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Jing Guan,1 Yue Wang,1 Changjun Dong,1 Yuwen Chen,1 Bingqing Li,1 Yilu Zhou,1 Fanke Huang,1 Peiyuan Sun,1,2 Xue Tian,1,2 Feng Ran,1,2 Jianfeng Lv2 1ChinaThree Gorges University, Yichang, People’s Republic of China; 2Department of Cardiology, Affiliated Renhe Hospital of China Three Gorges University, Yichang, People’s Republic of ChinaCorrespondence: Jianfeng Lv, Department of Cardiology, Affiliated Renhe Hospital of China Three Gorges University, No. 410 Yiling Avenue, Yichang, Hubei Province, People’s Republic of China, Tel +86-18745290427, Fax +86 0717-6558362, Email ljfzxm@163.comBackground: Depression is common among patients with coronary atherosclerotic heart disease and is a prevalent mental health issue, particularly among those with cardiovascular diseases. Depression is commonly associated with elevated blood glucose and lipid levels. The triglyceride-glucose index is a novel indicator reflecting insulin resistance, which has been proven in numerous studies to be associated with cardiovascular diseases.Purpose: Study on the impact of the triglyceride-glucose index (TyG index) on the development of depression in patients with coronary atherosclerotic heart disease (CHD).Patients and methods: Using the Patient Health Questionnaire-9 (PHQ-9), 197 CHD patients were classified into a non-depressed group (n = 44, PHQ-9 < 5) and a depressed group (n = 153, PHQ-9 ≥ 5). Fasting blood glucose (GLU), HDL, total cholesterol (TC), LDL, triglycerides (TG), and TyG index were compared between groups. Depression risk factors were identified via logistic regression, and the predictive value of TyG index was evaluated using ROC analysis.Results: In depressed patients, TyG index, TG, TC, LDL, and GLU were significantly higher, while HDL was lower than in the non-depressed group (p < 0.05). Logistic regression identified TyG index, LDL, GLU, TG, TC, HDL, female sex, smoking, alcohol consumption, and older age as independent risk factors for depression in CHD patients (p < 0.05). ROC analysis showed the TyG index had an AUC of 0.76 (95% CI 0.687– 0.829, p < 0.001) for predicting depression, with a cutoff of 1.613, sensitivity of 45.1%, and specificity of 97.7%. Endpoint events were more frequent in the depression group (χ² = 8.015, p = 0.005).Conclusion: The TyG index is an independent risk factor for depression in patients with CHD, indicating a significant predictive value. Depressed patients have a higher rate of readmission, and managing depression effectively contributes to better prognosis.Keywords: depression, coronary atherosclerotic cardiopathy, triglyceride-glucose index

Xueyun Fu,&ast; Xue Tian,&ast; Jing Lin, Qian Wang, Lingwen Gu, Ziyi Wang, Menghui Chi, Bing Yu, Zhuhui Feng, Wenyao Liu, Lina Zhang, Cui Li, Guiqiu Zhao Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cui Li; Guiqiu Zhao, Department of Ophthalmology, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong, 266003, People’s Republic of China, Email yankelicui@126.com; zhaoguiqiu_good@126.comBackground: Fungal keratitis is a serious blinding eye disease. Traditional drugs used to treat fungal keratitis commonly have the disadvantages of low bioavailability, poor dispersion, and limited permeability.Purpose: To develop a new method for the treatment of fungal keratitis with improved bioavailability, dispersion, and permeability.Methods: Zeolitic Imidazolate Framework-8 (ZIF-8) was formed by zinc ions and 2-methylimidazole linked by coordination bonds and characterized by Scanning electron microscopy (SEM), X-ray diffraction (XRD), and Zeta potential. The safety of ZIF-8 on HCECs and RAW 264.7 cells was detected by Cell Counting Kit-8 (CCK-8). Safety evaluation of ZIF-8 on mice corneal epithelium was conducted using the Draize corneal toxicity test. The effects of ZIF-8 on fungal growth, biofilm formation, and hyphae structure were detected by Minimal inhibit concentration (MIC), crystal violet staining, Propidium Iodide (PI) testing, and calcofluor white staining. The anti-inflammatory effects of ZIF-8 on RAW 246.7 cells were evaluated by Quantitative Real-Time PCR Experiments (qPCR) and Enzyme-linked immunosorbent assay (ELISA). Clinical score, Colony-Forming Units (CFU), Hematoxylin-eosin (HE) staining, and immunofluorescence were conducted to verify the therapeutic effect of ZIF-8 on C57BL/6 female mice with fungal keratitis.Results: In vitro, ZIF-8 showed outstanding antifungal effects, including inhibiting the growth of Aspergillus fumigatus over 90% at 64 μg/mL, restraining the formation of biofilm, and destroying cell membranes. In vivo, treatment with ZIF-8 reduced corneal fungal load and mitigated neutrophil infiltration in fungal keratitis, which effectively reduced the severity of keratitis in mice and alleviated the infiltration of inflammatory factors in the mouse cornea. In addition, ZIF-8 reduces the inflammatory response by downregulating the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β after Aspergillus fumigatus infection in vivo and in vitro.Conclusion: ZIF-8 has a significant anti-inflammatory and antifungal effect, which provides a new solution for the treatment of fungal keratitis.Keywords: fungal keratitis, MOFs, antifungal, anti-inflammatory, ZIF-8

Xiaotong Tian,1,2 Jing Lin,1,2 Menglan Zhou,3,4 Ying Ge,1 Taisheng Li,1 Li Zhang,1 Zhengyin Liu1 1Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 2Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 4Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, People’s Republic of ChinaCorrespondence: Zhengyin Liu; Li Zhang, Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China, Email liuzhy@pumch.cn; zhangli36@pumch.cnPurpose: To evaluate the clinical outcomes and safety of tigecycline (TGC) plus cefoperazone/sulbactam (CPS) or TGC monotherapy in patients with hospital-acquired pneumonia (HAP) caused by Carbapenem-Resistant Acinetobacter baumannii (CRAB).Methods: This was a retrospective analysis of multicenter data from 62 Chinese hospitals with CRAB HAP. Risk factors for receiving TGC with CPS therapy and predictors of mortality were assessed using multivariate logistic and Cox regression analyses, respectively. Propensity score matching (PSM) evaluated the efficacy and safety of antimicrobial regimens.Results: A total of the 180 patients were included, with 95 receiving TGC monotherapy and 85 receiving combination therapy. Multivariate logistic regression analysis revealed that older age (P = 0.011), and intensive care unit (ICU) admission (P = 0.007) were significant risk factors for combination therapy. Multivariate Cox regression demonstrated that combination therapy was associated with a significantly higher risk of 90-day mortality (P = 0.031). Patients in the standard-dose TGC (SDT) plus CPS subgroup had significantly higher rates of SOFA scores ≥ 7 (P = 0.009) and MV used (P = 0.028), as well as higher 30-/90-day mortality compared to high-dose TGC (HDT) plus CPS group. TGC plus CPS significantly reduced CRP levels (P = 0.009), while the variations in ALT, TBIL, Cr, Hb, and PLT levels did not differ between different antimicrobial regimens after PSM.Conclusion: HDT and CPS combination therapy was more effective in patients with advanced age and more severe condition. Safety profiles of different antimicrobial regimens were similar with liver, kidneys, and coagulation functions.Keywords: carbapenem-resistant Acinetobacter baumannii, hospital acquired pneumonia, tigecycline, cefoperazone/sulbactam, risk factors

Ruyu Han,1,&ast; Leijuan Gan,1,&ast; Liyu Sun,1 Mengran Lang,2 Xindi Tian,1 Kangwei Zhu,1 Lu Chen,1 Guangtao Li,1 Tianqiang Song1 1Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, People’s Republic of China; 2Hepatobiliary Surgery Department, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianqiang Song, Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, People’s Republic of China, Tel +86-22-23340123, Fax +86-22-23537796, Email songtianqiangtj@163.comPurpose: This study aimed to investigate the benefit of conversion therapy for patients with unresectable hepatocellular carcinoma (HCC).Patients and Methods: A retrospective cohort study was conducted involving 40 patients initially deemed unresectable HCC (uHCC). They received surgery following successful conversion therapy involving lenvatinib. The patients were matched in a 1:1 ratio to with a control group who underwent direct surgery, based on pre-treatment clinical data.Results: The median recurrence-free survival (RFS) duration for the conversion therapy cohort was notably longer than that of the direct surgery cohort (25 months vs 11 months). Furthermore, the 1- and 2-year RFS rates were significantly higher in the conversion therapy group compared to the direct surgery group (1 year: 70.5% vs 40.1%; 2 years: 49.0% vs 19.1%). The survival curves indicated a statistically significantly longer RFS in the conversion therapy cohort compared to the direct surgery cohort (P = 0.007). While patients achieving good remission based on both RECIST 1.1 and mRECIST criteria showed superior median RFS, no significant disparity was observed in the survival curves. The subgroup analysis revealed significantly improved prognosis among patients in the conversion therapy group who were male, older, had a history of alcohol consumption, were non-smokers, had liver cirrhosis, possessed Child-Pugh A liver function, had a tumor diameter exceeding 5 cm, and had an AFP ≥ 400 ng/mL. Among the cohort of 40 patients, only 8 individuals encountered severe adverse reactions, which were managed through dose reduction. None of the patients experienced multiple severe adverse reactions concurrently.Conclusion: For patients with unresectable hepatocellular carcinoma, conversion therapy offers a significantly better prognosis than direct surgery for uHCC patients.Keywords: hepatocellular carcinoma, conversion therapy, recurrence-free survival, hepatic resection

Xu Tian,1,&ast; Fangrong Liu,2,&ast; Feili Li,3 Yi Ren,4 Hongcai Shang5 1Chongqing Center for Evidence-Based Traditional Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400020, People’s Republic of China; 2Outpatient Department, Chongqing University Cancer Hospital, Chongqing, 400030, People’s Republic of China; 3Department of Nursing, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400020, People’s Republic of China; 4Department of Classic Traditional Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400020, People’s Republic of China; 5Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 101121, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Ren, Department of Classic Traditional Chinese Medicine, Chongqing Traditional Chinese Medicine Hospital, No. 6 of 7th Branch of Panxi Road, Jiangbei District, Chongqing, People’s Republic of China, Tel/Fax +86 023 67776180, Email cqszyyrenyi@163.com Hongcai Shang, Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 of Haiyuncang, Dongcheng District, Beijing, People’s Republic of China, Tel/Fax +86 010 84013276, Email yxtx880919@163.comPurpose: While the benefits of exercises for chronic obstructive pulmonary disease (COPD) are well-established, the relative effectiveness of different exercise types for stable COPD remains unclear. This network meta-analysis aims to investigate the comparative effects of aerobic exercise (AE), resistance training (RT), endurance training (ET), and high-intensity interval training (HIIT) in stable COPD.Methods: Electronic searches were performed in PubMed, Embase, and the Cochrane library to identify relevant randomized controlled trials (RCTs) investigating the effects of exercises on 6-minute walk test distance (6MWD), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC), and St. George’s Respiratory Questionnaire (SGRQ) score. Two authors screened the retrieved articles, extracted relevant data, and assessed the risk of bias. Network meta-analysis was conducted using Stata 14.0.Results: This study included a total of 19 studies involving 951 patients with stable COPD. HIIT emerged as the most favorable exercise type for enhancing 6MWD, with a probability of 82.9%. RT exhibited the greatest efficacy in reducing SGRQ scores, with probability of 49.8%. Notably, ET demonstrated superiority in improving FEV1 and FVC, with probabilities of being most effective at 78.1% and 42.0%, respectively.Conclusion: This study suggests that HIIT may be a viable intervention for improving exercise capacity in stable COPD patients, compared to AE, RR, and ET. RT may hold promise for improving quality of life, and ET may demonstrate superiority in improving pulmonary function. However, variation in response likely depends on patient characteristics, program parameters, and delivery context. Future research should explore the synergistic effects of combining RT with ET/HIIT, focusing on patient subgroups, optimal dosing, and settings, as current guidelines indicate this combination may offer the most significant benefits.Keywords: COPD, exercise, pulmonary function, quality of life, network meta-analysis

Bing Yu,1,&ast; Zhimei Xing,2,&ast; Xiaoxuan Tian,2 Rui Feng1 1Department of Breast Surgery, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, 300100, People’s Republic of China; 2State Key Laboratory of Component‑Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rui Feng, Department of Breast Surgery, Tianjin Central Hospital of Obstetrics and Gynecology, No. 156 of Nankai SAN Road, Nankai District, Tianjin, 300100, People’s Republic of China, Tel +86 022-58287167, Email dr.fr@126.comBackground: Triple-negative breast cancer (TNBC) is recognized as the most aggressive molecular subtype of breast cancer. Recent studies have highlighted the complex role of autophagy in the pathogenesis of TNBC.Methods: In this study, we evaluated 18,330 genes, including 1111 autophagy-related genes, (ARGs), across 579 TNBC samples from online databases. Differentially expressed ARGs in TNBC were identified using high-throughput RNA-seq data from the Cancer Genome Atlas (TCGA). Prognostic factors were examined through Cox regression and multivariate Cox analyses, with predictive efficacy assessed using receiver operating characteristic (ROC) curves. A nomogram integrating the risk signature with clinicopathological factors, such as TNM stage, was developed. Immunohistochemical analysis of clinical samples was also conducted.Results: EIF4EBP1 and NPAS3 were significantly correlated with prognostic outcomes in patients with TNBC. Multivariate Cox regression analysis demonstrated that the expression levels of these two genes were accurate predictors of disease progression in TNBC samples from TCGA and the GSE31519 dataset. The efficacy of this predictive model was validated using ROC curve analysis and calibration plots, confirming its ability to accurately estimate the 1-, 2-, and 3-year survival rates for individuals with TNBC. Additionally, EIF4EBP1 and NPAS3 expression influenced drug sensitivity in TNBC cell lines, with notably lower NPAS3 expression in TNBC tissues, particularly in Stage III cases. This study is the first to report NPAS3 expression in patients with TNBC.Conclusion: The autophagy-related genes EIF4EBP1 and NPAS3 may serve as independent prognostic factors for individuals with TNBC.Keywords: autophagy, nomogram, prognosis, risk signature, triple-negative breast cancer

