bluuebunny/crossref_metadata_2025_split huggingface dataset:
HbA1c-based rather than fasting plasma glucose-based definitions of prediabetes identifies high-risk patients with angiographic coronary intermediate lesions: a prospective cohort study
Authors: Song Chenxi , Yuan Sheng , Cui Kongyong , Cai Zhongxing , Zhang Rui , He Jining , Qiao Zheng , Bian Xiaohui , Wu Shaoyu , Wang Haoyu , Shi Boqun , Lin Zhangyu , Fu Rui , Wang Chunyue , Liu Qianqian , Jia Lei , Dong Qiuting , Dou Kefei 
Published: March 2023

Abstract
Background
Prediabetes is common and associated with poor prognosis in patients with acute coronary syndrome and those undergoing revascularization. However, the impact of prediabetes on prognosis in patients with coronary intermediate lesions remains unclear. The objective of the current study is to explore the impact of prediabetes and compare the prognostic value of the different definitions of prediabetes in patients with coronary intermediate lesions.

Methods
A total of 1532 patients attending Fuwai hospital (Beijing, China), with intermediate angiographic coronary lesions, not undergoing revascularization, were followed-up from 2013 to 2021. Patients were classified as normal glucose tolerance (NGT), prediabetes and diabetes according to various definitions based on HbA1c or admission fasting plasma glucose (FPG). The primary endpoint was defined as major adverse cardiovascular events (MACE), the composite endpoint of all-cause death, non-fatal myocardial infarction and repeated revascularization therapy. Multivariate cox regression model was used to explore the association between categories of abnormal glucose category and MACE risk.

Results
The proportion of patients defined as prediabetes ranged from 3.92% to 47.06% depending on the definition used. A total of 197 MACE occurred during a median follow-up time of 6.1 years. Multivariate cox analysis showed that prediabetes according to the International Expert Committee (IEC) guideline (6.0 ≤ HbA1c < 6.5%) was associated with increased risk of MACE compared with NGT (hazard ratio [HR]: 1.705, 95% confidence interval [CI] 1.143–2.543) and after confounding adjustment (HR: 1.513, 95%CI 1.005–2.277). Consistently, the best cut-off point of glycated haemoglobin (HbA1c) identified based on the Youden’s index was also 6%. Restricted cubic spline analysis delineated a linear positive relationship between baseline HbA1c and MACE risk. Globally, FPG or FPG-based definition of prediabetes was not associated with patients’ outcome.

Conclusions
In this cohort of patients with intermediate coronary lesions not undergoing revascularization therapy, prediabetes based on the IEC-HbA1c definition was associated with increased MACE risk compared with NGT, and may assist in identifying high-risk patients who can benefit from early lifestyle intervention.
Time-dependent effect of GLP-1 receptor agonists on cardiovascular benefits: a real-world study
Authors: Piccini Sara , Favacchio Giuseppe , Panico Cristina , Morenghi Emanuela , Folli Franco , Mazziotti Gherardo , Lania Andrea Gerardo , Mirani Marco 
Published: March 2023

Abstract
Background
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in cardiovascular outcome trials in type 2 diabetes mellitus. However, the most convincing evidence was obtained in subjects with established cardiovascular (CV) disease. We analyzed the determinants of GLP-1 RA-mediated CV protection in a real-world population of persons with type 2 diabetes with and without a history of CV events with long-term follow-up.

Methods
Retrospective cohort study of 550 individuals with type 2 diabetes (395 in primary CV prevention, 155 in secondary CV prevention), followed at a single center after the first prescription of a GLP-1 RA between 2009 and 2019. CV and metabolic outcomes were assessed.

