bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subclinical left ventricular deformation and microvascular dysfunction in T2DM patients with and without peripheral neuropathy: assessed by 3.0 T cardiac magnetic resonance imaging
Authors: Li Xue-Ming , Shi Rui , Shen Meng-Ting , Yan Wei-Feng , Jiang Li , Min Chen-Yan , Liu Xiao-Jing , Guo Ying-Kun , Yang Zhi-Gang 
Published: September 2023

Abstract
Background
Diabetic peripheral neuropathy (DPN) has been shown to be independently associated with cardiovascular events and mortality. This study aimed to evaluate changes in left ventricular (LV) microvascular perfusion and myocardial deformation in type 2 diabetes mellitus (T2DM) patients with and without DPN, as well as to investigate the association between myocardial perfusion and LV deformation.

Methods
Between October 2015 and July 2022, one hundred and twenty-three T2DM patients without DPN, fifty-four patients with DPN and sixty age‑ and sex‑matched controls who underwent cardiovascular magnetic resonance imaging were retrospectively analyzed. LV myocardial perfusion parameters at rest, including upslope, time to maximum signal intensity (TTM), max signal intensity (max SI), and myocardial strains, including global radial, circumferential and longitudinal strain (GRS, GCS and GLS, respectively), were calculated and compared among the groups with One‑way analysis of variance. Univariable and multivariable linear regression analyses were performed to explore the independent factors influencing LV myocardial perfusion indices and LV strains in diabetes.

Results
The LV GLS, upslope and max SI were significantly deteriorated from controls, through patients without DPN, to patients with DPN (all P < 0.001). Compared with controls, TTM was increased and LV GRS and GCS were decreased in both patient groups (all P < 0.05). Multivariable regression analyses considering covariates showed that DPN was independently associated with reduced upslope, max SI and LV GLS (β = − 0.360, − 2.503 and 1.113, p = 0.021, 0.031 and 0.010, respectively). When the perfusion indices upslope and max SI were included in the multivariable analysis for LV deformation, DPN and upslope (β = 1.057 and − 0.870, p = 0.020 and 0.018, respectively) were significantly associated with LV GLS.

Conclusion
In patients with T2DM, there was more severe LV microvascular and myocardial dysfunction in patients with complicated DPN, and deteriorated subclinical LV systolic dysfunction was associated with impaired myocardial circulation.
Cumulative exposure to high remnant-cholesterol concentrations increases the risk of cardiovascular disease in patients with hypertension: a prospective cohort study
Authors: Wu Weiqiang , Chen Guanzhi , Wu Kuangyi , Zheng Huancong , Chen Yanjuan , Wang Xianxuan , Huang Zegui , Cai Zefeng , Cai Zhiwei , Chen Zhichao , Lan Yulong , Chen Shuohua , Wu Shouling , Chen Youren 
Published: September 2023

Abstract
Background
The relationship of cumulative remnant-cholesterol (Cum-RC) concentration with the risk of cardiovascular disease (CVD) in patients with hypertension remains unclear.

Methods
We studied data for 28,698 individuals for whom three consecutive total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and triglyceride concentrations were available, and who did not have CVD (14,349 with hypertension and 14,349 without), that was collected between 2006 and 2010. Participants with hypertension were placed into four groups based on Cum-RC quartile: a Q1 group (< 26.40 mg/dl), a Q2 group (26.40–39.56 mg/dl), a Q3 group (39.57–54.65 mg/dl), and a Q4 group (≥ 54.66 mg/dl). Cox proportional hazards models were used to evaluate the relationship between Cum-RC and the risk of CVD.

Results
Over a median 10.9 (interquartile range, 10.5–11.3) years, 1,444 participants with hypertension developed CVD. After adjustment for multiple potential confounding factors, and compared with the Q1 Cum-RC group of the participants with hypertension, the adjusted hazard ratios for CVD for the Q2–Q4 groups were 1.07(0.92,1.26), 1.08(0.91,1.28), and 1.26(1.03,1.54) (P = 0.0405); those for myocardial infarction were 1.51(1.00,2.31), 2.02(1.22,3.27), and 2.08(1.41,3.28) (P < 0.0001); and those for ischemic stroke were 1.02(0.84,1.24), 1.04(0.86,1.25), and 1.29(1.02,1.62), respectively (P = 0.0336). However, no significant relationship was found between Cum-RC and the risk of hemorrhage stroke. At the same Cum-RC, the risk of CVD was significantly higher in participants with hypertension than in those without.

