bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel Chr1-miR-200 driven whole transcriptome signature shapes tumor immune microenvironment and predicts relapse in early-stage lung adenocarcinoma
Authors: Garinet Simon , Didelot Audrey , Marisa Laetitia , Beinse Guillaume , Sroussi Marine , Le Pimpec-Barthes Françoise , Fabre Elizabeth , Gibault Laure , Laurent-Puig Pierre , Mouillet-Richard Sophie , Legras Antoine , Blons Hélène 
Published: May 2023

Abstract
Background
In Lung adenocarcinoma (LUAD), targeted therapies and immunotherapies have moved from metastatic to early stage and stratification of the relapse risk becomes mandatory. Here we identified a miR-200 based RNA signature that delineates Epithelial-to-mesenchymal transition (EMT) heterogeneity and predicts survival beyond current classification systems.

Methods
A miR-200 signature was identified using RNA sequencing. We scored the miR-200 signature by WISP (Weighted In Silico Pathology), used GSEA to identify pathway enrichments and MCP-counter to characterize immune cell infiltrates. We evaluate the clinical value of this signature in our series of LUAD and using TCGA and 7 published datasets.

Results
We identified 3 clusters based on supervised classification: I is miR-200-sign-down and enriched in TP53 mutations IIA and IIB are miR-200-sign-up: IIA is enriched in EGFR (p < 0.001), IIB is enriched in KRAS mutation (p < 0.001). WISP stratified patients into miR-200-sign-down (n = 65) and miR-200-sign-up (n = 42). Several biological processes were enriched in MiR-200-sign-down tumors, focal adhesion, actin cytoskeleton, cytokine/receptor interaction, TP53 signaling and cell cycle pathways. Fibroblast, immune cell infiltration and PDL1 expression were also significantly higher suggesting immune exhaustion. This signature stratified patients into high-vs low-risk groups, miR-200-sign-up had higher DFS, median not reached at 60 vs 41 months and within subpopulations with stage I, IA, IB, or II. Results were validated on TCGA data on 7 public datasets.

Conclusion
This EMT and miR-200-related prognostic signature refines prognosis evaluation independently of tumor stage and paves the way towards assessing the predictive value of this LUAD clustering to optimize perioperative treatment.
The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII
Authors: Chen Liangmei , Li Xiaofan , Deng Yiyao , Chen Jianwen , Huang Mengjie , Zhu Fengge , Gao Zhumei , Wu Lingling , Hong Quan , Feng Zhe , Cai Guangyan , Sun Xuefeng , Bai Xueyuan , Chen Xiangmei 
Published: May 2023

Abstract
Background
Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-β1 (TGF-β1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes.

Methods
Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRβ + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-β1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on hexokinase (HK). The hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration.

Results
An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-β1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-β1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition.

Conclusions
The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.
IL-10 production by granulocytes promotes Staphylococcus aureus craniotomy infection
Authors: Kak Gunjan , Van Roy Zachary , Heim Cortney E. , Fallet Rachel W. , Shi Wen , Roers Axel , Duan Bin , Kielian Tammy 
Published: May 2023

Abstract
Background
Treatment of brain tumors, epilepsy, or hemodynamic abnormalities requires a craniotomy to access the brain. Nearly 1 million craniotomies are performed in the US annually, which increase to ~ 14 million worldwide and despite prophylaxis, infectious complications after craniotomy range from 1 to 3%. Approximately half are caused by Staphylococcus aureus (S. aureus), which forms a biofilm on the bone flap that is recalcitrant to antibiotics and immune-mediated clearance. However, the mechanisms responsible for the persistence of craniotomy infection remain largely unknown. The current study examined the role of IL-10 in promoting bacterial survival.

Methods
A mouse model of S. aureus craniotomy infection was used with wild type (WT), IL-10 knockout (KO), and IL-10 conditional KO mice where IL-10 was absent in microglia and monocytes/macrophages (CX3CR1CreIL-10 fl/fl) or neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs; Mrp8CreIL-10 fl/fl), the major immune cell populations in the infected brain vs. subcutaneous galea, respectively. Mice were examined at various intervals post-infection to quantify bacterial burden, leukocyte recruitment, and inflammatory mediator production in the brain and galea to assess the role of IL-10 in craniotomy persistence. In addition, the role of G-MDSC-derived IL-10 on neutrophil activity was examined.

