Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 23 3 2024 04 27 235 244 Hami Ashraf Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran Farid Kosari Department of Pathology and Laboratory Medicine, Tehran University of Medical Sciences, Tehran, Iran 2023 08 29 2024 02 05 Graft-versus-host disease (GvHD), a frequent and severe complication following allogeneic hematopoietic stem cell transplantation, presents substantial morbidity and mortality risks. The crucial role of histopathological examination in diagnosing and grading GvHD, particularly within animal models, is pivotal for elucidating disease mechanisms and assessing emerging therapies. This systematic review aims to critically evaluate the various grading systems for GvHD in animal models, emphasizing histopathological characteristics. In this endeavor, we meticulously examined original research articles sourced from PubMed, Scopus, Web of Science, and Google Scholar. Our findings reveal a diverse array of grading systems, each differing in the tissues examined, criteria evaluated, severity scoring scales, and the granularity of the information provided. Predominantly, skin, liver, and gut tissues are assessed, though some systems also incorporate lung and thymus evaluations. This review will delve into the alignment between clinical and histological grading in animal models of GvHD, also casting light on prospective advancements and the impact of technological progress. In conclusion, our analysis underscores the imperative need for uniform criteria and consistent application of grading systems. Such standardization is essential to foster comparability across studies and enhance the translation of preclinical discoveries into clinical applications. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/3907 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/3907/2070

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 23 3 2024 05 27 245 256 Emel Atayik Department of Allergy and Clinical Immunology, Konya City Hospital, University of Health Sciences, Konya, Turkey Gokhan Aytekin Department of Allergy and Clinical Immunology, Konya City Hospital, University of Health Sciences, Konya, Turkey İsa Aydin Department of ENT, University of Health Sciences, Konya City Hospital, Konya, Turkey Etem Omeroglu Department of Pathology, Konya City Hospital, University of Health Sciences, Konya, Turkey 2023 01 22 2024 01 29 Chronic rhinosinusitis whit nasal polyps (CRSwNP) is the most common comorbid disease accompanying asthma. Omalizumab is a recombinant anti-immunoglobulin (Ig) E antibody, and studies suggest that omalizumab may also affect CRSwNP regardless of asthma. We aimed to assess the effect of omalizumab treatment on CRSwNP accompanying severe allergic asthma (SAA) patients. Clinical data including spirometry measurements, serum/nasal secretion biomarker levels were collected. NP scores and CRS scores (Lund-Mancay [LM] scores) were also recorded before omalizumab treatment, as well as at the 4th and 12th months of omalizumab treatment. Twenty-one patients with both CRSwNP and SAA who underwent omalizumab therapy were assessed. There was a significant difference among forced expiratory volume (FEV1), ACT scores, NP scores, LM scores, serum IgE, and blood eosinophil levels of the patients before omalizumab therapy at the 4th and 12th months of omalizumab treatment. A significant negative correlation was observed between ∆FEV1 and ∆NP scores (r=−0.485), between ∆ACT and ∆NP scores (r=−0.469), and ∆ACT and ∆LM scores (r=−0.436). When we grouped the patients who benefited from 1 year of omalizumab therapy and those who did not in terms of NP, there was no difference between the two groups related to local eosinophil and local IgE levels in the nasal polyp biopsy. Omalizumab treatment is effective for asthma and CRSwNP in patients with CRSwNP accompanied by SAA. Improvement in asthma is associated with improvement in CRSwNP. The efficacy of omalizumab on NP in patients with CRSwNP accompanied by SAA is independent of local IgE and eosinophil counts. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/3752 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/3752/2071

