bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tongue Cancer Cell-Derived CCL20 Induced by Interaction With Macrophages Promotes CD163 Expression on Macrophages
Authors: Shigeoka Manabu , Koma Yu-ichiro , Kodama Takayuki , Nishio Mari , Akashi Masaya , Yokozaki Hiroshi 
Published: June 2021

BackgroundCD163-positive macrophages contribute to the aggressiveness of oral squamous cell carcinoma. We showed in a previous report that CD163-positive macrophages infiltrated not only to the cancer nest but also to its surrounding epithelium, depending on the presence of stromal invasion in tongue carcinogenesis. However, the role of intraepithelial macrophages in tongue carcinogenesis remains unclear. In this study, we assessed the biological behavior of intraepithelial macrophages on their interaction with cancer cells.Materials and MethodsWe established the indirect coculture system (intraepithelial neoplasia model) and direct coculture system (invasive cancer model) of human monocytic leukemia cell line THP-1-derived CD163-positive macrophages with SCC25, a tongue squamous cell carcinoma (TSCC) cell line. Conditioned media (CM) harvested from these systems were analyzed using cytokine array and enzyme-linked immunosorbent assay and extracted a specific upregulated cytokine in CM from the direct coculture system (direct CM). The correlation of both this cytokine and its receptor with various clinicopathological factors were evaluated based on immunohistochemistry using clinical samples from 59 patients with TSCC. Moreover, the effect of this cytokine in direct CM on the phenotypic alterations of THP-1 was confirmed by real-time polymerase chain reaction, western blotting, immunofluorescence, and transwell migration assay.ResultsIt was shown that CCL20 was induced in the direct CM specifically. Interestingly, CCL20 was produced primarily in SCC25. The expression level of CCR6, which is a sole receptor of CCL20, was higher than the expression level of SCC25. Our immunohistochemical investigation showed that CCL20 and CCR6 expression was associated with lymphatic vessel invasion and the number of CD163-positive macrophages. Recombinant human CCL20 induced the CD163 expression and promoted migration of THP-1. We also confirmed that a neutralizing anti-CCL20 antibody blocked the induction of CD163 expression by direct CM in THP-1. Moreover, ERK1/2 phosphorylation was associated with the CCL20-driven induction of CD163 expression in THP-1.ConclusionsTongue cancer cell-derived CCL20 that was induced by interaction with macrophages promotes CD163 expression on macrophages.
Low Concordance Between T-Cell Densities in Matched Primary Tumors and Liver Metastases in Microsatellite Stable Colorectal Cancer
Authors: Dagenborg Vegar Johansen , Marshall Serena Elizabeth , Grzyb Krzysztof , Fretland Åsmund Avdem , Lund-Iversen Marius , Mælandsmo Gunhild Mari , Ree Anne Hansen , Edwin Bjørn , Yaqub Sheraz , Flatmark Kjersti 
Published: June 2021

BackgroundThe subtype, density and location of tumor infiltrating T-cells are being explored as prognostic and predictive biomarkers in primary colorectal cancer (pCRC) and colorectal liver metastases (CLM). Very limited data exist comparing findings in pCRC and matched CLM.Patients and methodsFifty-eight patients with available pCRC and matched CLM (57/58 microsatellite stable) were included in this OSLO-COMET substudy. In immunohistochemically stained sections, total (Ttot), helper (TH), cytotoxic (CTL), and regulatory (Treg) T-cells were manually counted in hotspots from the invasive margin (IM), intratumor (IT), and tumor adjacent regions to determine T-cell densities.ResultsA striking accumulation of T-cells was found in IM of both pCRC and CLM with much lower densities in the IT region, exemplified by Ttot of 2838 versus 340 cells/mm2, respectively, in CLM. The correlation at the individual level between T-cell densities in pCRC and corresponding CLM was poor for all regions and T-cell subtypes; for instance, the correlation coefficient (R2) for IM Ttot was 0.07. The IT TH : CTL and Treg : TH ratios were 2.94 and 0.44, respectively, in pCRC, and 1.84 and 0.24, respectively, in CLM.ConclusionThe observed accumulation of T-cells in the IM regions of pCRC and CLM with low penetration to the IT regions, combined with high TH : CTL and Treg : TH ratios, point to the presence of an immune suppressive microenvironment. T-cell densities of CLM differed markedly from the matched pCRC, indicating that to evaluate T-cell biomarkers in metastasis, the commonly available pCRC cannot serve as a surrogate for the metastatic tumor.
Serum Soluble CD40 Ligand in Predicting Simple Appendicitis and Complicated Appendicitis at Different Time Points in Children
Authors: Huang Wun-Yan , Chen Chun-Yu , Chang Yu-Jun , Lee En-Pei , Wu Han-Ping 
Published: June 2021