Ruijing Su,&ast; Yue Yang,&ast; Haiyan Wu, Bo Liu, Xinyuan Tian, Chaoyu Zhou, Yanxin Hu, Tianlong Liu Laboratory of Veterinary Pathology and Nanopathology, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianlong Liu; Yanxin Hu, Email liutianlong@cau.edu.cn; huyx@cau.edu.cnBackground: A successful immune response against tumors depends on various cellular processes. Hence, there is an urgent need to construct a proficient nanoplatform for immunotherapy that can concurrently regulate the activities of various cells participating in the immune process. We have developed zeolitic imidazolate framework-8 (ZIF-8) formula, with good pH sensitivity, which is conducive to the release of drugs in the tumor site (acidic environment) and significantly improves immunotherapy. This is achieved through the coordinated action of different therapeutic agents, such as the photothermal agent polydopamine (PDA), the chemodrug camptothecin (CPT), and the immunomodulator 1-methyl-D-tryptophan (1-MT).Materials and Methods: In this study, we evaluated the antitumor effect of PDA/(CPT + 1-MT) @ZIF-8 (PCMZ) nanoparticles (NPs) in vitro and in vivo and investigated the molecular mechanism of PCMZ NPs in tumor suppression via photothermal-chemo-immunotherapy.Results: MTT and Annexin V-FITC/PI double staining apoptosis test showed that PCMZ NPs could induce apoptosis of 4T1 cell, and PCMZ NPs could cause 4T1 cell necrosis under 808 nm laser irradiation. The objective is to establish a unilateral breast cancer model in mice and investigate the effect of PCMZ NPs on tumor growth and tumor suppression in tumor bearing mice. The results showed that PCMZ NPs showed good heating effect in vivo and effectively inhibited tumor growth under 808 nm laser irradiation. In addition, PCMZ NPs could induce the immunogenic death of tumor cells, promote the maturation of DCs, inhibit IDO pathway, and finally differentiate T cells into cytotoxic T cells and helper T cells, so as to effectively activate the anti-tumor immune response.Conclusion: The PCMZ NPs, possessing good photothermal conversion capabilities due to join of PDA, effectively overcome two main challenges in immunotherapy: insufficient stimulation of the immune response and evasion of the immune system. This provides a robust platform against invasive cancer and recurrent tumors. Keywords: zeolitic imidazolate framework-8, photothermal agent polydopamine, 1-methyl-D-tryptophan, photoluminescence, camptothecin

Xiang Li,1 Mengtian Pan,1 Xinjuan Tian,1 Lele Zixin Yang,2 Jingjing Zhang,1 Dongmei Yan,3 Baohui Xu,4 Li Zhao,1 Weirong Fang1 1Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China; 2The Pennsylvania State University, Eberly College of Science, State College, PA, USA; 3Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, People’s Republic of China; 4Department of Surgery, Stanford University School of Medicine, Stanford, CA, USACorrespondence: Li Zhao; Weirong Fang, Email zhaoli@cpu.edu.cn; weirongfang@cpu.edu.cnBackground: Tripartite motif containing 59 (TRIM59) is a ubiquitin ligase and is involved in the pathogenesis of various diseases, including cancers, sepsis, and other immune-related diseases. However, it has not been defined whether TRIM59 plays a role in ischemic stroke in mice.Methods: This study determined the influence of Trim59 deficiency on experimental stroke outcomes and the cerebral proteomic profile using myeloid cell Trim59 conditional knockout (Trim59-cKO) mice and a label-free quantitative proteomic profiling technique. The possible mechanisms by which TRIM59 affected stroke onset were elucidated by in vivo and in vitro experiments.Results: Immunofluorescence staining results showed that TRIM59 expression was up-regulated after cerebral ischemia and co-localized with macrophages. Myeloid cell Trim59 deficiency exacerbated ischemic injury on day 3 after experimental stroke. In proteomic analysis, 23 differentially expressed proteins were identified in ischemic brain of Trim59-cKO mice as compared to Trim59flox/flox mice. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the differentially expressed proteins were enriched in complement and coagulation cascades. Protein–protein interaction analysis suggested the central role of clusterin in the interaction network. ELISA and Western blot assays confirmed the reduced levels of clusterin protein in the ischemic brains of Trim59-cKO mice. Further experimental results showed that clusterin was expressed in neurons. Conditional co-culture experiments of primary neurons and bone marrow-derived macrophages demonstrated that LPS stimulated macrophages to secrete complement C3. In addition, TRIM59 may affect the changes in clusterin expression in an indirect manner by influencing the secretion of complement C3 in macrophages. In vivo experiments also proved a significant increase in C3 levels in the brains of Trim59-cKO mice after ischemia.Conclusion: Myeloid cell Trim59 deficiency aggravated ischemic stroke outcomes in conjunction with a distinct cerebral proteomic profile, and the underlying mechanism may be related to the regulation of macrophage C3 expression by TRIM59.Keywords: Trim59, ischemic stroke, proteomic profile, complement and coagulation cascades, C3

Xingqiang Wang,1,2,&ast; Xianna Yang,3,&ast; Shiqi Wang,3,&ast; Xiaofang Tian,1 Jianmei Yin,3 Nian Liu,3 Pengtao Di,1 Jipeng Qi,3 Ya Li,3 Jimin Chen,3,4 Yang Wu,1 Jingjin Wu,1,2 Weiqing Zhao,5 Jiangyun Peng,1,2 Ling Zhang,1,2 Lingli Gu1 1Department of Rheumatology, The No. 1 Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650021, People’s Republic of China; 2Yunnan Provincial Clinical Medicine Research Center of Rheumatism in TCM, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming, Yunnan, 650021, People’s Republic of China; 3The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650021, People’s Republic of China; 4Department of Integrative Internal Medicine, The Lijiang Hospital of Traditional Chinese Medicine, Lijiang, Yunnan, 674100, People’s Republic of China; 5Department of Rheumatology and Immunology, The First People’s Hospital of Yunnan Province and The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, 650034, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Zhang; Lingli Gu, Email zebaiyuan@126.com; guyuxin82@126.comAbstract: Glucocorticoids (GC) are crucial in the treatment of rheumatoid arthritis (RA), but discontinuing GC effectively in RA patients poses a significant challenge for rheumatologists. In this two-stage, single-center, non-randomized controlled trial, we investigated the benefits of combining Chinese traditional herbal treatment with csDMARDs to aid GC discontinuation in terms of GC tapering, disease control, and safety. A total of 231 participants were enrolled, of which 150 eligible subjects were included in the first phase and allocated to three groups (control group, treatment group 1, and treatment group 2) based on their willingness to take traditional Chinese medicine and syndrome differentiation, in a 1:1:1 ratio. All groups received basic treatment consisting of methotrexate tablets (10 mg, qw), leflunomide (10 mg, qd), and stratified GC bridging therapy and tapering regimen (The intervention regimen was developed based on rigorous adherence to available evidence). Treatment group 1 received basic treatment combined with Juanbi Granule, while treatment group 2 received basic treatment combined with Yupingfeng Guizhi Decoction Granule. Efficacy was evaluated after a 12-week follow-up, with slightly adjustments to the treatment group based on efficacy and change of syndrome, followed by continued observation until 24 weeks to complete the study. The efficacy evaluation and data analysis were conducted in a blinded manner, including group label concealment, data cleaning, confounder and control regimen analysis, and outcome analysis. This project has received ethical approval from the Ethics Committee of Yunnan Provincial Hospital of Traditional Chinese Medicine (YLZ [2022] Ethical Review No. (006)-01) and has been registered with the China Clinical Trials Registry (Registration number: ChiCTR2300067676, Registered 17 January 2023, https://www.chictr.org.cn/showproj.html?proj=184908). This trial was the first to evaluate the clinical efficacy of combining Chinese herbal medicines with standard Western medicines to facilitate the discontinuation of glucocorticoid (GC) therapy in patients with rheumatoid arthritis (RA).Keywords: rheumatoid arthritis, glucocorticoids tapering, clinical trial, traditional Chinese medicine, Yupingfeng Guizhi Decoction, Juanbi Decoction

Pingyang Ke,1,&ast; Jing Liu,1,2,&ast; Chengzhi Chen,3,&ast; Sen Luo,3,&ast; Huiwen Gu,3,&ast; Juan Gu,4 Yan Liu,1 Yuanlin Ma,1 Yuan Meng,1 Liqin Hu,1 Xin Tian,1 Fei Xiao1 1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, People’s Republic of China; 2Department of Neurology, Chongqing University Three Gorges Hospital, Chongqing, People’s Republic of China; 3Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of China; 4Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fei Xiao; Xin Tian, Email feixiao81@126.com; xintian@cqmu.edu.cnBackground: Zinc oxide nanoparticles (ZnO NPs) has been widely used in various fields and has had an important impact on human public health. In addition, it inevitably damages human health, including neurological diseases. Therefore, this study explored the effect of ZnO NPs on epilepsy.Methods: The effect of ZnO NPs on epilepsy was observed by behavioral analysis. TLR4 expression and autophagy related pathways were detected by RNA-seq and Western blot. In addition, the cell types of autophagy were detected by immunofluorescence. Further, the electrophysiological changes of ZnO NPs induced autophagy were detected by whole-cell patch-clamp. Finally, the recovery experiment was carried out by TLR4 inhibitor (TAK-242).Results: We found that ZnO NPs enhanced epilepsy susceptibility and severity. Through RNA-seq analysis and Western blot, it was found that ZnO NPs affected the changes of TLR4 and autophagy related pathways. In addition, we found that ZnO NPs mainly affects autophagy of inhibitory neurons, resulting in excitation/inhibition imbalance. The autophagy and epileptic phenotypes were reversed with TAK-242. In general, ZnO NPs exacerbate epileptic seizures by modulating the TLR4-autophagy axis.Conclusion: ZnO NPs enhanced the susceptibility and severity of epilepsy. Mechanistically, ZnO NPs affected autophagy by changing the expression of TLR4. In particular, the ZnO NPs mainly affected the synaptic function of inhibitory neuron, leading to excitation/inhibition imbalances.Keywords: zinc oxide nanoparticles, epilepsy, excitation/inhibition balance, autophage

Ruyu Han,&ast; Leijuan Gan,&ast; Mengran Lang,&ast; Guangtao Li, Lu Chen, Xindi Tian, Kangwei Zhu, Liyu Sun, Tianqiang Song Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianqiang Song, Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin, 300060, People’s Republic of China, Tel +86-022-23340123, Fax +86-022-23537796, Email songtianqiangtj@163.comPurpose: This study aimed to investigate the potential benefits of radical therapy in patients with stage B disease.Patients and Methods: A retrospective analysis was conducted on a cohort of 437 patients diagnosed with stage B hepatocellular carcinoma, who underwent either hepatic resection (HR) or radiofrequency ablation (RFA) at the Cancer Institute and Hospital of Tianjin Medical University from May 2011 to May 2022. Multivariate COX regression analysis was performed to identify the independent prognostic factors related to recurrence-free survival (RFS). The performance of the developed nomogram was evaluated using various statistical measures, including the concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA).Results: Multivariate analysis revealed that tumor diameter, number of tumors, number of involved liver segments, alpha-fetoprotein (AFP), carbohydrate antigen 19– 9 (CA19-9), lactate dehydrogenase (LDH), and systemic immune inflammation index (SII) were independent prognostic factors influencing patients’ RFS, and these factors were incorporated into the nomogram. The C-index of the nomogram in the training cohort was 0.721, and the AUC at 2 and 3 years was 0.772 and 0.790, respectively. These values were appreciably higher than commonly used clinic staging systems and other predictive models. The calibration curve and DCA demonstrated good calibration and net benefit. Survival analysis comparing stage B patients who received radical treatment with stage A patients with multiple lesions did not reveal a significant difference in Kaplan-Meier survival curves (P=0.91).Conclusion: The nomogram provided a precise prediction of the recurrence for stage B hepatocellular carcinoma patients undergoing radical treatment. Furthermore, certain stage B patients may benefit from radical treatment.Keywords: nomogram, Barcelona clinic Liver cancer system, recurrence-free survival, hepatic resection, radiofrequency ablation

