disrupted children’s ability to fulfill their basic needs, as framed by Maslow’s hierarchy of needs. This situation exacerbates their vulnerability and mental health challenges.

Main body
This literature review systematically analyzed studies and reports focusing on the conflict’s psychological, emotional, and social impacts on children in Gaza. A comprehensive search of academic databases was conducted using specific keywords, including 15 relevant articles published post-October 2023. The findings highlight critical challenges across all levels of Maslow’s hierarchy. Physiological needs remain unmet due to food insecurity and limited access to healthcare. Safety needs are jeopardized by ongoing violence, leading to increased trauma among children. The breakdown of social structures impairs belongingness and love, while disruptions to education hinder children’s esteem and self-actualization needs.

Conclusion
The multifaceted nature of these challenges underscores the urgent need for a coordinated humanitarian response. Addressing children’s immediate psychological and physical needs is essential for fostering resilience and ensuring their future well-being.