Search

Xiang Han,1 Yunhong You,1 Xiuhui Guo,2 Youxin Ji,1 Keke Nie1 1Department of Oncology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital), Qingdao, 266042, People’s Republic of China; 2Department of Oncology, Pingdu People’s Hospital, Qingdao, 266077, People’s Republic of ChinaCorrespondence: Youxin Ji; Keke Nie, Department of Oncology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, 127 Si Liu South Road, Qingdao, People’s Republic of China, Tel +86532-6866-5078, Fax +86532-8486-3506, Email jiyouxin@uor.edu.cn; niekeke@uor.edu.cnPurpose: To investigate the efficiency and safety of afatinib in combination with bevacizumab in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) G719X, S768I, and L861Q mutations.Patients and Methods: We retrospective studied treatment naïve patients with local advanced or metastatic non-small cell lung cancer harboring EGFR G719X, S768I, and L861Q mutations from January 2017 to August 2021. EGFR tyrosine kinase inhibitors (TKIs) were the first-line treatment in all patients. The demographic, clinical data and treatment results were collected and analyzed.Results: A total of 12 Chinese patients were studied. There were seven EGFR G719X mutations, three of the seven patients with single mutation and the others with compound mutations. Four patients had EGFR S768I mutations and one of them with single mutation. Four patients had EGFR L861Q/P mutations and one of them with compound mutations. The overall response rate of the EGFR TKIs treatment was 58.33% (7/12). The median progression-free survival (PFS) was 11.0 months, and median overall survival (OS) was 35.40 months. Two of five (40%) patients had required EGFR T790M mutations after TKIs were resistant. The side effects were mild to moderate hand-foot-syndrome, hypertension, and proteinuria.Conclusion: Afatinib in combination with bevacizumab are effective and safe in the management of patients with NSCLC harboring EGFR G719X, S768I, L861Q/P single or compound mutations.Keywords: epidermal growth factor receptor tyrosine kinase inhibitor, uncommon EGFR mutations, non-small-cell lung cancer, afatinib, bevacizumab

Xiumei Han,1,* Die Jiang,1,* Chaomang Zhu,2,* Duojie Li,1 Hongmei Yin1 1Department of Radiotherapy, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233000, People’s Republic of China; 2Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, Anhui, 233000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongmei Yin, Department of Radiotherapy, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233000, People’s Republic of China, Tel/Fax +86 182 2655 8221, Email yhm062573@163.comPurpose: This study aimed to investigate the efficacy and survival analysis of internal mammary lymph nodes (IMLNI) radiotherapy after modified radical mastectomy for T1-3N3M0 The lateral quadrant breast cancer.Materials and Methods: A total of 124 patients who underwent adjuvant radiotherapy after modified radical mastectomy for breast cancer in the First Affiliated Hospital of Bengbu Medical University were included. The patients were divided into the internal mammary lymph node (IMLN) irradiation group, and sixty-two patients received postoperative chest wall + upper and infraclavicular lymph nodes + IMLNI,sixty-two patients in the non-IMLN irradiation group received postoperative radiotherapy to the chest wall + upper and infraclavicular lymph nodes. The radiotherapy dose was 45– 50GY, The disease-free survival rate (DFS), survival rate (OS), local recurrence rate (LRR), distant metastasis rate (DM), and adverse radiation reactions were analyzed.Results: Median follow-up was 56 months (range 12– 96). The 5-year OS in the IMLNI group and the non-IMLNI group were 80.6% and 79.8% (P> 0.05), DFS was 62.9% and 59.7% (P> 0.05), LRR was 22.6 and 21.0% (P> 0.05), and DM was 25.8% and 33.9% (P> 0.05), respectively. Multifactorial showed that T stage, PR status, vascular cancer embolism, it was an independent prognostic factor affecting the 5-year OS of patients, and PR expression status (P=0.038) was an independent prognostic factor affecting the 5-year LRR.Conclusion: For breast cancer patients located in the outer quadrant and more than 9 axillary lymph node positives, increasing IMNI failed to improve the 5-year prognosis of the patients, and for patients with late N stage, PR receptor-negative, and vascularity cancer thrombosis positive, the 5-year OS of breast cancer postoperative patients could be reduced, and the PR receptor positivity could reduce the 5-year LRR of patients. There was no significant difference in 5-year late radiation adverse effects between the IMLNI and non-IMLNI groups.Keywords: breast cancer, internal mammary lymph node irradiation, radiotherapy, survival rate, retrospective study

Minghui Li,1,* Yuelin Liu,1,* Xu Han,1,* Tao Li,2 Zhizheng Zhang,1 Ningyi Xue,1 Mengdi Liang,1 Ge Ma,1 Tiansong Xia1 1Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tiansong Xia; Ge Ma, Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Tel +86-25-83718836, Email xiatsswms@163.com; ntmage@sina.comBackground: Aneuploid circulating endothelial cells (CECs) are an indicator in breast cancer (BC). Significant changes of aneuploid CECs occurred during neoadjuvant chemotherapy (NCT). This study aimed to explore the predictive and prognostic values of aneuploid CECs in locally advanced breast cancer (LABC) patients with different NCT responses.Methods: Breast cancer patients received an EC4-T4 NCT regimen. A novel subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) strategy was applied for the detection of CECs (CD45–/CD31+/DAPI+). Receiver operating characteristic (ROC) curves were plotted to evaluate the predictive value of aneuploid CEC counts in distinguishing NCT-resistant patients from sensitive ones. All patients were observed for progression-free survival (PFS) and overall survival (OS).Results: The CEC counts at any time point did not show the ability to predict the efficacy of NCT. The difference in the CECs between post-chemotherapy levels and baseline could be sufficient to distinguish chemotherapy-resistant cases from other cases in Hormone+Her-2-/+ (HR+) BC patients. Patients with reduction of CECs after all courses of NCT were associated with higher probability of PFS.Conclusion: Variations in aneuploid CECs during NCT may predict chemotherapy response in patients with HR+ breast cancer. The decrease in the number of aneuploid CECs after all courses of NCT indicates better treatment outcomes in patients with LABC.Keywords: circulating endothelial cells, aneuploidy, neoadjuvant chemotherapy, prognosis, locally advanced breast cancer