Yue Chen, Aili Gao, Xin Tian Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, People’s Republic of ChinaCorrespondence: Xin Tian, Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, Guangdong, People’s Republic of China, Tel/Fax +86-20-83593472, Email xinzisue@163.comAbstract: Adult-onset xanthogranuloma (AOX) is one of the four rare syndromes collectively referred to as adult xanthogranulomatous disease (AXD). It primarily occurs in the orbit and ocular adnexa and displays distinctive histopathological features, characterized by the infiltration of non-Langerhans-derived foam-like histiocytes and Touton giant cells. The presence of diffuse yellow plaques on the eyelids serves as a highly indicative feature. In this report, we present a compelling case of bilateral periorbital AOX. Initially, the patient received a diagnosis of necrotizing xanthogranuloma (NBX) and underwent treatment with dapsone, which yielded a poor response. Subsequently, through repeated biopsy, immunoprotein electrophoresis, and high-throughput sequencing, the diagnosis was revised to AOX. Subsequently, the patient’s treatment was modified to include oral hormone therapy, and no further progression of the periorbital plaque was observed. Notably, the patient’s sister was diagnosed with xanthelasma palpebrarum (XP), suggesting a potential genetic association between AOX and XP. Unfortunately, the sister declined further histologic examination and genetic sequencing of her skin lesions, impeding the acquisition of additional evidence regarding the genetic link between these two disorders. Despite the divergent pathological features, pathogenesis, and clinical presentation of AOX and xanthelasma palbrarum, clinicians should remain cognizant of the plausible genetic correlation between these two conditions and pursue further investigations when feasible.Keywords: adult-onset xanthogranuloma, adult xanthogranulomatous disease, histopathology, protein electrophoresis

Gangjiao Zhu,1,2 Rahul Malhotra,3– 5 Shangzhi Xiong,6 Xinyue Chen,7 Mingyang Zhang,2 You Wu,2 Enying Gong,8 Zhan Wang,9 Xiangyang Tian,10 Weixia Peng,11 Truls Østbye,2,3,12 Lijing L Yan1,2,12 1School of Public Health, Wuhan University, Wuhan, People’s Republic of China; 2Global Health Research Center, Duke Kunshan University, Kunshan, People’s Republic of China; 3Health Services and Systems Research, Duke-NUS Medical School, Singapore; 4Centre for Ageing Research and Education, Duke-NUS Medical School, Singapore; 5Singhealth, Duke-NUS Global Health Institute Medical School, Singapore; 6The George Institute for Global Health, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia; 7Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; 8School of Population Medicine and Public Health, China Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China; 9Department of Agricultural Economics, College of Agriculture, Purdue University, West Lafayette, IN, USA; 10Chinese Health Education Center, Beijing, People’s Republic of China; 11School of Public Health, Fudan University, Shanghai, People’s Republic of China; 12Duke Global Health Institute, Duke University, Durham, NC, USACorrespondence: Lijing L Yan, School of Public Health, Wuhan University, Wuhan, People’s Republic of China, Email lijing.yan@duke.eduPurpose: We assess whether the sequential mediating effects of self-efficacy and depressive symptoms on the relationship between community efficacy for non-communicable disease management (COEN) and medication adherence and whether these relationships differed by sex and age.Patients and Methods: Overall, 662 individuals from 12 communities in China were interviewed twice 1 year apart. Serial mediation analysis examined whether the relationship between COEN and medication adherence was mediated by self-efficacy and depressive symptoms. Model invariance across sex and age groups was assessed using multi-group analysis.Results: Serial mediation analysis indicated that self-efficacy and depressive symptoms sequentially mediated relationship between COEN and medication adherence. Multi-group analysis by sex showed that the path from self-efficacy to medication adherence was significant only for females and from depressive symptoms to medication adherence was significant only for males.Conclusion: Interventions that enhance individual self-efficacy may be beneficial in decreasing depressive symptoms and improving medication adherence.Keywords: medication adherence, neighborhood, community, self-efficacy, depressive symptoms, non-communicable chronic diseases, social cognitive theory, China

Weilu Cheng,1,* Lili Zhang,1,* Biwei Chen,1 Xin Tian,1 Yaqi Yao,1 Zezhou Zhang,1 Shaozong Chen2,3 1Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 2Institute of Acupuncture and Moxibustion and Massage, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 3Shaozong Chen, Cross-Regional Acupuncture Data Open Application Laboratory in the Yellow River Basin, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaozong Chen, Cross-regional Acupuncture Data Open Application Laboratory in the Yellow River Basin, Jinan, 250355, People’s Republic of China, Email ccsz1963@163.comObjective: This study aims to explore formula patterns and application rules for SP6 as the main acupoint in prescriptions, utilizing association rules.Methods: We conducted an extensive search in databases including China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (CDDB), China Science and Technology Journal Database (CSTJ), PubMed and Web of Science databases for literature published between January 2013 and June 2023, focusing on acupuncture prescriptions with SP6 as the main acupoint for various diseases. Inclusion and exclusion criteria were applied for literature screening. Relevant data was extracted, creating a database. Acupoints in conjunction with SP6 were analyzed using SPSS Modeler 18.0 and Cytoscape 3.7.2 software for acupoints appearing ≥ 15 times. Gephi software constructed a complex network model. The frequency of acupuncture points was analyzed to summarize the composition rules and clinical application rules of acupuncture points.Results: A total of 902 articles met inclusion criteria, yielding 672 prescriptions with SP6 as the main acupoint, paired with 197 different acupoints including ST36, CV4, and LI4. Neurological, obstetric, and gynecologic, as well as urological diseases, were predominantly treated. Among them, the predominant diseases include insomnia, primary dysmenorrhea, sequelae of stroke, and others, totaling 42 types.Conclusion: SP6-based prescriptions exhibit diverse applications, effectively treating insomnia, post-stroke sequelae, and primary dysmenorrhea. Commonly paired acupoints belong to Conception Vessel, Stomach meridian of foot-yangming, and Governor Vessel, and there are certain rules in their composition.Keywords: Sanyinjiao, SP6, acupuncture prescriptions, acupoint combinations regularity, application regularity

Yue Chen, Xin Tian Guangzhou Institute of Dermatology, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Xin Tian, Dermatology, Associate Director of Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, Guangdong, People’s Republic of China, Tel/Fax +86-20-83593472, Email xinzisue@163.comAbstract: Eccrine Syringofibroadenoma (ESFA) is an infrequent benign adnexal cutaneous lesion distinguished by hyperplastic epithelium and differentiation into eccrine ducts, displaying diverse clinical presentations. In the present case, a 48-year-old Chinese female patient exhibited a decade-long history of palmoplantar erythema, which clinically resembled Dyshidrotic Eczema. Histological examination suggested the presence of ESFA. Ultimately, considering both the clinical manifestations and histological outcomes, the patients received a diagnosis of reactive ESFA.Keywords: reactive eccrine syringofibroadenoma, dyshidrotic eczema, histopathology

Xianpeng Tian,1 Xiangwei Liu,2 Zhiqi Xiao,1 Qiao Lin1 1Department of Education, Jiangnan University, Wuxi, Jiangsu, People’s Republic of China; 2School of Distance Education, Universiti Sains Malaysia, Gelugor, Penang, MalaysiaCorrespondence: Xiangwei Liu, School of Distance Education, Universiti Sains Malaysia, Gelugor, Penang, Malaysia, Email lxwvkii@163.comIntroduction: This study aims to investigate the impact of COVID-19 on undergraduate students’ academic procrastination and negative emotions. It seeks to examine the relationship between negative affect and academic procrastination among university students, considering the mediating role of life autonomy and the moderating effect of a sense of school belonging.Methods: The study sample consisted of 776 university students from the Guangxi Zhuang Autonomous Region, China. Data collection involved the use of the Negative Affect Scale, Academic Procrastination Scale, Life Autonomy Scale, and Sense of School Belonging Scale. SPSS version 26.0 and PROCESS V3.580 to conduct relationship analysis, test the mediation model (model 4) and the moderated mediating model (model 7).Results: The findings revealed significant relationships among the variables. Negative emotions were negatively related with life autonomy and sense of school belonging, and positively related with academic procrastination. Academic procrastination showed a negative correlation with both life autonomy and sense of school belonging. Sense of school belonging exhibited a positive relationship with life autonomy. The study also identified life autonomy as a mediator in the relationship between negative emotions and academic procrastination. Additionally, the sense of school belonging moderated the initial segment of the negative emotion-life autonomy-academic procrastination pathway.Discussion: This study contributes to a better understanding of the association between negative affect and academic procrastination. It highlights that negative emotions have a direct and indirect influence on academic procrastination through the mediating role of life autonomy. Moreover, the moderating role of sense of school belonging suggests that the relationship between negative affect and life autonomy is stronger when the sense of school belonging is weaker.Keywords: negative emotions, academic procrastination, undergraduates, life autonomy, school belonging

Yimin Liang,&ast; Jingyao Liang,&ast; Qiongxiao Huang, Xin Tian, Lei Shao, Manqi Xia, Yumei Liu Institute of Dermatology, Guangzhou Medical University, Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yumei Liu, Department of Dermatology, Guangzhou Institute of Dermatology, 56 HengFu Road, Guangzhou, 510095, People’s Republic of China, Tel +86-13660403350, Email liuyumei1109@163.comAbstract: Knuckle pads (KPs) are benign hyperkeratotic fibrous thickening skin disorder characterized by nodules or plaques located on the extensor surface of the joints. However, there are no specific treatments for KPs so far. Here, we reported a case of KPs successfully treated with 2% crisaborole ointment combined with triamcinolone acetonide and neomycin plaster. This combined therapy might be a new therapeutic option for KPs.Keywords: knuckle pads, crisaborole, PDE-4 inhibitors, primary, emerging therapy

Yanqing Xing,1 Liting Feng,1 Yangdou Dong,2 Yupeng Li,1 Lulu Zhang,1 Qiannan Wu,1 Rujie Huo,1 Yanting Dong,1 Xinrui Tian,1 Xinli Tian3 1Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2College of Basic Medicine, Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Cardiology, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xinrui Tian, Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan, People’s Republic of China, Tel +8613834575570, Email tianxr@126.com Xinli Tian, Department of Cardiology, Chinese PLA General Hospital, No. 7 Medical Center No. 5 Nanmencang, Dongsijiao, Dongcheng District, Beijing, People’s Republic of China, Email 18600501329@126.comPurpose: Asthma is a chronic inflammatory airway disease involving multiple mechanisms, of which ferroptosis is a form of programmed cell death. Recent studies have shown that ferroptosis may play a crucial role in the pathogenesis of asthma, but no specific ferroptosis gene has been found in asthma, and the exact mechanism is still unclear. The present study aimed to screen ferroptosis genes associated with asthma and find therapeutic targets, in order to contribute a new clue for the diagnosis and therapy of asthma.Methods: Ferroptosis-related differentially expressed genes (FR-DEGs) in asthma were selected by the GSE41861, GSE43696 and ferroptosis datasets. Next, the FR-DEGs were subjected by GO and KEGG enrichment, and the mRNA-miRNA network was constructed. Then, GSEA and GSVA enrichment analysis and Immune infiltration analysis were performed, followed by targeted drug prediction. Finally, the expression of FR-DEGs was confirmed using GSE63142 dataset and RT-PCR assay.Results: We found 13 FR-DEGs by the GSE41861, GSE43696 and ferroptosis database. Functional enrichment analysis revealed that the 13 FR-DEGs were enriched in oxidative stress, immune response, ferroptosis, lysosome, necrosis, apoptosis etc. Moreover, our results revealed the mRNA-miRNA network of the FR-DEGs and identified candidate drugs. Also, immune infiltration revealed that ELAVL1, CREB5, CBR1 and NR1D2 are associated with the immune cells and may be potential targets in asthma. Finally, 10 FR-DEGs were validated by the GSE63142 database. It was verified that 7 FR-DEGs were differentially expressed by collecting asthma patients and healthy controls.Conclusion: This study ultimately identified 7 FR-DEGs for the diagnosis and therapy of asthma. These 7 FR-DEGs contribute to oxidative stress and immune responses. This study provides potential therapeutic targets and biomarkers for asthma patients, shedding further light on the pathogenesis of asthma as well as providing new insights into the treatment of asthma.Keywords: asthma, bioinformatics, ferroptosis, GSEA, GSVA, immune microenvironment

Yanqing Xing,1 Yupeng Li,1 Liting Feng,1 Rujie Huo,1 Xinkai Ma,1 Yanting Dong,1 Dai Liu,1 Yuheng Niu,2 Xinrui Tian,1,&ast; Erjing Chen1,&ast; 1The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2The First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinrui Tian; Erjing Chen, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan, Shanxi, People’s Republic of China, Email tianxr@126.com; mayyoubehappy44@163.comPurpose: To analyze the clinical characteristics and prognosis of patients hospitalized with non-severe, severe pneumonia and death in Omicron COVID-19.Patients and Methods: We collected clinical data from 118 patients with COVID-19 in China from 18 December, 2022 and 5 February, 2023. According to the outcome, the patients were divided into non-severe group, severe group and death group. Subsequently, we statistically analyzed the general condition, clinical manifestations, laboratory parameters, NLR, MLR, PLR and HALP of these groups. We also retrospectively analyzed the possible factors affecting the prognostic regression of patients with COVID-19.Results: A total of 118 COVID-19 patients were enrolled in this study, including 64 non-severe patients, 38 severe patients and 16 death patients. Compared with the non-severe group, T lymphocytes, B lymphocytes, Th1, Th2, Th17, Treg cells, IgA, IgG, IgM in the severe and death groups decreased more significantly (P< 0.05). The levels of myocardial markers, ALT, AST, BUN, Cr, D-dimer, fibrinogen, NLR, MLR and PLR in the severe and death groups were significantly higher than those in the non-severe group (P< 0.05). The level of HALP was significantly lower than that of non-severe group (P< 0.05). MLR is not only an independent risk factor for the transition from non-severe to severe disease, but also an independent risk factor for predicting the possibility of death in COVID-19 patients.Conclusion: The analysis of COVID-19 patients in China showed that severe patients were older, more likely to have related complications, lower lymphocyte count, liver and kidney function disorder, glucose and lipid metabolism disorders, myocardial injury, and abnormal coagulation function, suggesting the need for early anticoagulant therapy. In addition, NLR, MLR, PLR and HALP can be used as biomarkers to evaluate the severity and prognosis of COVID-19 patients.Keywords: COVID-19, omicron, clinical characteristics, lymphocyte subpopulation, Shanxi

