bluuebunny/crossref_metadata_2025_split huggingface dataset:
The combination of transcriptome and Mendelian randomization reveals clinical and immuno-functional biomarkers of alternative splicing regulation associated with planar cell polarity signaling pathways in pan-cancer
Authors: Li Haojun , Xu Jian , Li Qinlan , Xu Guoqiang , Liang Yanjun , Shen Junxin , Zeng Ziran , Zhou Xiaorong , Zhu Xiao , Wei Yong 
Published: March 2024

Abstract
Background
The intricate interplay between alternative splicing (AS) events and the planar cell polarity (PCP) signaling pathway is known to play a crucial role in cancer initiation and progression. Understanding the prognostic implications and immunological features of PCP-related AS events can unveil novel biological markers and potential targets for immunotherapy.
Methods
We sourced genes associated with the PCP signaling pathway from diverse databases and extracted RNA-seq, clinical records, and AS profiles from TCGA and TCGA SpliceSeq databases. Employing the least absolute shrinkage and selection operator (LASSO), we identified prognostically significant AS events and developed risk scoring models and nomograms. Immune distinctions within risk subgroups were assessed using the ESTIMATE algorithm, CIBERSORT analysis, and single-sample gene set enrichment analysis (ssGSEA). Furthermore, we analyzed selected differentially expressed AS genes for their relevance to prognosis and immunity. A regulatory network connecting AS and splicing factors (SFs) was delineated using Cytoscape. Mendelian randomization (MR) and Bayesian weighted MR (BWMR) were employed to validate causal links among AS genes identified in multivariable Cox regression analysis.
Results
Analysis of 115 AS events across 9812 pan-cancer-related genes revealed 80 AS events significantly associated with prognosis. A risk score model based on 12 carefully selected AS events effectively predicted overall survival (OS) in tumor patients and correlated with clinical parameters. The risk score also showed associations with the tumor microenvironment, immune cell infiltration, and immune checkpoint genes. Notably, PRICKLE3, PSMA4, and AP2S1 AS genes were identified as influential in immune characteristics and prognosis across various cancers. A correlation network between AS events and SF genes provided insights into potential biomarkers. MR analysis identified NPHP3 and UBA52 as protective factors against cancer occurrence.
Conclusion
This study elucidates the role of AS events in cancer prognosis and tumor immunology, providing risk-scoring models and nomogram prognostic tools for the PCP signaling pathway in pan-cancer patients. Furthermore, the causal relationship between PCP-related AS genes and cancer was confirmed using genetic approaches, underscoring the potential for targeted therapeutic interventions.
Clinical study on the treatment of mild-to-moderate Cervical Spondylotic Radiculopathy by Supine Pulling Manipulation (SPM): study protocol of a randomized controlled trial
Authors: Zhang Dihui , Meng Licui , Liao Shaojun , Lin Yongpeng , Lin Guandai , Su Guoyi , Li Yongjin , Chen Bolai , Lin Dingkun 
Published: March 2024

Abstract

Background:Cervical spondylotic radiculopathy is a common clinical disease that often presents with neck pain and upper extremity pain. Manipulation has been widely used to treat cervical spondylotic radiculopathy. However,high-quality clinical evidence supporting the efficacy of manipulative therapy remains limited.
Methods: A single-centre, participant self-assessment,double-blinded, randomised, wait-controlled trial will be conducted. A total of 66 participants in cervical spondylotic radiculopathy will be recruited from Guangdong Provincial Hospital of Chinese Medicine and randomly assigned to the intervention group or the wait-list group.The intervention group will receive treatment three times a week for 3 weeks,while the wait-list group will enter a 3-week waiting period without any treatment and at the end of the waiting period will be given the same treatment as the intervention group. The use of the Visual Analogue Scale, Neck Disability Index and participant Specific Functional Scaleas outcome measures will be performed at baseline, 1, 2 and 3 weeks. Adverse events during the study period will also be recorded.
Discussion:This is a practical clinical trial to evaluate the efficacy and safety of Supine Pulling Manipulation in participants with cervical spondylotic radiculopathy.The results of this study will provide a valuable clinical basis for manipulation treatment of cervical spondylotic radiculopathy.
Ethics and Dissemination: This study has been approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (ECGPHCM).Whether the result is positive or negative, we will publish it in a peer-reviewed journal as well as public, academic presentations at national and international conferences.
Trial Registration:China Registered Cinical Trial Registration Center ChiCTR2200065140.Registered on 29 October 2022.
Quercetin enhances decidualization through AKT-ERK-p53 signaling and supports a role for senescence in endometriosis
Authors: Delenko Julia , Xue Xiangying , Chatterjee Prodyot K , Hyman Nathaniel , Shih Andrew J , Adelson Robert P , Tepes Polona Safaric , Gregersen Peter K , Metz Christine N 
Published: March 2024

