bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative analysis of eQTL and GWAS summary statistics reveals transcriptomic alteration in Alzheimer brains
Authors: Varathan Pradeep , Gorijala Priyanka , Jacobson Tanner , Chasioti Danai , Nho Kwangsik , Risacher Shannon L. , Saykin Andrew J. , Yan Jingwen 
Published: April 2022

Abstract
Background
Large-scale genome-wide association studies have successfully identified many genetic variants significantly associated with Alzheimer’s disease (AD), such as rs429358, rs11038106, rs723804, rs13591776, and more. The next key step is to understand the function of these SNPs and the downstream biology through which they exert the effect on the development of AD. However, this remains a challenging task due to the tissue-specific nature of transcriptomic and proteomic data and the limited availability of brain tissue.In this paper, instead of using coupled transcriptomic data, we performed an integrative analysis of existing GWAS findings and expression quantitative trait loci (eQTL) results from AD-related brain regions to estimate the transcriptomic alterations in AD brain.

Results
We used summary-based mendelian randomization method along with heterogeneity in dependent instruments method and were able to identify 32 genes with potential altered levels in temporal cortex region. Among these, 10 of them were further validated using real gene expression data collected from temporal cortex region, and 19 SNPs from NECTIN and TOMM40 genes were found associated with multiple temporal cortex imaging phenotype.

Conclusion
Significant pathways from enriched gene networks included neutrophil degranulation, Cell surface interactions at the vascular wall, and Regulation of TP53 activity which are still relatively under explored in Alzheimer’s Disease while also encouraging a necessity to bind further trans-eQTL effects into this integrative analysis.
Association and mediation analyses among multiple metals exposure, plasma folate, and community-based impaired estimated glomerular filtration rate in central Taiwan
Authors: Chung Mu-Chi , Hsu Hui-Tsung , Mao Yan-Chiao , Wu Chin-Ching , Ho Chih-Te , Liu Chiu-Shong , Chung Chi-Jung 
Published: April 2022

Abstract
Background
Chronic kidney disease (CKD) is increasing, with heavy metal exposure an important risk factor. Additionally, the antioxidant folic acid has been studied for reducing blood arsenic levels and related tissue damage. Therefore, we explored the association and mediation effects among various heavy metal levels in blood, plasma folate, other CKD risk factors, and impaired estimated glomerular filtration rate (eGFR).

Methods
We constructed a community-based cross-sectional study from the Human Biomonitoring and Environmental Health Program in central Taiwan. A total of 1643 participants had lived locally for > 5 years, > 40 years old, and completely received health examinations and biospecimen collections. Impaired eGFR was defined as one single eGFR < 60 mL/min/1.73 m2. Plasma folate and metal levels in blood were determined, as well as urinary 8-hydroxy-2′-deoxyguanosine as an oxidative stress marker. Generalized weighted quantile sum (WQS) regression analysis was used to calculate a WQS score, reflecting overall body-burden of multiple metals (arsenic, cadmium, chromium, nickel, and lead) in blood.

Results
Impaired eGFR was identified in 225 participants. Participants with high WQS scores had increased risk of impaired eGFR (odds ratio = 1.67; 95% confidence interval [CI]: 1.34, 2.07). Of five metals, arsenic, lead, and cadmium were weighted highly in impaired eGFR. Participants with high WQS and folate insufficiency (< 6 ng/mL) had 2.38-fold risk of impaired eGFR compared to those with low WQS and high folate (≥6 ng/mL) (95% CI: 1.55, 5.17). Similar increased 4.16-fold risk of impaired eGFR was shown in participants with high WQS and uric acid levels (95% CI: 2.63, 6.58). However, there were no significant WQS–folate (p = 0.87) or WQS–uric acid (p = 0.38) interactions on impaired eGFR risk. As a mediator, uric acid contributed 24% of the association between WQS score and impaired eGFR risk (p < 0.0001). However, no mediation effect of plasma folate was observed.