Jingmin Li,1,2 Xuefei Du,1 Zhenzhen Mu,1 Xiuping Han1 1Department of Dermatology, Shengjing Hospital, China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Department of Dermatology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Tongji Shanxi Hospital, Taiyuan, People’s Republic of ChinaCorrespondence: Xiuping Han, Department of Dermatology, Shengjing Hospital, China Medical University, Shenyang, People’s Republic of China, Tel + 86 18940251646, Email hanxiuping66@126.comPurpose: Atopic dermatitis (AD) is a prevalent skin condition worldwide. The immune response plays a crucial role in the pathogenesis of AD. Arctiin (ARC), a natural lignan, has been extensively investigated because of its anti-inflammatory, antioxidant, and anticancer properties. However, the impact of ARC on AD remains uncertain. Therefore, this study investigated the therapeutic effects of ARC in AD.Methods: AD-like lesions were induced in mice by applying 2,4-dinitrochlorobenzene (DNCB). The efficacy of ARC in AD was assessed by measuring skin lesion scores and thickness, pathological observation, and serum IgE concentrations. The expression of relevant proteins and genes in the back skin of the mice was assessed. Moreover, the TLR4/MyD88/NF-κB and NLRP3/Caspase-1/GSDMD signaling pathways were assessed in HaCaT cells stimulated with TNF-α and IFN-γ.Results: ARC effectively alleviated AD-like dermatitis induced by DNCB in mice, reducing the skin thickness, mast cell infiltration in skin tissue, and serum total IgE levels. In addition, the expression of IL-1β and the mRNA transcription of TSLP and IFN-γ were downregulated. ARC also suppressed the TLR4/MyD88/NF-κB pathway, and molecular docking confirmed that ARC had exceptional binding properties with TLR4. Moreover, ARC ameliorated pyroptosis by inhibiting the activation of the nod-like receptor protein-3/Caspase-1/GSDMD cascade.Conclusion: ARC has remarkable anti-AD effects by inhibiting inflammation and pyroptosis through the TLR4/MyD88/NF-κB and NLRP3/Caspase-1/GSDMD signaling pathways. This suggests that ARC has potential as a new drug candidate for treating AD, which provides a novel approach to the clinical management of AD. Keywords: arctiin, atopic dermatitis, inflammation, pyroptosis

Jingdong Xia,1,2 Xiudan Li,1,2 Chunying Bai,2 Xuchen Han1 1Affiliated Hospital of Chifeng University, Chifeng, The Inner Mongol Autonomous Region, Chifeng, People’s Republic of China; 2Key Laboratory of Research on Human Genetic Diseases at Universities of Inner Mongolia Autonomous Region, Chifeng, People’s Republic of ChinaCorrespondence: Xuchen Han; Xiudan Li, Email hanxuchen2004@163.com; 1248337580@qq.comAbstract: Coenzyme Q has garnered significant attention due to its potential role in enhancing cellular energy production and its antioxidant properties. We delve into the therapeutic potential of coenzyme Q in managing diabetes mellitus and its complications, highlighting its capacity to improve mitochondrial function, reduce inflammation and oxidative stress, and correct lipid profiles. Coenzyme Q has shown promise in ameliorating insulin resistance and alleviating complications such as diabetic peripheral neuropathy, kidney disease, retinopathy, and cardiomyopathy. However, its clinical application is limited by poor bio-availability. This review also provides a comprehensive overview of current therapeutic strategies for diabetes complications involving coenzyme Q, including stimulating endogenous synthesis and utilizing carrier transport systems, offering insights into mechanisms for enhancing coenzyme Q bio-availability. These findings suggest that, with improved delivery methods, coenzyme Q could become a valuable adjunct therapy in the management of diabetes mellitus.Keywords: coenzyme Q, diabetes mellitus, diabetic complications

Lijie Ren,1 Ye Chen,2 Xianguo Han,3 Ziyi Chen,2 Zhi Wang,4 Wenxiao Li,2 Hongyuan Chen2 1Mental Health Center, Shanghai Customs University, Shanghai, People’s Republic of China; 2School of Customs and Public Administration, Shanghai Customs University, Shanghai, People’s Republic of China; 3School of Psychology, Shanghai Normal University, Shanghai, People’s Republic of China; 4School of Customs and Public Economics, Shanghai Customs University, Shanghai, People’s Republic of ChinaCorrespondence: Xianguo Han, School of Psychology, Shanghai Normal University, 100 Guilin Street, Xuhui District, Shanghai, 200234, People’s Republic of China, Email hanxg.psy@aliyun.comBackground: Suicide is a global public health issue. This study examined the role of COVID-19 burnout and reappraisal in suicidal ideation caused by depressive symptoms among Chinese college students.Methods: 587 students (261 boys, Mage = 19.53, SD = 1.42) were assessed using the Short Depression-Happiness Scale (SDHS), Positive and Negative Suicide Ideation (PANSI) inventory, and Emotion Regulation Scale (ERS).Results: Correlation analysis indicated depressive symptoms were negatively correlated with reappraisal and positively correlated with suicidal ideation and COVID-19 burnout. Reappraisal was negatively correlated with suicidal ideation and COVID-19 burnout. The moderated mediation model showed COVID-19 burnout enhanced the direct effect of depressive symptoms on suicidal ideation and indirectly enhanced this effect by weakening the protective role of reappraisal.Conclusion: These finding show that reappraisal acts as a protective factor against suicidal ideation in individuals with depressive symptoms, while COVID-19 burnout exacerbates this effect by weakening reappraisal’s protective role.Keywords: depressive symptoms, suicidal ideation, reappraisal, COVID-19 burnout, moderated mediation model