Results
Granulocytes (neutrophils and G-MDSCs) were the major producers of IL-10 during craniotomy infection. Bacterial burden was significantly reduced in IL-10 KO mice in the brain and galea at day 14 post-infection compared to WT animals, concomitant with increased CD4+ and γδ T cell recruitment and cytokine/chemokine production, indicative of a heightened proinflammatory response. S. aureus burden was reduced in Mrp8CreIL-10 fl/fl but not CX3CR1CreIL-10 fl/fl mice that was reversed following treatment with exogenous IL-10, suggesting that granulocyte-derived IL-10 was important for promoting S. aureus craniotomy infection. This was likely due, in part, to IL-10 production by G-MDSCs that inhibited neutrophil bactericidal activity and TNF production.

Conclusion
Collectively, these findings reveal a novel role for granulocyte-derived IL-10 in suppressing S. aureus clearance during craniotomy infection, which is one mechanism to account for biofilm persistence.
An examination of the association between forced sex history and reproductive coercion experiences among Black women attending STD clinics in Baltimore, MD, USA
Authors: Campbell Danielle M. , Lucea Marguerite B. , Cimino Andrea N. , Campbell Jacquelyn C. , Stockman Jamila K. 
Published: May 2023

Abstract
Background
Reproductive coercion victimization (RCV) is a significant public health issue that negatively affects women’s sexual and reproductive health outcomes. Less is known about reproductive coercion perpetration (RCP). Few studies have examined these phenomena among representative samples of Black women.

Methods
Retrospective data of women (n = 298) attending STD clinics in Baltimore, MD were analyzed. We calculated lifetime and 12-month prevalence reports of reproductive coercion, and reported values stratified by forced sex history. Binomial logistic regression models were used to examine the association between forced sex history and RCV, accounting for other types of violence typologies.

Results
Lifetime and past 12-month RCV and RCP prevalence were higher among women with forced sex experiences than their counterparts (Lifetime RCV: 46.9% versus 17.5%; past 12-month RCV: 19.4% versus 8.5%. Lifetime RCP: 24.5% versus 17%; past 12-month RCP: 13.3% versus 10.5%). Adjusted models, lifetime reproductive coercion: Women reporting forced sex had a 3.58 times higher odds of having had experienced RCV compared to women not reporting forced sex (AOR 3.58; 95% CI 2.00, 6.46). Women reporting forced sex had a 3.66 times higher odds of having ever experienced pregnancy coercion compared to their counterparts (AOR 3.66; 95% CI 1.93, 7.03) and 4.30 times higher odds of having ever experienced condom manipulation (AOR 4.30; 95% CI 2.15, 8.86). Adjusted models, past 12-month reproductive coercion: Women reporting forced sex had a 2.72 times higher odds of having had experienced past 12-month RCV compared to women not reporting forced sex (AOR 2.72; 95% CI 1.27, 5.91). Women reporting forced sex had a 3.25 times higher odds of having experienced past 12-month pregnancy coercion compared to their counterparts (AOR 3.25; 95% CI 1.38, 7.83) and 3.41 times higher odds of having experienced past 12-month condom manipulation (AOR 3.41; 95% CI 1.14, 10.98).

Conclusions
Participants in our study reported high rates of RCV. Our novel exploration revealed significantly high rates of co-occurring forced sex experiences and RCV and initial prevalence report of RCP. Agencies have a unique opportunity to intervene by implementing screening protocols and referrals for supportive services. These findings may inform future intervention research efforts aimed at improving reproductive health outcomes among Black women.
Implementing pharmacist-prescriber collaboration to improve evidence-based anticoagulant use: a randomized trial
Authors: Smith Shawna N. , Lanham Michael , Seagull F. Jacob , Dorsch Michael , Errickson Josh , Barnes Geoffrey D. 
Published: May 2023

Abstract
Background
Direct oral anticoagulant medications are commonly used to treat or prevent thrombotic conditions, such as pulmonary embolism, deep vein thrombosis, and atrial fibrillation. However, up to 10–15% of patients receiving these medications get unsafe doses based on a patient’s kidney or liver function, potential interactions with other medications, and indication for taking the medication. Alert systems may be beneficial for improving evidence-based prescribing, but can be burdensome and are not currently able to provide monitoring after the initial prescription is written.

Methods/design
This study will improve upon existing alert systems by testing novel medication alerts that encourage collaboration between prescribers (e.g., physicians, nurse practitioners, physician assistants) and expert pharmacists working in anticoagulation clinics. The study will also improve upon the existing alert system by incorporating dynamic long-term monitoring of patient needs and encouraging collaboration between prescribers and expert pharmacists working in anticoagulation clinics. Incorporating state-of-the-art user-centered design principles, prescribing healthcare providers will be randomized to different types of electronic health record medication alerts when a patient has an unsafe anticoagulant prescription. We will identify which alerts are most effective at encouraging evidence-based prescribing and will test moderators to tailor alert delivery to when it is most beneficial. The aims of the project are to (1) determine the effect of notifications targeting existing inappropriate DOAC prescriptions; (2) examine the effect of alerts on newly prescribed inappropriate DOACs; and (3) examine changes in the magnitude of effects over time for both the new prescription alerts and existing prescription notifications for inappropriate DOACs over the 18-month study period.

