bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast cancer patient-derived organoids for the investigation of patient-specific tumour evolution
Authors: Mazzucchelli Serena , Signati Lorena , Messa Letizia , Franceschini Alma , Bonizzi Arianna , Castagnoli Lorenzo , Gasparini Patrizia , Consolandi Clarissa , Mangano Eleonora , Pelucchi Paride , Cifola Ingrid , Camboni Tania , Severgnini Marco , Villani Laura , Tagliaferri Barbara , Carelli Stephana , Pupa Serenella M. , Cereda Cristina , Corsi Fabio 
Published: June 2024

Abstract
Background
A reliable preclinical model of patient-derived organoids (PDOs) was developed in a case study of a 69-year-old woman diagnosed with breast cancer (BC) to investigate the tumour evolution before and after neoadjuvant chemotherapy and surgery. The results were achieved due to the development of PDOs from tissues collected before (O-PRE) and after (O-POST) treatment.

Methods
PDO cultures were characterized by histology, immunohistochemistry (IHC), transmission electron microscopy (TEM), scanning electron microscopy (SEM), confocal microscopy, flow cytometry, real-time PCR, bulk RNA-seq, single-cell RNA sequencing (scRNA-seq) and drug screening.

Results
Both PDO cultures recapitulated the histological and molecular profiles of the original tissues, and they showed typical mammary gland organization, confirming their reliability as a personalized in vitro model. Compared with O-PRE, O-POST had a greater proliferation rate with a significant increase in the Ki67 proliferation index. Moreover O-POST exhibited a more stem-like and aggressive phenotype, with increases in the CD24low/CD44low and EPCAMlow/CD49fhigh cell populations characterized by increased tumour initiation potential and multipotency and metastatic potential in invasive lobular carcinoma. Analysis of ErbB receptor expression indicated a decrease in HER-2 expression coupled with an increase in EGFR expression in O-POST. In this context, deregulation of the PI3K/Akt signalling pathway was assessed by transcriptomic analysis, confirming the altered transcriptional profile. Finally, transcriptomic single-cell analysis identified 11 cell type clusters, highlighting the selection of the luminal component and the decrease in the number of Epithelial–mesenchymal transition cell types in O-POST.

Conclusion
Neoadjuvant treatment contributed to the enrichment of cell populations with luminal phenotypes that were more resistant to chemotherapy in O-POST. PDOs represent an excellent 3D cell model for assessing disease evolution.
Inhibition of ABI2 ubiquitination-dependent degradation suppresses TNBC cell growth via down-regulating PI3K/Akt signaling pathway
Authors: Lv Linlin , Li Shujing , Kang Jie , Li Yulin , Zhao Nannan , Ye Dongman , Qin Fengying , Sun Jing , Yu Tao , Wu Huijian 
Published: June 2024

AbstractTriple negative breast cancer (TNBC) is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-ABI2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2, acting as a crucial factor of tumor suppression, can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, based on TNBC drug target ABI2, we screened and found that FDA-approved drug Colistimethate sodium(CS) has significant potential in suppressing the proliferation of TNBC cells and inducing cell apoptosis, making it a promising candidate for impeding the progression of TNBC.
WZ-3146 acts as a novel small molecule inhibitor of KIF4A to inhibit glioma progression by inducing apoptosis
Authors: Yan Tao , Jiang Qing , Ni Guangpu , Ma Haofeng , Meng Yun , Kang Guiqiong , Xu Meifang , Peng Fei , Li Huadong , Chen Xin , Wang Mingguang 
Published: June 2024

Abstract
Background
Glioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed.

Methods
The gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot.

Results
In the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects.

Conclusion
In conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression.
Associations between urine glyphosate levels and metabolic health risks: insights from a large cross-sectional population-based study
Authors: Otaru Sarah , Jones Laura E. , Carpenter David O. 
Published: June 2024

Abstract
Background
The prevalence of metabolic syndrome (MetS) in American adults increased from 37.6% in the 2011–12 period to 41.8% in 2017–2018. Environmental exposure, particularly to common compounds such as glyphosate, has drawn increasing attention as a potential risk factor.

Methods
We employed three cycles of data (2013–2018) from the National Health and Nutrition Examination Survey (NHANES) in a cross-sectional study to examine potential associations between urine glyphosate measurements and MetS incidence. We first created a MetS score using exploratory factor analysis (EFA) of the International Diabetes Federation (IDF) criteria for MetS, with data drawn from the 2013–2018 NHANES cycles, and validated this score independently on an additional associated metric, the albumin-to-creatinine (ACR) ratio. The score was validated via a machine learning approach in predicting the ACR score via binary classification and then used in multivariable regression to test the association between quartile-categorized glyphosate exposure and the MetS score.