Xuebin Tian,1,2,&ast; Yiwen Xie,1,2,&ast; Jingjing Chen,3,&ast; Wanpeng Yin,1,2 Yu Long Zhao,1 Peng Yao,4 Mingqing Dong,4 Changzhong Jin,1,2 Nanping Wu1,2 1Cell Biology Research Platform, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3Hospital Office, Shandong Second Provincial General Hospital, Jinan, Shandong, People’s Republic of China; 4Department of Infectious Disease, Zhejiang Qingchun Hospital, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changzhong Jin; Nanping Wu, Email changzhongjin@163.com; flwnp2013@163.comBackground: Microbial translocation (MT) is a characteristic of human immunodeficiency virus (HIV) infection. Whether MT is also a biomarker of different immune responses to antiretroviral therapy (ART) received by people living with HIV (PLWH) is not known.Methods: We examined the presence of MT in a cohort of 33 HIV-infected immunological responders (IRs) and 28 immunological non-responders (INRs) (≥ 500 and < 200 cluster of differentiation (CD)4+ T-cell counts/μL after 2 years of HIV-1 suppression, respectively) with no comorbidities. Plasma samples were used to measure the circulating levels of MT markers. All enrolled study participants had received 2 years of viral-suppression therapy.Results: Levels of lipopolysaccharide (P = 0.0185), LPS-binding protein (P < 0.0001), soluble-CD14 (P < 0.0001), and endogenous endotoxin-core antibody (P < 0.0001) at baseline were significantly higher in INRs than in IRs and were associated with an increased risk of an immunological non-response, whereas the level of intestinal fatty acid-binding protein did not show this association. Analysis of receiver operating characteristic (ROC) curves demonstrated the utility of these individual microbial markers in discriminating INRs after ART in people living with HIV with high sensitivity, specificity, and area under the ROC curve.Conclusion: INRs in HIV infection are characterized by increased MT at baseline. These markers could be used as a rapid prognostic tool for predicting immune responses in people infected with the HIV.Keywords: HIV, immunological non-responders, microbial translocation

Leijuan Gan,1– 3,&ast; Mengran Lang,1– 4,&ast; Xindi Tian,1– 3 Shaohua Ren,1– 3 Guangtao Li,1– 3 Yayue Liu,1– 3 Ruyu Han,1– 3 Kangwei Zhu,1– 3 Huikai Li,1– 3 Qiang Wu,1– 3 Yunlong Cui,1– 3 Wei Zhang,1– 3 Feng Fang,1– 3 Qiang Li,1– 3 Tianqiang Song1– 3 1Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China; 2Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China; 3Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 4Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, Hebei, 065001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianqiang Song, Tel +86-022-23340123, Fax +86 022-23537796, Email songtianqiangtj@163.comPurpose: The purpose of this study was to investigate the triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy as a conversion therapy for initially unresectable hepatocellular carcinoma (HCC).Patients and Methods: We retrospectively analyzed data from all HCC patients who underwent lenvatinib plus sintilimab plus arterially-directed therapy at Tianjin Medical University Cancer Hospital between December 2018 and October 2020. Of 98 enrolled patients, 37 patients were classified as potentially resectable. We compared the potentially resectable population (PRP) with the non-potentially resectable population (NPRP). The primary study endpoint was conversion rate, and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.Results: The baseline characteristics were comparable between populations except for a higher proportion of patients with extrahepatic metastases in the NPRP versus PRP (23/61 [37.7%] vs 3/37 [8.1%], respectively; p=0.003). For PRP, the ORR was 67.6% based on RECIST v1.1 (75.7% based on mRECIST), conversion rate was 40.5% (15/37). Of the 15 patients who underwent surgical resection, three achieved complete pathological remission. The median follow-up for all patients was 28 months (range: 2– 47). For NPRP, the ORR was 22.9% based on RECIST v1.1 (31.1% based on mRECIST), The median PFS for PRP was significantly longer than that of NPRP (25 vs 13 months, p = 0.0025). The median OS for PRP was significantly longer than that of NPRP (not reached VS 21 months, p=0.014). Hypertension was the most common grade ≥ 3 adverse reaction in both PRP and NPRP. No new safety signals were observed for any of the treatments.Conclusion: The triple-combination therapy of lenvatinib plus sintilimab plus arterially-directed therapy can convert potentially unresectable HCC into resectable disease and improve long-term survival.Keywords: lenvatinib, sintilimab, conversion therapy, unresectable hepatocellular carcinoma, TACE, HAIC

Abstract Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells. Single-cell RNA sequencing of circulating immune cells isolated from low dose IL2-treated patients reveals an increase in plasmablast and plasma cell populations that are enriched for a regulatory B cell gene signature. The transcriptional repressor BACH2 is significantly down-regulated in plasma cells from IL-2-treated patients, BACH2 binds to the IL-10 gene promoter, and Bach2 depletion or genetic deficiency increases B cell IL-10, implicating BACH2 suppression as an important mechanism by which IL-2 may promote an immunoregulatory phenotype in B cells.

Cantao Yang,1,&ast; Zhaohong Lu,1,&ast; Yinyin Xia,1 Jun Zhang,2,3 Zhen Zou,2,3 Chengzhi Chen,1,3 Xiaoliang Wang,4 Xin Tian,5 Shuqun Cheng,1,3 Xuejun Jiang3,6 1Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Molecular Biology Laboratory of Respiratory Diseases, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 4Medical Sciences Research Center, University-Town Hospital of Chongqing Medical University, Chongqing, 401331, People’s Republic of China; 5Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 6Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuqun Cheng; Xuejun Jiang, Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Number 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-68485008, Fax +86-23-68485207, Email 100077@cqmu.edu.cn; xuejunjiang@cqmu.edu.cnPurpose: The widespread use of zinc oxide nanoparticles (ZnONPs) has raised concerns about its potential toxicity. Melatonin is a neurohormone with tremendous anti-toxic effects. The enterochromaffin cells are an essential source of melatonin in vivo. However, studies on the effects of ZnONPs on endogenous melatonin are minimal. In the present study, we aimed to investigate the effects of ZnONPs exposure on gut-derived melatonin.Methods: In the present study, 64 adult male mice were randomly and equally divided into four groups, and each group was exposed to ZnONPs (0, 6.5, 13, 26 mg/kg/day) for 30 days. Subsequently, the neurobehavioral changes were observed. The effects of ZnONPs on the expression of melatonin-related genes arylalkylamine N-acetyltransferase (Aanat), melatonin receptor1A (Mt1/Mtnr1a), melatonin receptor1B (Mt2/Mtnr1b), and neuropeptide Y (Npy) on melatonin synthesis and secretion in duodenum, jejunum, ileum and colon during day and night were also assessed.Results: The results revealed that oral exposure to ZnONPs induced impairments of locomotor activity and anxiety-like behavior in adult mice during the day. The transcriptional analysis of brain tissues revealed that exposure to ZnONPs caused profound effects on genes and transcriptional signaling pathways associated with melatonin synthesis and metabolic processes during the day and night. We also observed that, in the duodenum, jejunum, ileum and colon sites, ZnONPs resulted in a significant reduction in the expression of the gut-derived melatonin rate-limiting enzyme Aanat, the membrane receptors Mt1 and Mt2 and Npy during the day and night.Conclusion: Taken together, this is the first study shows that oral exposure to ZnONPs interferes with melatonin synthesis and secretion in different intestinal segments of adult mice. These findings will provide novelty insights into the neurotoxic mechanisms of ZnONPs and suggest an alternative strategy for the prevention of ZnONP neurotoxicity.Graphical Abstract: Keywords: gut-derived melatonin, neurobehavioral impairment, transcriptome sequencing, zinc oxide nanoparticle exposure

Yan Zhang,1 Wenjie Li,1 Xiaomin Tian,1 Ruanyang Sun,1 Shidan Zhou,2 Ling Jia,1 Jian Sun,1,3,4 Xiao-Ping Liao,1,3,4 Ya-Hong Liu,1,3,4 Yang Yu1,3,4 1Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, People’s Republic of China; 2Intensive Care Unit, Huizhou Municipal Central Hospital, Huizhou, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Microbial Safety and Health, Guangdong Institute of Microbiology, Guangdong Academy of Science, Guangzhou, People’s Republic of China; 4Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, People’s Republic of ChinaCorrespondence: Yang Yu, Email graceyyu@scau.edu.cnObjective: Carbapenem-resistant Enterobacteriaceae (CRE) have become an increasingly common cause of healthcare-related infections and present a serious challenge to clinical treatment. This study examined the phenotypic, genotypic characterization, clinical, and microbiological data of CRE in the Huizhou Municipal Central Hospital.Methods: We conducted a phenotypic susceptibility evaluation and whole genome sequence analysis for 52 CRE strains isolated from 37 patients and 2 medical device-related samples during 2013– 2017 to characterize risk factors, antimicrobial resistance profiles, dominant clones and hospital transmission.Results: Long-term hospitalization, treatment time with antibiotics and use of invasive devices were linked to the risk of CRE infection. The carbapenem resistance genes (CRGs) we found included blaNDM (82.7%), blaIMP (19.2%) and blaKPC (3.8%), Escherichia coli (44.2%) and Klebsiella pneumoniae (44.2%) were the dominant species we identified, and the type of CRG carried by isolates was highly correlated with species. The coexistence of CRGs with a variety of other antibiotic resistance genes leads to an increased prevalence of high resistance levels for CRE to β-lactams and other antibiotic classes such as aminoglycosides and fluoroquinolones. These isolates were sensitive only to colistin and tigecycline. In addition to this, we observed significantly genomic diversity of CRE isolates in this hospital. Importantly, we found that long-term transmission of multiple CRE clones had occurred at this hospital between various wards.Conclusion: Evaluating and improving the current infection control strategies may be necessary, and reducing nosocomial transmission remains the primary control element for CRE infections in China.Keywords: carbapenem-resistant Enterobacteriaceae, bacteremia, carbapenem resistance genes, nosocomial transmission

Xiaolin Tian,1 Xiaoshuang Xia,2 Haibo Yu,3 Haiyan Chen,3 Aili Jiang,3 Li Xin2 1Department of Rehabilitation Medicine, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 2Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 3Blood Purification Center, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Li Xin, Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China, Tel +86 22-88329030, Email lixim4035@126.com Aili Jiang, Blood Purification Center, The Second Hospital of Tianjin Medical University, No. 23, Pingjiang Road, Hexi District, Tianjin Municipality, Tianjin, 300211, People’s Republic of China, Tel +86 22-88326563, Email jiamgailimm@21cn.comObjective: Cognitive impairment (CI) in Maintenance hemodialysis (MHD) is attracting increasing attention. This study aims to clarify the prevalence and risk factors for cognitive dysfunction in patients on MHD who have no history of stroke.Methods: A total of 99 patients with no history of stroke undergoing MHD were enrolled. Global cognitive function was evaluated using the Montreal Cognitive Assessment scale. Attention and executive functions were evaluated by the Digital Span (DS) test and the Color Trail Test (CTT). The Hamilton Depression and Anxiety scales were used to assess depression and anxiety status. The effects of patient background factors, laboratory indicators, anxiety, and depression on cognitive dysfunction were examined by regression analysis.Results: There were 69.70% of the patients had general CI, 65.65% had depression, and 57.57% had anxiety. The forward and backward DS in the cognitively impaired (CI) group were shorter than in the normal cognitive function (NCF) group (P< 0.05). Times required for CTT–I, CTT–II, and CTT II − CTT I were longer in the CI group than in the NCF group (P< 0.05). Hemoglobin levels were lower, and parathyroid hormone (PTH) and uric acid levels were higher in the CI group than in the NCF group (P< 0.05). Hemoglobin levels were negatively correlated with CI in these patients (odds ratio [OR] 0.634, P< 0.05) and PTH, and uric acid levels were positively correlated with CI (OR 1.028, P< 0.05; and OR 1.011, P< 0.05). The proportions of patients with diabetes and depression were higher in the CI group (P< 0.05).Conclusion: There was a high prevalence of CI with significant impairment of attention and executive ability in MHD patients who had no stroke history. Hemoglobin may protect cognitive function, while diabetes, PTH, and uric acid levels may be risk factors. Depressive and anxiety states may aggravate CI in MHD patients.Keywords: end-stage renal disease, maintenance hemodialysis, cognitive impairment, executive ability, risk factors