Conclusions
A consistently high remnant-cholesterol concentration increases the risk of CVD in individuals with hypertension. Therefore, the achievement of blood pressure and RC concentration targets should help reduce the risk of CVD in individuals with hypertension.
Association between the atherogenic index of plasma and adverse long-term prognosis in patients diagnosed with chronic coronary syndrome
Authors: Alifu Jiasuer , Xiang Lanqing , Zhang Wen , Qi Penglong , Chen Huiying , Liu Lu , Yin Guoqing , Mohammed Abdul-Quddus , Lv Xian , Shi Tingting , Abdu Fuad A. , Che Wenliang 
Published: September 2023

Abstract
Background
The Atherogenic Index of Plasma (AIP) is a newly identified biomarker associated with lipid metabolism, demonstrating significant prognostic capabilities in individuals diagnosed with cardiovascular disease. However, its impact within the context of chronic coronary syndromes (CCS) remains unexplored. Thus, the present investigation sought to examine the potential association between AIP levels and long-term clinical outcomes in patients diagnosed with CCS.

Methods
A total of 404 patients diagnosed with CCS and who underwent coronary angiography were included in this study. The AIP index was calculated as log (triglycerides / high-density lipoprotein-cholesterol). The patients were categorized into four groups based on their AIP values: Q1 (< -0.064), Q2 (-0.064 to 0.130), Q3 (0.130 to 0.328), and Q4 (> 0.328). The occurrence of major adverse cardiovascular events (MACE) was monitored during the follow-up period for all patients. Cox regression analysis and Kaplan-Meier curve analysis were employed to examine the relationship between AIP and MACE. Furthermore, ROC analysis was utilized to determine the optimal cut-off value of AIP for predicting clinical MACE.

Results
During the median 35 months of follow-up, a total of 88 patients experienced MACE. Notably, the group of patients with higher AIP values (Q4 group) exhibited a significantly higher incidence of MACE compared to those with lower AIP values (Q1, Q2, and Q3 groups) (31.7% vs. 16.8%, 15.7%, and 23.0% respectively; P = 0.023). The Kaplan-Meier curves illustrated those patients in the Q4 group had the highest risk of MACE relative to patients in the other groups (log-rank P = 0.014). Furthermore, the multivariate Cox regression analysis demonstrated that individuals in the Q4 group had a 7.892-fold increased risk of MACE compared to those in the Q1 group (adjusted HR, 7.892; 95% CI 1.818–34.269; P = 0.006). Additionally, the ROC curve analysis revealed an optimal AIP cut-off value of 0.24 for predicting clinical MACE in patients with CCS.

Conclusion
Our data indicate, for the first time, that AIP is independently associated with poor long-term prognosis in patients suffering from CCS. The optimal AIP cut-off value for predicting clinical MACE among CCS patients was 0.24.
High willingness to use overdose prevention sites among suburban people who use drugs who do not inject
Authors: Schneider Kristin E. , Urquhart Glenna J. , Rouhani Saba , Allen Sean T. , Morris Miles , Sherman Susan G. 
Published: September 2023

Abstract
Introduction
Overdose prevention sites (OPS) are evidence-based interventions to improve public health, yet implementation has been limited in the USA due to a variety of legal impediments. Studies in various US settings have shown a high willingness to use OPS among urban and rural people who inject drugs, but data among people who use drugs (PWUD) via non-injection routes of administration in suburban areas are lacking.

Methods
We utilized cross-sectional data from a sample of suburban PWUD who have not injected drugs in the past 3 months (N = 126) in Anne Arundel County, Maryland. We assessed PWUDs’ likelihood of using a hypothetical OPS and perceived potential barriers to accessing OPS. We tested for associations between sociodemographic characteristics, drug use, service access, and overdose experiences with willingness to utilize OPS.