Objectives: Appendicitis is a common abdominal emergency in children. It is difficult for clinicians to distinguish between simple appendicitis (SA), gangrenous appendicitis (GA), and ruptured appendicitis (RA) in children based on physical and current laboratory tests. Abdominal computed tomography with the disadvantage of excess radiation exposure is usually used in the emergency room for appendicitis surveys. Serum soluble CD40 ligand (sCD40L) is an inflammatory biomarker. This study aimed to use sCD40L to distinguish SA, GA, and RA.Methods: All patients aged &lt;18 years old with suspected appendicitis were tested once for serum sCD40L within 72 h of appendicitis symptoms. We compared sCD40L levels of SA, GA, and RA individually on days 1, 2, and 3 in patients with normal appendix (NA), a total of nine subgroups. Thereafter, the diagnostic performance of sCD40L in predicting appendicitis and the receiver operating characteristic curves were carried out.Results: Of 116 patients, 42 patients had SA, 20 GA, 44 RA, and 10 NA. We found six subgroups with significant p-values of sCD40L predicting appendicitis as follows: SA on day 2, GA on days 2 and 3, and RA on days 1–3. The sensitivity and specificity of sCD40L at the best cutoff point with 178 pg/mL in these six subgroups range from 0.75 to 1.00 and 0.90, respectively.Conclusions: SCD40L is a good predictor of pediatric appendicitis. Clinicians can use sCD40L to distinguish from SA, GA, and RA in children with suspected appendicitis.
Multi-Platform Metabolomics Analyses Revealed the Complexity of Serum Metabolites in LPS-Induced Neuroinflammed Rats Treated with Clinacanthus nutans Aqueous Extract
Authors: Ahmad Azam Amalina , Ismail Intan Safinar , Shaikh Mohd Farooq , Abas Faridah , Shaari Khozirah 
Published: June 2021

The use of metabolomics as a comprehensive tool in the analysis of metabolic profiles in disease progression and therapeutic intervention is rapidly advancing. Yet, a single analytical platform could not be applied to cover the entire spectrum of a biological sample’s metabolome. In the present paper, multi-platform metabolomics approaches were explored to determine the diverse rat sera metabolites extracted from intracerebroventricular lipopolysaccharides (LPS)-induced neuroinflammed rats treated with oral therapeutic interventions of positive drug (dextromethorphan, 5 mg/kg BW); with Clinacanthus nutans (CN) aqueous extract (CNE, 500 mg/kg BW); and with phosphate buffer saline (PBS) as the control group for 14 days. Analyzed by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) techniques, this study depicted the potential of metabolites associated with neuroinflammation and verified by MetDisease. The key observations in the perturbed metabolic pathways that showed ameliorative effects were linked to the class of amino acid and peptide metabolism involving valine, leucine, and isoleucine biosynthesis; phenylalanine, tyrosine, and tryptophan biosynthesis; and phenylalanine metabolism. Lipid metabolism of arachidonic acid metabolism, glycerophospholipid metabolism, terpenoid backbone biosynthesis, and glycosphingolipid metabolism were also affected. Current findings suggested that the putative biomarkers, especially lysophosphatidic acid (LPA) and 5-diphosphomevalonic acid from glycerophospholipid and squalene/terpenoid and cholesterol biosynthesis, respectively, showed the ameliorative effects of the drug and CN treatments by controlling cell differentiation and proliferation. Our study proved that the complex and dynamic sera profiling affected during the CN treatment was greatly influenced by the analytical platform selection as integration between the two data yielded a more holistic summary of the metabolite pattern changes. Hence, an evidence-based herb, such as CN, can be used for novel diagnostic tools in the quest for ethnopharmacological studies.
Exosomes in Intestinal Inflammation
Authors: Ayyar Kanchana K. , Moss Alan C. 
Published: June 2021