Results
In adjusted multivariable regressions, regressions between quartile-categorized glyphosate exposure and MetS score showed a significant inverted U-shaped or saturating dose‒response profile, often with the largest effect for exposures in quartile 3. Exploration of potential effect modification by sex, race, and age category revealed significant differences by race and age, with older people (aged > 65 years) and non-Hispanic African American participants showing larger effect sizes for all exposure quartiles.

Conclusions
We found that urinary glyphosate concentration is significantly associated with a statistical score designed to predict MetS status and that dose–response coefficient is nonlinear, with advanced age and non-Hispanic African American, Mexican American and other Hispanic participants exhibiting greater effect sizes.
Sphingolipid changes in mouse brain and plasma after mild traumatic brain injury at the acute phases
Authors: Mondal Koushik , Del Mar Nobel A. , Gary Ashlyn A. , Grambergs Richard C. , Yousuf Mohd , Tahia Faiza , Stephenson Benjamin , Stephenson Daniel J. , Chalfant Charles E. , Reiner Anton , Mandal Nawajes 
Published: June 2024

Abstract
Background
Traumatic brain injury (TBI) causes neuroinflammation and can lead to long-term neurological dysfunction, even in cases of mild TBI (mTBI). Despite the substantial burden of this disease, the management of TBI is precluded by an incomplete understanding of its cellular mechanisms. Sphingolipids (SPL) and their metabolites have emerged as key orchestrators of biological processes related to tissue injury, neuroinflammation, and inflammation resolution. No study so far has investigated comprehensive sphingolipid profile changes immediately following TBI in animal models or human cases. In this study, sphingolipid metabolite composition was examined during the acute phases in brain tissue and plasma of mice following mTBI.

Methods
Wildtype mice were exposed to air-blast-mediated mTBI, with blast exposure set at 50-psi on the left cranium and 0-psi designated as Sham. Sphingolipid profile was analyzed in brain tissue and plasma during the acute phases of 1, 3, and 7 days post-TBI via liquid-chromatography-mass spectrometry. Simultaneously, gene expression of sphingolipid metabolic markers within brain tissue was analyzed using quantitative reverse transcription-polymerase chain reaction. Significance (P-values) was determined by non-parametric t-test (Mann–Whitney test) and by Tukey’s correction for multiple comparisons.

Results
In post-TBI brain tissue, there was a significant elevation of 1) acid sphingomyelinase (aSMase) at 1- and 3-days, 2) neutral sphingomyelinase (nSMase) at 7-days, 3) ceramide-1-phosphate levels at 1 day, and 4) monohexosylceramide (MHC) and sphingosine at 7-days. Among individual species, the study found an increase in C18:0 and a decrease in C24:1 ceramides (Cer) at 1 day; an increase in C20:0 MHC at 3 days; decrease in MHC C18:0 and increase in MHC C24:1, sphingomyelins (SM) C18:0, and C24:0 at 7 days. Moreover, many sphingolipid metabolic genes were elevated at 1 day, followed by a reduction at 3 days and an absence at 7-days post-TBI. In post-TBI plasma, there was 1) a significant reduction in Cer and MHC C22:0, and an increase in MHC C16:0 at 1 day; 2) a very significant increase in long-chain Cer C24:1 accompanied by significant decreases in Cer C24:0 and C22:0 in MHC and SM at 3 days; and 3) a significant increase of C22:0 in all classes of SPL (Cer, MHC and SM) as well as a decrease in Cer C24:1, MHC C24:1 and MHC C24:0 at 7 days.

Conclusions
Alterations in sphingolipid metabolite composition, particularly sphingomyelinases and short-chain ceramides, may contribute to the induction and regulation of neuroinflammatory events in the early stages of TBI, suggesting potential targets for novel diagnostic, prognostic, and therapeutic strategies in the future.
Using qualitative system dynamics modeling to understand overdose bystander behavior in the context of Connecticut’s Good Samaritan Laws and identify effective policy options
Authors: Thompson Rachel L. , Sabounchi Nasim S. , Ali Syed Shayan , Heimer Robert , D’Onofrio Gail , Heckmann Rebekah 
Published: June 2024

Abstract
Background
Good Samaritan Laws are a harm reduction policy intended to facilitate a reduction in fatal opioid overdoses by enabling bystanders, first responders, and health care providers to assist individuals experiencing an overdose without facing civil or criminal liability. However, Good Samaritan Laws may not be reaching their full impact in many communities due to a lack of knowledge of protections under these laws, distrust in law enforcement, and fear of legal consequences among potential bystanders. The purpose of this study was to develop a systems-level understanding of the factors influencing bystander responses to opioid overdose in the context of Connecticut’s Good Samaritan Laws and identify high-leverage policies for improving opioid-related outcomes and implementation of these laws in Connecticut (CT).