Findings
Participants’ median age was 42, and the majority were men (67%) and non-Hispanic Black (79%). Sixty-six percent reported willingness to use an OPS. Concerns about confidentiality (29%), arrest (20%), and transportation costs (22%) were the most anticipated barriers to using OPS. Men (75% vs 55%, p = 0.015), participants who used heroin (53% vs 32%, p = 0.017), and participants who used multiple overdose prevention behaviors (e.g., using fentanyl test strips) (36% vs 19%, p = 0.006) were more likely to report willingness to use OPS.

Conclusion
Most suburban non-injecting PWUD in the sample were willing to use an OPS. OPS implementation strategies in suburban settings should be tailored to reach PWUD via non-injection routes of administration while meeting the unique needs of suburban contexts.
Acute myeloid leukemia-derived exosomes deliver miR-24-3p to hinder the T-cell immune response through DENN/MADD targeting in the NF-κB signaling pathways
Authors: Otmani Khalid , Rouas Redouane , Lagneaux Laurence , Krayem Mohammad , Duvillier Hugues , Berehab Mimoune , Lewalle Philippe 
Published: September 2023

Abstract
Background
microRNAs (miRNAs) are known as potent gene expression regulators, and several studies have revealed the prognostic value of miRNAs in acute myeloid leukemia (AML) patient survival. Recently, strong evidence has indicated that miRNAs can be transported by exosomes (EXOs) from cancer cells to recipient immune microenvironment (IME) cells.

Results
We found that AML blast-released EXOs enhance CD3 T-cell apoptosis in both CD4 and CD8 T cells. We hypothesized that miRNAs present in EXOs are key players in mediating the changes observed in AML T-cell survival. We found that miR-24-3p, a commonly overexpressed miRNA in AML, was present in released EXOs, suggesting that EXO-miR-24-3p was linked to the increased miR-24-3p levels detected in isolated AML T cells. These results were corroborated by ex vivo-generated miR-24-3p-enriched EXOs, which showed that miR-24-3p-EXOs increased apoptosis and miR-24-3p levels in T cells. We also demonstrated that overexpression of miR-24-3p increased T-cell apoptosis and affected T-cell proliferation by directly targeting DENN/MADD expression and indirectly altering the NF-κB, p-JAK/STAT, and p-ERK signaling pathways but promoting regulatory T-cell (Treg) development.

Conclusions
These results highlight a mechanism through which AML blasts indirectly impede T-cell function via transferred exosomal miR-24-3p. In conclusion, by characterizing the signaling network regulated by individual miRNAs in the leukemic IME, we aimed to discover new nonleukemic immune targets to rescue the potent antitumor function of T cells against AML blasts.
The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways
Authors: Bakhtiyari Maryam , Liaghat Mahsa , Aziziyan Fatemeh , Shapourian Hooriyeh , Yahyazadeh Sheida , Alipour Maedeh , Shahveh Shaghayegh , Maleki-Sheikhabadi Fahimeh , Halimi Hossein , Forghaniesfidvajani Razieh , Zalpoor Hamidreza , Nabi-Afjadi Mohsen , Pornour Majid 
Published: September 2023

AbstractAcute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML.
Integrating single-nucleus sequence profiling to reveal the transcriptional dynamics of Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis
Authors: Fan Li-Yuan , Yang Jing , Liu Ruo-Yu , Kong Ying , Guo Guang-Yu , Xu Yu-Ming 
Published: September 2023

Abstract
Background
Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are three nervous system diseases that partially overlap clinically and genetically. However, bulk RNA-sequencing did not accurately detect the core pathogenic molecules in them. The availability of high-quality single cell RNA-sequencing data of post-mortem brain collections permits the generation of a large-scale gene expression in different cells in human brain, focusing on the molecular features and relationships between diseases and genes. We integrated single-nucleus RNA-sequencing (snRNA-seq) datasets of human brains with AD, PD, and MS to identify transcriptomic commonalities and distinctions among them.

Methods
The snRNA-seq datasets were downloaded from Gene Expression Omnibus (GEO) database. The Seurat package was used for snRNA-seq data processing. The uniform manifold approximation and projection (UMAP) were utilized for cluster identification. The FindMarker function in Seurat was used to identify the differently expressed genes. Functional enrichment analysis was carried out using the Gene Set Enrichment Analysis (GSEA) and Gene ontology (GO). The protein‐protein interaction (PPI) analysis of differentially expressed genes (DEGs) was analyzed using STRING database (http://string-db.org). SCENIC analysis was performed using utilizing pySCENIC (v0.10.0) based on the hg19-tss-centered-10 kb-10species databases. The analysis of potential therapeutic drugs was analyzed on Connectivity Map (https://clue.io).