Zhangnan Sun,1,&ast; Ji Shi,2,&ast; Chaolei Liu,1 Jingjing Zhang,1 Yue Liu,1 Yini Wu,3 Xin Han,3 Hong Dai,3 Jimin Wu,3 Lijun Bo,1 Faxing Wang3 1Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Anesthesiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3Department of Anesthesiology, Lishui People’s Hospital, Lishui Hospital of Wenzhou Medical University, Lishui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Faxing Wang, Department of Anesthesiology, Lishui People’s Hospital, Lishui Hospital of Wenzhou Medical University, No. 15, Dazhong Street, Lishui, Zhejiang Province, 323000, People’s Republic of China, Email wfx2023@wmu.edu.cn Lijun Bo, Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email 27901566@hebmu.edu.cnObjective: This study investigates the effect of low-dose dexmedetomidine infusion on perioperative neurocognitive function in elderly patients undergoing endoscopic retrograde cholangiopancreatography (ERCP).Patients and Methods: This double-blind trial enrolled 80 elderly ERCP patients randomized to receive dexmedetomidine (Group D) or placebo (Group S). Group D received dexmedetomidine at 0.4 μg·kg− 1·h− 1 starting 15 minutes before surgery until completion, along with propofol at 1.5 mg/kg for anesthesia. Group S received saline and propofol in a similar manner. Anesthesia was maintained with dexmedetomidine at 0.4 μg·kg− 1·h− 1 and propofol at 1– 2 mg/kg during surgery. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) preoperatively and on postoperative days 1, 3, and 5. Primary outcome was perioperative neurocognitive disorder (PND) incidence on day 5; secondary outcomes included changes in perioperative IL-6, cortisol, S100-β, hemodynamics, anesthesia parameters, postoperative pain, agitation scores, and adverse events.Results: All 80 patients completed the trial. On postoperative day 5, the cumulative probability of PND incidence was significantly lower in Group D than in Group S (12.5% vs 35%, P=0.018). Group D also had lower levels of IL-6 (F=199.472, P< 0.001), S100-β (F=2681.964, P< 0.001), and cortisol (F=137.637, P< 0.001). Propofol doses were lower in Group D (706.1 ± 202.4 vs 1003.3 ± 203.7, P< 0.001), and bradycardia rates were higher (45% vs 15%, P=0.003), though atropine use did not significantly differ between groups. Group D showed greater stability in mean arterial pressure. Postoperative complications and adverse reactions were similar across groups.Conclusion: Perioperative low-dose dexmedetomidine infusion with propofol in elderly ERCP patients ensures safe and effective monitored anesthesia care (MAC), reducing PND incidence by mitigating peripheral inflammation and stress responses. Long-term follow-up is needed to fully evaluate PND incidence.Keywords: ERCP, PND, dexmedetomidine, elderly patients

Yue Li,1,2,&ast; Yuhui Wang,2,3,&ast; Yonghong Cao,1,2 Xinxiu Zhang,1,2 Wu Dai,1,2 Yiran Zhao,1,2 Lei Zhang,1,2 Xiaofang Han1,2 1Department of Endocrinology, Hefei Hospital Affiliated to Anhui Medical University, Hefei, People’s Republic of China; 2The Fifth Clinical College of Anhui Medical University, Hefei, People’s Republic of China; 3Department of Cardiology, Hefei Hospital Affiliated to Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaofang Han, Email hxfanghf@sina.comPurpose: To inquire into the relationship between diabetic peripheral neuropathy (DPN) and serum levels of growth differentiation factor-15 (GDF-15) in individuals with type 2 diabetes mellitus (T2DM).Patients and Methods: Out of 162 T2DM patients classified according to the diagnostic criteria of DPN, 75 were allocated to the non-DPN group and 87 to the DPN group. In turn, based on serum GDF-15 quartiles, all patients were additionally divided (GDF-15 low to high) into group A (40 cases), group B (41 cases), group C (41 cases), and group D (40 cases). General data and laboratory indexes of patients were collected, and enzyme-linked immunosorbent assay (ELISA) was used to determine serum GDF-15 levels.Results: Compared to the non-DPN group, in the DPN group GDF-15 levels were noticeably greater (P < 0.001). Using serum GDF-15 as a grouping variable, DPN prevalence and body mass index were gradually increased, motor and sensory nerve latencies were gradually lengthened, and amplitude (Amp) and nerve conduction velocity (NCV) were gradually decreased with increasing GDF-15 levels (P < 0.05). Linear regression modeling revealed that GDF-15 levels correlated positively with the latencies of sensory and motor nerves, and negatively with their corresponding NCV (P < 0.05). Binary logistic regression results indicated GDF-15 as an independent predictor for DPN (P < 0.05), whereas restricted cubic spline analysis indicated a dose-response, nonlinear relationship between GDF-15 and DPN.Conclusion: Serum GDF-15 level strongly correlates with DPN, and may represent an independent predictor and a biological marker for the disease.Keywords: growth differentiation factor 15, diabetic neuropathy, nerve conduction study, type 2 diabetes mellitus