Conclusion
WQS analysis could be applied to evaluate the joint effects of multiple metals exposure. High WQS scores may influence impaired eGFR risk through increased uric acid levels. A large-scale and prospective cohort study is necessary to validate these results and demonstrate any causal relationship.
FOXO transcriptional activity is associated with response to chemoradiation in EAC
Authors: Creemers A. , van der Zalm A. P. , van de Stolpe A. , Holtzer L. , Stoffels M. , Hooijer G. K. J. , Ebbing E. A. , van Ooijen H. , van Brussel A. G. C. , Aussems-Custers E. M. G. , van Berge Henegouwen M. I. , Hulshof M. C. C. M. , Bergman J. J. G. H. M. , Meijer S. L. , Bijlsma M. F. , van Laarhoven H. W. M. 
Published: April 2022

AbstractIn this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.
IFI16 induces inflammation in hepatitis B virus-associated glomerulonephritis by regulating the Caspase-1/ IL-1 ß pathway
Authors: Liu Li , Xie Shuangshuang , Li Cheng , Guo Yue , Liu Xiaoyan , Zhao Xiuhua , Li Qiang , Du Wenjun 
Published: April 2022

Abstract
Aims and background
IFI16 plays an important role in innate immunity against invasive microbial infection by sensing double-stranded DNA viruses due to caspase-1-dependent inflammasome activation and subsequent maturation and secretion of IL-1β. However, the role of IFI16 in regulating the immune response to viruses in Hepatitis B Virus-Associated Glomerulonephritis (HBV-GN), especially in sensing hepatitis B virus (HBV), has not been determined. In this study, we investigated the inflammatory role of IFI16 in HBV-GN.

Methods
A total 75 kidney tissue including 50 HBV-GN and 25 chronic glomerulonephritis (CCN) were collected to determine the expression of IFI16, Caspase-1 and IL-1β using immunohistochemistry (IHC), then the correlation between them was analyzed. In vitro, the primary human glomerular mesangial (HGM) cells and HEK-293 T cell lines were used in this study. The cell lines were both co-transfected with HBVDNA and overexpression or silencing IFI16. Quantitative Real-time PCR and western blotting were used to determine the expression of IFI16, Caspase-1 and IL-1β.

Results
IFI16 expression in HBV-GN biopsies (80.0%) was significantly higher than in CGN (24.0%) and positively correlated with HBVDNA,caspase-1 and IL-1β expression in HBV-GN. Meanwhile, over expression of IFI16 increased caspase-1 and IL-1β expression in HBV-infected HGM and HEK-293 T cell lines, knockdown of IFI16 mRNA by siRNA resulted in downregulation of the caspase-1 and IL-1β expression in both cell lines.

Conclusions
The elevation of IFI16 during HBV infection or replication may contribute to renal damage due to inflammation, thus providing a putative therapeutic target and a new avenue for researching the pathogenesis of HBV-GN.
Analysis of prognostic factors for in-hospital mortality in patients with unplanned re-exploration after cardiovascular surgery
Authors: Deng Jianying , Zhong Qianjin 
Published: April 2022

Abstract
Objective
To explore the prognostic factors for in-hospital mortality in patients with unplanned re-exploration after cardiovascular surgery.

Methods
We retrospectively analyzed the data of 100 patients who underwent unplanned re-exploration after cardiovascular surgery in our hospital between May 2010 and May 2020. There were 77 males and 23 females, aged (55.1 ± 15.2) years. Demographic characteristics, surgical information, perioperative complications were collected to establish a database. These patients were divided into surviving and non-surviving groups according to in-hospital mortality. Logistic regression was used for multivariable analysis to explore the prognostic factors of in-hospital mortality. These statistically significant indicators were selected for drawing the receiver operating characteristic curve of the evaluation model, calculating the area under the curve (AUC) and evaluating the effectiveness of the new model with Hosmer–Lemeshow C-statistic.

Results
In-hospital mortality in patients with unplanned re-exploration after cardiovascular surgery was 26.0% (26/100). Multivariate logistics regression revealed that the operation time of unplanned re-exploration, the worst blood creatinine value within 48 h before the re-exploration, the worst lactate value within 24 h after the re-exploration, cardiac insufficiency, respiratory insufficiency, and acute kidney injury were independent prognostic factors (P < 0.05). The AUC of the new assessment model constituted by these prognostic factors was 0.910, and the Hosmer–Lemeshow C-statistic was 4.153 (P = 0.762).