Abstract

Background
Patients with endometriosis suffer with chronic pelvic pain and infertility, and from the lack of pharmacologic therapies that consistently halt disease progression. Differences in the endometrium of patients with endometriosis vs. unaffected controls are well-documented. Specifically, shed endometrial tissues (delivered to the pelvic cavity via retrograde menstruation) reveal that a subset of stromal cells exhibiting pro-inflammatory, pro-fibrotic, and pro-senescence-like phenotypes is enhanced in endometriosis patients compared to controls. Additionally, cultured biopsy-derived endometrial stromal cells from endometriosis patients exhibit impaired decidualization, a defined differentiation process required for human embryo implantation and pregnancy. Quercetin, a senolytic agent, shows therapeutic potential for pulmonary fibrosis, a disorder attributed to senescent pulmonary fibroblasts. In rodent models of endometriosis, quercetin shows promise, and quercetin improves decidualization in vitro. However, the exact mechanisms are not completely understood. Therefore, we investigated the effects of quercetin on menstrual effluent-derived endometrial stromal cells from endometriosis patients and unaffected controls to define the signaling pathways underlying quercetin’s effects on endometrial stromal cells.
Methods
Menstrual effluent-derived endometrial stromal cells were collected and cultured from unaffected controls and endometriosis patients and then, low passage cells were treated with quercetin (25 µM) under basal or standard decidualization conditions. Decidualization responses were analyzed by measuring the production of IGFBP1 and PRL. Also, the effects of quercetin on intracellular cAMP levels and cellular oxidative stress responses were measured. Phosphokinase arrays, western blotting, and flow cytometry methods were performed to define the effects of quercetin on various signaling pathways and the potential mechanistic roles of quercetin.
Results
Quercetin significantly promotes decidualization of control- and endometriosis-endometrial stromal cells. Quercetin substantially reduces the phosphorylation of multiple signaling molecules in the AKT and ERK1/2 pathways, while enhancing the phosphorylation of p53 and total p53 levels. Furthermore, p53 inhibition blocks decidualization while p53 activation promotes decidualization. Finally, we provide evidence that quercetin increases apoptosis of endometrial stromal cells with a senescent-like phenotype.
Conclusions
These data provide insight into the mechanisms of action of quercetin on endometrial stromal cells and warrant future clinical trials to test quercetin and other senolytics for treating endometriosis.
Deficiency of IL-20 receptor subunit A decreases enterovirus A71 lethality of mice with enhanced M1 macrophage polarization and cytokine
Authors: Chen Shun-Hua , Hung Cheng-Huei , Hsiao Yi-Ling , Tsai Yi-Ping , Chang Ming-Shi , Liu Ching-Chuan , Wang Li-Chiu , Wang Shih-Min 
Published: March 2024

Abstract
Enterovirus A71 (EV-A71) can cause fatality in patients with increases of cytokines, IL-10, IL-12, and IFN-γ, which are mutually regulated. IFN-γ is induced and protects the host from EV-A71 in a murine infection model. IFN-γ and IL-10 promote the polarization of M1 and M2 macrophages, which produce IL-12 and IL-10, respectively. IL-10 suppresses IL-12, which enhances itself and IFN-γ. The IL-10 family cytokines, IL-19, IL-20, and IL-24, which signal through the two-subunit receptor complex with IL-20RA as one subunit, are therefore designated as IL-20RA cytokines. Previous in vitro T cell studies showed that IL-19 or IL-20 treatment suppresses IFN-γ and that IL-19 treatment enhances IL-10. In the present study of human plasma, IL-19 was detected in healthy controls, and EV-A71 infection increased IL-19 in patients. In the serum of mice, IL-20RA cytokines, but not IL-10, IL-12, and IFN-γ, were detected in mock-infected mice, and EV-A71 infection enhanced IL-19. Compared to wild-type mice, IL-20RA knockout mice were resistant to infection with reduced viral loads in peripheral organs, including the spleen. In infected mice, IL-20RA deficiency sequentially reduced IL-10, but increased IL-12 and IFN-γ, in the serum with T cells expressing IL-10 and macrophages expressing IL-12 and IFN-γ in the spleen. Notably, IL-20RA deficiency increased spleen M1 macrophages. In vitro study showed that treatment with IL-19 or IL-20, but not IL-24, increased IL-10 in CD4 T cells, but reduced IL-12 in macrophages. Our study is novel to show that IL-20RA cytokines affect virus infection, cytokines regulating macrophage polarization, and macrophage polarization.
Autotaxin as a novel biomarker of migraine
Authors: Ouro Alberto , Castro-Mosquera Mónica , Leira Yago , Rodríguez-Arrizabalaga Mariña , Debasa-Mouce Manuel , Romaus-Sanjurjo Daniel , Aramburu-Nuñez Marta , Iglesias-Rey Ramón , Casas Josefina , Lema Isabel , Castillo José , Leira Rogelio , Sobrino Tomás 
Published: March 2024