Methods
We conducted six group model building (GMB) workshops that engaged a diverse set of participants with medical and community expertise and lived bystander experience. Through an iterative, stakeholder-engaged process, we developed, refined, and validated a qualitative system dynamics (SD) model in the form of a causal loop diagram (CLD).

Results
Our resulting qualitative SD model captures our GMB participants’ collective understanding of the dynamics driving bystander behavior and other factors influencing the effectiveness of Good Samaritan Laws in the state of CT. In this model, we identified seven balancing (B) and eight reinforcing (R) feedback loops within four narrative domains: Narrative 1 - Overdose, Calling 911, and First Responder Burnout; Narrative 2 - Naloxone Use, Acceptability, and Linking Patients to Services; Narrative 3 - Drug Arrests, Belief in Good Samaritan Laws, and Community Trust in Police; and Narrative 4 - Bystander Naloxone Use, Community Participation in Harm Reduction, and Cultural Change Towards Carrying Naloxone.

Conclusions
Our qualitative SD model brings a nuanced systems perspective to the literature on bystander behavior in the context of Good Samaritan Laws. Our model, grounded in local knowledge and experience, shows how the hypothesized non-linear interdependencies of the social, structural, and policy determinants of bystander behavior collectively form endogenous feedback loops that can be leveraged to design policies to advance and sustain systems change.
Harnessing peer mentorship as a tool to turn human resource for health brain drain into brain gain: a case study of a Nigerian peer-mentored research group
Authors: Toyin-Thomas Patience , Wariri Oghenebrume , Ikhurionan Paul 
Published: June 2024

Abstract
Background
Peer mentorship can be a potential tool to reduce the disparities in health research capacity between high- and low- and middle-income countries. This case study describes the potential of peer mentorship to tackle two critical issues: bridging health research capacity of doctors from low- and middle-income countries (LMICs) and the transformation of human resource for health brain drain into "brain gain".

Case presentation
In 2021, a virtual peer mentorship group was established by 16 alumni of the University of Benin College of Medical Sciences' 2008 graduating class, residing across three continents. This program aimed to facilitate research collaboration and skill development among colleagues with diverse research experience levels, fostering a supportive environment for career development in research. The group relied heavily on digital technology to carry out its activities due to the different geographical locations of the group members. Led by experienced peer leaders, the group fostered a collaborative learning environment where members leveraged each other's expertise. Within 18 months, we published two research papers in high-impact peer-reviewed global health journals, launched a mixed-methods research study, and conducted training sessions on research design and implementation. Findings from our work were presented at conferences and workshops. However, logistical hurdles, competing priorities, structural constraints, and uneven participation presented challenges.

Conclusion
The peer mentorship collaboration has achieved some successes so far, and this model can be emulated by other cohorts of medical professionals across LMICs. Despite the group's success at a micro- or individual level, there remain significant structural barriers to research capacity building in LMICs that can only be addressed at the meso- and macro-levels by institutions and government, respectively. A systems-level approach is required to develop and support research capacity building and foster global research collaboration and effectively turn brain drain into brain gain.
Exploring the oncogenic potential of circSOD2 in clear cell renal cell carcinoma: a novel positive feedback loop
Authors: Yao Gao-sheng , Fu Liang-min , Dai Jun-shang , Chen Jin-wei , Liu Ke-zhi , Liang Hui , Wang Zhu , Deng Qiong , Wang Jie-yan , Jin Mei-yu , Chen Wei , Fang Yong , Luo Jun-hang , Cao Jia-zheng , Wei Jin-huan 
Published: June 2024

Abstract
Background
Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated.

Methods
Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing.

Results
CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor.