Conclusions
Operation time of unplanned re-exploration, worst serum creatinine value within 48 h before re-exploration, worst lactate value within 24 h after re-exploration, cardiac insufficiency, respiratory insufficiency, and acute kidney injury are the main prognostic factors for in-hospital mortality in patients with unplanned re-exploration after cardiovascular surgery. Identifying these prognostic factors can effectively facilitate preventive measures and improve patient outcomes.
Roles of Rufy3 in experimental subarachnoid hemorrhage-induced early brain injury via accelerating neuronal axon repair and synaptic plasticity
Authors: Wang Yang , Xu Jianguo , You Wanchun , Shen Haitao , Li Xiang , Yu Zhengquan , Li Haiying , Chen Gang 
Published: April 2022

Abstract
RUN and FYVE domain-containing 3 (Rufy3) is a well-known adapter protein of a small GTPase protein family and is bound to the activated Ras family protein to maintain neuronal polarity. However, in experimental subarachnoid hemorrhage (SAH), the role of Rufy3 has not been investigated. Consequently, we aimed to investigate the potential role of Rufy3 in an in vivo model of SAH-induced early brain injury (EBI). In addition, we investigated the relevant brain-protective mechanisms. Oxyhemoglobin (OxyHb) stimulation of cultured primary neurons simulated vitro SAH condition. The SAH rat model was induced by infusing autologous blood into the optic chiasma pool and treating the rats with lentivirus-negative control 1 (LV-NC1), lentivirus-Rufy3 shRNA (LV-shRNA), lentivirus-negative control 2 (LV-NC2), lentivirus-Rufy3 (LV-Rufy3), or 8-pCPT-2′-O-Me-cAMP (8p-CPT) (Rap1 agonist). In experiment one, we found that the protein level of Rufy3 decreased and neuronal axon injury in the injured neurons but was rectified by LV-Rufy3 treatment. In experiment two, mRNA and protein levels of Rufy3 were downregulated in brain tissue and reached the lowest level at 24 h after SAH. In addition, the expression of Myelin Basic Protein was downregulated and that of anti-hypophosphorylated neurofilament H (N52) was upregulated after SAH. In experiments three and four, Rufy3 overexpression (LV-Rufy3) increased the interactions between Rufy3 and Rap1, the level of Rap1-GTP, and the ratio of Rap1-GTP/total GTP. In addition, LV-Rufy3 treatment inhibited axon injury and accelerated axon repair by activating the Rap1/Arap3/Rho/Fascin signaling pathway accompanied by upregulated protein expression levels of ARAP3, Rho, Fascin, and Facin. LV-Rufy3 also enhanced synaptic plasticity by activating the Rap1/MEK/ERK/synapsin I signaling pathway accompanied by upregulated protein expression levels of ERK1, p-ERK1, MEK1, p-MEK1, synaspin I, and p-synaspin I. Moreover, LV-Rufy3 also alleviated brain damage indicators, including cortical neuronal cell apoptosis and degeneration, brain edema, and cognitive impairment after SAH. However, the downregulation of Rufy3 had the opposite effect and aggravated EBI induced by SAH. Notably, the combined application of LV-Rufy3 and 8p-CPT showed a significant synergistic effect on the aforementioned parameters. Our findings suggest that enhanced Rufy3 expression may reduce EBI by inhibiting axon injury and promoting neuronal axon repair and synaptic plasticity after SAH.
RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers
Authors: Xia Li , Tian Enming , Yu Mingcheng , Liu Chenglong , Shen Lian , Huang Yafei , Wu Zhongen , Tian Jinlong , Yu Ker , Wang Yonghui , Xie Qiong , Zhu Di 
Published: April 2022

Abstract
Background
The overall response rate to checkpoint blockade remains unsatisfactory, partially due to the immune-suppressive tumor microenvironment. A retinoic acid-related orphan receptor γt (RORγt) agonist (LYC-55716) is currently used in clinical trials combined with anti-PD-1, but how the Th17 cell transcription factor RORγt enhances antitumor immunity of PD-1 in the tumor microenvironment remains elusive.

Methods
The expression of mRNA was analyzed using qPCR assays. Flow cytometry was used to sort and profile cells. Cell migration was analyzed using Transwell assays. Biacore was used to determine the binding affinity to the RORγt protein. The RORγt GAL4 cell-based reporter gene assay was used to measure activity in the RORγt driven luciferase reporter gene expression.

Results
We designed a potent and selective small-molecule RORγt agonist (8-074) that shows robust antitumor efficacy in syngeneic tumor models and improves the efficacy of anti‑PD‑1 in a murine lung cancer model. RORγt agonist treatment increased intratumoral CD8+ T cells, which were correlated with CXCL10 and monocyte-derived dendritic cells (MoDCs). In addition, the RORγt agonist promoted Type 17 T cell migration by upregulating CCL20 and CCR6 expression, and Type 17 T cell tumor infiltration. CCL20 induces MoDCs migration, and CXCL10 derived from MoDCs promotes CD8+ T cell migration.