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 23 3 2024 05 27 257 271 EN Hamid Nickho Immunology Research Center, Institute of Immunology and Infectious Disease, Iran University of Medical Sciences, Tehran, Iran AND Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran Reza Falak Immunology Research Center, Institute of Immunology and Infectious Disease, Iran University of Medical Sciences, Tehran, Iran AND Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran Fereshteh Rezagholizadeh Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran AND Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran AND Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran Majid Khoshmirsafa Immunology Research Center, Institute of Immunology and Infectious Disease, Iran University of Medical Sciences, Tehran, Iran AND Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran Mohammad Taghi Joghataei Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran AND Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran AND Department of Innovation in Medical Education (DIME), Faculty of Medicine, University of Ottawa, Ottawa, Canada Shabnam Mollazadeh Ghomi Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran AND Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran Elaheh Safari Immunology Research Center, Institute of Immunology and Infectious Disease, Iran University of Medical Sciences, Tehran, Iran AND Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran 2023 10 23 2024 01 02 V-domain Imuunoglobulin suppressor of T-cell activation (VISTA) seems a promising immune checkpoint target in cancer treatment; however, its prognostic significance in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Herein, 29 fresh PDAC tissue samples were used to evaluate the mRNA expression level of VISTA by real-time polymerase chain reaction (PCR). Besides, 40 formalin-fixed paraffin-embedded PDAC tissues were collected to evaluate VISTA protein expression by immunohistochemistry. Real-time PCR indicated that high expression of VISTA was significantly correlated with advanced stages of the cancer, based on the tumor/node/metastasis (TNM) stagingand tumor cell differentiation.  Immunohistochemistry results also showed significant correlation of the elevated cytoplasmic expression of VISTA with advanced TNM stages, older age of the patients and was a worsening indicator, regarding the disease-specific survival. In conclusion, we found that the expression levels of VISTA can be a potential prognostic biomarker in PDAC patients and its elevated levels are correlated with poor prognostic outcomes. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/3935 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/3935/2072

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 23 3 2024 05 27 272 287 Nasrin Noshadi Department of Biology, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran AND Department of Biology, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran Ramin Yaghoubi Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Afsoon afshari Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Mohsen Forouzanfar Department of Biology, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran Saeede Soleimanian Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran 2024 01 03 2024 03 28 Reactivation of Polyomavirus BK (BKPyV) is related to reduction of T cells response in kidney transplant recipients (KTRs). Here, we examined the differentiation of CD4+ T cells subsets in response to BKPyV KTRs, using the BKPyV VP1 (viral capsid protein 1) as a stimulator. We categorized our samples into three distinct groups: 1. Reactive BKPyV (BKPyV+), 2. non-reactive (BKPyV-) KTRs and 3. Healthy controls. BKPyV- KTRs and healthy controls stimulated with VP1 and BKPyV+ unstimulated with VP1. The human CD4+ T cells was stimulation with VP1-Ag. The proportion of CD4+ T lymphocytes and their various subsets, including naive T cells, central memory T cells (TCM), and effector memory T cells (TEM) was measured using flowcytometry. BKPyV- KTRs VP1+ indicated significantly lower TCM CD4+ T cells in contrast with both BKPyV+ KTRs VP1-, and healthy controls VP1+. This indicates that VP1 stimulation may reduce TCM cell levels in these patients. The percentage of TEM in the BKPyV- KTRs VP1+ group was significantly less prevalent than the BKPyV+ KTRs VP1- group. The percentage of TEM cells in BKPyV+ KTRs VP1- was significantly lower than the healthy controls VP1+. Stimulation with VP1 protein significantly increased the frequency of cytotoxic CD4+ T cells in BKPyV- KTRs VP1+ compared to BKPyV+ KTRs VP1-. The present research has shown that the VP1 stimulation of CD4+ T cells can induce cytotoxic CD4+ T cells responses that may help overcome BKPyV infection in KTRs. However, VP1 stimulation may also differentially affect TCM and TEM CD4+ T cells subsets. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/3984 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/3984/2073