Shufeng Liang,1,2 Xin Tian,3 Chunyan Wang4 1Department of Molecular Biology, Shanxi Province Cancer Hospital/Shanxi Hospital, Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, People’s Republic of China; 2Institute of Environmental Sciences, Shanxi University, Taiyuan, People’s Republic of China; 3State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, People’s Republic of China; 4Department of Transfusion, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Xin Tian; Chunyan Wang, Department of Transfusion, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, No 3 Zhigongxin Street, Xinghualing, Taiyuan, Shanxi, People’s Republic of China, Tel +86 15110313926, Email xtian@suda.edu.cn; chunyanwang2007@163.comAbstract: Excessive reactive oxygen species (ROS) may generate deleterious effects on biomolecules, such as DNA damage, protein oxidation and lipid peroxidation, causing cell and tissue damage and eventually leading to the pathogenesis of diseases, such as neurodegenerative diseases, ischemia/reperfusion ((I/R)) injury, and inflammatory diseases. Therefore, the modulation of ROS can be an efficient means to relieve the aforementioned diseases. Several studies have verified that antioxidants such as Mitoquinone (a mitochondrial-targeted coenzyme Q10 derivative) can scavenge ROS and attenuate related diseases. Nanozymes, defined as nanomaterials with intrinsic enzyme-like properties that also possess antioxidant properties, are hence expected to be promising alternatives for the treatment of ROS-related diseases. This review introduces the types of nanozymes with inherent antioxidant activities, elaborates on various strategies (eg, controlling the size or shape of nanozymes, regulating the composition of nanozymes and environmental factors) for modulating their catalytic activities, and summarizes their performances in treating ROS-induced diseases.Keywords: nanozymes, enzyme-mimic, oxidative stress, antioxidant, ROS-related diseases

Pengyi Hou,1,2 Yangyang Pi,1,2 Ziming Jiao,1 Xueyan Tian,1 Wenxuan Hu,1 Yuhong Zhang,1,2 Yi Zhao,1,2 Faxuan Wang1,2 1School of Public Health and Management, Ningxia Medical University, Yinchuan, People’s Republic of China; 2Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, People’s Republic of ChinaCorrespondence: Faxuan Wang, Email faxuan203@163.comBackground: In recent decades, obesity has become an epidemic worldwide and is a risk factor for many chronic diseases. Lung function is also a predictor of various chronic diseases. However, research results on the association between obesity and lung function are inconsistent and few studies have evaluated the association between central obesity indicators and lung function. Therefore, this study explored the correlation between central obesity and lung function.Methods: This study is a cross-sectional study. The basic participant characteristics were collected by questionnaire. A tape measure was used to measure waist circumference (WC) and hip circumference (HC). Body fat percentage was measured using an InBody370. Lung function parameters were measured using a digital spirometer connected to a computer (Chestgraph HI-101). R (R4.0.5) software was used for data analysis. A generalized linear model was used to analyze the association between obesity and lung function.Results: This study found that body mass index (BMI) adjusted for WC was negatively correlated with forced vital capacity (FVC) (β=− 0.05 [− 0.06, − 0.03] in men, β=− 0.05 [− 0.07, − 0.04] in women) and forced expiratory volume in 1 s (FEV1)(β=− 0.02 [− 0.03, − 0.00] in men, β=− 0.03 [− 0.04, − 0.02] in women). Body fat percentage was negatively correlated with FVC (β=− 0.01 [− 0.01, − 0.01] in men, β=− 0.01 [− 0.01, − 0.00] in women).Conclusion: Central obesity and combined central and general obesity were more strongly positively correlated with lung function. WC-adjusted BMI was negatively correlated with lung function. Body fat percentage was negatively correlated with lung function.Keywords: lung function, central obesity, body mass index, waist circumference

Jiaoquan Chen,&ast; Xin Tian,&ast; Nanji Yu, Liqian Peng, Huilan Zhu Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, 510095, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huilan Zhu, Department of Dermatology Guangzhou Institute of Dermatology, 56 Hengfu Road, Guangzhou, 510095, People’s Republic of China, Email Zhlhuilan@126.comAbstract: T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy derived from T-cells that more commonly affects teens and males. Most commonly, T-LBL exhibits signs of lymph nodes, bone marrow, and mediastinal mass invasion, but in rare cases, the disease manifests cutaneously. We present a case of both cutaneous and systemic presentation of T-LBL in 9-year-old man in which the skin immunophenotype analysis showed TdT expression with positivity of CD3, CD4 and CD99. Review of all currently described cases of cutaneous T-LBL revealed that the most frequently positive tumor markers were TdT (100%), CD3 (100%), CD4 (59.1%) and CD99 (40.9%). Cutaneous involvement may be a prognostic factor in treating T-LBL with chemotherapy.Keywords: T-cell lymphoblastic lymphoma, cutaneous lymphoma, diagnosis

Lingyu Liu,1 Jing Chen,2 Jing Li,1 Yunjiao Yang,1 Xiaofeng Zeng,1 Xinping Tian1 1Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, People’s Republic of China; 2Department of Rheumatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of ChinaCorrespondence: Xiaofeng Zeng; Xinping Tian, Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, People’s Republic of China, Tel +86 10 69158795, Email xiaofeng.zeng@cstar.org.cn; tianxp6@126.comPurpose: To conduct the first whole exome sequencing (WES) on Takayasu arteritis (TAK) to identify common and rare variants responsible for disease susceptibility.Patients and Methods: A total of 200 patients and 1675 healthy controls from China were recruited for this study. Site-based association analysis for common variants and gene-based burden analysis for rare variants were conducted. A weighted genetic risk score (wGRS) was calculated for each patient with TAK based on the independent risk alleles identified in the association analyses. The ability of the patient wGRS to discriminate between different phenotypes was evaluated.Results: In the site-based analysis, the top association signal was CCHCR1 (rs1265067, p = 8.27 × 10− 12, OR = 2.41), a proxy for HLA-B&ast;52:01. HLA-DQB1 (rs9273902), HLA-DQB2 (rs34109750), and a haplotype block in the human leukocyte antigen (HLA) class III region (represented by rs3130618) also exhibited significant associations independently. In addition, four novel non-HLA susceptibility loci were identified: PRRT4, TLL2, LRP1B, and DLGAP2. Twelve independently associated single nucleotide polymorphisms were used to calculate the wGRS. TAK patients with a higher wGRS were found to have an increased risk of pulmonary artery involvement compared with those with a lower wGRS (p = 5.76 × 10− 7, OR = 13.92). The wGRS algorithm showed good predictive capability for pulmonary artery involvement in TAK (sensitivity, 92.1%; specificity, 59.9%). In the gene-based analysis, risk genes that reached exome-wide significance were not identified.Conclusion: This WES study on TAK supports a previously reported association within the HLA region. Moreover, novel susceptibility loci were identified outside the HLA region. These risk alleles showed potential associations with pulmonary artery involvement in TAK. However, additional studies are warranted to verify our findings.Keywords: Takayasu arteritis, whole exome sequencing, pulmonary artery, human leukocyte antigen

Xiangyong Tian,1,&ast; Nan Jing,2,&ast; Wenjing Duan,3 Xiaoqiang Wu,1 Chan Zhang,1 Shanmei Wang,2 Tianzhong Yan1 1Department of Urology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, People’s Republic of China; 2Department of Clinical Microbiology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, People’s Republic of China; 3Department of the Clinical Research Center, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianzhong Yan, Department of Urology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan Province, 450003, People’s Republic of China, Email ytz460@hotmail.com Wenjing Duan, Department of the Clinical Research Center, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan Province, 450003, People’s Republic of China, Email duanwenjingzzu@zzu.edu.cnBackground: Ralstonia mannitolilytica, an emerging opportunistic pathogen, can infect immunocompromised patients but is a rare cause of severe sepsis and septic shock in kidney transplant recipients (KTRs).Case Presentation: We present a case of septic shock after renal transplant in a 41-year-old male, which was finally proven to be caused by Ralstonia mannitolilytica through blood cultures and mass spectrometric analysis following the negative result of metagenomic next-generation sequencing (mNGS). He was finally cured after the application of sensitive antibiotics (sulfamethoxazole-trimethoprim, amikacin and piperacillin-tazobactam) based on the drug sensitivity test results. The patient had a satisfactory recovery with no complications during a 6-month follow-up period.Conclusion: This study highlights that Ralstonia mannitolilytica is an easily overlooked cause of septic shock in KTRs requiring a detailed inquiry of medical history with inflammatory markers monitored closely. Traditional blood cultures still should be taken seriously. It also provides a cautionary tale that negative results of mNGS have to be interpreted with caution.Keywords: Ralstonia mannitolilytica, kidney transplant, sepsis, metagenomic next-generation sequencing, mNGS, blood cultures

Jinyu Wang,&ast; Cuiping Xia,&ast; Yue Wu, Xin Tian, Ke Zhang, Zhongxin Wang Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhongxin Wang, Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China, Tel +8613866709500, Fax +5516-5908076, Email aywzhx87@163.comBackground: Rapid detection of carbapenem-resistant Klebsiella pneumoniae (CRKP) is essential for specific antimicrobial therapy. Machine learning techniques combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) can be used as a rapid, reliable, sensitive, and low-cost species identification method.Methods: Clinically collected K. pneumoniae were subjected to MALDI-TOF MS analysis. A random forest (RF) algorithm and non-linear support vector machine (SVM) were used to construct the RF, SVM, and dimension reduction (SVM-K) models, and their performance was assessed for accuracy, sensitivity, specificity, and area under the subject worker curve (AUC).Results: The RF, SVM and SVM-K models showed good classification performance with 0.88, 0.88, and 0.91 accuracy, 0.82, 0.85, and 0.89 sensitivity, 0.93, 0.92, and 0.94 specificity with an AUC of 0.9013, 0.9298, and 0.9356, respectively. For the SVM-K model, the optimal dimension reduction was 105 to 153, and the average accuracy was > 0.9. The top 10 peak features of significance according to the RF algorithm with 6515 Da appeared in 56.8% of CRKP isolates and 5.3% of CSKP isolates, which indicated the best classification performance.Conclusion: The three RF, SVM, and SVM-K models showed excellent classification performance differentiating the CRKP from CSKP; the SVM-K model was the best. Data analysis with machine learning combined with MALDI-TOF MS can be employed as a rapid and inexpensive alternative to existing detection methods.Keywords: Klebsiella pneumoniae, RF, SVM, SVM-K, MALDI-TOF MS

Wangji Zhou,1,&ast; Keqiang Liu,2,3,&ast; Kai-Feng Xu,1 Yaping Liu,4 Xinlun Tian1 1Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 2Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Shanghai Institute of Pediatric Research, Shanghai, People’s Republic of China; 4McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinlun Tian, Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, #1 Shuaifuyuan, Wangfujing, Beijing, 100730, People’s Republic of China, Tel +86 13911204657, Email tianxl@pumch.cn Yaping Liu, McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, People’s Republic of China, Email ypliu@ibms.pumc.edu.cnBackground: Birt–Hogg–Dubé syndrome (BHD), also named Hornstein–Knickenberg syndrome, is a rare autosomal dominant disease characterized by lung cysts, recurrent pneumothoraxes, renal cell carcinoma and skin fibrofolliculomas.Purpose: This study summarizes the clinical and genetic information of Chinese BHD patients from all available reported cases and explores the relationship between the clinical and genetic spectrum in the hope of improving the prognosis of Chinese BHD patients.Methods: Relative studies were collected by searching PubMed, Cochrane Library, Embase, OVID medicine, SinoMed, Web of Science, China National Knowledge Infrastructure, Wanfang Data and China Hospital Knowledge Database from January 1, 1977 to December 31, 2021. The search strategy included the following term keys: (Birt–Hogg–Dubé syndrome OR Hornstein-Kinckenberg syndrome OR familial pulmonary cysts OR familial spontaneous pneumothorax OR fibrofolliculomas OR trichodiscomas OR inherited renal cancer syndromes OR FLCN) AND (Chinese OR China).Results: In total, 287 Chinese patients from 143 families described in 31 references were included in this article. Chinese BHD patients tended to present more pulmonary symptoms but fewer skin lesions and renal malignancies, which appeared to be atypical when compared with Caucasian patients. The FLCN mutation spectrum among Chinese BHD patients was established with the mutational hot spot c.1285depC/delC as the most frequent mutation. In addition, this mutation spectrum also showed some differences from other races, with a relatively frequent large deletion c.872– 429_1740+1763del (exon 9– 14 deletion) reported only in Chinese individuals but no observation of the two mutational hot spots found in Japanese individuals. We also attempted to establish potential pheno-genotype correlations in Chinese BHD patients, but the results were negative.Conclusion: To improve the prognosis of BHD patients, physicians need to increase their awareness of BHD by focusing on the family history of pneumothorax as well as skin lesions in patients with lung cysts and promptly advising patients on genetic sequencing.Keywords: Birt–Hogg–Dubé syndrome, Chinese, FLCN, genetics, phenotype

