bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of ERBB Signaling Pathway-Related Genes in Kidney Renal Clear Cell Carcinoma and Establishing a Prognostic Risk Assessment Model for Patients
Authors: Wang Zicheng , Li Jiayi , Zhang Peizhi , Zhao Leizuo , Huang Bingyin , Xu Yingkun , Wu Guangzhen , Xia Qinghua 
Published: July 2022

Objective: We aimed to investigate the potential role of ERBB signaling pathway–related genes in kidney renal clear cell carcinoma (KIRC) and establish a new predictive risk model using various bioinformatics methods.Methods: We downloaded the KIRC dataset and clinicopathological information from The Cancer Genome Atlas database. Univariate Cox analysis was used to identify essential genes significantly associated with KIRC progression. Next, we used the STRING website to construct a protein–protein interaction network of ERBB signaling pathway–related molecules. We then used the least the absolute shrinkage and selection operator (LASSO) regression analysis to build a predictive risk model for KIRC patients. Next, we used multiple bioinformatics methods to analyze the copy number variation, single-nucleotide variation, and overall survival of these risk model genes in pan-cancer. At last, we used the Genomics of Drug Sensitivity in Cancer to investigate the correlation between the mRNA expression of genes associated with this risk model gene and drug sensitivity.Results: Through the LASSO regression analysis, we constructed a novel KIRC prognosis–related risk model using 12 genes: SHC1, GAB1, SOS2, SRC, AKT3, EREG, EIF4EBP1, ERBB3, MAPK3, transforming growth factor-alpha, CDKN1A, and PIK3CD. Based on this risk model, the overall survival rate of KIRC patients in the low-risk group was significantly higher than that in the high-risk group (p = 1.221 × 10−15). Furthermore, this risk model was associated with cancer metastasis, tumor size, node, stage, grade, sex, and fustat in KIRC patients. The receiver operating characteristic curve results showed that the model had better prediction accuracy. Multivariate Cox regression analysis showed that the model’s risk score was an independent risk factor for KIRC. The Human Protein Atlas database was used to validate the protein expression of risk model–associated molecules in tumors and adjacent normal tissues. The validation results were consistent with our previous findings.Conclusions: We successfully established a prognostic-related risk model for KIRC, which will provide clinicians with a helpful reference for future disease diagnosis and treatment.
Exploring Potential Causal Genes for Uterine Leiomyomas: A Summary Data-Based Mendelian Randomization and FUMA Analysis
Authors: Dai Yuxin , Liu Xudong , Zhu Yining , Mao Su , Yang Jingyun , Zhu Lan 
Published: July 2022

Objective: To explore potential causal genetic variants and genes underlying the pathogenesis of uterine leiomyomas (ULs).Methods: We conducted the summary data-based Mendelian randomization (SMR) analyses and performed functional mapping and annotation using FUMA to examine genetic variants and genes that are potentially involved in the pathogenies of ULs. Both analyses used summarized data of a recent genome-wide association study (GWAS) on ULs, which has a total sample size of 244,324 (20,406 cases and 223,918 controls). We performed separate SMR analysis using CAGE and GTEx eQTL data.Results: Using the CAGE eQTL data, our SMR analysis identified 13 probes tagging 10 unique genes that were pleiotropically/potentially causally associated with ULs, with the top three probes being ILMN_1675156 (tagging CDC42, PSMR = 8.03 × 10−9), ILMN_1705330 (tagging CDC42, PSMR = 1.02 × 10−7) and ILMN_2343048 (tagging ABCB9, PSMR = 9.37 × 10−7). Using GTEx eQTL data, our SMR analysis did not identify any significant genes after correction for multiple testing. FUMA analysis identified 106 independent SNPs, 24 genomic loci and 137 genes that are potentially involved in the pathogenesis of ULs, seven of which were also identified by the SMR analysis.Conclusions: We identified many genetic variants, genes, and genomic loci that are potentially involved in the pathogenesis of ULs. More studies are needed to explore the exact underlying mechanisms in the etiology of ULs.
Essential Role of the Innate Immune Adaptor RIP2 in the Response to Otitis Media
Authors: Kurabi Arwa , Lee Jasmine , Pak Kwang , Leichtle Anke , Ryan Allen F 
Published: July 2022