Results
Median duration of follow-up was 5.0 years (0.25–10.8) in primary prevention and 3.6 years (0–10.3) in secondary prevention, with a median duration of treatment of 3.2 years (0–10.8) and 2.5 years (0–10.3) respectively. In the multivariable Cox regression model considering GLP-1 RA treatment as a time-dependent covariate, in the primary prevention group, changes in BMI and glycated hemoglobin did not have an impact on MACE risk, while age at the time of GLP-1 initiation (HR 1.08, 95% CI 1.03–1.14, p = 0.001) and GLP-1 RA cessation by time (HR 3.40, 95% CI 1.82–6.32, p < 0.001) increased the risk of MACE. Regarding the secondary prevention group, only GLP-1 RA cessation by time (HR 2.71, 95% CI 1.46–5.01, p = 0.002) increased the risk of MACE. With respect to those who withdrew treatment, subjects who continued the GLP-1 RA had significantly greater weight loss and lower glycated hemoglobin levels during follow-up.

Conclusions
In this real-world type 2 diabetes population, discontinuation of GLP-1 RA treatment was associated to a higher risk of major cardiovascular events, in both subjects with and without a history of CV events.
The five continuum of care criteria that should accompany rectal artesunate interventions: lessons learned from an implementation study in Malawi
Authors: Oliff Monique S. , Muniina Pamela , Babigumira Kenneth , Phuka John , Rietveld Hans , Sande John , Nsona Humphreys , Lugand Maud M. 
Published: March 2023

Abstract
Background
Rectal artesunate (RAS) is a World Health Organization (WHO) recommended intervention that can save lives of children 6 years and younger suffering from severe malaria and living in remote areas. Access to RAS and a referral system that ensures continuity of care remains a challenge in low resource countries, raising concerns around the value of this intervention. The objective of this study was to inform RAS programming, using practical tools to enhance severe malaria continuum of care when encountered at community level.

Methods
A single country two-arm-controlled study was conducted in Malawi, where pre-referral interventions are provided by community health workers (CHWs). The study populations consisted of 9 and 14 village health clinics (VHCs) respectively, including all households with children 5 years and younger. CHWs in the intervention arm were trained using a field-tested toolkit and the community had access to information, education, and communication (IEC) mounted throughout the zone. The community in the control arm had access to routine care only. Both study arms were provided with a dedicated referral booklet for danger signs, as a standard of care.

Results
The study identified five continuum of care criteria (5 CoC Framework) to reinforce RAS programming: (1) care transitions emerged as to be dependent on a strong cue to action and proximity to an operational VHC with a resident CHWs; (2) consistency of supplies assured the population of the VHC’s functionality for severe danger signs management; (3) comprehensiveness care ensured correct assessment and dosing; (4) connectivity of care between all tiers using the referral slip was feasible and perceived positively by caregivers and CHWs and (5) communication between providers from different points of care. Compliance was high throughout but optimized when administered by a sensitized CHW. Over 93% experienced a rapid improvement in the status of their child post RAS.

Conclusion
RAS cannot operate within a vacuum. The impact of this lifesaving intervention can be easily lost, unless administered as part of a system-based approach. Taken together, the 5CC Framework, identified in this study, provides a structure for future RAS practice guidelines.
Trial registration number and date of registration PACTR201906720882512- June 20, 2019.
Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment
Authors: Ruan Ruiwen , Li Li , Li Xuan , Huang Chunye , Zhang Zhanmin , Zhong Hongguang , Zeng Shaocheng , Shi Qianqian , Xia Yang , Zeng Qinru , Wen Qin , Chen Jingyi , Dai Xiaofeng , Xiong Jianping , Xiang Xiaojun , Lei Wan , Deng Jun 
Published: March 2023

Abstract
Background
Fibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cell fate and angiogenesis, with dysregulation of the signaling axis driving tumorigenesis. Therefore, many studies have targeted FGF/FGFR signaling for cancer therapy and several FGFR inhibitors have promising results in different tumors but treatment efficiency may still be improved. The clinical use of immune checkpoint blockade (ICB) has resulted in sustained remission for patients.

Main
Although there is limited data linking FGFR inhibitors and immunotherapy, preclinical research suggest that FGF/FGFR signaling is involved in regulating the tumor microenvironment (TME) including immune cells, vasculogenesis, and epithelial-mesenchymal transition (EMT). This raises the possibility that ICB in combination with FGFR-tyrosine kinase inhibitors (FGFR-TKIs) may be feasible for treatment option for patients with dysregulated FGF/FGFR signaling.