Xinyu Han,1 Tian Qiang Wu,1 Ruiting Yao,1 Chang Liu,1 Lu Chen,2 Xiaoling Feng2 1Department of First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China; 2Department of Gynecology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of ChinaCorrespondence: Xiaoling Feng, Department of Gynecology, The First Affiliated Hospital of Heilongjiang University, No. 26, Heping Road, Xiang-Fang District, Harbin City, Heilongjiang Province, People’s Republic of China, Email Doctorfxl@163.comBackground: Observational studies have established a connection between Gastroesophageal reflux disease (GERD) and preterm birth (PTB). Nevertheless, these correlations can be affected by residual confounding or reverse causality, resulting in ambiguity regarding the connection. The objective of this study was to assess the relationship between genetically predicted GERD and PTB.Methods: Initially, we performed bidirectional univariate Mendelian randomization (UVMR) analysis utilizing publicly accessible genome-wide association studies (GWAS) data. The primary analytical approach employed to determine the causal impact between GERD and PTB is the inverse variance weighted technique (IVW). Subsequently, we utilized multivariate Mendelian randomization (MVMR) to adjust for potential factors that could influence the results, such as body mass index (BMI), maternal smoking around birth, educational attainment, household income, and Townsend deprivation index (TDI). Furthermore, we performed a sequence of comprehensive sensitivity analyses to assess the reliability of our MR findings.Results: The UVMR analysis results showed a significant correlation between GERD and PTB (odds ratio [OR]: 1.810; 95% confidence interval [CI]: 1.344– 2.439; P=9.60E-05) in the IVW model, and the Weighted median method (OR=1.591, 95% CI=1.094– 2.315, P=0.015) revealed consistent results. The inverse MR findings suggest no causal link between PTB and the incidence of GERD. In addition, the sensitivity analysis did not detect heterogeneity or horizontal pleiotropy, and the “leave-one-out” examination confirmed that the causal estimation is unlikely to be influenced by the single nucleotide polymorphisms (SNPs) effect. The MVMR analysis demonstrated that the causal association between GERD and PTB still existed after considering BMI, maternal smoking around birth, educational attainment, household income, and TDI (OR=1.921, 95% CI=1.401– 2.634, P=5.08E-05).Conclusion: This study presents evidence indicating that genetically predicted GERD can heighten the risk of PTB. Therefore, it is advisable to perform focused screening for pregnant women with GERD in order to find the initial signs of PTB and promptly apply intervention strategies to extend the duration of pregnancy.Keywords: Mendelian randomization, gastroesophageal reflux disease, preterm birth, causality

Zhongbiao Nie,1 Cuilv Liang,2 Zhihong Li,1 Xinqiang Han,3 Ran Zhang4 1Department of Pharmacy, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People’s Republic of China; 2Department of Pharmacy, Second Affiliated Hospital, Fujian Medical University, Quanzhou, 362000, People’s Republic of China; 3Department of General, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People’s Republic of China; 4Department of Nephrology, Affiliated Hospital of Shanxi University of Chinese Medicine, Taiyuan, 030024, People’s Republic of ChinaCorrespondence: Ran Zhang, Department of Nephrology, Affiliated Hospital of Shanxi University of Traditional Chinese Medicine, Taiyuan, 030024, People’s Republic of China, Tel +86-13633516515, Email 115462888@qq.comPurpose: This study comprehensively describes and evaluates the correlation between gabapentinoids and all types of delirium.Methods: We used AERSMine to select all adverse reaction data from 2004 Q1 to the 2022 Q4 in the FDA Adverse Event Reporting System (FAERS) database, and delirium events reported by gabapentinoids drugs were included in this study. Collected and analyzed the clinical details of these reports. We have developed four models. Among the four models, reporting odds ratio (ROR) and proportional reporting ratio (PRR) were used to evaluate the potential association between and delirium. We undertook a subgroup analysis for the age and sex cohorts.Results: A total of 2950 reports of gabapentinoids-related delirium was collected. Excluding cases with a history of delirium (Model 2), opioid drugs (Model 3), and other adverse events related to gabapentinoids drugs (Model 4), pain cases with gabapentin drugs as the main suspected drug were selected. In model 1, the reporting rates of delirium at the delirium and delirium tremens levels were higher in the gabapentinoids group than in the non-gabapentinoids group (ROR 1.09(1.05,1.13); ROR 1.54(1.16,2.04)). In model 2.3 the delira and the delirium level were higher in the gabapentinoids group (ROR 1.42(1.29,1.56), ROR 1.44(1.31,1.59); ROR 1.43(1.30,1.58), ROR 1.46(1.33,1.61)). There is no difference in delirium levels in Model 4. Delirium levels were higher in the gabapentinoids group than in the non-gabapentinoids group in ≥ 65 years old. The delirium and deliria levels were higher in the male group than in the female group.Conclusion: The delirium adverse reactions of the gabapentinoids group were significantly higher than those of non-gabapentinoids group in the first three models. However, with the removal of confounding factors, there was no significant difference in this type of adverse reaction in Model 4. In elderly and male patients, the incidence of delirium with gabapentinoids was significantly increased.Keywords: gabapentinoids, delirium, adverse reactions, FAERS, pharmacovigilance

