bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of causal associations between uric acid and 25-hydroxyvitamin D levels
Authors: Han Yingdong , Zhang Yun , Zeng Xuejun 
Published: December 2022

BackgroundPrevious observational studies have revealed the association between serum uric acid and 25-hydroxyvitamin D. However, the causality and the direction of the associations remain unknown. Thus, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis to investigate the causal association between uric acid and 25-hydroxyvitamin D and to determine the direction of the association.MethodBased on the summary-level GWAS data from large genome-wide association studies, several steps were taken in our analysis to select eligible single-nucleotide polymorphisms (SNPs), which were strongly related to exposure as the instrumental variables. We used different analytical methods, such as inverse-variance weighting (IVW) method, weighted median, MR-Egger regression, and weighted mode method, to make our result more robust and reliable. The IVW method was used as the primary analysis. The Cochran’s Q test, MR-Egger intercept test, MR-PRESSO method, and “leave-one-out” sensitivity analysis was performed to evaluate the heterogeneities, horizontal pleiotropy, and robustness of the results. MR analyses were also conducted using genetic risk scores (GRS) as instrumental variables in both directions by using the same summary-level GWAS data.ResultsOur two-sample MR analysis suggested a causal association of genetically predicted uric acid on 25-hydroxyvitamin D [IVW method: β(SE), −0.0352(0.0149); p = 0.0178], which suggested that a per mg/dl increase in uric acid was associated with a decrease of 0.74 nmol/L of 25-hydroxyvitamin D, and the above results remained stable in the sensitivity analysis. By contrast, four MR methods suggested no causal relationship of 25-hydroxyvitamin D on serum uric acid [IVW β(SE), 0.0139 (0.0635); p = 0.826; MR-Egger β(SE), 0.0671 (0.108); p = 0.537; weighted median β(SE), 0.0933 (0.0495); p = 0.0598; weighted mode β(SE), 0.0562 (0.0463); p = 0.228, respectively]. After excluding the SNPs, which were associated with confounding factors and outlier SNPs, the IVW method suggested that there was still no causal association of 25-hydroxyvitamin D on serum uric acid. The GRS approach showed similar results.ConclusionsSerum uric acid may causally affect the 25-hydroxyvitamin D levels, whereas the causal role of 25-hydroxyvitamin D on uric acid was not supported in our MR analysis. Our findings suggest that increased levels of uric acid should prompt investigation for vitamin D deficiency.
Vitamin D pathway gene variation rs3740165 is associated with serological uric acid levels in healthy Chinese women
Authors: Gu Jiemei , Yue Hua , Wang Chun , Zhang Hao , Hu Weiwei , Zhang Zhenlin 
Published: December 2022

AimTo investigate the relationship between gene polymorphisms involved in the vitamin D metabolic pathway and serum uric acid (UA) levels in Chinese women.MethodsFifteen key genes within the vitamin D metabolic pathway were screened using 96 single nucleotide polymorphisms in a group of 1,206 (37.96 ± 13.08 years) unrelated healthy Chinese women (aged 20–85 years). Blood and urine tests were performed at the same time. The Wilcoxon Mann–Whitney test was used to compare groups aged ≤50 years and &gt;50 years. The mean serum UA values were computed within each group of homozygous referent, heterozygous, and homozygous variant genotypes for each single nucleotide polymorphism.ResultsThe exclusion process left 1,169 participants (38.16 ± 13.13 years) for analysis. One single nucleotide polymorphism in the CUBN gene (rs3740165) was identified as being significantly associated with serum UA levels in the group aged over 50 years. The wild type (C/C) population had higher serum UA levels in this group (P&lt;0.001). In women aged over 50 years, allele C was associated with a higher risk of hyperuricemia than allele T (odds ratio 2.752, 95% confidence interval 1.458–5.192; P = 0.002). There was also a higher risk of hyperuricemia in genotype TC + CC compared with genotype TT (odds ratio 3.326, 95% confidence interval 1.513–7.313; P = 0.003) in women over 50 years of age.ConclusionThe results suggest that the CUBN gene contributes to variability in serum UA levels in healthy Chinese Han women over 50 years of age.
Applying the RE-AIM implementation framework to evaluate diabetes health coaching in individuals with type 2 diabetes: A systematic review and secondary analysis
Authors: Racey Megan , Jovkovic Milos , Alliston Paige , Sherifali Diana 
Published: December 2022