Exosomes are 30–150 nm sized vesicles released by a variety of cells, and are found in most physiological compartments (feces, blood, urine, saliva, breast milk). They can contain different cargo, including nucleic acids, proteins and lipids. In Inflammatory Bowel Disease (IBD), a distinct exosome profile can be detected in blood and fecal samples. In addition, circulating exosomes can carry targets on their surface for monoclonal antibodies used as IBD therapy. This review aims to understand the exosome profile in humans and other mammals, the cargo contained in them, the effect of exosomes on the gut, and the application of exosomes in IBD therapy.
Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1
Authors: Han Shiqian , Zhang Huiwen , Yi Mengni , Liu Xiaoqing , Maegawa Gustavo H. B. , Zou Yunding , Wang Qijun , Wu Dianqing , Ye Zhijia 
Published: June 2021

Background: Niemann-Pick disease type C1 (NP-C1) is a rare, autosomal-recessive neurodegenerative disorder with no United States Food and Drug Administration (FDA)-approved drug. Lithium has been shown to have considerable neuroprotective effects for neurological disorders such as bipolar disorder, Alzheimer’s disease and stroke and has been tested in many clinical trials. However, the pharmacological effect of lithium on NP-C1 neurodegenerative processes has not been investigated. The aim of this study was to provide an initial evaluation of the safety and feasibility of lithium carbonate in patients with NP-C1.Methods: A total of 13 patients diagnosed with NP-C1 who met the inclusion criteria received lithium orally at doses of 300, 600, 900, or 1,200 mg daily. The dose was reduced based on tolerance or safety observations. Plasma 7-ketocholesterol (7-KC), an emerging biomarker of NP-C1, was the primary endpoint. Secondary endpoints included NPC Neurological Severity Scores (NNSS) and safety.Results: Of the 13 patients with NP-C1 (12–33 years) enrolled, three withdrew (discontinuation of follow-up outpatient visits). The last observed post-treatment values of 7-KC concentrations (128 ng/ml, SEM 20) were significantly lower than pretreatment baselines values (185 ng/ml, SEM 29; p = 0.001). The mean NNSS was improved after lithium treatment at 12 months (p = 0.005). Improvement in swallowing capacity was observed in treated patients (p = 0.014). No serious adverse events were recorded in the patients receiving lithium.Conclusion: Lithium is a potential therapeutic option for NP-C1 patients. Larger randomized and double-blind clinical trials are needed to further support this finding.Clinical Trial Registration:ClinicalTrials.gov, NCT03201627.
Physician–Pharmacist Collaborative Clinic Model to Improve Anticoagulation Quality in Atrial Fibrillation Patients Receiving Warfarin: An Analysis of Time in Therapeutic Range and a Nomogram Development
Authors: Wang Na , Qiu Sha , Yang Ya , Zhang Chi , Gu Zhi-Chun , Qian Yan 
Published: June 2021

Background: Poor time in therapeutic range (TTR) control is associated with an increased risk of stroke and bleeding in atrial fibrillation (AF) patients receiving warfarin. This study aimed to determine whether the physician–pharmacist collaborative clinic (PPCC) model could improve the anticoagulation quality as well as to create a nomogram for predicting anticoagulation quality in AF patients.Methods: This retrospective observational study enrolled AF patients who either initially received warfarin or returned to warfarin after withdrawal between January 1, 2016 and January 1, 2021, at our institution. The primary outcome was dynamic changes in TTRs (a TTR of ≥60% considered high anticoagulation quality). The secondary outcomes were thromboembolic and bleeding events during follow-up. We compared the dynamic changes in TTRs between the general clinic (GC) and PPCC groups in both the original and propensity score matching (PSM) cohorts. In addition, we explored the potential predictors of high anticoagulation quality and subsequently formulated a nomogram to predict anticoagulation quality.Results: A total of 265 patients with AF were included, comprising 57 patients in the PPCC group and 208 patients in the GC group. During a median follow-up period of 203 days, the PPCC group had a shorter time (76 vs. 199 days, p &lt; 0.001) and more patients achieved a TTR ≥60% (73.7 vs. 47.1%, p = 0.002 by log-rank test) than the GC group. The results from the PSM cohort confirmed this finding. No significant differences in the incidences of thromboembolic events (5.3 vs. 5.3%, p = 1.000) and bleeding events (4.3 vs. 3.5%, p = 1.000) were observed between the two groups. Four variables were explored as predictors related to high anticoagulation quality: treatment within a PPCC, history of bleeding, history of bleeding, and the presence of more than four comorbidities. The nomogram revealed a moderate predictive ability (c-index: 0.718, 95% confidence interval (95%CI): 0.669–0.767) and a moderately fitted calibration curve.Conclusion: The PPCC model contributed to improved anticoagulation quality in AF patients receiving warfarin. The nomogram might be an effective tool to predict anticoagulation quality and could aid physicians and pharmacists in the selection of patients who will likely benefit from sustained and active intervention.
Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices
Authors: Martinec Ondrej , Biel Carin , de Graaf Inge A. M. , Huliciak Martin , de Jong Koert P. , Staud Frantisek , Cecka Filip , Olinga Peter , Vokral Ivan , Cerveny Lukas 
Published: June 2021