Discussion
Findings from this project will establish a framework for implementing prescriber-pharmacist collaboration for high-risk medications, including anticoagulants. If effectively implemented at the more than 3000 anticoagulation clinics that exist nationally, hundreds of thousands of patients taking direct oral anticoagulants stand to benefit from safer, evidence-based healthcare.

Trials registration
NCT05351749.
Tanshinone IIA inhibits osteoclastogenesis in rheumatoid arthritis via LDHC-regulated ROS generation
Authors: Peng Qiuwei , Wang Jian , Han Man , Zhao Minghong , Li Kesong , Lu Tianming , Guo Qiuyan , Jiang Quan 
Published: May 2023

AbstractRheumatoid arthritis (RA) is characterized by bone destruction in the afflicted joints, and during the process of bone destruction, osteoclasts play a crucial role. Tanshinone IIA (Tan IIA) has shown anti-inflammatory effects in RA. However, the exact molecular mechanisms by which it delays bone destruction remain largely unexplained. Here, we found that Tan IIA decreased the severity of and ameliorated bone loss in an AIA rat model. In vitro, Tan IIA inhibited RANKL-induced osteoclast differentiation. By activity-based protein analysis (ABPP) combined with LC‒MS/MS, we discovered that Tan IIA covalently binds to the lactate dehydrogenase subunit LDHC and inhibits its enzymatic activity. Moreover, we found that Tan IIA inhibits the generation of osteoclast-specific markers by reducing the accumulation of reactive oxygen species (ROS), thus reducing osteoclast differentiation. Finally, our results reveal that Tan IIA suppresses osteoclast differentiation via LDHC-mediated ROS generation in osteoclasts. Tan IIA can thus be regarded as an effective drug for the treatment of bone damage in RA.
The value of 18F-FDG PET/CT in the systemic evaluation of patients with Rosai–Dorfman disease: a retrospective study and literature review
Authors: Lu Xinyu , Wang Rongxi , Zhu Zhaohui 
Published: May 2023

Abstract
Background
Rosai–Dorfman disease (RDD) is a rare form of non-Langerhans cell histiocytic disease. The aim of this study was to review the characteristics of RDD using 18F-FDG PET/CT and determine its efficacy in the disease management.

Results
A total of 28 RDD patients underwent 33 18F-FDG PET/CT scans for systematic assessment and follow-up. The common involved sites included the lymph nodes (17, 60.7%), upper respiratory tract (11, 39.3%), and skin (9, 32.1%). Five patients had more lesions detected in PET/CT images than in CT and/or MRI, including inapparent nodules (n = 5) and bone destruction (n = 3). After thorough treatment evaluation using PET/CT, the treatment strategies of 14 patients (14/16, 87.5%) were changed. Five patients underwent PET/CT twice during follow-up and the SUVs were significantly decreased (15.3 ± 3.4 vs. 4.4 ± 1.0, p = 0.02), which demonstrated disease improvement.

Conclusions
18F-FDG PET/CT contributed to displaying the holistic characteristics of RDD, in particular during initial assessment, treatment strategy adjustment, or efficacy evaluation, and could compensate for some disadvantages of CT and MRI images.
Human exposure to pesticides and thyroid cancer: a worldwide systematic review of the literatures
Authors: Norouzi Fatemeh , Alizadeh Ismaeil , Faraji Maryam 
Published: May 2023

AbstractThyroid cancer is considered as one of the most prevalent cancers in the world. Some pesticides can play a role as a potentially important risk factor in thyroid cancer by affecting thyroid morphology and thyroid hormone homeostasis. The aim of present study was to systematically review the available epidemiological evidence for human exposure to pesticides and thyroid cancer. Articles were searched in PubMed, Scopus and Web of Science by suitable keywords from January 2000 to May 2021. Standard techniques for systematic reviews were followed in the current study and results reported according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Based on the inclusion and exclusion criteria, finally seven studies including four cohort studies and three case-control studies were reviewed. Organochlorines (OCPs) in more cases, Organophosphates (OPs) and Carbamates insecticides, herbicides and fungicides were the studied pesticides. Inconsistent results were reported in the surveyed articles on the OCPs. Two articles on the Carbamates (Carbaryl and Mancozeb) showed consistently an inverse association between exposure and thyroid cancer. Increased risk of thyroid cancer due to the exposure to the Malathion was reported in one article on the OPs. Due to the limited current knowledge about the effect of pesticides on thyroid cancer in humans, human health policies must be implemented to control individual’s exposure to chemicals through using of botanical pesticides in agricultural. Also, more studies must be done to fill this gap of knowledge.
Size matters in telomere biology disorders ‒ expanding phenotypic spectrum in patients with long or short telomeres
Authors: Byrjalsen Anna , Brainin Anna Engell , Lund Thomas Kromann , Andersen Mette Klarskov , Jelsig Anne Marie 
Published: May 2023