BackgroundDiabetes health coaching continues to emerge as an effective intervention to support diabetes self-management. While previous systematic reviews have focused on the effectiveness of diabetes health coaching programs in adults with type 2 diabetes (T2DM), limited literature is available on its implementation. This review examines what aspects of diabetes health coaching interventions for adults living with type 2 diabetes have been reported using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to optimize implementation.MethodsWe examined the included studies from our recently completed systematic review, which searched 6 databases for randomized controlled trials (RCTs) of health coaching interventions delivered by a health professional for adults with T2DM. Reviewers screened citations and extracted data for study characteristics and the 5 dimensions (62 criteria) of the RE-AIM framework.Results9 diabetes health coaching RCTs were included in this review. 12 criteria were reported by all the included studies and 21 criteria were not reported by any of the studies. The included studies all reported on more than 20 RE-AIM criteria, ranging from 21 to 27. While Reach was the best reported construct by the included studies, followed by Effectiveness and Implementation, the criteria within the Adoption and Maintenance constructs were rarely mentioned by these studies. In general, there was also wide variation in how each of the criteria were reported on by study authorsConclusionsDue to the paucity of reporting of the RE-AIM components for diabetes health coaching, limited implementation and clinical practice implications can be drawn. The lack of detail regarding implementation approaches to diabetes health coaching greatly limits the interpretation and comparisons across studies to best inform the application of this intervention to support diabetes self-management.Systematic review registrationPROSPERO identifier, CRD42022347478
Etoricoxib as a treatment of choice for patients with SLCO2A1 mutation exhibiting autosomal recessive primary hypertrophic osteoarthropathy: A case report
Authors: Albawa'neh Areej , Al Mansoori Mariam Ghareeb , Diab Sehriban , Al Jasmi Fatma , Akawi Nadia 
Published: December 2022

We reported a 22-year-old Emirati male with autosomal recessive primary hypertrophic osteoarthropathy caused by a possibly pathogenic homozygous non-synonymous variant in the SLCO2A1 gene (NM_005630.3: c.289C&gt;T, p. Arg97Cys) presenting with joint swelling, forehead furrowing, and significant clubbing in all fingers and toes. Currently, no standard treatments are approved for this disease; medical care is palliative and includes non-steroidal anti-inflammatory drugs, corticosteroids, tamoxifen, retinoids, and risedronate. Colchicine may be helpful for the pain due to subperiosteal new bone formation. Our patient was treated with etoricoxib 60 mg once daily and showed a significant clinical improvement at the 6-month mark that was reversed upon the withdrawal of this medication. This case report highlights the importance of placing etoricoxib among first-line therapy recommendations for cases with confirmed primary hypertrophic osteoarthropathy diagnosis. To the best of our knowledge, this is the only case of primary hypertrophic osteoarthropathy from the Middle Eastern population of Arab ethnicity that has responded to non-steroidal anti-inflammatory drug therapy.
High-risk genotypes for type 1 diabetes are associated with the imbalance of gut microbiome and serum metabolites
Authors: Yue Tong , Tan Huiling , Wang Chaofan , Liu Ziyu , Yang Daizhi , Ding Yu , Xu Wen , Yan Jinhua , Zheng Xueying , Weng Jianping , Luo Sihui 
Published: December 2022