P-glycoprotein (ABCB1), an ATP-binding cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug–drug interactions. Drug-mediated induction of intestinal ABCB1 is a clinically relevant phenomenon associated with significantly decreased drug bioavailability. Currently, there are no well-established human models for evaluating its induction, so drug regulatory authorities provide no recommendations forin vitro/ex vivotesting drugs’ ABCB1-inducing activity. Human precision-cut intestinal slices (hPCISs) contain cells in their natural environment and express physiological levels of nuclear factors required for ABCB1 induction. We found that hPCISs incubated in William’s Medium E for 48 h maintained intact morphology, ATP content, and ABCB1 efflux activity. Here, we asked whether rifampicin (a model ligand of pregnane X receptor, PXR), at 30 μM, induces functional expression ofABCB1in hPCISs over 24- and 48-h incubation (the time to allow complete induction to occur). Rifampicin significantly increased gene expression, protein levels, and efflux activity of ABCB1. Moreover, we described dynamic changes in ABCB1 transcript levels in hPCISs over 48 h incubation. We also observed that peaks of induction are achieved among donors at different times, and the extent ofABCB1gene induction is proportional to PXR mRNA levels in the intestine. In conclusion, we showed that hPCISs incubated in conditions comparable to those used for inhibition studies can be used to evaluate drugs’ ABCB1-inducing potency in the human intestine. Thus, hPCISs may be valuable experimental tools that can be prospectively used in complex experimental evaluation of drug–drug interactions.
Exploring the Appropriate Price of Semaglutide for Type 2 Diabetes Patients Based on Cost-Utility Analysis in China
Authors: Hu Shanshan , Su Xiaorong , Deng Xun , Wang Yong 
Published: June 2021

Introduction: Semaglutide is the first and only oral version of a glucagon-like peptide-1 analogue approved by the FDA for the treatment of type 2 diabetes (T2D). This research was designed to explore the appropriate price of once-weekly (OW) semaglutide for T2D patients in China based on cost-utility analysis.Methods: The baseline patient cohorts of OW semaglutide and once-daily (OD) empagliflozin were sourced from a patient-level meta-analysis integrating the SUSTAIN 2, SUSTAIN 3, SUSTAIN 8 and PIONEER 2 trials. The long-term health and economic outcomes were simulated using the United Kingdom Prospective Diabetes Study Outcome Model 2 from the Chinese healthcare provider’s perspective. The appropriate price of semaglutide was explored by binary search. One-way sensitivity analysis (one-way SA), probabilistic sensitivity analysis and scenario analysis were applied to solve the uncertainty.Results: Under the assumption that the annual cost of semaglutide is equal to that of OD empagliflozin, OW semaglutide was superior to OD empagliflozin due to its higher quality adjusted life years and lower total costs. After binary search, the incremental cost-utility ratio of OW semaglutide vs. OD empagliflozin was approximately equal to 3λ with an annual cost of semaglutide of $1,007.18 and approximately equal to λ with an annual cost of semaglutide of $708.11. Subsequently, the incremental cost-utility ratio of OW semaglutide vs. OD empagliflozin was approximately 3λ and λ, with annual costs of semaglutide of $877.43 and $667.04, respectively, adjusted by one-way SA. Ultimately, the cost-utility results with annual costs of semaglutide of $877.43 and $667.04 were robust to probabilistic sensitivity analysis and scenario analysis.Conclusion: In conclusion, the annual cost of semaglutide appears to be appropriate between $667.04 and $877.43 for T2D patients in China.
Can Physical Activity and Healthy Diet Help Long-Term Cancer Survivors Manage Their Fear of Recurrence?
Authors: Séguin Leclair Caroline , Lebel Sophie , Westmaas J. Lee 
Published: June 2021