Intracellular nucleotide binding and oligomerization domain (NOD) and Toll-like (TLR) receptors have emerged as pivotal sensors of infection. Both Nod1 and Nod2 contain a caspase activation and recruitment domain (CARD) that interacts with the adaptor protein RIP2 (receptor-interaction protein-2). This leads to ubiquitination of RIP2 and in turn to the activation of NFκB and MAPK transcription factors, to command the host defensive response against pathogenic infections. RIP2 is also activated by TLRs 2 and 4, although the mechanism of this activation is less. The role of RIP2 in otitis media (OM) pathogenesis has yet to be examined. Herein, we used in vivo animal models including C57BL/6 wild-type (WT) and RIP2−/− knockout mice inoculated in the middle ear (ME) with non-typeable Haemophilus influenzae (NTHi), a common human OM pathogen, to evaluate the expression of RIP2 and its signaling genes at the cellular level to determine the role of RIP2 in OM pathogenesis and recovery. The Nod1, Nod2, and Ripk2 genes are minimally expressed in the normal ME. However, they are strongly upregulated during acute OM, as are many genes related to RIP2 signaling. However, while signaling genes were expressed by various ME cell types, only mucosal epithelial and stromal cells expressed the NODs, RIP2, and signaling genes required for the activation of the host defensive response. Whereas WT mice clear ME bacteria and recover from OM within 5 days after infection, RIP2-deficient mice show persistent ME bacterial carriage and inflammation to at least 15 days. This includes significantly prolonged mucosal hyperplasia and ME leukocytic infiltration. Recruitment of macrophages is also delayed in comparison to WT mice. Thus, RIP2 is required to elicit a robust innate immune response that promotes bacterial clearance and increases host innate resistance. The results also identify the structural cells of the ME mucosa, as opposed to leukocytes, as the primary sites of NOD/RIP2 activity in the infected ME.
Case Report: DNAAF4 Variants Cause Primary Ciliary Dyskinesia and Infertility in Two Han Chinese Families
Authors: Guo Ting , Lu Chenyang , Yang Danhui , Lei Cheng , Liu Ying , Xu Yingjie , Yang Binyi , Wang Rongchun , Luo Hong 
Published: July 2022

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder, predominantly autosomal recessive. The dynein axonemal assembly factor 4 (DNAAF4) is mainly involved in the preassembly of multisubunit dynein protein, which is fundamental to the proper functioning of cilia and flagella. There are few reports of PCD-related pathogenic variants of DNAAF4, and almost no DNAAF4-related articles focused on sperm phenotype. Moreover, the association between DNAAF4 and scoliosis has never been reported, to the best of our knowledge.Materials and Methods: We recruited two patients with a clinical diagnosis of PCD. One came from a consanguineous and another from a non-consanguineous family. Clinical data, laboratory test results, and imaging data were analyzed. Through whole exome sequencing, immunofluorescence, electron microscopy, high-speed video microscopy analysis, and hematoxylin–eosin (HE) staining, we identified the disease-associated variants and validated the pathogenicity.Results: Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a non-consanguineous family-I, and proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-II. Both had sinusitis, bronchiectasis, situs inversus, and scoliosis. P1 also had asthenoteratozoospermia, and P2 had an immature uterus. Two homozygous pathogenic variants in DNAAF4 (NM_130810.4), c.988C &gt; T, p.(Arg330Trp), and DNAAF4 (NM_130810.4), c.733 C &gt; T, p.(Arg245*), were identified through whole exome sequencing. High-speed microscopy analysis showed that most of the cilia were static in P1, with complete static of the respiratory cilia in P2. Immunofluorescence showed that the outer dynein arms (ODA) and inner dynein arms (IDA) were absent in the respiratory cilia of both probands, as well as in the sperm flagellum of P1. Transmission electron microscopy revealed the absence of ODA and IDA of respiratory cilia of P2, and HE staining showed irregular, short, absent, coiled, and bent flagella.Conclusion: Our study identified a novel variant c.733C &gt; T, which expanded the spectrum of DNAAF4 variants. Furthermore, we linked DNAAF4 to asthenoteratozoospermia and likely scoliosis in patients with PCD. This study will contribute to a better understanding of PCD.
Humoral Response Following Triple Dose of mRNA Vaccines Against SARS-CoV-2 in Hemodialysis Patients: Results After 1 Year of Follow-Up
Authors: Gallego-Valcarce Eduardo , Shabaka Amir , Leon-Poo Mariana , Gruss Enrique , Acedo-Sanz Juan Manuel , Cordón Alfredo , Cases-Corona Clara , Fernandez-Juarez Gema 
Published: July 2022