Results
The gene regulatory network analysis identified several hub genes regulated in AD, PD, and MS, in which HSPB1 and HSPA1A were key molecules. These upregulated HSP family genes interact with ribosome genes in AD and MS, and with immunomodulatory genes in PD. We further identified several transcriptional regulators (SPI1, CEBPA, TFE3, GRHPR, and TP53) of the hub genes, which has important implications for uncovering the molecular crosstalk among AD, PD, and MS. Arctigenin was identified as a potential therapeutic drug for AD, PD, and MS.

Conclusions
Together, the integrated snRNA-seq data and findings have significant implications for unraveling the shared and unique molecular crosstalk among AD, PD, and MS. HSPB1 and HSPA1A as promising targets involved in the pathological mechanisms of neurodegenerative diseases. Additionally, the identification of arctigenin as a potential therapeutic drug for AD, PD, and MS further highlights its potential in treating these neurological disorders. These discoveries lay the groundwork for future research and interventions to enhance our understanding and treatment of AD, PD, and MS.
Proteome-wide mendelian randomization study implicates therapeutic targets in common cancers
Authors: Ren Feihong , Jin Qiubai , Liu Tongtong , Ren Xuelei , Zhan Yongli 
Published: September 2023

Abstract
Background
The interest in targeted cancer therapies has been growing rapidly. While numerous cancer biomarkers and targeted treatment strategies have been developed and employed, there are still significant limitations and challenges in the early diagnosis and targeted treatment of cancers. Accordingly, there is an urgent need to identify novel targets and develop new targeted drugs.

Methods
The study was conducted using combined cis-Mendelian randomization (cis-MR) and colocalization analysis. We analyzed data from 732 plasma proteins to identify potential drug targets associated with eight site-specific cancers. These findings were further validated using the UK Biobank dataset. Then, a protein–protein interaction network was also constructed to examine the interplay between the identified proteins and the targets of existing cancer medications.

Results
This MR analysis revealed associations between five plasma proteins and prostate cancer, five with breast cancer, and three with lung cancer. Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. Our study indicatied that genetically predicted KDELC2 (OR: 0.89, 95% CI 0.86–0.93) and TNFRSF10B (OR: 0.74, 95% CI 0.65–0.83) are inversely associated with prostate cancer. Furthermore, we observed an inverse association between CPNE1 (OR: 0.96, 95% CI 0.94–0.98) and breast cancer, while PDIA3 (OR: 1.19, 95% CI 1.10–1.30) were found to be associated with the risk of breast cancer. In addition, we also propose that SPINT2 (OR: 1.05, 95% CI 1.03–1.06), GSTP1 (OR: 0.82, 95% CI 0.74–0.90), and CTSS (OR: 0.91, 95% CI 0.88–0.95) may serve as potential therapeutic targets in prostate cancer. Similarly, GDI2 (OR: 0.85, 95% CI 0.80–0.91), ISLR2 (OR: 0.87, 95% CI 0.82–0.93), and CTSF (OR: 1.14, 95% CI 1.08–1.21) could potentially be targets for breast cancer. Additionally, we identified SFTPB (OR: 0.93, 95% CI 0.91–0.95), ICAM5 (OR: 0.95, 95% CI 0.93–0.97), and FLRT3 (OR: 1.10, 95% CI 1.05–1.15) as potential targets for lung cancer. Notably, TNFRSF10B, GSTP1, and PDIA3 were found to interact with the target proteins of current medications used in prostate or breast cancer treatment.

Conclusions
This comprehensive analysis has highlighted thirteen plasma proteins with potential roles in three site-specific cancers. Continued research in this area may reveal their therapeutic potential, particularly KDELC2, TNFRSF10B, CPNE1, and PDIA3, paving the way for more effective cancer treatments.
Age, brood fate, and territory quality affect nest-site fidelity in white stork Ciconia ciconia
Authors: Bialas Joanna T. , Siekiera Joachim , Siekiera Artur , Chromik Wiesław , Dylewski Łukasz , Tobolka Marcin 
Published: September 2023

Abstract
Background
A particular type of site fidelity is faithfulness to the nest site, where birds are not only reoccupying breeding territories but also reusing nests built in previous breeding seasons. Staying faithful to the nest site is believed to be an adaptive strategy, and based on the ability to predict an individual's own breeding success, a hypothesis of “win-stay:loose-switch” was proposed. In this study, we aimed to resolve which factors affect the nest-site fidelity of white stork Ciconia ciconia, species known for reusing nests available in the breeding sites. Basing on ring recoveries from 31 years of studies in Western and Southern Poland, we analysed the impact of intrinsic and extrinsic factors on nest-site fidelity.