Conclusion
Our results revealed that the RORγt agonist improved the efficacy of anti-PD-1. The RORγt agonist increased the migration of MoDCs, which increased the local levels of CXCL10, thus promoting CD8+ T cell tumor infiltration. Our findings provide the mechanistic insights implicating the RORγt agonist in immunotherapy and offer a strategy for targeting the RORγt agonist to improve PD-1 antibody efficacy in cancers.
Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma
Authors: Chen Zhi-Wen , Hu Jian-Fei , Wang Zu-Wei , Liao Cheng-Yu , Kang Feng-Ping , Lin Cai-Feng , Huang Yi , Huang Long , Tian Yi-Feng , Chen Shi 
Published: April 2022

Abstract
Background
Chemoresistance of pancreatic cancer is the main reason for the poor treatment effect of pancreatic cancer patients. Exploring chemotherapy resistance-related genes has been a difficult and hot topic of oncology. Numerous studies implicate the key roles of circular RNAs (circRNAs) in the development of pancreatic cancer. However, the regulation of circRNAs in the process of pancreatic ductal adenocarcinoma (PDAC) chemotherapy resistance is not yet fully clear.

Methods
Based on the cross-analysis of the Gene Expression Omnibus (GEO) database and the data of our center, we explored a new molecule, hsa_circ_0078297 (circ-MTHFD1L), related to chemotherapy resistance. QRT-PCR was used to detect the expression of circRNAs, miRNAs, and mRNAs in human PDAC tissues and their matched normal tissues. The interaction between circ-MTHFD1L and miR-615-3p/RPN6 signal axis was confirmed by a series of experiments such as Dual-luciferase reporter assay, fluorescence in situ hybridization (FISH) RNA immunoprecipitation (RIP) assays.

Results
Circ-MTHFD1L was significantly increased in PDAC tissues and cells. And in PDAC patients, the higher the expression level of circ-MTHFD1L, the worse the prognosis. Mechanism analysis showed that circ-MTHFD1L, as an endogenous miR-615-3p sponge, upregulates the expression of RPN6, thereby promoting DNA damage repair and exerting its effect on enhancing gemcitabine chemotherapy resistance. More importantly, we also found that Silencing circ-MTHFD1L combined with olaparib can increase the sensitivity of pancreatic cancer to gemcitabine.

Conclusion
Circ-MTHFD1L maintains PDAC gemcitabine resistance through the miR-615-3p/RPN6 signal axis. Circ-MTHFD1L may be a molecular marker for the effective treatment of PDAC.
Genome-wide CRISPR screen identified Rad18 as a determinant of doxorubicin sensitivity in osteosarcoma
Authors: Du Mingrui , Gu Jintao , Liu Chenlin , Liu Nannan , Yu Zhe , Zhou Chengpei , Heng Wei , Cao Zhengcong , Wei Feilong , Zhu Kailong , Wang Yingwen , Zhang Wei , Xue Xiaochang , Zhang Yong , Qian Jixian 
Published: April 2022

Abstract
Background
Osteosarcoma (OS) is a malignant bone tumor mostly occurring in children and adolescents, while chemotherapy resistance often develops and the mechanisms involved remain challenging to be fully investigated.

Methods
Genome-wide CRISPR screening combined with transcriptomic sequencing were used to identify the critical genes of doxorubicin resistance. Analysis of clinical samples and datasets, and in vitro and in vivo experiments (including CCK-8, apoptosis, western blot, qRT-PCR and mouse models) were applied to confirm the function of these genes. The bioinformatics and IP-MS assays were utilized to further verify the downstream pathway. RGD peptide-directed and exosome-delivered siRNA were developed for the novel therapy strategy.

Results
We identified that E3 ubiquitin-protein ligase Rad18 (Rad18) contributed to doxorubicin-resistance in OS. Further exploration revealed that Rad18 interact with meiotic recombination 11 (MRE11) to promote the formation of the MRE11-RAD50-NBS1 (MRN) complex, facilitating the activation of the homologous recombination (HR) pathway, which ultimately mediated DNA damage tolerance and leaded to a poor prognosis and chemotherapy response in patients with OS. Rad18-knockout effectively restored the chemotherapy response in vitro and in vivo. Also, RGD-exosome loading chemically modified siRad18 combined with doxorubicin, where exosome and chemical modification guaranteed the stability of siRad18 and the RGD peptide provided prominent targetability, had significantly improved antitumor activity of doxorubicin.