Conclusion
A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients.
A robust clustering strategy for stratification unveils unique patient subgroups in acutely decompensated cirrhosis
Authors: Palomino-Echeverria Sara , Huergo Estefania , Ortega-Legarreta Asier , Uson Raposo Eva M. , Aguilar Ferran , Peña-Ramirez Carlos de la , López-Vicario Cristina , Alessandria Carlo , Laleman Wim , Queiroz Farias Alberto , Moreau Richard , Fernandez Javier , Arroyo Vicente , Caraceni Paolo , Lagani Vincenzo , Sánchez-Garrido Cristina , Clària Joan , Tegner Jesper , Trebicka Jonel , Kiani Narsis A. , Planell Nuria , Rautou Pierre-Emmanuel , Gomez-Cabrero David 
Published: June 2024

Abstract
Background
Patient heterogeneity poses significant challenges for managing individuals and designing clinical trials, especially in complex diseases. Existing classifications rely on outcome-predicting scores, potentially overlooking crucial elements contributing to heterogeneity without necessarily impacting prognosis.

Methods
To address patient heterogeneity, we developed ClustALL, a computational pipeline that simultaneously faces diverse clinical data challenges like mixed types, missing values, and collinearity. ClustALL enables the unsupervised identification of patient stratifications while filtering for stratifications that are robust against minor variations in the population (population-based) and against limited adjustments in the algorithm’s parameters (parameter-based).

Results
Applied to a European cohort of patients with acutely decompensated cirrhosis (n = 766), ClustALL identified five robust stratifications, using only data at hospital admission. All stratifications included markers of impaired liver function and number of organ dysfunction or failure, and most included precipitating events. When focusing on one of these stratifications, patients were categorized into three clusters characterized by typical clinical features; notably, the 3-cluster stratification showed a prognostic value. Re-assessment of patient stratification during follow-up delineated patients’ outcomes, with further improvement of the prognostic value of the stratification. We validated these findings in an independent prospective multicentre cohort of patients from Latin America (n = 580).

Conclusions
By applying ClustALL to patients with acutely decompensated cirrhosis, we identified three patient clusters. Following these clusters over time offers insights that could guide future clinical trial design. ClustALL is a novel and robust stratification method capable of addressing the multiple challenges of patient stratification in most complex diseases.
Macrophages as determinants and regulators of systemic sclerosis-related interstitial lung disease
Authors: Lee Shih-Ching , Huang Chen-Hao , Oyang Yen-Jen , Huang Hsuan-Cheng , Juan Hsueh-Fen 
Published: June 2024

Abstract
Background
Interstitial lung disease (ILD) is the primary cause of mortality in systemic sclerosis (SSc), an autoimmune disease characterized by tissue fibrosis. SSc-related ILD (SSc-ILD) occurs more frequently in females aged 30–55 years, whereas idiopathic pulmonary fibrosis (IPF) is more prevalent in males aged 60–75 years. SSc-ILD occurs earlier than IPF and progresses rapidly. FCN1, FABP4, and SPP1 macrophages are involved in the pathogenesis of lung fibrosis; SPP1 macrophages demonstrate upregulated expression in both SSc-ILD and IPF. To identify the differences between SSc-ILD and IPF using single-cell analysis, clarify their distinct pathogeneses, and propose directions for prevention and treatment.

Methods
We performed single-cell RNA sequencing on NCBI Gene Expression Omnibus (GEO) databases GSE159354 and GSE212109, and analyzed lung tissue samples across healthy controls, IPF, and SSc-ILD. The primary measures were the filtered genes integrated with batch correction and annotated cell types for distinguishing patients with SSc-ILD from healthy controls. We proposed an SSc-ILD pathogenesis using cell–cell interaction inferences, and predicted transcription factors regulating target genes using SCENIC. Drug target prediction of the TF gene was performed using Drug Bank Online.

Results
A subset of macrophages activates the MAPK signaling pathway under oxidative stress. Owing to the lack of inhibitory feedback from ANNEXIN and the autoimmune characteristics, this leads to an earlier onset of lung fibrosis compared to IPF. During initial lung injury, fibroblasts begin to activate the IL6 pathway under the influence of SPP1 alveolar macrophages, but IL6 appears unrelated to other inflammatory and immune cells. This may explain why tocilizumab (an anti-IL6-receptor antibody) only preserves lung function in patients with early SSc-ILD. Finally, we identified BCLAF1 and NFE2L2 as influencers of MAPK activation in macrophages. Metformin downregulates NFE2L2 and could serve as a repurposed drug candidate.

Conclusions
SPP1 alveolar macrophages play a role in the profibrotic activity of IPF and SSc-ILD. However, SSc-ILD is influenced by autoimmunity and oxidative stress, leading to the continuous activation of MAPK in macrophages. This may result in an earlier onset of lung fibrosis than in IPF. Such differences could serve as potential research directions for early prevention and treatment.