Conclusion
Here, we review the role of FGF/FGFR signaling in TME regulation and the potential mechanisms of FGFR-TKI in combination with ICB. In addition, we review clinical data surrounding ICB alone or in combination with FGFR-TKI for the treatment of FGFR-dysregulated tumors, highlighting that FGFR inhibitors may sensitize the response to ICB by impacting various stages of the “cancer-immune cycle”.
Machine-learning screening of luminogens with aggregation-induced emission characteristics for fluorescence imaging
Authors: Zhang Yibin , Fan Miaozhuang , Xu Zhourui , Jiang Yihang , Ding Huijun , Li Zhengzheng , Shu Kaixin , Zhao Mingyan , Feng Gang , Yong Ken-Tye , Dong Biqin , Zhu Wei , Xu Gaixia 
Published: March 2023

AbstractDue to the excellent biocompatible physicochemical performance, luminogens with aggregation-induced emission (AIEgens) characteristics have played a significant role in biomedical fluorescence imaging recently. However, screening AIEgens for special applications takes a lot of time and efforts by using conventional chemical synthesis route. Fortunately, artificial intelligence techniques that could predict the properties of AIEgen molecules would be helpful and valuable for novel AIEgens design and synthesis. In this work, we applied machine learning (ML) techniques to screen AIEgens with expected excitation and emission wavelength for biomedical deep fluorescence imaging. First, a database of various AIEgens collected from the literature was established. Then, by extracting key features using molecular descriptors and training various state-of-the-art ML models, a multi-modal molecular descriptors strategy has been proposed to extract the structure-property relationships of AIEgens and predict molecular absorption and emission wavelength peaks. Compared to the first principles calculations, the proposed strategy provided greater accuracy at a lower computational cost. Finally, three newly predicted AIEgens with desired absorption and emission wavelength peaks were synthesized successfully and applied for cellular fluorescence imaging and deep penetration imaging. All the results were consistent successfully with our expectations, which demonstrated the above ML has a great potential for screening AIEgens with suitable wavelengths, which could boost the design and development of novel organic fluorescent materials.
Identification of prognostic and therapeutic biomarkers in type 2 papillary renal cell carcinoma
Authors: Wang Yue , Tian Xi , Zhu Shu-Xuan , Xu Wen-Hao , Anwaier Aihetaimujiang , Su Jia-Qi , Gan Hua-Lei , Qu Yuan-Yuan , Zhao Jian-Yuan , Zhang Hai-Liang , Ye Ding-Wei 
Published: March 2023

AbstractBackgroundPapillary renal cell carcinoma (PRCC) can be divided into type 1 (PRCC1) and type 2 (PRCC2) and PRCC2 share a more invasive phenotype and worse prognosis. This study aims to identify potential prognostic and therapeutic biomarkers in PRCC2.MethodsA cohort from The Cancer Genome Atlas and two datasets from Gene Expression Omnibus were examined. Common differentially expressed genes (DEGs) were screened and potential biomarkers were explored by using Kaplan–Meier method and cox regression analysis. Functional enrichment analysis was utilized to evaluate the potential biological functions. Tumor infiltrating immune cells were estimated by CIBERSORT algorithm. Ninety-two PRCC2 samples from Fudan University Shanghai Cancer Center were obtained, and immunostaining was performed to validate prognostic and therapeutic significance of the potential biomarker.ResultsPRCC2 has worse overall survival and shares distinct molecular characteristics from PRCC1. There was significant higher expression level of Targeting protein for Xklp2 (TPX2) in PRCC2 compared with normal tissues. Higher expression level of TPX2 was significantly associated with worse overall survival in PRCC2 and kinesin family genes expression were found significantly elevated in high risk PRCC2. Abundance of tumor infiltrating M1 macrophage was significantly higher in PRCC2 and it was also associated with worse overall survival. In the FUSCC cohort, higher TPX2 expression was significantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater efficacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater efficacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%).ConclusionsTPX2 was a prognostic and therapeutic biomarker in PRCC2. Higher abundance of tumor infiltrating M1 macrophage was significantly associated with worse overall survival in PRCC2. mTOR inhibitors may have good efficacy in patients with high-risk PRCC2.
Reference values for wrist-worn accelerometer physical activity metrics in England children and adolescents
Authors: Fairclough Stuart J. , Rowlands Alex V. , del Pozo Cruz Borja , Crotti Matteo , Foweather Lawrence , Graves Lee E. F. , Hurter Liezel , Jones Owen , MacDonald Mhairi , McCann Deborah A. , Miller Caitlin , Noonan Robert J. , Owen Michael B. , Rudd James R. , Taylor Sarah L. , Tyler Richard , Boddy Lynne M. 
Published: March 2023