Conclusions
Collectively, our study identifies Rad18 as a driver of OS doxorubicin resistance that promotes the HR pathway and indicates that targeting Rad18 is an effective approach to overcome chemotherapy resistance in OS.
Are 5-level triage systems improved by using a symptom based approach?—a Danish cohort study
Authors: Kongensgaard Frederik Trier , Fløjstrup Marianne , Lassen Annmarie , Dahlin Jan , Brabrand Mikkel 
Published: April 2022

Abstract
Background
Five-level triage systems are being utilized in Danish emergency departments with and without the use of presenting symptoms. The aim of this study was to validate and compare two 5-level triage systems used in Danish emergency departments: “Danish Emergency Process Triage” (DEPT) based on a combination of vital signs and presenting symptoms and a locally adapted version of DEPT (VITAL-TRIAGE) using vital signs only.

Methods
This was a retrospective cohort using data from five Danish emergency departments. All patients attending an emergency department during the period of 1 April 2012 until 31 December 2015 were included. Validity of the two triage systems was assessed by comparing urgency categories determined by each triage system with critical outcomes: admission to Intensive care unit (ICU) within 24 h, 2-day mortality, diagnosis of critical illness, surgery within 48 h, discharge within 4 h and length of hospital stay.

Results
We included 632,196 ED contacts. Sensitivity for 24-h ICU admission was 0.79 (95% confidence interval 0.78–0.80) for DEPT and 0.44 (0.41–0.47) for VITAL-TRIAGE. The sensitivity for 2-day mortality was 0.69 (0.67–0.70) for DEPT and 0.37 (0.34–0.41) for VITAL-TRIAGE. The sensitivity to detect diagnoses of critical illness was 0.48 (0.47–0.50) for DEPT and 0.09 (0.08–0.10) for VITAL-TRIAGE. The sensitivity for predicting surgery within 48 h was 0.30 (0.30–0.31) in DEPT and 0.04 (0.04–0.04) in VITAL-TRIAGE. Length of stay was longer in VITAL-TRIAGE than DEPT. The sensitivity of DEPT to predict patients discharged within 4 h was 0.91 (0.91–0.92) while VITAL-TRIAGE was higher at 0.99 (0.99–0.99). The odds ratio for 24-h ICU admission and 2-day mortality was increased in high-urgency categories of both triage systems compared to low-urgency categories.

Conclusions
High urgency categories in both triage systems are correlated with adverse outcomes. The inclusion of presenting symptoms in a modern 5-level triage system led to significantly higher sensitivity measures for the ability to predict outcomes related to patient urgency. DEPT achieves equal prognostic performance as other widespread 5-level triage systems.
Central precocious puberty during COVID-19 pandemic and sleep disturbance: an exploratory study
Authors: Umano Giuseppina R , Maddaluno Ivan , Riccio Simona , Lanzaro Francesca , Antignani Rachele , Giuliano Maria , Luongo Caterina , Festa Adalgisa , Miraglia del Giudice Emanuele , Grandone Anna 
Published: April 2022

Abstract
Background
Increased incidence of central precocious puberty (CPP) after coronavirus infectious disease-19 lockdown has been reported. Our study aims in investigating changes in CPP rates and in sleep patterns in CPP and healthy controls.

Methods
CPP were retrospectively evaluated from April 2020 to April 2021. Parents of girls diagnosed with CPP during lockdown and of matched healthy controls filled out a questionnaire about sleep disturbances (SDSC questionnaire) and sleep schedules.

Results
Thirty-five CPP and 37 controls completed the survey. Incidence of new CPP cases significantly increased in 2020–2021 compared to 2017–2020 (5:100 vs 2:100, p = 0.02). Sleep disturbance rates did not differ between CPP and healthy controls before lockdown. During lockdown, CPP reported higher rates of sleep disturbs for total score (p = 0.005), excessive somnolence (p = 0.049), sleep breathing disorders (p = 0.049), and sleep–wake transition disorders (p = 0.005). Moreover, CPP group more frequently shifted toward later bedtime (p = 0.03) during lockdown compared to controls. Hours of sleep and smartphone exposure around bedtime did not differ between groups.

Conclusions
Our study confirms the observation of increased incidence of CPP after lockdown measures. Additionally, CPP showed higher rates of sleep disturbances and later bedtime compared to controls. The causality link between sleep disturbances and CPP should be further investigated to gain knowledge in this association.