Suhua Wang,1,2 Siyuan Han,1,2 Weiyan Cheng,1,2 Ruoyang Miao,1,2 Shasha Li,1,2 Xin Tian,1,2 Quancheng Kan1,2 1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China; 2Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of ChinaCorrespondence: Xin Tian; Quancheng Kan, Email tianx@zzu.edu.cn; kanqc@zzu.edu.cnPurpose: To enhance the cytotoxicities of our obtained CDK4 inhibitors and get CDK4/HDACs inhibitors with potent enzymatic inhibitory and anti-proliferative activities.Methods: A series of novel CDK4/HDACs inhibitors were designed and synthesized by incorporating the HDAC pharmacophores (hydroxylamine or o-diaminoaniline) into the basic structure of our newly obtained 2-anilino-4-triazolpyrimidine based CDK4 inhibitors. The enzymatic inhibitory (HDAC1, CDK2, CDK4, and CDK6) activities and cytotoxicities of these compounds were evaluated. Moreover, HDAC isoforms inhibitory activity, cell cycle arrest assay, cell apoptosis analysis, cell migration, and cell colony formation assay were performed for the representative compound 11k.Results: Most of these compounds showed excellent HDAC1 inhibitory activities (IC50s: 0.68∼ 244.5 nM) and anti-proliferative activities against cancer cell lines. Some compounds displayed potent CDK4 inhibitory activities and a certain selectivity towards CDK2 and CDK6. Compound 11k exhibited potent enzymatic (CDK4: IC50=23.59 nM; HDAC1: IC50=61.11 nM; HDAC2: IC50=80.62 nM; HDAC6: IC50=45.33 nM) and anti-proliferative activities against H460, MDA-MB-468, HCT116, and HepG2 cell lines with IC50 values 1.20, 1.34, 2.07, and 2.66 μM, respectively. Further mechanistic studies revealed that compound 11k could arrest the cell cycle in G0/G1 phase and induce apoptosis in HCT116 and MDA-MB-468 cells. In addition, compound 11k significantly inhibited the migration and cell colony formation of H460 and HCT116 cells.Conclusion: This study suggested that the incorporation of the HDAC pharmacophore into CDK4 inhibitor scaffold to design CDK/HDAC inhibitors might be a tractable strategy to enhance the antitumor potency of compounds.Keywords: CDK4, HDAC, inhibitor, 2-anilino-4-triazolpyrimidine, cancer

Lihong Li, Heyu Meng, Xue Wang, Jianjun Ruan, Xiaomin Tian, Fanbo Meng Department of Cardiology, The Third Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Fanbo Meng, Department of Cardiology, The Third Hospital of Jilin University, Changchun, People’s Republic of China, Tel +86-15948346855, Fax + 86-431-84995228, Email mengfb@jlu.edu.cnPurpose: ZCCHC9 is a zinc finger protein with a CCHC zinc finger structure and has important roles in several cellular processes. This study was conducted on an expanded number of samples to evaluate The usefulness of ZCCHC9 gene expression in peripheral blood as a molecular marker for the prediction of AMI (acute myocardial infarction) risk.Patients and Methods: Peripheral blood samples were collected from 117 patients with stable CAD (coronary atherosclerotic disease) and 126 patients with AMI. The mRNA level of the ZCCHC9 gene was assessed by qRT-PCR, and its protein level was determined by Western blotting.Results: The AMI group exhibited reduced expression of the ZCCHC9 gene, at both transcript and protein levels, than the stable CAD group. The low expression of the ZCCHC9 gene was not related to blood glucose level (P=0.635), blood lipid level, and troponin level (P=0.715), and may cause AMI through the MAPK signaling pathway. Compared with other patients, patients with low ZCCHC9 gene expression in their peripheral blood have a 2.597-fold higher risk of AMI.Conclusion: ZCCHC9 gene expression in peripheral blood was significantly lower in patients with AMI than in stable CAD patients. Individuals with low expression of ZCCHC9 in peripheral blood have higher a probability to develop AMI than those with stable CAD. Thus, lowered ZCCHC9 gene expression can act as an independent risk factor for AMI.Keywords: genetics, molecular marker, oxidative stress, MAPK

Ti Wu,1,&ast; Haipeng Zhang,2,&ast; Xiaolin Tian,3 Yang Cao,2 Dianjun Wei,4 Xiangkun Wu4 1Department of Neurology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Department of Clinical Laboratory, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of Neurology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 4Department of Clinical Laboratory, Hebei Yanda Hospital, Langfang, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangkun Wu Tel +8615613682051Email wuxiangkun_2021@163.comPurpose: To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and stroke-associated pneumonia (SAP) in patients with acute ischemic stroke (AIS) without fever and to clarify whether NLR has an advantage over high-sensitivity C-reactive protein (hs-CRP) in predicting SAP.Patients and Methods: A total of 434 patients with AIS without fever were assessed in this study. Multivariable analysis was used to evaluate the relationship between NLR and SAP, and the receiver operating characteristic (ROC) curve was used to compare the predictive value of NLR and hs-CRP.Results: Among the total patients, 18 (4.1%) developed SAP. After adjusting for confounders, NLR (adjusted odds ratio [aOR] = 1.60; 95% confidence interval [CI], 1.30– 1.96; p < 0.001) remained independently associated with an increased risk of SAP. In addition, the area under the curve (AUC) of NLR (0.862 [0.826– 0.893]) was higher than that of hs-CRP (0.738 [0.694– 0.779]).Conclusion: We found that compared with hs-CRP, NLR was significantly associated with the occurrence of SAP in patients with AIS without fever and showed a more effective predictive value for SAP.Keywords: stroke, pneumonia, neutrophil, lymphocyte, high-sensitivity C-reactive protein, inflammation

Xue Tian,1,&ast; Feiyue Yang,2,&ast; Fenghu Li,1 Li Ran,1 Jianying Chang,1 Jiehui Li,1 Wei Hong,3 Lang Shan,1 Yanjun Du,1 Lili Hu,1 Fan Mei,1 Mingyuan He,1 Yongxia Li,1 Heran Wang,1 Kai Zuo,1 Bo Zhou,4 Shuying Chen,1 Wanli Mao1 1Department of Oncology, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 2Department of Gynecologic Oncology, Guizhou Provincial People’s Hospital, Guiyang, 550004, People’s Republic of China; 3Department of Radiotherapy, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 4Surgical Department of Gynecological Oncology, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fenghu Li; Li Ran Email 769654418@qq.com; ranli171@hotmail.comPurpose: To examine the clinical significance of unoperated cervical cancer patients treated with different neoadjuvant chemotherapy (NACT) schemes followed by concurrent chemotherapy and radiotherapy (CCRT).Methods: This retrospective analysis included women with locally advanced cervical cancer treated with NACT-CCRT between September 2011 and September 2014. Neoadjuvant chemotherapy included paclitaxel plus cisplatin (TP group; 62 patients) or paclitaxel plus loplatin (TL group; 58 patients), which were administered three weekly, and cisplatin or loplatin, which were administered weekly for synchronous chemotherapy. External beam radiation therapy (50.4– 56.35 Gy/28 f, 180– 215 cGy/f, 5 f/w) was followed by intracavitary brachytherapy (5 Gy per fraction, mostly 5 fractions, Ir192 based).Results: One hundred twenty women were included in the analysis. The complete/partial response rate was 99.2% after treatment. The one-year, three-year, and five-year survival rates were 99.2%, 82.5%, and 70.8%, respectively. In the TP and TL groups, the three-year and five-year survival rates were 85.5% vs 77.6% and 75.8% vs 65.5%, respectively, with no significant difference. The 5-year overall survival (OS) rates between patients with stage IIB and stage IIIB disease were not significantly different (69.2% vs 64.7%). In the TP group, grade 3 or 4 digestive reactions were more frequent than those in the TL group. Leukopenia, neutropenia, and thrombocytopenia were more common in the TL group. No significant difference was found in anemia, radiation enteritis, radiation proctitis, or radiation cystitis between the groups.Conclusion: Lobaplatin may be used as an alternative drug for patients with severe digestive system reactions or contraindications to cisplatin, but hematological toxicity must be considered, particularly in dose-intensive schemes. Neoadjuvant chemotherapy followed by concurrent chemotherapy and radiotherapy (NACT-CCRT) warrants further prospective study in cervical cancer patients with a wide range of tumor invasion (eg, mass size ≥ 5 cm or stage IIIB).Keywords: cervical cancer, neoadjuvant chemotherapy, survival benefit, side effects

Xiaobing Tian,1,&ast; Yan Li,2,3,&ast; Jie Liu,1,2,4,5,&ast; Qiuxing Lin,1,2,4,5 Qiaoxia Yang,6 Jun Tu,1,2,4,5 Jinghua Wang,1,2,4,5 Jidong Li,2,7 Xianjia Ning1,2,4,5 1Department of Neurology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Center of Clinical Epidemiology & Evidence-Based Medicine, The Jizhou People’s Hospital, Tianjin, People’s Republic of China; 3Department of Anesthesiology, The Jizhou People’s Hospital, Tianjin, People’s Republic of China; 4Laboratory of Epidemiology, Tianjin Neurological Institute, Tianjin, People’s Republic of China; 5Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, People’s Republic of China; 6Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 7Department of Neurosurgery, The Jizhou People’s Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xianjia Ning; Jidong Li Email xning@tmu.edu.cn; jd_li_doctor@163.comIntroduction: Isolated impaired glucose tolerance (i–IGT) is a subtype of prediabetes in which an individual demonstrates elevated 2-h post-glucose load glucose levels but normal fasting plasma glucose levels. However, few studies have explored the prevalence and risk factors of i–IGT among adults in rural China. Thus, we aimed to explore the prevalence and risk factors of i–IGT among adults ≥ 50 years old in a low-income, rural population in China.Materials and Methods: Individuals aged ≥ 50 years with normal fasting plasma glucose levels were included in the final analysis. Fasting and 2-h venous blood samples were collected to assess the selected parameter measurements.Results: A total of 2175 individuals were included in this study. The i–IGT prevalence was 22.9% and significantly higher among females than among males (P< 0.05). Older age [odds ratio (OR), 1.606; 95% confidence interval (CI), 1.101– 2.342; P=0.014), hypertension (OR, 1.554; 95% CI, 1.152– 2.019; P=0.004), and central obesity (OR, 1.395; 95% CI, 1.099– 1.771; P=0.006) were associated with i–IGT. Moreover, white blood cell (OR, 1.089; 95% CI, 1.009– 1.175; P=0.029), high-sensitivity C-reactive protein (OR, 1.049; 95% CI, 1.020– 1.078; P=0.001), serum uric acid (OR, 1.0003; 95% CI, 1.001– 1.004; P=0.001), triglyceride (OR, 1.540; 95% CI, 1.105– 2.147; P=0.011), and alanine aminotransferase (OR, 1.012; 95% CI, 1.004– 1.021; P=0.004) levels were also linked to i–IGT in the analyzed population.Conclusion: Health promotion education and a standardized approach to managing body weight, BP, and lipid and uric acid levels would benefit this low-income population in rural China for reducing the risk of cardiovascular disease.Keywords: impaired glucose tolerance, prevalence, risk factors, normal fasting plasma glucose, epidemiology

Xiaoning Cen,1,&ast; Yunmei Huang,2,&ast; Zhuangnian Lu,3,&ast; Wenjun Shao,4 Chenyi Zhuo,1 Chongchan Bao,5 Shi Feng,5 Cheng Wei,5 Xiqiang Tang,5 Lijun Cen,5 Wenwen Guo,5 Xinru Tian,5 Qianli Tang,5 Xusen Huang1 1General Surgery, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 3Department of Pediatrics, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 4Medical college of Soochow University, Suzhou, Jiangsu, 215000, People’s Republic of China; 5YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qianli TangYouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of ChinaEmail htmgx@163.comXusen HuangGeneral Surgery, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of ChinaEmail hxsfy@163.comBackground: LncRNAs play an important role in tumor initiation and development. However, the underlying involvement of lncRNA expression in colorectal carcinoma remains to be clarified.Methods: All analyses were performed in R software v4.0, SPSS v13.0, and GraphPad Prism 8. The “limma” package was used to identify differentially expressed lncRNAs between two groups with the threshold of |logFC| > 1 and P < 0.05. The “Survival” package was used to conduct survival analysis. HCT8 and SE480 cell lines were used to conduct further phenotype experiments, including transwell, wound-healing, CCK8 and colony formation assay. Gene set enrichment analysis was used to explore the biological pathway difference in high and low IGFL2-AS1 patients.Results: The lncRNA IGFL2-AS1 was highly expressed in colon adenocarcinoma (COAD) tissue and cell lines (HCT116, HCT8, HCT129, and SW480). The COAD patients with high IGFL2-AS1 were associated with a worse prognosis. Meanwhile, the knockdown of IGFL2-AS1 could significantly suppress the proliferation and invasion of COAD cells. Gene set enrichment analysis showed that the top five biological pathways involving IGFL2-AS1 were angiogenesis, epithelial–mesenchymal transition, KRAS signaling, myogenesis, and coagulation. Western blot results showed that the inhibition of IGFL2-AS1 could significantly reduce the N-cadherin, HIF1A and KRAS protein expression, yet increase the E-cadherin protein level. IGFL2-AS1 was also positively correlated with M0 macrophages, M2 macrophages, and neutrophils but negatively correlated with CD4+ memory T cells and CD8+ T cells.Conclusion: IGFL1-AS1 could seriously worsen patient outcomes and facilitate COAD progression, thus serving as an independent tumor marker.Keywords: IGFL2-AS1, lncRNA, colon cancer, immune