Abstract
Background
Over the last decade use of raw acceleration metrics to assess physical activity has increased. Metrics such as Euclidean Norm Minus One (ENMO), and Mean Amplitude Deviation (MAD) can be used to generate metrics which describe physical activity volume (average acceleration), intensity distribution (intensity gradient), and intensity of the most active periods (MX metrics) of the day. Presently, relatively little comparative data for these metrics exists in youth. To address this need, this study presents age- and sex-specific reference percentile values in England youth and compares physical activity volume and intensity profiles by age and sex.

Methods
Wrist-worn accelerometer data from 10 studies involving youth aged 5 to 15 y were pooled. Weekday and weekend waking hours were first calculated for youth in school Years (Y) 1&2, Y4&5, Y6&7, and Y8&9 to determine waking hours durations by age-groups and day types. A valid waking hours day was defined as accelerometer wear for ≥ 600 min·d−1 and participants with ≥ 3 valid weekdays and ≥ 1 valid weekend day were included. Mean ENMO- and MAD-generated average acceleration, intensity gradient, and MX metrics were calculated and summarised as weighted week averages. Sex-specific smoothed percentile curves were generated for each metric using Generalized Additive Models for Location Scale and Shape. Linear mixed models examined age and sex differences.

Results
The analytical sample included 1250 participants. Physical activity peaked between ages 6.5–10.5 y, depending on metric. For all metrics the highest activity levels occurred in less active participants (3rd-50th percentile) and girls, 0.5 to 1.5 y earlier than more active peers, and boys, respectively. Irrespective of metric, boys were more active than girls (p < .001) and physical activity was lowest in the Y8&9 group, particularly when compared to the Y1&2 group (p < .001).

Conclusions
Percentile reference values for average acceleration, intensity gradient, and MX metrics have utility in describing age- and sex-specific values for physical activity volume and intensity in youth. There is a need to generate nationally-representative wrist-acceleration population-referenced norms for these metrics to further facilitate health-related physical activity research and promotion.
Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-β2
Authors: Zhao Yu , Weng Zuyi , Zhou Xuan , Xu Zhi , Cao Bei , Wang Bin , Li Juan 
Published: March 2023

Abstract
Background
Gastrointestinal stromal tumors (GISTs) are the prevailing sarcomas of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) therapy, exemplified by Imatinib mesylate (IM), constitutes the established adjuvant therapy for GISTs. Nevertheless, post-treatment resistance poses a challenge that all patients must confront. The presence of tumor heterogeneity and secondary mutation mechanisms fail to account for some instances of acquired drug resistance. Certain investigations suggest a strong association between tumor drug resistance and mesenchymal stromal cells (MSC) in the tumor microenvironment, but the underlying mechanism remains obscure. Scarce research has explored the connection between GIST drug resistance and the tumor microenvironment, as well as the corresponding mechanism.

Methods
Immunofluorescence and fluorescence-activated cell sorting (FACS) methodologies were employed to detect the presence of MSC in GIST samples. The investigation encompassed the examination of MSC migration towards tumor tissue and the impact of MSC on the survival of GIST cells under IM treatment. Through ELISA, western blotting, and flow cytometry analyses, it was confirmed that Transforming Growth Factor Beta 2 (TGF-β2) triggers the activation of the PI3K-AKT pathway by MSC, thereby facilitating drug resistance in GIST.

Results
Our findings revealed a positive correlation between a high proportion of MSC and both GIST resistance and a poor prognosis. In vitro studies demonstrated the ability of MSC to migrate towards GIST. Additionally, MSC were observed to secrete TGF-β2, consequently activating the PI3K-AKT pathway and augmenting GIST resistance.