Peijun Li,1,&ast; Yingqi Wang,1,&ast; Yuanyuan Cao,2 Jiacheng Shi,1 Meiling Jiang,2 Xiaoyu Han,2 Linhong Jiang,1 Yidie Bao,1 Weibing Wu,2 Xiaodan Liu1,3,4 1School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Department of Sports Rehabilitation, Shanghai University of Sport, Shanghai, 200438, People’s Republic of China; 3Institute of Rehabilitation Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 4Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, 201203, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaodan Liu; Weibing Wu, Email hzhp403@126.com; wwb75@126.comBackground: Exercise is an indispensable component of pulmonary rehabilitation with strong anti-inflammatory effects. However, the mechanisms by which exercise prevents diaphragmatic atrophy in COPD (chronic obstructive pulmonary disease) remain unclear.Methods: Forty male C57BL/6 mice were assigned to the control (n=16) and smoke (n=24) groups. Mice in the smoke group were exposed to the cigarette smoke (CS) for six months. They were then divided into model and exercise training groups for 2 months. Histological changes were observed in lung and diaphragms. Subsequently, agonist U46639 and antagonist Y27632 of RhoA/ROCK were subjected to mechanical stretching in LPS-treated C2C12 myoblasts. The expression levels of Atrogin-1, MuRF-1, MyoD, Myf5, IL-1β, TNF-α, and RhoA/ROCK were determined by Western blotting.Results: Diaphragmatic atrophy and increased RhoA/ROCK expression were observed in COPD mice. Exercise training attenuated diaphragmatic atrophy, decreased the expression of MuRF-1, and increased MyoD expression in COPD diaphragms. Exercise also affects the upregulation of RhoA/ROCK and inflammation-related proteins. In in vitro experiments with C2C12 myoblasts, LPS remarkably increased the level of inflammation and protein degradation, whereas Y27632 or combined with mechanical stretching prevented this phenomenon considerably.Conclusion: RhoA/ROCK plays an important role in the prevention of diaphragmatic atrophy in COPD.Keywords: chronic obstructive pulmonary disease, diaphragmatic atrophy, exercise training, inflammation, RhoA/ROCK signaling

Zhaoli Geng,1– 3 Renping Dong,3 Xinlin Li,1,2 Xinyi Xu,1,2 Lin Chen,1,2 Xu Han,1,2 Dongxu Liu,1,2 Yi Liu1,2 1Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, 250012, People’s Republic of China; 3Department of Stomatology, Qingdao West Coast New Area People’s Hospital, Qingdao, Shandong, 266400, People’s Republic of ChinaCorrespondence: Yi Liu, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong, 250012, People’s Republic of China, Tel +86-531-88381630, Email yiliu@sdu.edu.cnBackground: Implants are widely used in the field of orthopedics and dental sciences. Titanium (TI) and its alloys have become the most widely used implant materials, but implant-associated infection remains a common and serious complication after implant surgery. In addition, titanium exhibits biological inertness, which prevents implants and bone tissue from binding strongly and may cause implants to loosen and fall out. Therefore, preventing implant infection and improving their bone induction ability are important goals.Purpose: To study the antibacterial activity and bone induction ability of titanium–copper alloy implants coated with nanosilver/poly (lactic-co-glycolic acid) (NSPTICU) and provide a new approach for inhibiting implant-associated infection and promoting bone integration.Methods: We first examined the in vitro osteogenic ability of NSPTICU implants by studying the proliferation and differentiation of MC3T3-E1 cells. Furthermore, the ability of NSPTICU implants to induce osteogenic activity in SD rats was studied by micro-computed tomography (micro-CT), hematoxylin-eosin (HE) staining, masson staining, immunohistochemistry and van gieson (VG) staining. The antibacterial activity of NSPTICU in vitro was studied with gram-positive Staphylococcus aureus (Sa) and gram-negative Escherichia coli (E. coli) bacteria. Sa was used as the test bacterium, and the antibacterial ability of NSPTICU implanted in rats was studied by gross view specimen collection, bacterial colony counting, HE staining and Giemsa staining.Results: Alizarin red staining, alkaline phosphatase (ALP) staining, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis showed that NSPTICU promoted the osteogenic differentiation of MC3T3-E1 cells. The in vitro antimicrobial results showed that the NSPTICU implants exhibited better antibacterial properties. Animal experiments showed that NSPTICU can inhibit inflammation and promote the repair of bone defects.Conclusion: NSPTICU has excellent antibacterial and bone induction ability, and has broad application prospects in the treatment of bone defects related to orthopedics and dental sciences.Keywords: nanosilver/PLGA coating, implant infection, antibacterial, osteogenesis, titanium copper alloy