BackgroundThe profile of gut microbiota, serum metabolites, and lipids of type 1 diabetes (T1D) patients with different human leukocyte antigen (HLA) genotypes remains unknown. We aimed to explore gut microbiota, serum metabolites, and lipids signatures in individuals with T1D typed by HLA genotypes.MethodsWe did a cross-sectional study that included 73 T1D adult patients. Patients were categorized into two groups according to the HLA haplotypes they carried: those with any two of three susceptibility haplotypes (DR3, DR4, DR9) and without any of the protective haplotypes (DR8, DR11, DR12, DR15, DR16) were defined as high-risk HLA genotypes group (HR, n=30); those with just one or without susceptibility haplotypes as the non-high-risk HLA genotypes group (NHR, n=43). We characterized the gut microbiome profile with 16S rRNA gene amplicon sequencing and analyzed serum metabolites with liquid chromatography-mass spectrometry.ResultsStudy individuals were 32.5 (8.18) years old, and 60.3% were female. Compared to NHR, the gut microbiota of HR patients were characterized by elevated abundances of Prevotella copri and lowered abundances of Parabacteroides distasonis. Differential serum metabolites (hypoxanthine, inosine, and guanine) which increased in HR were involved in purine metabolism. Different lipids, phosphatidylcholines and phosphatidylethanolamines, decreased in HR group. Notably, Parabacteroides distasonis was negatively associated (p ≤ 0.01) with hypoxanthine involved in purine metabolic pathways.ConclusionsThe present findings enabled a better understanding of the changes in gut microbiome and serum metabolome in T1D patients with HLA risk genotypes. Alterations of the gut microbiota and serum metabolites may provide some information for distinguishing T1D patients with different HLA risk genotypes.
MYCBP2 expression correlated with inflammatory cell infiltration and prognosis immunotherapy in thyroid cancer patients
Authors: Wang Guilin , Miao Chen , Mo Lijun , Kahlert Ulf D. , Wu Jinfeng , Ou Minglin , Huang Renxiang , Feng Ruifa , Pang Weiyi , Shi Wenjie 
Published: December 2022

IntroductionImmune checkpoint inhibitors (ICIs) have shown promising results for the treatment of multiple cancers. ICIs and related therapies may also be useful for the treatment of thyroid cancer (TC). In TC, Myc binding protein 2 (MYCBP2) is correlated with inflammatory cell infiltration and cancer prognosis. However, the relationship between MYCBP2 expression and ICI efficacy in TC patients is unclear.MethodsWe downloaded data from two TC cohorts, including transcriptomic data and clinical prognosis data. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict the efficacy of ICIs in TC patients. MCPcounter, xCell, and quanTIseq were used to calculate immune cell infiltration scores. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to evaluate signaling pathway scores. Immunohistochemical (IHC) analysis and clinical follow up was used to identify the MYCBP2 protein expression status in patients and associated with clinical outcome.ResultsA higher proportion of MYCBP2-high TC patients were predicted ICI responders than MYCBP2-low patients. MYCBP2-high patients also had significantly increased infiltration of CD8+ T cells, cytotoxic lymphocytes (CTLs), B cells, natural killer (NK) cells and dendritic cells (DC)s. Compared with MYCBP2-low patients, MYCBP2-high patients had higher expression of genes associated with B cells, CD8+ T cells, macrophages, plasmacytoid dendritic cells (pDCs), antigen processing and presentation, inflammatory stimulation, and interferon (IFN) responses. GSEA and ssGSEA also showed that MYCBP2-high patients had significantly increased activity of inflammatory factors and signaling pathways associated with immune responses.In addiation, Patients in our local cohort with high MYCBP2 expression always had a better prognosis and greater sensitivity to therapy while compared to patients with low MYCBP2 expression after six months clinic follow up.ConclusionsIn this study, we found that MYCBP2 may be a predictive biomarker for ICI efficacy in TC patients. High MYCBP2 expression was associated with significantly enriched immune cell infiltration. MYCBP2 may also be involved in the regulation of signaling pathways associated with anti-tumor immune responses or the production of inflammatory factors.
Novel potential biomarkers for severe alcoholic liver disease
Authors: Huang Jia , Yu Jiachi , Wang Jianan , Liu Jiayu , Xie Wei , Li Ruibing , Wang Chengbin 
Published: December 2022