IntroductionCOVID-19 is associated with an increased mortality in hemodialysis patients. Therefore, achieving a long-lasting effective immune response to SARS-CoV-2 vaccines is essential. This study describes the humoral immune response in hemodialysis patients following three doses of mRNA vaccines against SARS-CoV-2, and explores the factors associated with a sustained immune response.Materials and MethodsWe analyzed the monthly serological evolution of SARS-CoV-2 anti-S(RBD) antibodies for 1 year in 178 chronic hemodialysis patients who received three doses of SARS-CoV-2 mRNA vaccines. The primary outcome was sustained effective humoral response defined as anti-S(RBD) levels &gt; 1,000 AU/ml after 4 months from the third dose. Multivariate logistic regression analyses were used to identify features associated with a sustained humoral immune response.ResultsAfter the initial two SARS-CoV-2 mRNA vaccine doses, 77.8% of patients showed an immediate effective humoral response, decreasing to 52.5% after 4 months. Antibody levels were significantly higher in COVID-exposed patients and HBV vaccine responders. After the third dose, 97% of patients showed an effective humoral response, and remained in 91.7% after 4 months. The mean monthly rate of antibody titer decline decreased from 33 ± 14.5 to 25 ± 16.7%. Multivariate regression analysis showed that previous exposure to COVID-19 and response to HBV vaccines were associated with an effective sustained humoral immune response.ConclusionImmunization with SARS-CoV-2 mRNA vaccines elicits an effective immediate humoral immune response in hemodialysis patients, with a progressive waning in antibody levels. A third booster dose enhances the immune response with significantly higher antibody levels and more sustained humoral immune response. COVID-naïve patients and patients without previous response to HBV vaccines are likely to benefit from receiving more booster doses to maintain an effective immune response.
Effects of Normal Reference Range of Phosphorus and Corresponding PTH on Endothelial Function in CKD Patients
Authors: Lee Shina , Kim Seung-Jung 
Published: July 2022

IntroductionEndothelial dysfunction commonly occurs in chronic kidney disease (CKD) patients and increases the risk for cardiovascular disease. Among CKD patients, biomarkers involved in the pathogenesis of CKD-mineral bone disorder (CKD-MBD), such as phosphorus, parathyroid hormone, and fibroblast growth factor 23, are associated with endothelial dysfunction. We investigated whether these biomarkers induce endothelial dysfunction in CKD patients with normal phosphorus levels.MethodsThis cross-sectional study examined CKD patients with normal phosphorus levels; patients with an estimated glomerular filtration rate (eGFR) &lt;15 or who were under dialysis were excluded. Iontophoresis with laser doppler flowmetry (ILDF) and peripheral arterial tonometry were performed to assess endothelial function in 85 patients. Pearson's correlation coefficient, multiple regression, and mediation analyses were performed to examine the association between CKD-MBD biomarkers and endothelial dysfunction.ResultsEndothelial dysfunction was observed in all subjects with a low response to ILDF and 27% of subjects according to peripheral arterial tonometry. Acetylcholine (Ach)-induced ILDF was significantly associated with eGFR (r = 0.22, P = 0.04), intact parathyroid hormone (iPTH; r = −0.46, P &lt; 0.01), and VCAM-1 (r = −0.36, P &lt; 0.01). The reactive hyperemia index (RHI) was significantly related to phosphorus levels (r = 0.32, P &lt; 0.01) and iPTH (r = −0.39, P = 0.02). After adjusting for eGFR, iPTH and VCAM-1 remained independent factors for predicting endothelial dysfunction measured using Ach-induced ILDF. In addition, iPTH and phosphorus levels were independent predictors for endothelial dysfunction measured using RHI in the eGFR-adjusted model. Mediation analyses showed that the individual indirect effects of iPTH were significantly affected ILDF and RHI.ConclusionSerum levels of phosphorus and iPTH are associated with endothelial dysfunction, even in CKD patients with normal phosphorus levels.
The Cardiovascular Literature-Based Risk Algorithm (CALIBRA): Predicting Cardiovascular Events in Patients With Non-Dialysis Dependent Chronic Kidney Disease
Authors: Neri Luca , Lonati Caterina , Titapiccolo Jasmine Ion , Nadal Jennifer , Meiselbach Heike , Schmid Matthias , Baerthlein Barbara , Tschulena Ulrich , Schneider Markus P. , Schultheiss Ulla T. , Barbieri Carlo , Moore Christoph , Steppan Sonia , Eckardt Kai-Uwe , Stuard Stefano , Bellocchio Francesco 
Published: July 2022