Maria González-Cao,1 Xueting Cai,2 Jilian Wilhelmina Paulina Bracht,3 Xuan Han,2 Yang Yang,2 Carlos Pedraz-Valdunciel,4 Teresa Morán,5 Javier García-Corbacho,6 Andrés Aguilar,1 Reyes Bernabé,7 Pedro De Marchi,8,9 Luciane Sussuchi da Silva,8 Leticia Ferro Leal,8 Rui Manuel Reis,8,10,11 Jordi Codony-Servat,4 Eloisa Jantus-Lewintre,12– 14 Miguel Angel Molina-Vila,4 Peng Cao,2,15 Rafael Rosell1,16 1Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital, Barcelona, Spain; 2Integrated Traditional Chinese and Western Medicine Department of Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 3Amsterdam University Medical Center (UMC), Amsterdam, The Netherlands; 4Laboratory of Oncology, Pangaea Oncology, Quirón Dexeus University Hospital, Barcelona, Spain; 5Medical Oncology Department, Catalan Institute of Oncology (ICO), Germans Trias i Pujol Hospital, Badalona, Spain; 6Medical Oncology Department (Hospital Clinic)/Translational Genomics and Targeted Therapies in Solid Tumors (IDIBAPs), Barcelona, Spain; 7Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 8Molecular Oncology Research Center; Barretos Cancer Hospital, Barretos, Brazil; 9Oncoclinicas, Rio de Janeiro, Brazil; 10Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; 11ICVS/3b’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal; 12Valencian Community Foundation Principe Felipe Research Center, Laboratory of Molecular Oncology, Valencia, Spain; 13Centro de Investigación Biomédica en Red (CIBERONC), Madrid, Spain; 14Universitat Politècnica de Valencia, Biotechnology Department, Valencia, Spain; 15College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 16Laboratory of Molecular Biology, Germans Trias i Pujol Health Sciences Institute and Hospital (IGTP), Badalona, SpainCorrespondence: Rafael Rosell, Laboratory of Molecular Biology, Germans Trias i Pujol Health Sciences Institute and Hospital (IGTP), Camí de les Escoless/n, Badalona, Barcelona, 08916, Spain, Tel +34 930330520, Email rrosell@iconcologia.net Peng Cao, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China, Tel +86 85608666, Email cao_peng@njucm.edu.cnPurpose: High-mobility group box 1 protein (HMGB1) is subject to exportin 1 (XPO1)-dependent nuclear export, and it is involved in functions implicated in resistance to immunotherapy. We investigated whether HMGB1 mRNA expression was associated with response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC).Patients and Methods: RNA was isolated from pretreatment biopsies of patients with advanced NSCLC treated with ICI. Gene expression analysis of several genes, including HMGB1, was conducted using the NanoString Counter analysis system (PanCancer Immune Profiling Panel). Western blotting analysis and cell viability assays in EGFR and KRAS mutant cell lines were carried out. Evaluation of the antitumoral effect of ICI in combination with XPO1 blocker (selinexor) and trametinib was determined in a murine Lewis lung carcinoma model.Results: HMGB1 mRNA levels in NSCLC patients treated with ICI correlated with progression-free survival (PFS) (median PFS 9.0 versus 18.0 months, P=0.008, hazard ratio=0.30 in high versus low HMGB1). After TNF-α stimulation, HMGB1 accumulates in the cytoplasm of PC9 cells, but this accumulation can be prevented by using selinexor or antiretroviral drugs. Erlotinib or osimertinib with selinexor in EGFR-mutant cells and trametinib plus selinexor in KRAS mutant abolish tumor cell proliferation. Selinexor with a PD-1 inhibitor with or without trametinib abrogates the tumor growth in the murine Lewis lung cancer model.Conclusion: An in-depth exploration of the functions of HMGB1 mRNA and protein is expected to uncover new potential targets and provide a basis for treating metastatic NSCLC in combination with ICI.Keywords: HMGB1, immunotherapy, non-small cell lung cancer, Lewis lung cancer murine model, K-Ras mutations

Shengfang Bao, Hua Huang, Yingying Jin, Fei Ding, Zhen Yang, Xuemei Xu, Chenxi Liu, Xiqiong Han, Liping Wang, Jingyi Lu, Jiani Ma, Yanliang Jin Department of Rheumatology & Immunology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People’s Republic of ChinaCorrespondence: Yanliang Jin, Email jinyanliang@scmc.com.cnAbstract: Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare, benign, and self-limiting condition characterized by lymph node inflammation. While KFD is rarely associated with ocular manifestations, our case report highlights bilateral optic neuritis in a 13-year-old male patient with KFD. We also provide a comprehensive review of similar cases in the literature.Keywords: Kikuchi-Fujimoto disease, optic neuritis, neuromyelitis optica spectrum disorder, vision deficiency

Shuai Li, Xue Han, Jing Ma, Guo-Hong Huang, Shu-Ting Yang, Chang-Min Wang Clinical Laboratory Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, 830001, People’s Republic of ChinaCorrespondence: Chang-Min Wang, Department of Clinical Laboratory Center, People’s Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Street, Tianshan District, Urumqi, Xinjiang, 830001, People’s Republic of China, Tel +86 13609992616, Fax +86− 9918564168, Email wang_c3223min@yeah.netObjective: To investigate the value of metagenomic Next-Generation Sequencing (mNGS) in diagnosing Pneumocystis jirovecii pneumonia (PJP) in non-human immunodeficiency virus (HIV)-infected patients.Methods: In this retrospective study, non-HIV-infected patients with PJP and those diagnosed with non-PJP from August 2022 to December 2024 were selected as subjects. The presence of Pneumocystis jirovecii (PJ) and other co-pathogens in bronchoalveolar lavage fluid (BALF) was analyzed, and the diagnostic efficacy of NGS, polymerase chain reaction (PCR) and serum 1,3-β-D-glucan (BDG) in PJP was compared with the reference standard of clinical compound diagnosis.Results: Eighty-nine non-HIV-infected patients were recruited, with dyspnea as the primary symptom (69.66%) and solid malignant tumor as the most common underlying disease (20.22%). Taking clinical compound diagnosis as the reference standard, the sensitivity, specificity, negative predictive value and positive predictive value of mNGS were higher than those detected by PCR and serum BDG. Among 42 non-HIV-infected patients with PJP who underwent mNGS and conventional pathogen detection of BALF, 6 had simple PJ infection and 36 had combined PJ infection. The detection rate of mNGS in mixed infections was significantly higher than that of conventional pathogen detection (85.71 vs 61.70%, P = 0.012). A total of 127 pathogens were detected in BALF using mNGS, among which fungi had the highest detection rate (46.46%). The fungi, viruses and bacteria detected were mainly Pneumocystis jirovecii, human gammaherpesvirus 4 and Acinetobacter baumannii.Conclusion: mNGS is highly effective in diagnosing non-HIV-infected patients with PJP and exhibits ideal performance in the detection of co-pathogens. In addition, it has certain value for clinical diagnosis and guidance of targeted anti-infective drug treatment.Keywords: metagenomic next-generation sequencing, Pneumocystis jirovecii pneumonia, polymerase chain reaction, non-HIV infection