AbstractThe end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment.
Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome
Authors: Liu Kailu , He Xi , Huang Jingyu , Yu Simin , Cui Meiting , Gao Mengya , Liu Li , Qian Yu , Xie Ying , Hui Miao , Hong Yanli , Nie Xiaowei 
Published: May 2023

AbstractPolycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by chronic low-grade inflammation. Previous studies have demonstrated that the gut microbiome can affect the host tissue cells’ mRNA N6-methyladenosine (m6A) modifications. This study aimed to understand the role of intestinal flora in ovarian cells inflammation by regulating mRNA m6A modification particularly the inflammatory state in PCOS. The gut microbiome composition of PCOS and Control groups was analyzed by 16S rRNA sequencing, and the short chain fatty acids were detected in patients’ serum by mass spectrometry methods. The level of butyric acid was found to be decreased in the serum of the obese PCOS group (FAT) compared to other groups, and this was correlated with increased Streptococcaceae and decreased Rikenellaceae based on the Spearman’s rank test. Additionally, we identified FOSL2 as a potential METTL3 target using RNA-seq and MeRIP-seq methodologies. Cellular experiments demonstrated that the addition of butyric acid led to a decrease in FOSL2 m6A methylation levels and mRNA expression by suppressing the expression of METTL3, an m6A methyltransferase. Additionally, NLRP3 protein expression and the expression of inflammatory cytokines (IL-6 and TNF-α) were downregulated in KGN cells. Butyric acid supplementation in obese PCOS mice improved ovarian function and decreased the expression of local inflammatory factors in the ovary. Taken together, the correlation between the gut microbiome and PCOS may unveil crucial mechanisms for the role of specific gut microbiota in the pathogenesis of PCOS. Furthermore, butyric acid may present new prospects for future PCOS treatments.
Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration
Authors: Wang Zijie , Chen Chuying , Zhang Jiayi , He Jiangdie , Zhang Lin , Wu Jiayuan , Tian Zhihui 
Published: May 2023

Abstract
Background
Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3), a secreted multifunctional glycoprotein whose transcript expression is restricted to the tooth germ epithelium during the development of embryonic mouse teeth, has been demonstrated to play a crucial role in the regulation of tooth development. Based on this, we hypothesized that epithelium-derived SCUBE3 contributes to bio-function in dental mesenchymal cells (Mes) via epithelium–mesenchyme interactions.

Methods
Immunohistochemical staining and a co-culture system were used to reveal the temporospatial expression of the SCUBE3 protein during mouse tooth germ development. In addition, human dental pulp stem cells (hDPSCs) were used as a Mes model to study the proliferation, migration, odontoblastic differentiation capacity, and mechanism of rhSCUBE3. Novel pulp–dentin-like organoid models were constructed to further confirm the odontoblast induction function of SCUBE3. Finally, semi-orthotopic animal experiments were performed to explore the clinical application of rhSCUBE3. Data were analysed using one-way analysis of variance and t-tests.

Results
The epithelium-derived SCUBE3 translocated to the mesenchyme via a paracrine pathway during mouse embryonic development, and the differentiating odontoblasts in postnatal tooth germ subsequently secreted the SCUBE3 protein via an autocrine mechanism. In hDPSCs, exogenous SCUBE3 promoted cell proliferation and migration via TGF-β signalling and accelerated odontoblastic differentiation via BMP2 signalling. In the semi-orthotopic animal experiments, we found that SCUBE3 pre-treatment-induced polarized odontoblast-like cells attached to the dental walls and had better angiogenesis performance.

Conclusion
SCUBE3 protein expression is transferred from the epithelium to mesenchyme during embryonic development. The function of epithelium-derived SCUBE3 in Mes, including proliferation, migration, and polarized odontoblastic differentiation, and their mechanisms are elaborated for the first time. These findings shed light on exogenous SCUBE3 application in clinic dental pulp regeneration.