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 23 3 2024 05 27 288 298 EN Ava Misaghian Department of Immunology, School of Medicine Ahvaz Jundishapur University of Medical sciences, Ahvaz, Iran Ata A Ghadiri Department of Immunology, School of Medicine Ahvaz Jundishapur University of Medical sciences, Ahvaz, Iran AND Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Ali Asadirad Department of Immunology, School of Medicine Ahvaz Jundishapur University of Medical sciences, Ahvaz, Iran AND Cancer Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Sareh Amirzadeh Department of Infertility, Infertility Research and Treatment Center of ACECR, Ahvaz, Iran Afshin Amari Department of Immunology, School of Medicine Ahvaz Jundishapur University of Medical sciences, Ahvaz, Iran AND Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 2024 01 11 2024 04 17 Mesenchymal stem cells (MSCs) are a potential cell therapy candidate for autoimmune and inflammatory diseases due to their multilineage capacity and immune modulating function. MSCs exert immunomodulatory effects on target cells through the secretion of exosomes. Inflammatory conditions such as Toll-like receptors (TLRs) engagement can change the biological functions and immunomodulatory activities of MSCs and the contents of exosomes derived from MSCs are changed. Regulatory T-cells (Treg) are crucial for maintaining immune cell homeostasis and self-tolerance. Our study aimed to investigate the impact of isolated exosomes from hWJ-MSCs that were treated with Poly (I:C) on regulatory CD4 CD25 Foxp3 T-cells. MSCs were harvested from human umbilical cord Wharton’s Jelly by explant method. Stem cells were treated by Polyinosinic-polycytidylic acid sodium salt (Poly (I:C)) for 48 hours. Exosomes were extracted from supernatant of cells and Scanning electron microscopy (SEM) and Dynamic light scattering (DLS) were performed for them. Peripheral blood mononuclear cells (PBMCs) isolated from the healthy donors were stimulated with PHA (Phytohemagglutinin) and co-cultured with Poly (I:C) treated hWJ-MSCs derived exosome and untreated hWJ-MSCs derived exosome or without hWJ-MSCs-derived exosome for 6 days. Then, frequency of CD4+CD25+ Foxp3+ regulatory T cells was measured by flow cytometry. Our results showed that exosomes isolated from Poly (I:C) treated hWJ-MSCs significantly increased frequency of CD4+CD25+ Foxp3+ regulatory T cells compared to the untreated hWJ-MSCs derived exosome group and control group. Stimulation by TLR3 improved the anti-inflammatory features of exosomes that were derived from hWJ-MSCs by increasing the frequency of Treg cells. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/3996 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/3996/2074

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 23 3 2024 05 27 299 310 Yaqi Wang Medical School of Hebei University, Baoding, China AND Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases, Baoding, China Min Zhang Medical School of Hebei University, Baoding, China AND Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases, Baoding, China Shengde Chen Medical School of Hebei University, Baoding, China AND Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases, Baoding, China Zheng Li Affiliated Hospital of Hebei University, Baoding, China Ming Meng Medical School of Hebei University, Baoding, China AND Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases, Baoding, China 2023 11 27 2024 02 16 Rheumatoid arthritis (RA) is a type of autoimmune disease that results in immune disorder and excessive inflammatory response due to a reduction of self-tolerance. Invariant natural killer T (iNKT) cells can effectively alleviate clinical symptoms and hyper-inflammation in RA, but their mechanism of action is not well-defined. This study aims to investigate the mechanism of iNKT cell therapy for RA. We established a DBA/1 mouse model for RA and treated it with specific iNKT cells. A cytometric bead array was used to measure the amounts of cytokines in the serum. Flow cytometry was then employed to identify different subsets of helper T cells (Th), the frequency of conventional dendritic cells (cDC), the expression of CD80, CD86, programmed cell death ligand 1 (PD-L1), and PD-L2 on cDC surfaces, and associated pathway proteins. iNKT cell treatment reduced Th1/Th2 and Th17/ regulatory T (Treg) cell ratios while increasing interleukin-4 (IL-4) andg recovery time. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4338 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4338/2267