Conclusions
Our investigation has revealed that MSC within GISTs possess the capacity to augment drug resistance, thereby highlighting their novel mechanism and offering a promising target for intervention in GIST therapy.
Mitochondrial ROS driven by NOX4 upregulation promotes hepatocellular carcinoma cell survival after incomplete radiofrequency ablation by inducing of mitophagy via Nrf2/PINK1
Authors: Peng Chao , Li Xi , Ao Feng , Li Ting , Guo Jingpei , Liu Junfeng , Zhang Xiaoting , Gu Jinyan , Mao Junjie , Zhou Bin 
Published: March 2023

AbstractBackgroundThe recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains a major clinical problem. Cells that survive the sublethal heat stress that is induced by incomplete RFA are the main source of HCC relapse. Heat stress has long been reported to increase intracellular reactive oxygen species (ROS) generation. Although ROS can induce apoptosis, a pro-survival effect of ROS has also been demonstrated. However, the role of ROS in HCC cells exposed to sublethal heat stress remains unclear.MethodsHepG2 and HuH7 cells were used for this experiment. Insufficient RFA was performed in cells and in a xenograft model. ROS and antioxidant levels were measured. Apoptosis was analyed by Annexin-V/PI staining and flow cytometry. Protein expression was measured using western blotting. Colocalization of lysosomes and mitochondria was analyzed to assess mitophagy. Corresponding activators or inhibitors were applied to verify the function of specific objectives.ResultsHere,we showed that sublethal heat stress induced a ROS burst, which caused acute oxidative stress. This ROS burst was generated by mitochondria, and it was initiated by upregulated NOX4 expression in the mitochondria.n-acetylcysteine (NAC) decreased HCC cell survival under sublethal heat stress conditions in vivo and in vitro. NOX4 triggers the production of mitochondrial ROS (mtROS), and NOX4 inhibitors or siNOX4 also decreased HCC cell survival under sublethal heat stress conditions in vitro. Increased mtROS trigger PINK1-dependent mitophagy to eliminate the mitochondria that are damaged by sublethal heat stress and to protect cells from apoptosis. Nrf2 expression was elevated in response to this ROS burst and mediated the ROS burst-induced increase in PINK1 expression after sublethal heat stress.ConclusionThese data confirmed that the ROS burst that occurs after iRFA exerted a pro-survival effect. NOX4 increased the generation of ROS by mitochondria. This short-term ROS burst induced PINK1-dependent mitophagy to eliminate damaged mitochondria by increasing Nrf2 expression.
Microglial aryl hydrocarbon receptor enhances phagocytic function via SYK and promotes remyelination in the cuprizone mouse model of demyelination
Authors: Wang Yumeng , Sun Jingxian , Zhu Keying , Wang Danjie , Zhao Xiaoqiang , Zhang Hongyu , Wu Shuai , Wang Yanqing , Wang Jun 
Published: March 2023

AbstractMultiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the central nervous system (CNS). Although studies have demonstrated that microglia facilitate remyelination in demyelinating diseases, the underlying mechanisms are still not fully characterized. We found that aryl hydrocarbon receptor (AhR), an environment sensor, was upregulated within the corpus callosum in the cuprizone model of CNS demyelination, and upregulated AhR was mainly confined to microglia. Deletion of AhR in adult microglia inhibited efficient remyelination. Transcriptome analysis using RNA-seq revealed that AhR-deficient microglia displayed impaired gene expression signatures associated with lysosome and phagocytotic pathways. Furthermore, AhR-deficient microglia showed impaired clearance of myelin debris and defected phagocytic capacity. Further investigation of target genes of AhR revealed that spleen tyrosine kinase (SYK) is the downstream effector of AhR and mediated the phagocytic capacity of microglia. Additionally, AhR deficiency in microglia aggravated CNS inflammation during demyelination. Altogether, our study highlights an essential role for AhR in microglial phagocytic function and suggests the therapeutic potential of AhR in demyelinating diseases.Graphical Abstract