BackgroundAlcoholic liver disease (ALD) is a leading cause of advanced liver disease; however, minor clinical symptoms in the early stage frequently result in delayed diagnosis and therapy. Invasive liver biopsy, the gold standard for diagnosing ALD, is unsuitable for repetitive analysis. This study aims to identify potential serum biomarkers that could contribute to non-invasive disease screening and monitoring.MethodsLabel-free LC-MS/MS quantitative proteomics analysis was performed to identify differentially expressed proteins in the discovery cohort, followed by bioinformatics analysis based on the KEGG, GO, and String databases. Prioritized proteins were validated subsequently by quantitative assays. The area under the receiver operating characteristic curve (AUROC) was used to assess the diagnosis performance of potential biomarkers.ResultsA total of 161 differentially expressed proteins were identified in the discovery cohort, of which 123 were up-regulated and 38 were down-regulated. B2M, IGFALS, and IGFBP3 were evaluated, and all demonstrated excellent diagnosis performance with AUROCs of over 0.9 when distinguishing patients with severe ALD from healthy controls. The AUROC values of B2M, IGFBP3, and IGFALS were 0.7131, 0.8877, and 0.9896 for differentiating severe ALD from non-severe ALD to indicate disease severity. B2M could distinguish patients with non-severe ALD and HC participants with an AUROC value of 0.8985. The efficiency of multiple combinations of these biomarkers was superior to that of the existing liver fibrosis evaluation indices used to monitor disease progression, with AUROC values of over 0.9. IGFALS showed a positive correlation with ALT/AST (r=0.4648, P=0.0009) and may be developed as a therapeutic target.ConclusionThis proteomic study identified three novel candidate proteins as promising circulating biomarkers for clinical diagnosis and disease progression and also provided the proteomic atlas for ALD pathophysiological mechanisms.
Engineered M2a macrophages for the treatment of osteoarthritis
Authors: Liang Chi , Wu Song , Xia Guang , Huang Junjie , Wen Zi , Zhang Wenxiu , Cao Xu 
Published: December 2022

BackgroundMacrophage is a central regulator of innate immunity. Its M2 subsets, such as interstitial synovial macrophages, have been found to play critical roles in suppressing chronic inflammation and maintaining homeostasis within the joint. These macrophages have great potential as a disease-modifying cell therapy for osteoarthritis (OA). However, this has not yet been studied.MethodsMacrophages were isolated from the bone marrow of rats. We constructed a stable macrophage that “locked” in anti-inflammatory and pro-regenerative M2a polarity (L-M2a) by simultaneously knocking out tumor necrosis factor receptor 1 (TNFR1) and overexpressing IL-4 using Cas9-ribonuclear proteins (Cas9-RNP) and electroporation. In vitro, these L-M2a macrophages were treated with OA synovial fluid or co-cultured with OA chondrocytes or fibroblast-like synoviocytes (FLS). In vivo, L-M2a macrophages were injected intra-articularly to evaluate their homing and engrafting abilities and therapeutic effects on OA progression using a rat model.ResultsL-M2a macrophages displayed a typical anti-inflammatory phenotype similar to that of M2 macrophages in vitro. In OA microenvironment, L-M2a macrophages maintained a stable anti-inflammatory phenotype, whereas unmodified M2 macrophages lost their phenotype and switched to M1 polarity. L-M2a macrophages demonstrated a potent anti-inflammatory effect in crosstalk with OA-FLSs and an anti-degenerative effect in crosstalk with senescent OA chondrocytes. In vivo, compared with M2 macrophages and exosomes, L-M2a macrophages exhibited significantly superior therapeutic effects in OA by successfully resolving inflammation, restoring tissue homeostasis, and promoting cartilage regeneration.ConclusionThe engineered L-M2a macrophages maintained a superior anti-inflammatory and pro-regenerative capacity in the inflammatory OA microenvironment and represents an ideal new strategy for the disease-modifying therapy of OA.
A first-in-human phase 1 study of cavrotolimod, a TLR9 agonist spherical nucleic acid, in healthy participants: Evidence of immune activation
Authors: Daniel Weston L. , Lorch Ulrike , Mix Scott , Bexon Alice S. 
Published: December 2022

IntroductionTumor immunotherapy is designed to control malignancies through the host immune response but requires circumventing tumor-dysregulated immunomodulation through immunostimulation, relieving immunorepression, or a combination of both approaches. Here we designed and characterized cavrotolimod (formerly AST-008), an immunostimulatory spherical nucleic acid (SNA) compound targeting Toll-like receptor 9 (TLR9). We assessed the safety and pharmacodynamic (PD) properties of cavrotolimod in healthy participants in a first-in-human Phase 1 study under protocol AST-008-101 (NCT03086278; https://clinicaltrials.gov/ct2/show/NCT03086278).MethodsHealthy participants aged 18 to 40 years were enrolled to evaluate four dose levels of cavrotolimod across four cohorts. Each cohort included four participants, and all received a single subcutaneous dose of cavrotolimod. The dose levels were 5, 10, 12.5 and 18.8 µg/kg.Results and discussionCavrotolimod was well tolerated and elicited no serious adverse events or dose limiting toxicities at the doses tested. The results demonstrated that cavrotolimod is a potent innate immune activator, specifically stimulating Th1-type immune responses, and exhibits PD properties that may result in anti-tumor effects in patients with cancer. This study suggests that cavrotolimod is a promising clinical immunotherapy agent.
Immune-related gene-based prognostic index for predicting survival and immunotherapy outcomes in colorectal carcinoma
Authors: Liang Zhongqing , Sun Ruolan , Tu Pengcheng , Liang Yan , Liang Li , Liu Fuyan , Bian Yong , Yin Gang , Zhao Fan , Jiang Mingchen , Gu Junfei , Tang Decai 
Published: December 2022