Objective: Fear of cancer recurrence (FCR) adversely affects quality of life, but health behaviors such as physical activity (PA) and fruit and vegetable intake (FVI) may help alleviate FCR for some survivors. This cross-sectional study tested the common-sense model (CSM) of FCR by investigating associations between constructs from the CSM (perceived illness consequences, control over health, and timeline), and survivors’ health behaviors, health self-efficacy, and FCR.Methods: Using wave 3 data from the American Cancer Society Longitudinal Study of Cancer Survivorship-I, path analyses were conducted among mixed-cancer participants (N = 2,337) who were on average 8.8 mean years post-diagnosis.Results: A final good fitting model [χ2 (5, N = 2,337) = 38.12, p &lt; 0.001; SRMR = 0.02; CFI = 0.99; RMSEA = 0.05] indicated that perceiving fewer illness consequences, and greater control over one’s health, were directly associated with higher PA (β = 0.15 and −0.24, p &lt; 0.01, respectively) and higher health self-efficacy (β = 0.24, −0.38, p &lt; 0.01, respectively). Timeline (i.e., perceiving cancer as chronic) was directly associated with lower health self-efficacy (β = −0.15, p &lt; 0.01) and higher FCR (β = 0.51, p &lt; 0.01). Both greater PA and FVI were directly associated with higher health self-efficacy (β = 0.10 and 0.11, p &lt; 0.01, respectively) which in turn showed a direct association with lower FCR (β = −0.15, p &lt; 0.01).Conclusion: Increasing survivors’ sense of control over health, decreasing perceived chronicity of the illness, and mitigating its consequences may increase their health behaviors and health self-efficacy, which in turn could decrease their FCR. Longitudinal and experimental studies are needed to confirm these findings.
Development of a Clinic Screening Tool to Identify Burdensome Health-Related Issues Affecting People Living With HIV in Spain
Authors: Fuster-RuizdeApodaca Maria José , Safreed-Harmon Kelly , Pastor de la Cal Marta , Laguia Ana , Naniche Denise , Lazarus Jeffrey V. 
Published: June 2021

BackgroundNumerous health-related issues continue to undermine the health and health-related quality of life (HRQoL) of people living with HIV (PLHIV). We developed a clinic screening tool (CST-HIV) for the purpose of identifying these issues in routine specialist clinical care in Spain.MethodsWe used the following established instrument development procedures: (1) a literature review; (2) four focus group discussions (FGDs), two that convened 16 expert HIV care providers, and two that convened 15 PLHIV; (3) prioritisation, selection and definition of constructs (health-related issues) to include in the CST-HIV and drafting of initial item pool; and (4) a pilot study to analyse psychometric properties and validity of items and to determine which to retain in the final CST-HIV. The FGD interview scripts incorporated an exercise to prioritise the health-related issues perceived to have the greatest negative effect on HRQoL. The online questionnaire used for the pilot study included the pool of CST-HIV items and validated measures of each construct.ResultsWe identified 68 articles that reported on factors associated with the HRQoL of PLHIV. The most burdensome health-related issues identified in the FGDs related to stigma, socioeconomic vulnerability, sleep/fatigue, pain, body changes, emotional distress, and sexuality. Based on the literature review and FGD findings, we selected and defined the following constructs to include in the initial CST-HIV: anticipated stigma, emotional distress, sexuality, social support, material deprivation, sleep/fatigue, cognitive problems, and physical symptoms. Two researchers wrote six to eight items for each construct. Next, 18 experts rated 47 items based on their clarity, relevance, and representativeness. Pilot testing was carried out with 226 PLHIV in Spain. We retained 24 items based on empirical criteria that showed adequate psychometric properties. Confirmatory factor analysis confirmed the eight-factor structure with a good fit to the data (RMSEA = 0.035, AGFI = 0.97, CFI = 0.99). We found strong positive correlations between the instrument’s eight dimensions and validated measures of the same constructs. Likewise, we found negative associations between the dimensions of the CST-HIV and HRQoL.ConclusionThe CST-HIV is a promising tool for use in routine clinical care to efficiently identify and address health-related issues undermining the HRQoL of PLHIV.