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 25 3 2026 04 22 345 354 Huadong Zeng Department of Respiratory and Critical Care Medicine, Shenzhen Hospital of Southern Medical University, Shenzhen, China Xuan Huang Department of Respiratory and Critical Care Medicine, Shenzhen Hospital of Southern Medical University, Shenzhen, China Guansheng Zeng Department of Respiratory and Critical Care Medicine, Shenzhen Hospital of Southern Medical University, Shenzhen, China Xian Qiu Health Management Center, Southern University of Science and Technology Hospital, Shenzhen, China Xiaoli Li Department of Respiratory and Critical Care Medicine, Shenzhen Hospital of Southern Medical University, Shenzhen, China Dandan Zhang Department of Respiratory and Critical Care Medicine, Shenzhen Hospital of Southern Medical University, Shenzhen, China Shaoqiang Zheng Department of Respiratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China 2025 02 11 2025 08 31 T helper 1 (TH1) and T helper 2 (TH2) cells can secrete various proinflammatory and anti-inflammatory factors, which can serve as indicators for predicting the severity of pneumonia. However, they are rarely used in combination with procalcitonin (PCT) and high-sensitivity C-reactive protein (hsCRP) detection to predict the severity of pneumonia. The purpose of this study is to investigate the combination of serum TH1/TH2 cytokines, PCT, and hsCRP for predicting the severity of community-acquired pneumonia (CAP). This study observed 58 inpatients with CAP. Analyses were conducted on the serum levels of TH1/TH2 cytokines, PCT, and hsCRP; imaging examination results; underlying diseases; pathogens; and the pneumonia severity index (PSI). The severe pneumonia group showed significantly higher PSI scores, age, and complication rates. Serum IL-2 was notably elevated in severe cases, while a combination of PCT, IL-4, TNF-α, and IFN-γ effectively predicted severe pneumonia, with an AUC of 0.712. Specific alterations in cytokines and biomarkers were identified as risk factors for higher PSI, complications, and prolonged hospitalization. The combined detection of PCT, IL-4, TNF-α, and IFN-γ provides a potential tool for predicting severe CAP, and distinct biomarker profiles are associated with different clinical outcomes. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4340 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4340/2268

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 25 3 2026 04 22 355 362 EN Amir Pedram Moghis Department of Medicine, Faculty of Medicine, Hamadan University Medical Sciences, Hamadan, Iran Mehdi Behzad Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran Alireza Soltanian Modeling of Noncommunicable Diseases Research Center, Hamadan University of Medical Sciences, Hamadan, Iran Shiva Borzouei Department of Endocrinology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran 2025 05 26 2025 10 20 Type 2 diabetes (T2D) is defined by persistent inflammatory processes. This study evaluated the anti-inflammatory properties of empagliflozin in combination with metformin therapy in patients with T2D. In this prospective cohort study, 50 individuals with type 2 diabetes were non-randomly assigned to receive metformin (MTF, n = 25) or empagliflozin (10 mg/day) and metformin (EMPA+MTF, n = 25) and followed for 6 months. Fasting blood glucose (FPG), HbA1c, body mass index (BMI), glomerular filtration rate (GFR), and urinary albumin were measured at baseline and then 6 months later. Interleukin-1beta (IL-1β) and interleukin-6 (IL-6) secretion from isolated and stimulated peripheral blood mononuclear cells were measured using ELISA and compared in the different study groups. The MTF+EMPA group showed significantly decreased levels of FPG, HbA1C, and body mass index compared to the baseline. FPG and HbA1c in the MTF+EMPA group showed a significant decrease six months after treatment versus the MTF group. A significant reduction in IL-1β levels was observed at the six months post-treatment compared to baseline and in relation to the MTF group after six months. The levels of IL-6 exhibited no significant differences, both within and between the study groups. Significant direct correlations were observed between IL-1β levels and FPG as well as HbA1c within the MTF+EMPA group following six months of treatment. Incorporating empagliflozin (10 mg/day) into metformin treatment markedly enhanced glycemic regulation and lowered IL-1β secretions, indicating a possible anti-inflammatory benefit in overweight individuals with T2D following six months of treatment. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4466 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4466/2305