Zhenwen Chen,1,2,&ast; Ning Zhao,1,&ast; Qi Wang,1 Yanfeng Xi,3 Xiaoai Tian,2 Huiwen Wu,1 Yirong Xu1,2 1Department of Pathology, Fenyang College of Shanxi Medical University, Fenyang, 032200, Shanxi Province, People’s Republic of China; 2Department of Pathology, Shanxi Fenyang Hospital, Fenyang, Shanxi Province, People’s Republic of China; 3Department of Pathology, Shanxi Cancer Hospital (Shanxi Institute of Oncology), Taiyuan, Shanxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huiwen Wu; Yirong XuDepartment of Pathology, Fenyang College of Shanxi Medical University, No. 16 Xueyuan Road, Fenyang, 032200, Shanxi Province, People’s Republic of ChinaTel +86 151 3588 2981Email yirongxu@163.comPurpose: To investigate PD-L1 protein expression and gene amplification in lung squamous cell carcinoma (LUSC) and analyse their correlation with the clinicopathological characteristics and prognosis of LUSC patients.Patients and Methods: Tissue samples from 164 LUSC patients were collected. PD-L1 protein was detected by immunochemistry (IHC), and PD-L1 gene amplification was investigated by fluorescence in situ hybridization in LUSC patients.Results: The positive expression rate of PD-L1 in LUSC was 47.6% (78/164), and the amplification rate of PD-L1 was 6.7% (11/164); both rates were higher than those of paratumor tissue. Both PD-L1 positive expression and gene amplification were correlated with clinical stage and lymph node metastasis (P< 0.05). PD-L1 protein expression, PD-L1 gene amplification, late stage, lymph node metastasis and distant metastasis were significantly correlated with the prognosis of patients. Among these factors, late stage, lymph node metastasis, PD-L1 protein expression and PD-L1 gene amplification were independent prognostic factors for LUSC.Conclusion: Positive PD-L1 protein expression and gene amplification are involved in the malignant progression and metastasis of LUSC. Both PD-L1 protein expression and gene amplification are associated with poor prognosis.Keywords: PD-L1 protein expression, PD-L1 gene amplification, lung squamous cell carcinoma, prognosis

Yan Zhou,1,&ast; Yishu Xue,1,&ast; Aihua Bao,1,&ast; Lei Han,1 Wuping Bao,1 Chao Xia,2 Xue Tian,1 Min Zhang1 1Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200081, People’s Republic of China; 2Department of Gerontology, Xin Hua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min ZhangDepartment of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai, 200080, People’s Republic of ChinaTel +86 21 63071428Email min.zhang@shgh.cnBackground and Objective: Vitamin D is involved in various physiological and pathological processes, including inflammation and autophagy. We aimed to investigate the effects of dietary vitamin D deficiency or supplementation initiated in lactation and early life on inflammation and autophagy in an ovalbumin (OVA) mouse model.Methods: Female BALB/c were fed with vitamin D-deficient, sufficient or supplemented diets throughout lactation and their offspring followed the same diet after weaning. Offspring were then sensitized and challenged with OVA, airway resistance (RL) was measured, and their serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected. Alveolar macrophages (AMs) were isolated from lung tissue and cultured with different concentrations of 1,25(OH)2D3. The expressions of autophagy-related (ATG) proteins including light-chain 3 (LC3), Beclin-1, and ATG5, and NF-κB p65 in lung tissue and AMs were measured.Results: OVA sensitization and challenge induced dramatic allergic airway inflammation and higher RL in the vitamin D-deficient group compared with vitamin D-sufficient or the supplemented group. The expression of ATGs including LC3, Beclin-1, and ATG5, and NF-κB p65 in lung tissue in the vitamin D-deficient OVA-mediated group was increased compared with vitamin D-supplemented OVA-mediated group. There was correlation between the expression of LC3 mRNA and inflammatory cell numbers and cytokines in BALF. In vitro, 1,25(OH)2D3 also regulated the expression of LC3, Beclin-1, ATG5, and NF-κB p65 mRNA in AMs in a time- and dose-dependent manner.Conclusion: Deficiency of vitamin D in early life may aggravate allergic airway inflammation, and maintaining sufficient vitamin D during early life is necessary for lung health. Vitamin D may modulate autophagy in lungs of OVA sensitized/challenged mice, thus playing a protective role in OVA-induced allergic airway inflammation.Keywords: vitamin D, allergic airway inflammation, asthma, autophagy, LC3, Beclin-1, ATG5

Abstract Background Incretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagon-like peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect. Methods We recruited 41 patients having percutaneous coronary intervention (PCI) for stable angina and allocated them into four groups administering a specific study-related infusion following successful PCI: GLP-1 infusion (Group G) (n = 10); Placebo, normal saline infusion (Group P) (n = 11); GLP-1 + Theophylline infusion (Group GT) (n = 10); and Theophylline infusion (Group T) (n = 10). A pressure wire assessment of coronary distal pressure and flow velocity (thermodilution transit time—Tmn) at rest and hyperaemia was performed after PCI and repeated following the study infusion to derive basal and index of microvascular resistance (BMR and IMR). Results There were no significant differences in the demographics of patients recruited to our study. Most of the patients were not diabetic. GLP-1 caused significant reduction of resting Tmn that was not attenuated by theophylline: mean delta Tmn (SD) group G − 0.23 s (0.27) versus group GT − 0.18 s (0.37), p = 0.65. Theophylline alone (group T) did not significantly alter resting flow velocity compared to group GT: delta Tmn in group T 0.04 s (0.15), p = 0.30. The resulting decrease in BMR observed in group G persisted in group GT: − 20.83 mmHg s (24.54 vs. − 21.20 mmHg s (30.41), p = 0.97. GLP-1 did not increase circulating adenosine levels in group GT more than group T: delta median adenosine − 2.0 ng/ml (− 117.1, 14.8) versus − 0.5 ng/ml (− 19.6, 9.4); p = 0.60. Conclusion The vasodilatory effect of GLP-1 is not abolished by theophylline and GLP-1 does not increase adenosine levels, indicating an adenosine-independent mechanism of GLP-1 coronary vasodilatation. Trial registration: The local research ethics committee approved the study (National Research Ethics Service-NRES Committee, East of England): REC reference 14/EE/0018. The study was performed according to institutional guidelines, was registered on http://www.clinicaltrials.gov (unique identifier: NCT03502083) and the study conformed to the principles outlined in the Declaration of Helsinki.

Rongli Cui,* Zhiqiang Song,* Baojun Suo, Xueli Tian, Yan Xue, Lingmei Meng, Zhanyue Niu, Zhu Jin, Hejun Zhang, Liya Zhou Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liya ZhouDepartment of Gastroenterology, Peking University Third Hospital, 49 Road Garden, Haidian District, Beijing, 100191, People’s Republic of ChinaTel +86-13911827827Fax +86-10-82265021Email zhouliya123456@163.comBackground: It has not been fully confirmed whether the detection of Helicobacter pylori resistance gene mutation can replace antibiotic drug sensitivity test to guide the clinical individualized treatment. Therefore, we have studied this aspect and discussed the application value of antibiotic sensitivity gene test.Materials and Methods: The biopsy specimen of gastric mucosa from the patients examined by endoscopy and positive for rapid urease test were collected continuously for histopathological analysis, H. pylori culture, antibiotic drug sensitivity test (E-test drug sensitivity test), and antibiotic sensitivity gene test (high-throughput nucleotide sequencing). The participants received triple plus bismuth solution eradication treatment (esomeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth potassium citrate 220 mg, twice daily for 14 days) for follow-up, and the eradication effect was determined.Results: The 551/602 subjects, who met the inclusion criteria, were subjected to culture for H. pylori and antibiotic drug sensitivity determination; among them 506 were cultured successfully. The results showed that the resistance rates of H. pylori were 38.9% for clarithromycin and 31.0% for levofloxacin. In 489 H. pylori strains, the mutations were detected in clarithromycin and levofloxacin resistance genes, indicating the genotype resistance. The resistance genes of clarithromycin and levofloxacin were consistent with phenotype resistance with respect to sensitivity (81.2% and 69.7% for clarithromycin and levofloxacin, respectively) and specificity (88.9% and 93.7% for clarithromycin and levofloxacin, respectively). The eradication rate of H. pylori in the clarithromycin-resistant group was significantly lower than that in the sensitive group (ITT: 52.1% vs 85.0%, P < 0.001).Conclusion: A correlation was established between the resistance genes of clarithromycin and levofloxacin and their phenotypic resistance and clinical efficacy. The detection of H. pylori resistance genes has a good clinical application prospect.Keywords: Helicobacter pylori, drug resistance, clarithromycin, levofloxacin, mutation, high-throughput nucleotide sequencing

Yifang Li, Yanzhen Chen, Xing Tian, Shanshan Zhang, Jian Jiao Department of Gastroenterolgy & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, People’s Republic of ChinaCorrespondence: Jian JiaoDepartment of Gastroenterology & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, People’s Republic of ChinaTel +86 13756009567Fax +86 0431-84995850Email jjian@jlu.edu.cnObjective: Non-alcoholic fatty liver disease (NAFLD), previously thought to predominantly affect obese individuals, has also been shown to occur in subjects who have a relatively normal body mass index (BMI). Due to the normal BMI, non-obese NAFLD are easily to be ignored and eventually lead to potential liver injuries.Methods: A population-based cross-sectional study was conducted on 1608 cases with normal serum alanine aminotransferase (ALT) levels who were divided into an obese group (BMI ≥ 25 kg/m2) and a non-obese group (BMI < 25 kg/m2). NAFLD was diagnosed by ultrasound and Fibro Scan examination. Non-obese populations were divided into NAFLD group (CAP ≥ 240 db/m) and non-NAFLD group (CAP < 240 db/m). The incidence of NAFLD in the obese and non-obese populations and constituent ratios of genders, age, and serum levels of triglycerides (TG), cholesterol (CHOL), and blood glucose were compared. Risk factors of NAFLD in non-obese people were analyzed by multivariate logistics regression.Results: The occurrence of NAFLD was higher in the obese group than in the non-obese group, regardless of gender (P < 0.001). In the non-obese group, the occurrence of NAFLD in female patients was lower than that in male (P=0.001). The occurrence of NAFLD increased with age, with 50– 59 years being the peak age of incidence in both male and female. The peak age of NAFLD occurrence in non-obese male patients was more delayed than that in obese male patients. BMI (OR=1.311, P=0.000) and TG (OR=2.545, P=0.000) were risk factors for NAFLD in the non-obese population.Conclusion: Compared with obese population, the incidence of NAFLD in non-obese population was relatively low and more frequently in male than in female, the peak age of NAFLD occurrence in non-obese male patients was also delayed. BMI and TG should still be controlled to avoid the occurrence of NAFLD although the BMI of such patients is normal.Keywords: obese, non-obese, non-alcoholic liver disease, gender, characteristic

Xiangkuo Zheng,1,* Renchi Fang,2,* Chong Wang,3 Xuebin Tian,4 Jie Lin,1 Weiliang Zeng,4 Tieli Zhou,1 Chunquan Xu1 1Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, People’s Republic of China; 3Department of Laboratory Medicine, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 4School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunquan Xu; Tieli ZhouDepartment of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of ChinaTel +86-577-5557-9725; +86-577-8668-9885Email 417242374@qq.com; wyztli@163.comBackground: Staphylococcus aureus (S. aureus) is a major contributor to nosocomial and community-acquired infections. S. aureus small colony variants (SCVs) which changed in relevant phenotype have made more limited and difficult for therapeutic options against S. aureus infections increasingly. Rifampicin is considered as the “last-resort” antibiotic against S. aureus. Our study investigated resistance profiles and biological characteristics of rifampicin-resistant S. aureus SCVs.Methods: We collected S. aureus SCVs that were selected from 41 rifampicin-resistant clinical isolates. Then, biological characteristics, resistance spectrum, and rifampicin resistance mechanisms of tested S. aureus SCVs and corresponding parental strains were investigated by classic microbiological methods, agar dilution method, polymerase chain reaction (PCR). Moreover, the fitness cost of S. aureus SCVs, including growth, biofilm formation ability, and virulence profile, was also determined by bacterial growth curve assay, biofilm formation assay, and Galleria mellonella infection model.Results: There were three S. aureus SCVs (JP310 SCVs, JP1450 SCVs, JP1486 SCVs) that were selected from 41 rifampicin-resistant S. aureus. S. aureus SCVs colonies were tiny, with decreased pigmentation, and the hemolysis circle was not obvious compared with corresponding parental strains. And SCVs could not be restored to normal-colony phenotype after hemin, menaquinone, or thymidine supplementation. Different rpoB mutations occurred in JP1486 SCVs. Antimicrobial susceptibility testing revealed MICs of SCVs were higher than corresponding parental strains. Besides, the growth ability and virulence of SCVs were lower, and biofilm formation ability of which increased compared with parental strains.Conclusion: S. aureus SCVs share the rifampicin resistance mechanisms with parental strains, although there were some differences in the position of rpoB mutations. Moreover, we found that the biological characteristics of SCVs were significantly different from corresponding parental strains. In contrast, decreased susceptibility to other antibiotics of SCVs was observed during phenotype switch. Furthermore, SCVs incur the fitness cost.Keywords: Staphylococcus aureus, small-colony variant, rifampicin resistance, resistance profile, biological characteristic