Abstract

Background
Migraine is the most common neurological disorder and the second most disabling human condition. As Autotaxin (ATX) may be a link between common mechanisms associated with migraine, we aimed to test its role as a novel biomarker of migraine.
Methods
In this cross-sectional study, healthy controls (n = 68), episodic migraine (EM) (n = 45), and chronic migraine (CM) patients (n = 38) were studied. Clinical outcomes, such as Visual Analogue Scale (VAS), frequency of headaches (days/month), evolution time (months) and the crisis of attacks (hours); as well as serum biomarkers for inflammation (interleukin-6, [IL-6], and interleukin-10 [IL-10]), trigeminovascular system activation (calcitonin gene-related peptide, [CGRP]), endothelial dysfunction (pentraxin-3, [PTX-3], cellular fibrinogen [cFn], soluble tumor necrosis factor-like weak inducer of apoptosis [sTWEAK]), and ATX, were investigated. Additionally, the serum lipidomic biomarkers profile was also performed.
Results
Serum ATX levels were found to be significantly elevated in both EM (310.7 ± 79.69 ng/mL) and CM (336.7 ± 66.93 ng/mL) compared to controls (212.3 ± 53.19 ng/mL) (p < 0.0001). Elevated ATX levels were associated with migraine outcomes in CM (VAS, frequency, evolution time and crisis duration). ATX was correlated with CGRP, PTX3, sTWEAK, Fn; and IL-6. A drastic decrease in serum lysophosphatidylcholine (LPC) levels indicates high ATX activity in migraine.
Conclusions
Serum levels of ATX were significantly increased in EM and CM. In addition, ATX correlates with clinical outcomes, as well as CGRP, endothelial dysfunction and inflammation biomarkers. Further studies are necessary to elucidate the potential role of ATX as a therapeutic target for migraine.
Enhancing Public Health Surveillance: Outbreak Detection Algorithms Deployed for Syndromic Surveillance during Arbaeenia Mass Gatherings in Iraq
Authors: Suraifi Mustafa , Delpisheh Ali , Karami Manoochehr , Mehrabi Yadollah , Jahangiri Katayoun , Lami Faris 
Published: March 2024

Abstract

Background
Mass gatherings frequently include close, prolonged interactions between people, which present opportunities for infectious disease transmission. Few published studies have used outbreak detection algorithm methods for real syndrome data collected during mass gatherings. This study aimed to describe the implementation and effectiveness of outbreak detection algorithms for syndromic surveillance during mass gatherings in Iraq.
Methods
The field data collection involved the participation of 10 data collectors, who carried out the data collection activities over ten days, specifically from August 25, 2023, to September 3, 2023. The data were obtained from 10 healthcare clinics along the major route from Najaf to Karbala, specifically on Ya Hussein Road. The numbers of syndromes reported by applied outbreak detection algorithms include moving average (MA), cumulative sum (CUSUM), and exponential weighted moving average (EWMA).
Results
A total of 12,202 pilgrims (49.5% females and 50.5% males) visited the 10 health clinics over 10 days from 25 Aug 2023 to 03 Sep 2023. More than three-quarters of the pilgrims (77.4%, n = 9,444), were between the ages of 20 and 59. More than half of the pilgrims were foreigners, accounting for 58.1% (n = 7,092) of the total, and approximately 41.9% (n = 5,110) originated from Iraq. Of those, 40.5% (n = 4,938) had syndromes, 48.8% (n = 2411) had ILI syndromes, 21.2% (n = 1048) had food poisoning syndrome, 17.7% (n = 875) had heatstroke syndrome, 9.0% (n = 446) had febrile rash syndrome, and 3.2% (n = 158) had gastroenteritis syndrome. The CUSUM algorithm was preferable for detecting small shifts compared to the EWMA and MA algorithms.
Conclusions
The importance of robust public health surveillance systems, particularly during mass gatherings, is to promptly detect and respond to emerging health threats. By leveraging advanced algorithms and real-time data analysis, authorities can enhance their preparedness and response capabilities, ultimately safeguarding public health during such events.
A Shared Point of Care Ultrasound Curriculum for Graduate Medical Education
Authors: Ferre Robinson M. , Kaine Joshua C , Lobo Daniela , Peterson Dina , Sarmiento Elisa , Adame John , Herbert Audrey , Wallach Paul M. , Russell Frances M. 
Published: March 2024