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 25 3 2026 04 22 363 392 Wei Wu Department of Anesthesia and Surgery Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China Yingji Wang Department of Geriatric Endocrinology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China Xiaocheng Zhao Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China Ke Dong Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China Maode Li Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China Xiang An Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China Yingyan Xu Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China Shuai Wang Department of Anesthesia and Surgery Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China Dexin Li Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China 2025 08 22 2025 10 11 Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer. This study aimed to elucidate the involvement of genes associated with 25 cell-death modalities in HCC development and progression. HCC transcriptomic datasets were integrated with curated cell death-related genes. Candidate genes were screened by differential expression analysis and protein–protein interaction network construction. Prognostic genes were identified using univariate Cox regression, proportional hazards assumption testing, and stepwise multivariate Cox regression. A risk score model and a nomogram were established, followed by risk stratification and analyses of immune infiltration, immune checkpoints, somatic mutations, and in silico drug sensitivity. Single-cell RNA sequencing was used to identify key cell types, infer temporal dynamics, and characterize intercellular communication, and findings were validated by quantitative real-time PCR (qRT-PCR). MAPT, CDKN2A, NQO1, CHGA, SERPINE1, and RET were identified as prognostic genes, and the risk model and nomogram showed good prognostic performance. Immune profiling revealed significant differences in multiple immune cell subsets between risk groups, including activated CD4+ T cells. Notably, CDKN2A correlated with activated CD4+ T cells, NQO1 with natural killer cells, RET with CD4+ central memory cells, and SERPINE1 with activated dendritic cells; RET also showed the strongest positive correlation with HAVCR2. Mutation spectra differed across risk groups, and ten drugs displayed significant predicted IC50 differences; all six genes were negatively correlated with KIN001.135. Single-cell analyses highlighted hepatocytes as a key cell type with strong hepatocyte–epithelial communication. qRT-PCR confirmed higher MAPT, CDKN2A, NQO1, and SERPINE1 expression in HCC tissues than in normal tissues. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4562 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4562/2300

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 25 3 2026 04 22 393 405 Haoju Lo Department of Orthopedic Surgery, Da-Chien General Hospital, Miaoli, Taiwan Chunhao Tsai School of Medicine, China Medical University, Taichung, Taiwan AND Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan AND Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan Tsanwen Huang Chang Gung University, Taoyuan, Taiwan AND Department of Orthopedic Surgery, Jen-Ai Hospital, Taichung, Taiwan 2025 08 21 2025 10 01 This study integrated and analyzed two sets of gene expression data related to intervertebral disc degeneration (IVDD) to elucidate its key molecular mechanisms. Through screening and enrichment analysis of differentially expressed genes (DEGs), 112 DEGs were identified, primarily involved in extracellular matrix remodeling, cytoplasmic translation, and signaling pathways such as PI3K-Akt. A protein-protein interaction network combined with LASSO and SVM-RFE machine learning algorithms identified 13 hub genes. Immune infiltration analysis revealed reduced infiltration of suppressor cells and monocytes in IVDD samples. In an IL-1β-induced human nucleus pulposus cell degeneration model, qPCR and Western blot experiments confirmed significant downregulation of ADM, ITGB5, RTN4, SLPI, and CSNK1E expression. This study systematically reveals the potential molecular networks and immune characteristics of IVDD, providing new candidate biomarkers and therapeutic insights for subsequent targeted drug development. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4560 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4560/2281

Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 25 3 2026 04 22 406 414 Wenru Wu School of Clinical Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China Lei Yang School of Clinical Medicine, Hangzho