IntroductionColorectal cancer shows high incidence and mortality rates. Immune checkpoint blockade can be used to treat colorectal carcinoma (CRC); however, it shows limited effectiveness in most patients.MethodsTo identify patients who may benefit from immunotherapy using immune checkpoint inhibitors, we constructed an immune-related gene prognostic index (IRGPI) for predicting the efficacy of immunotherapy in patients with CRC. Transcriptome datasets and clinical information of patients with CRC were used to identify differential immune-related genes between tumor and para-carcinoma tissue. Using weighted correlation network analysis and Cox regression analysis, the IRGPI was constructed, and Kaplan–Meier analysis was used to evaluate its predictive ability. We also analyzed the molecular and immune characteristics between IRGPI high-and low-risk subgroups, performed sensitivity analysis of ICI treatment, and constructed overall survival-related receiver operating characteristic curves to validate the IRGPI. Finally, IRGPI genes and tumor immune cell infiltration in CRC model mice with orthotopic metastases were analyzed to verify the results.ResultsThe IRGPI was constructed based on the following 11 hub genes: ADIPOQ, CD36, CCL24, INHBE, UCN, IL1RL2, TRIM58, RBCK1, MC1R, PPARGC1A, and LGALS2. Patients with CRC in the high-risk subgroup showed longer overall survival than those in the low-risk subgroup, which was confirmed by GEO database. Clinicopathological features associated with cancer progression significantly differed between the high- and low-risk subgroups. Furthermore, Kaplan–Meier analysis of immune infiltration showed that the increased infiltration of naïve B cells, macrophages M1, and regulatory T cells and reduced infiltration of resting dendritic cells and mast cells led to a worse overall survival in patients with CRC. The ORC curves revealed that IRGPI predicted patient survival more sensitive than the published tumor immune dysfunction and rejection and tumor inflammatory signatureDiscussionThus, the low-risk subgroup is more likely to benefit from ICIs than the high-risk subgroup. CRC model mice showed higher proportions of Tregs, M1 macrophages, M2 macrophages and lower proportions of B cells, memory B cell immune cell infiltration, which is consistent with the IRGPI results. The IRGPI can predict the prognosis of patients with CRC, reflect the CRC immune microenvironment, and distinguish patients who are likely to benefit from ICI therapy.
Fortnightly variability of horizontal salinity gradient affects exchange flow in the Sumjin River estuary
Authors: Cho Eun-Byeol , Tak Yong-Jin , Cho Yang-Ki , Na Hanna 
Published: December 2022

The horizontal salinity gradient has been reported to play a crucial role in fortnightly variability of estuarine exchange flow in short estuaries. However, spatiotemporal variations in the salinity gradient and exchange flow have not been examined over an entire short estuary, as only data observed only at specific points was available. We analyzed the variation in salinity gradient along the entire Sumjin River estuary and its effect on the exchange flow over fortnightly tidal cycles based on observations and numerical model experiments. The salinity gradient and exchange flow were in different phases between the lower and upper estuaries by 6–7 days. The maximum salinity gradient periodically reciprocated along the channel as a result of salt flux changes determined by vertical mixing. The stronger exchange flow (&gt; 0.04 m s-1) changed location from mouth to head of estuary while the tidal range decreased, resulting from variability of the salinity gradient. The horizontal salinity gradient is large enough to overwhelm the vertical mixing effect on the exchange flow. The spatiotemporal changes of strong exchange flow correspond well with the horizontal Richardson number value (&gt; 3). This study suggests that for the health of estuarine ecosystems, it is important to determine the spatiotemporal variation in exchange flow throughout the estuary.