Background and ObjectivesCardiovascular (CV) disease is the main cause of morbidity and mortality in patients suffering from chronic kidney disease (CKD). Although it is widely recognized that CV risk assessment represents an essential prerequisite for clinical management, existing prognostic models appear not to be entirely adequate for CKD patients. We derived a literature-based, naïve-bayes model predicting the yearly risk of CV hospitalizations among patients suffering from CKD, referred as the CArdiovascular, LIterature-Based, Risk Algorithm (CALIBRA).MethodsCALIBRA incorporates 31 variables including traditional and CKD-specific risk factors. It was validated in two independent CKD populations: the FMC NephroCare cohort (European Clinical Database, EuCliD®) and the German Chronic Kidney Disease (GCKD) study prospective cohort. CALIBRA performance was evaluated by c-statistics and calibration charts. In addition, CALIBRA discrimination was compared with that of three validated tools currently used for CV prediction in CKD, namely the Framingham Heart Study (FHS) risk score, the atherosclerotic cardiovascular disease risk score (ASCVD), and the Individual Data Analysis of Antihypertensive Intervention Trials (INDANA) calculator. Superiority was defined as a ΔAUC&gt;0.05.ResultsCALIBRA showed good discrimination in both the EuCliD® medical registry (AUC 0.79, 95%CI 0.76-0.81) and the GCKD cohort (AUC 0.73, 95%CI 0.70-0.76). CALIBRA demonstrated improved accuracy compared to the benchmark models in EuCliD® (FHS: ΔAUC=-0.22, p&lt;0.001; ASCVD: ΔAUC=-0.17, p&lt;0.001; INDANA: ΔAUC=-0.14, p&lt;0.001) and GCKD (FHS: ΔAUC=-0.16, p&lt;0.001; ASCVD: ΔAUC=-0.12, p&lt;0.001; INDANA: ΔAUC=-0.04, p&lt;0.001) populations. Accuracy of the CALIBRA score was stable also for patients showing missing variables.ConclusionCALIBRA provides accurate and robust stratification of CKD patients according to CV risk and allows score calculations with improved accuracy compared to established CV risk scores also in real-world clinical cohorts with considerable missingness rates. Our results support the generalizability of CALIBRA across different CKD populations and clinical settings.
Clinical Outcomes After Ventriculo-Peritoneal Shunting in Patients With Classic vs. Complex NPH
Authors: Goh Eng Tah , Lock Christine , Tan Audrey Jia Luan , Tan Bee Ling , Liang Sai , Pillay Robin , Kumar Sumeet , Ahmad-Annuar Azlina , Narayanan Vairavan , Kwok Janell , Tan Yi Jayne , Ng Adeline SL , Tan Eng King , Czosnyka Zofia , Czosnyka Marek , Pickard John D. , Keong Nicole C. 
Published: July 2022