Results
We found that increasing age and breeding success (i.e. producing any fledglings or not) increased the probability of reusing the nest, but in the oldest individuals, the probability decreased. In turn, the probability of breeding success increased with age, the increasing number of reproductive events on the particular nest, and the presence on the nest in the previous year. However, the oldest individuals had lower probability of success, as the relationship was curvilinear. The number of fledglings, however, was influenced only by an individual's age. The number of reproductive events on the nest was, in turn, affected by age, with the youngest and oldest individuals using the current nest for the least number of years.

Conclusions
Our study shows that the decision process of whether to stay faithful to the nest or switch is based on the experience from the previous breeding event, consistently with the “win-stay:loose-switch” hypothesis. Our results also show that site fidelity benefits white storks, as the probability of breeding success increases if the nest is reused. Results also show the senescence effect that lowers breeding success and site fidelity probabilities.
Different states of stemness of glioblastoma stem cells sustain glioblastoma subtypes indicating novel clinical biomarkers and high-efficacy customized therapies
Authors: Visioli Alberto , Trivieri Nadia , Mencarelli Gandino , Giani Fabrizio , Copetti Massimiliano , Palumbo Orazio , Pracella Riccardo , Cariglia Maria Grazia , Barile Chiara , Mischitelli Luigi , Soriano Amata Amy , Palumbo Pietro , Legnani Federico , DiMeco Francesco , Gorgoglione Leonardo , Pesole Graziano , Vescovi Angelo L. , Binda Elena 
Published: September 2023

Abstract
Background
Glioblastoma (GBM) is the most malignant among gliomas with an inevitable lethal outcome. The elucidation of the physiology and regulation of this tumor is mandatory to unravel novel target and effective therapeutics. Emerging concepts show that the minor subset of glioblastoma stem cells (GSCs) accounts for tumorigenicity, representing the true target for innovative therapies in GBM.

Methods
Here, we isolated and established functionally stable and steadily expanding GSCs lines from a large cohort of GBM patients. The molecular, functional and antigenic landscape of GBM tissues and their derivative GSCs was highlited in a side-by-side comprehensive genomic and transcriptomic characterization by ANOVA and Fisher’s exact tests. GSCs’ physio-pathological hallmarks were delineated by comparing over time in vitro and in vivo their expansion, self-renewal and tumorigenic ability with hierarchical linear models for repeated measurements and Kaplan–Meier method. Candidate biomarkers performance in discriminating GBM patients’ classification emerged by classification tree and patients’ survival analysis.

Results
Here, distinct biomarker signatures together with aberrant functional programs were shown to stratify GBM patients as well as their sibling GSCs population into TCGA clusters. Of importance, GSCs cells were demonstrated to fully resemble over time the molecular features of their patient of origin. Furthermore, we pointed out the existence of distinct GSCs subsets within GBM classification, inherently endowed with different self-renewal and tumorigenic potential. Particularly, classical GSCs were identified by more undifferentiated biological hallmarks, enhanced expansion and clonal capacity as compared to the more mature, relatively slow-propagating mesenchymal and proneural cells, likely endowed with a higher potential for infiltration either ex vivo or in vivo. Importantly, the combination of DCX and EGFR markers, selectively enriched among GSCs pools, almost exactly predicted GBM patients’ clusters together with their survival and drug response.

Conclusions
In this study we report that an inherent enrichment of distinct GSCs pools underpin the functional inter-cluster variances displayed by GBM patients. We uncover two selectively represented novel functional biomarkers capable of discriminating GBM patients’ stratification, survival and drug response, setting the stage for the determination of patient-tailored diagnostic and prognostic strategies and, mostly, for the design of appropriate, patient-selective treatment protocols.