Yanghaotian Wu,1– 3 Xuemei Han,3 Jingfu Qiu1 1Department of Social Medicine and Health Service Management, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Social Medicine, School of Public Health, Southwest Medical University, Luzhou, People’s Republic of China; 3Institute of Social Medicine and Health Management, School of Public Health, Lanzhou University, Lanzhou, People’s Republic of ChinaCorrespondence: Jingfu Qiu, School of Public Health, Chongqing Medical University, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Email jfqiucqmu@163.comBackground: In 2016, an innovative medical pricing reform called zero-markup drug policy (ZMDP) was implemented in selected pilot cities in China, which focuses on curbing the unreasonable growth of medical expenses. This study aimed to evaluate the impacts of ZMDP on medical expenditure of stroke in western China.Methods: The quantitative data of inpatients diagnosed with stroke was extracted from the medical insurance system in 7 tertiary public hospitals. An interrupted time series (ITS) was used to analyze the instantaneous level and long-term trend changes of hospitalization expenses per visit from January 2015 to November 2018.Results: A total of 22,407 stroke inpatients were extracted. The total hospitalization expense per visit had the highest proportion of 20,000 CNY and above (33.66%). After the ZMDP, the median total hospitalization expense and western medicine expense per visit decreased by 631.74 CNY and 966.35 CNY, respectively (P < 0.001). Before the policy, the total hospitalization expense, traditional Chinese medicine (TCM) expense, examination expense, treatment expense, laboratory expense and surgical expense per visit showed upward trends (P< 0.05), while the anesthesia expense per visit showed a downward trend (P< 0.001). When the policy was implemented, the anesthesia expense per visit instantaneously increased by 91.70% (P< 0.001). After the policy, the total hospitalization expense, western medicine expense, TCM expense, treatment expense and surgical expense per visit changed from upward trends to downward trends (P< 0.05). The anesthesia expense per visit changed from a downward trend to an upward trend (P< 0.001), and the examination expense per visit maintained an upward trend (P=0.005).Conclusion: The economic burden of stroke inpatients decreased significantly with the implementation of the ZMDP, especially for the drug expenses. The medical service expenses increased significantly, reflecting the improvement in the value of medical staff’s technical labor. However, the unexpected increase in the examination expenses was likely to be associated with the unreasonable medical compensation mechanism.Keywords: zero-markup drug policy, stroke, interrupted time series, hospitalization expenses, drug expenses

Minghao Gu,1,2 SenSen Lv,1 Yihui Song,3 Hong Wang,4 Xingyu Zhang,5 Jing Liu,1 Deshun Liu,1 Xiudi Han,1 Xuedong Liu1 1Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao, 266011, People’s Republic of China; 2School of Medicine, Qingdao University, Qingdao, 266071, People’s Republic of China; 3Department of Neurology, Weihai Municipal Hospital, Weihai, 264200, People’s Republic of China; 4Hospital-Acquired Infection Control Department, Qingdao Municipal Hospital, Qingdao, 266011, People’s Republic of China; 5Human Resources Department, Qingdao Municipal Hospital, Qingdao, 266011, People’s Republic of ChinaCorrespondence: Xuedong Liu; Xiudi Han, Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao, 266011, People’s Republic of China, Email xuedongliu0607@163.com; hanxiudi@163.comPurpose: To investigate the clinical value of serum lysophosphatidylcholine (LPC) as a predictive biomarker for determining disease severity and mortality risk in hospitalized elderly patients with community-acquired pneumonia (CAP).Methods: This prospective, single-center study enrolled 208 elderly patients, including 67 patients with severe CAP (SCAP) and 141 with non-SCAP between November 1st, 2020, and November 30th, 2021 at the Qingdao Municipal Hospital, Shandong Province, China. The demographic and clinical parameters were recorded for all the included patients. Serum LPC levels were measured on day 1 and 6 after admission using ELISA. Propensity score matching (PSM) was used to balance the baseline variables between SCAP and non-SCAP patient groups. Receiver operative characteristic (ROC) curve analysis was used to compare the predictive performances of LPC and other clinical parameters in discriminating between SCAP and non-SCAP patients and determining the 30-day mortality risk of the hospitalized CAP patients. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors associated with SCAP. Cox proportional hazard regression analysis was used to determine if serum LPC was an independent risk factor for the 30-day mortality of CAP patients.Results: The serum LPC levels at admission were significantly higher in the non-SCAP patients than in the SCAP patients (P = 0.011). Serum LPC level < 24.36 ng/mL, and PSI score were independent risk factors for the 30-day mortality in the elderly patients with CAP. The risk of 30-day mortality in the elderly CAP patients with low serum LPC levels (< 24.36ng/mL) was > 5-fold higher than in the patients with high serum LPC levels (≥ 24.36ng/mL).Conclusion: Low serum LPC levels were associated with significantly higher disease severity and 30-day mortality in the elderly patients with CAP. Therefore, serum LPC is a promising predictive biomarker for the early identification of elderly CAP patients with poor prognosis.Keywords: lysophosphatidylcholine, community-acquired pneumonia, biomarker, severity, mortality, propensity score matching