Abstract

Background
Point of care ultrasound (POCUS) education has grown significantly over the past two decades. Like most curricular items, POCUS education is siloed within individual graduate medical education (GME) programs. The purpose of this study was to evaluate the effectiveness of a shared GME POCUS curriculum between five GME programs at a single institution.
Methods
Post-graduate-year-1 (PGY-1) residents from emergency medicine (EM), family medicine (FM), internal medicine (IM), combined internal medicine-pediatrics (IM-Peds) and combined emergency medicine-pediatrics (EM-Peds) residency programs were enrolled in a core POCUS curriculum. The curriculum included eleven asynchronous online learning modules and ten hands-on training sessions proctored by sonographers and faculty physicians with POCUS expertise. Data was gathered about the curriculum’s effectiveness including participation, pre- and post-curricular surveys, pre- and post-knowledge assessments, and an objective skills assessment.
Results
Of the 85 residents enrolled, 61 (72%) participated in the curriculum. Engagement varied between programs, with attendance at hands-on sessions varying the most (EM 100%, EM-Peds 100%, FM 40%, IM 22%, Med-Peds 11%). Pre- and post-knowledge assessment scores improved for all components of the curriculum. Participants felt significantly more confident with image acquisition, anatomy recognition, interpreting images and incorporating POCUS findings into clinical practice (p < 0.001) after completing the curriculum.
Conclusion
In this shared GME POCUS curriculum, we found significant improvement in POCUS knowledge, attitudes, and psychomotor skills. This shared approach may be a viable way for other institutions to provide POCUS education broadly to their GME programs.
Mental Healthcare Practices from Entry to Release across Southeastern Jails
Authors: DiRosa Elena , Deinse Tonya Van , Cuddeback Gary , Murray-Lichtman Andrea , Carda-Auten Jessica , Rosen David 
Published: March 2024

Abstract
Background: Individuals with mental illnesses are disproportionately incarcerated in jails, which have become de facto mental health institutions across the US. Yet there is limited research describing mental healthcare practices from entry to release among multiple jails and states.
Methods: We conducted 34 semi-structured interviews with jail healthcare personnel across five Southeastern states.
Results: We report results on challenges and practices related to mental health staffing, screening, additional evaluations and services, and discharge planning in jails. Initial mental health screenings were often restricted to the detection of suicidality and history of treatment and medications as opposed to current mental health symptoms. Use of validated mental health screening forms was uncommon. We found delays in care between the initial health screening and being evaluated by a mental health professional. Most jails reported primary responsibilities for mental health care as preventing suicides and managing psychiatric medications. Jails reported mental health care as challenging to manage, with high volumes of individuals with mental health needs, yet limited resources, especially regarding staffing. Discharge planning was limited despite reports of poor continuity of mental healthcare.
Conclusions: Jails have a constitutional duty and opportunity to provide adequate healthcare to individuals with mental illnesses, yet practices are insufficient and resources are limited across jails. Based on our findings, we recommend 1) greater adoption and revisions of jail health standards 2) system improvement that expands identification of mental illnesses and quicker, less variable follow-up mental health evaluations, 3) improved linkages and supports for community resources that prevent incarceration of this population.
Transcriptional responses to direct and indirect TGFβ1 stimulation in cancerous and noncancerous mammary epithelial cells.
Authors: Janus Patryk , Kuś Paweł , Jaksik Roman , Vydra Natalia , Toma-Jonik Agnieszka , Gramatyka Michalina , Kurpas Monika , Kimmel Marek , Widłak Wiesława 
Published: March 2024