Guanghui Cao, Chan Zhang, Xiangyong Tian, Gaopeng Jing, Xiaolin Zhou, Tianzhong Yan Department of Urology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, 450003, People’s Republic of ChinaCorrespondence: Tianzhong YanDepartment of Urology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, No. 7, Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People’s Republic of ChinaTel +86-15515920410Email yantianzhong74@126.comBackground: Dysregulation of circular RNAs (circRNAs) is associated with bladder cancer progression. Nevertheless, the mechanisms of circRNA centrosomal protein 128 (circCEP128) underlying bladder cancer progression remain poorly understood.Methods: The levels of circCEP128, microRNA-515-5p (miR-515-5p) and syndecan-1 (SDC1) were determined via reverse transcription-quantitative polymerase chain reaction or Western blot. The effects of circCEP128, miR-515-5p and SDC1 on bladder cancer progression were investigated via MTT and colony formation assays, flow cytometry and transwell analysis and subcutaneous xenograft experiments. The interactions between miR-515-5p and circCEP128 or SDC1 were examined through bioinformatics prediction and luciferase reporter assay.Results: circCEP128 and SDC1 were highly expressed and miR-515-5p was low expressed in bladder cancer tissues and cells. circCEP128 knockdown hindered cell proliferation, migration and invasion and promoted cell apoptosis in bladder cancer. circCEP128 loss increased miR-515-5p expression through direct interaction in bladder cancer cells. MiR-515-5p depletion mitigated the influences of circCEP128 knockdown on bladder cancer cell phenotypes. SDC1 was a direct target of miR-515-5p. circCEP128 positively regulated SDC1 expression via miR-515-5p. MiR-515-5p restrained the malignant progression of bladder cancer cells by decreasing SDC1 expression. circCEP128 knockdown hindered the growth of bladder cancer xenograft tumors by up-regulating miR-515-5p and down-regulating SDC1.Conclusion: circCEP128 knockdown hampered the tumorigenesis and progression of bladder cancer by regulating miR-515-5p/SDC1 axis in vitro and in vivo, deepening our understanding on the molecular mechanisms of circCEP128 in bladder cancer.Keywords: bladder cancer, circCEP128, microRNA-515-5p, SDC1

Xiaoning Lin,1,* Rong Huang,2,* Yanlin Huang,1,* Kai Wang,3 Heng Li,1 Yiheng Bao,1 Chaohui Wu,4 Yi Zhang,5 Xinhua Tian,1 Xiaomin Wang6 1Department of Neurosurgery, Zhongshan Hospital Xiamen University, Xiamen, 361004, People’s Republic of China; 2Department of Child Health, Women and Children’s Hospital, Xiamen University, Xiamen, 361003, People’s Republic of China; 3School of Public Health, Xiamen University, Xiamen, 361102, People’s Republic of China; 4Department of Thoracic Surgery, Zhongshan Hospital Xiamen University, Xiamen, 361004, People’s Republic of China; 5Department of Breast Surgery, Xiamen TCM Hospital, Xiamen, 361001, People’s Republic of China; 6Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital Xiamen University, Xiamen, 361004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaomin WangFujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen University Affiliated Zhongshan Hospital, Xiamen, 361004, People’s Republic of ChinaEmail wxm2203@xmu.edu.cnXinhua TianDepartment of Neurosurgery, Zhongshan Hospital Xiamen University, Xiamen, 361004, People’s Republic of ChinaEmail txhmd@163.comIntroduction: Sonodynamic therapy (SDT) has good targeting and non-invasive advantages in the treatment of solid cancers, and checkpoint blockade immunotherapy is also a promising treatment to cure cancer. However, their antitumor effects are not sufficient due to some inherent factors. Some studies that combined SDT with immunotherapy or nanoparticles have managed to enhance its efficiency to treat cancers.Methods: In this work, an effective therapeutic strategy that can potentiate the antitumor efficacy of anti-PD-L1 antibody (aPD-L1) is developed by the use of cascade immuno-sonodynamic therapy (immuno-SDT). Titanium dioxide (TiO2), a nanostructured agent for SDT, sonosensitizer Chlorin e6 (Ce6), and immunological adjuvant CpG oligonucleotide (CpG ODN), are used to construct a multifunctional nanosonosensitizer (TiO2-Ce6-CpG). Then, we conducted in vitro and in vivo experiments to explore the antitumor effect of TiO2-Ce6-CpG under ultrasound (US) treatment.Results: The characterization tests showed that the nanosonosensitizers are polycrystalline structure with homogeneous sizes, resulting in a good drug loading efficiency. The innovative nanosonosensitizers (TiO2-Ce6-CpG) can not only effectively inhibit tumor growth but also stimulate the immune system to activate the adaptive immune responses, using the TiO2-Ce6 to augment SDT and the immune adjuvant CpG to enhance the immune response. After combined with the aPD-L1, the synergistic effect could not only efficiently inhibit the primary tumor growth but also lead to an inhibition of the non-irradiated pre-existing distant tumors by inducing a strong tumor-specific immune response.Conclusion: In this study, we present an effective strategy for tumor treatment by combining nanosonosensitizer-augmented SDT and aPD-L1 checkpoint blockade. This work provides a promising strategy and offers a new vision for treating malignant tumors.Keywords: cancer immunotherapy, sonodynamic therapy, titanium dioxide nanoparticles, sonosensitizer, checkpoint blockade

Xiangyang Tian,1 Shuyuan Li,2 Guoyan Ge2 1Department of Oncology, Peace Hospital, Changzhi Medical College, Changzhi, Shanxi Province, 046000, People’s Republic of China; 2Department of Tumor Spleen and Stomach, Hospital of Traditional Chinese Medicine of Changzhi City, Changzhi, Shanxi Province, 046013, People’s Republic of ChinaCorrespondence: Xiangyang TianPeace Hospital, Changzhi Medical College, No. 110 Yan’an South Road, Luzhou District, Changzhi, Shanxi Province, 046000, People’s Republic of ChinaEmail xiangyangd@163.comBackground: Colorectal cancer (CRC) is a common digestive system malignancy. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers.Objective: We aimed to study the role of apatinib in ferroptosis of CRC cells and its potential mechanisms.Materials and Methods: Human CRC HCT116 cells were exposed to apatinib. Cell viability was examined using a CCK-8 kit. The concentrations of intracellular iron and reactive oxygen species (ROS) were detected using kits. Additionally, Western blot analysis was used to determine the expression of ferroptosis-related proteins. Elongation of very long-chain fatty acids family member 6 (ELOVL6) was one of the targets of apatinib predicted by SwissTargetPrediction. Therefore, ELOVL6 expression was evaluated after treatment with apatinib. Subsequently, the effects of ELOVL6 overexpression on ferroptosis of HCT116 cells were investigated. Finally, STRING database was applied to predict the potential proteins interacting with ELOVL6, and co-immunoprecipitation (co-IP) assay was applied for confirmation.Results: Results indicated that apatinib decreased cell viability and increased the contents of intracellular iron ROS. Moreover, significantly upregulated ACSL4 expression was observed, accompanied by notable downregulation of GPx4 and FTH1 expression after apatinib exposure. Furthermore, ELOVL6 expression was remarkably enhanced in HCT116 cells, which was dramatically inhibited under apatinib intervention. ELOVL6 overexpression reversed the effects of apatinib on cell viability and ferroptosis of HCT116 cells. Moreover, ACSL4, a vital regulator of ferroptosis, could interact with ELOVL6 directly, which was confirmed by the result of co-IP.Conclusion: These findings demonstrated that apatinib promoted ferroptosis in CRC cells by targeting ELOVL6/ACSL4, providing a new mechanism support for apatinib application in the clinical treatment of CRC.Keywords: colorectal cancer, apatinib, ferroptosis, reactive oxygen species, ELOVL6

Ting Yang1 1, Yaqun Zhou1 1, Wen Zhang1 1, Longqing Zhang1 1, Shuping Chen1 1, Chao Chen1 1, Feng Gao1 1, Hui Yang1 1, Anne Manyande2 2, Jie Wang3 3, Yuke Tian1 1, Xuebi Tian1 1 1Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2School of Human and Social Sciences, University of West London, London, UK; 3State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Center for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Xuebi TianDepartment of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, Hubei, 430030, People’s Republic of ChinaTel +862783663423Fax +862783662853Email Tianxb@hust.edu.cnIntroduction: Cancer-induced bone pain (CIBP) is acknowledged as a multifactorial chronic pain that tortures advanced cancer patients, but existing treatment strategies for CIBP have not been satisfactory yet. Investigators have demonstrated that the activation of α 7-nAChRs exerts analgesic effects in some chronic pain models. However, the role of spinal α 7-nAChRs in CIBP remains unknown. This study was designed to investigate the role of α 7-nAChRs in a well-established CIBP model induced by Walker 256 rat mammary gland carcinoma cells.Methods: The paw withdrawal threshold (PWT) of the ipsilateral hind paw was measured using von Frey filament. The expressions of spinal α 7-nAChRs and NF-κB were measured with Western blotting analysis. Immunofluorescence was employed to detect the expression of α 7-nAChRs and co-expressed of α 7-nAChRs with NeuN or GFAP or Iba1.Results: Experiment results showed that the expression of spinal α 7-nAChRs was significantly downregulated over time in CIBP rats, and in both CIBP rats and sham rats, most of the α 7-nAChRs located in neurons. Behavioral data suggested PNU-282,987, a selective α 7-nAChRs agonist, dose-dependently produced analgesic effect and positive allosteric modulator could intensify its effects. Further, repeated administration of PNU-282,987 reversed the expression of α 7-nAChRs, inhibited the nuclear factor kappa B (NF-κB) signaling pathway, and attenuates CIBP-induced mechanical allodynia state as well.Conclusion: These results suggest that the reduced expression of spinal α 7-nAChRs contributes to the maintenance of CIBP by upregulating NF-κB expression, which implying a novel pharmacological therapeutic target for the treatment of CIBP.Keywords: cancer-induced bone pain, α 7-nAChR, NF-κB, PNU-282,987

Zhan T, Zhu Q, Han Z, et al. Cancer Manag Res. 2020;12:1483–1492. The authors have advised Figure 4C on page 1490 is incorrect. Due to an error at the time of figure assembly Figure 4D and Figure 4C were inadvertently duplicated. The correct Figure 4 is shown below. Figure 4 miR-455-3p restrains Wnt/β-catenin signaling via TAZ. (A and B) Expression of β-catenin, Cyclin D and C-myc in pancreatic cancer cells transfected with miR-455-3p mimic or miR-455-3p mimic plus TAZ expression vector was detected by qPCR. (C and D) Western blot analysis of β-catenin, Cyclin D and C-myc in PANC1 and MIAPaCa2 cells transfected with miR-455-3p mimic or miR-455-3p mimic plus TAZ expression vector β-actin is used as loading control vs miR-455-3p mimics/mimic control group, miR-455-3p mimics/miR-455-3p mimics+TAZ group. *p

Background Post–percutaneous coronary intervention (PCI) fractional flow reserve ≥0.90 is an accepted marker of procedural success, and a cutoff of ≥0.95 has recently been proposed for post‐PCI instantaneous wave‐free ratio. However, stability of nonhyperemic pressure ratios (NHPRs) post‐PCI is not well characterized, and transient reactive submaximal hyperemia post‐PCI may affect their precision. We performed this study to assess stability and reproducibility of NHPRs post‐PCI. Methods and Results Fifty‐seven patients (age, 63.77±10.67 years; men, 71%) underwent hemodynamic assessment immediately post‐PCI and then after a recovery period of 10, 20, and 30 minutes and repeated at 3 months. Manual offline analysis was performed to derive resting and hyperemic pressure indexes (Pd/Pa resting pressure gradient, mathematically derived instantaneous wave‐free ratio, resting full cycle ratio, and fractional flow reserve) and microcirculatory resistances (basal microvascular resistance and index of microvascular resistance). Transient submaximal hyperemia occurring post‐PCI was demonstrated by longer thermodilution time at 30 minutes compared with immediately post‐PCI; mean difference of thermodilution time was 0.17 seconds (95% CI, 0.07–0.26 seconds; P=0.04). Basal microcirculatory resistance was also higher at 30 minutes than immediately post‐PCI; mean difference of basal microvascular resistance was 10.89 mm Hg.s (95% CI, 2.25–19.52 mm Hg.s; P=0.04). Despite this, group analysis confirmed no significant differences in the values of resting whole cycle pressure ratios (Pd/Pa and resting full cycle ratio) as well as diastolic pressure ratios (diastolic pressure ratio and mathematically derived instantaneous wave‐free ratio). Whole cardiac cycle NHPRs demonstrated the best overall stability post‐PCI, and 1 in 5 repeated diastolic NHPRs crossed the clinical decision threshold. Conclusions Whole cycle NHPRs demonstrate better reproducibility and clinical precision post‐PCI than diastolic NHPRs, possibly because of less perturbation from predominantly diastolic reactive hyperemia and left ventricular stunning. Registration URL: https://clinicaltrials.gov/ct2/show/NCT03502083; Unique identifier: NCT03502083 and URL: https://clinicaltrials.gov/ct2/show/NCT03076476; Unique identifier: NCT03076476.