ObjectiveNormal pressure hydrocephalus (NPH) is a neurological condition characterized by a clinical triad of gait disturbance, cognitive impairment, and urinary incontinence in conjunction with ventriculomegaly. Other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and vascular dementia share some overlapping clinical features. However, there is evidence that patients with comorbid NPH and Alzheimer's or Parkinson's disease may still exhibit good clinical response after CSF diversion. This study aims to evaluate clinical responses after ventriculo-peritoneal shunt (VPS) in a cohort of patients with coexisting NPH and neurodegenerative disease.MethodsThe study has two components; (i) a pilot study was performed that specifically focused upon patients with Complex NPH and following the inclusion of the Complex NPH subtype into consideration for the clinical NPH programme, (ii) a retrospective snapshot study was performed to confirm and characterize differences between Classic and Complex NPH patients being seen consecutively over the course of 1 year within a working subspecialist NPH clinic. We studied the characteristics of patients with Complex NPH, utilizing clinical risk stratification and multimodal biomarkers.ResultsThere was no significant difference between responders and non-responders to CSF diversion on comorbidity scales. After VPS insertion, significantly more Classic NPH patients had improved cognition compared to Complex NPH patients (p = 0.005). Improvement in gait and urinary symptoms did not differ between the groups. 26% of the Classic NPH group showed global improvement of the triad, and 42% improved in two domains. Although only 8% showed global improvement of the triad, all Complex NPH patients improved in gait.ConclusionsOur study has demonstrated that the presence of neurodegenerative disorders co-existing with NPH should not be the sole barrier to the consideration of high-volume tap test or lumbar drainage via a specialist NPH programme. Further characterization of distinct cohorts of NPH with differing degrees of CSF responsiveness due to overlay from neurodegenerative or comorbidity risk burden may aid toward more precise prognostication and treatment strategies. We propose a simplistic conceptual framework to describe NPH by its Classic vs. Complex subtypes to promote the clinical paradigm shift toward subspecialist geriatric neurosurgery by addressing needs for rapid screening tools at the clinical-research interface.
Clinical Application of Different Vertical Position Tests for Posterior Canal-Benign Paroxysmal Positional Vertigo-Cupulolithiasis
Authors: Wang Wenting , Yan Shuangmei , Zhang Sai , Han Rui , Li Dong , Liu Yihan , Zhang Ting , Liu Shaona , Wu Yuexia , Li Ya , Yang Xu , Gu Ping 
Published: July 2022

BackgroundPosterior canal-benign paroxysmal positional vertigo-cupulolithiasis (PC-BPPV-cu) is a new and controversial type of benign paroxysmal positional vertigo (BPPV). At present, there are few relevant clinical studies as to whether the Half Dix-Hallpike test (Half D-HT) induces more obvious nystagmus than the Dix Hallpike test (D-HT) and straight head hanging test (SHH) in patients with PC-BPPV-cu.ObjectivesTo investigate the clinical characteristics of PC-BPPV-cu, and analyze the diagnostic significance of the Dix-Hallpike test (D-HT), Half D-HT, and straight head hanging (SHH) test in these patients.MethodsA total of 46 patients with PC-BPPV-cu were enrolled, and divided into two groups (N = 23): a group A (induction order: D-HT, Half D-HT, SHH) and a group B (induction order: Half D-HT, D-HT, SHH).ResultsAmong 46 patients with PC-BPPV-cu, the bilateral and unilateral abnormality rates of the disease side were 5 cases and 41 cases, respectively. There were significant differences in the proportion of torsional-upbeating nystagmus and upbeating nystagmus among the three headhanging positions in 46 patients with PC-BPPV-cu (P &lt; 0.001). The slow phase velocity (SPV) of induced nystagmus at half D-HT supine position was slower than D-HT supine position (P &lt; 0.05) and SHH supine position (P &lt; 0.05). The nystagmus latency of D-HT supine position was significantly shorter than half D-HT (P &lt; 0.05) and SHH (P &lt; 0.05). PC-BPPV-cu patients were accompanied by 53.5% semicircular canal paresis, 69.6% audiological abnormalities, 76% cervical vestibular evoked myogenic potential (cVEMP), and 75% video head impulse test (vHIT) abnormalities, the concordance rates of the four detection methods were similar (χ2 = 0.243, P = 0.970).ConclusionsThe Half D-HT is simple and feasible, but might have a risk of false-negative diagnoses of the torsional-upbeating nystagmus and upbeating nystagmus. The D-HT is still a classic induction method for PC-BPPV-cu. The two complement each other and may aid in the diagnosis of PC-BPPV-cu patients. Future clinical applications of Half D-HT require extensive research to determine its diagnostic efficacy.