Abstract

Background: Transforming growth factor-beta (TGFβ) is important for the morphogenesis and secretory function of the mammary gland. It is one of the main activators of the epithelial–mesenchymal transition (EMT), a process important for tissue remodeling and regeneration, but also providing cells with the plasticity to form metastases during tumor progression. Noncancerous and cancer cells respond differently to TGFβ. However, knowledge of the cellular signaling cascades triggered by TGFβ in various cell types is still limited.
Methods: MCF10A (noncancerous, originating from fibrotic breast tissue) and MCF7 (cancer, estrogen receptor-positive) breast epithelial cells were treated with TGFβ1 directly or through conditioned media from stimulated cells. Transcriptional changes (via RNA-seq) were assessed in untreated cells and after 1-6 days of treatment. Differentially expressed genes were detected with DESeq2 and the hallmark collection was selected for gene set enrichment analysis.
Results: TGFβ1 induces EMT in both the MCF10A and MCF7 cell lines but via slightly different mechanisms (signaling through SMAD3 is more active in MCF7 cells), and many EMT-related genes are expressed in MCF10A cells at baseline. Both cell lines respond to TGFβ1 by decreasing the expression of genes involved in cell proliferation: through the repression of MYC (and its targets) in MCF10A cells and the activation of p63-dependent signaling in MCF7 cells (CDKN1A and CDKN2B, which are responsible for the inhibition of cyclin-dependent kinases, are upregulated). In addition, estrogen receptor signaling is inhibited and caspase-dependent cell death is induced only in MCF7 cells. Moreover, direct incubation with TGFβ1 and treatment of cells with conditioned media similarly affected transcriptional profiles. However, TGFβ1-induced protein secretion is more pronounced in MCF10A cells; therefore, the signaling is propagated through conditioned media (bystander effect) more effectively in MCF10A cells than in MCF7 cells.
Conclusions: Estrogen receptor-positive breast cancer patients may benefit from high levels of TGFB1 expression due to the repression of estrogen receptor signaling, inhibition of proliferation, and induction of apoptosis in cancer cells. However, some TGFβ1-stimulated cells may undergo EMT, which increases the risk of metastasis.
Study of Corneal and Retinal Thicknesses at Five Years after FS-LASIK and SMILE for Myopia
Authors: Li Jiayu , Lv Xiaotong , Xu Yushan , Sun Mingshen , Zhang Fengju 
Published: March 2024

Abstract

BACKGUOND:This study aimed to compare corneal and retinal thicknesses at 5 years after femtosecond laser-assisted in situ keratomileusis (FS-LASIK) and small incision lenticule extraction (SMILE) for myopia, investigate the effect of epithelial remodeling on refractive status.METHODS:Patients who received FS-LASIK or SMILE 5 years before were enrolled in this cross-sectional study. After 1:1 propensity score matching, each surgical group obtained 177 patients (177 eyes). Visual acuity and refraction were measured in this visit at 5 years after surgery. Corneal and retinal thickness maps were generated by spectral domain optical coherence tomography (SD-OCT). The Quality of Vision (QoV) questionnaire was used to assess visual symptoms and overall satisfaction. Thicknesses between groups were compared, contributing factors were analyzed, and correlations between epithelial thickness (ET), postoperative refractive status and overall satisfaction were evaluated.RESULTS:Compared to SMILE group, central and paracentral ET of FS-LASIK group were thicker, pericentral ET was thinner, and the discrepancy of ET between central and pericentral zones was larger (all P<0.05). This discrepancy was correlated with postoperative spherical equivalent (SE) and myopic regression (all P<0.05) in both groups, but not correlated with QoV scores and overall satisfaction (both P>0.05). There was no statistical difference in stromal thickness (ST) and total corneal thickness (all P>0.05). Most annuluses of ET and ST were linearly related to preoperative SE (all P<0.05). Statistical difference of ET between high and super-high myopia groups only was found in supratemporal section of pericentral zone in SMILE group (P=0.012). Macular thickness, ganglion cell complex thickness and retinal nerve fiber layer thickness of two groups had no statistical difference (all P>0.05).CONCLUSION:The tendency that ET in central zone was thicker than peripheral zone was more obvious at 5 years after FS-LASIK compared to SMILE. This tendency was also more significant in patients with higher degree of myopia. Epithelial remodeling might be one of the reasons of myopic regression, but it had little effect on patients' subjective visual quality and satisfaction. Retinal thickness was not affected by these two surgical methods.