Meng Luo,1,2,&ast; Xue Han,1,2,&ast; Huan Li,1,2 Guangyue Zhou,1,2 Haoxuan Chen,1,2 Fang Gao1,2 1Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 2Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Gao, Department of Anesthesiology, the Affiliated Hospital of Xuzhou Medical University, No. 99 Huaihai West Road, Xuzhou, Jiangsu, 221002, People’s Republic of China, Tel +86-18052268331, Email gaofangxz@126.comBackground: Remifentanil-induced hyperalgesia (RIH) increases the risk of persistent postoperative pain, making early postoperative analgesic therapy ineffective and affecting postoperative patient satisfaction. This study aimed to verify the effects of gradual withdrawal of remifentanil combined with postoperative pump infusion of remifentanil on postoperative hyperalgesia and pain in patients undergoing laparoscopic hysterectomy.Methods: This trial was a factorial design, double-blind, randomized controlled trial. Patients undergoing laparoscopic hysterectomy were randomly allocated to the control group, postoperative pump infusion of remifentanil group, gradual withdrawal of remifentanil group, or gradual withdrawal plus postoperative pump infusion of remifentanil group (n = 35 each). The primary outcome was postoperative mechanical pain thresholds in the medial forearm. The secondary outcomes included postoperative mechanical pain thresholds around the incision, pain numeric rating scale scores, analgesic utilization, awakening agitation or sedation scores, a 15-item quality of recovery survey, and postoperative complications.Results: Gradual withdrawal of remifentanil significantly increased postoperative pain thresholds versus abrupt discontinuation (P < 0.05), whereas postoperative infusion did not show significant differences compared to the absence of infusion (P > 0.05). The combined gradual withdrawal and postoperative infusion group exhibited the highest thresholds and had the lowest postoperative pain scores and analgesic requirements as well as the highest quality of recovery scores (P < 0.05). No significant differences were observed for agitation scores, sedation scores, or complication rates (P > 0.05).Conclusion: The novel combined gradual withdrawal and postoperative infusion of remifentanil uniquely attenuates postoperative hyperalgesia, pain severity, analgesic necessity, and improves recovery quality after laparoscopic hysterectomy.Keywords: opioid-induced hyperalgesia, remifentanil-induced hyperalgesia, laparoscopic hysterectomy, mechanical pain thresholds, postoperative recovery

Yi Sun,1,2 Hong Wang,3 Minghao Gu,4 Xingyu Zhang,5 Xiudi Han,1, Xuedong Liu,1 1Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital Group, Qingdao, Shandong Province, 266000, People’s Republic of China; 2School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, 261000, People’s Republic of China; 3Hospital-Acquired Infection Control Department, Qingdao Municipal Hospital Group, Qingdao, Shandong Province, 266000, People’s Republic of China; 4School of Medicine, Qingdao University, Qingdao, Shandong Province, 266000, People’s Republic of China; 5Human Resources Department, Qingdao Municipal Hospital Group, Qingdao, Shandong Province, 266000, People’s Republic of ChinaCorrespondence: Xuedong Liu; Xiudi Han, Email xuedongliu0607@163.com; hanxiudi@163.comBackground: Data about eosinophil-to-lymphocyte ratio (ELR) and eosinophil-to-monocyte ratio (EMR) in patients with community-acquired pneumonia (CAP) are rare. We aimed to evaluate the role of EMR and ELR in predicting disease severity and mortality in patients with CAP.Methods: A total of 454 patients (76 with severe CAP (SCAP), 378 with non-SCAP) were enrolled from November 18, 2020, and November 21, 2021. Laboratory examination on day 1 after admission was measured. The ELR and EMR values were calculated for patients. Propensity score matching (PSM) was performed to balance potential confounding factors. Binary logistic regression model was fitted to identify the potential risk factors for disease severity and Cox proportional hazards regression model analysis for mortality in CAP. Receiver operating characteristic (ROC) analysis was performed to distinguish disease severity and mortality.Results: EMR and ELR at admission were significantly lower in SCAP patients than in non-SCAP patients (P< 0.001). EMR < 0.018 ([OR] =  12.104, 95% CI: 4.970– 29.479), neutrophil (NEU) ([OR]=1.098, 95% CI:1.005– 1.199), and age ([OR]=1.091, 95% CI:1.054– 1.130) were independent risk factors for disease severity of CAP. EMR < 0.032 ([HR] =  5.816, 95% CI: 1.704– 9.848) was an independent predictor of in-hospital mortality. Combining EMR or ELR with CRB-65 improved the overall accuracy of disease severity prediction (AUC from 0.894 to 0.937), the same as CURB-65. The area under the curve of EMR (AUC=0.704; 95% CI: 0.582– 0.827) to predict in-hospital mortality was higher than that of CURB-65 (AUC=0.619; 95% CI: 0.484– 0.754). Otherwise, EMR combined with CRB-65 (AUC=0.721; 95% CI: 0.592– 0.851) had significantly higher diagnostic accuracy for in-hospital mortality than that of CURB-65 alone.Conclusion: EMR combined with CRB-65 was superior to CURB-65 in predicting mortality in patients with CAP. This new combination was simpler and easier to obtain for physicians in clinics or admission, and it was more convenient for early recognition of patients with poor prognoses.Keywords: community-acquired pneumonia, EMR, ELR, CURB-65, CRB-65, severity of disease, mortality

Hong Di,&ast; Xinxin Han,&ast; Yue Yin, Yun Zhang, Xuejun Zeng Department of Family Medicine & Division of General Internal Medicine, Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, State Key Laboratory of Complex Severe and Rare Diseases (Peking Union Medical College Hospital), Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yun Zhang; Xuejun Zeng, Department of Family Medicine & Division of General Internal Medicine, Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, State Key Laboratory of Complex Severe and Rare Diseases (Peking Union Medical College Hospital), Beijing, 100730, People’s Republic of China, Tel/Fax +8610-69156098, Email zhangyun10806@pumch.cn; zxjpumch@126.comBackground: This study aimed to explore the potential roles of Vδ 2 T cells in the pathogenesis of acute gouty arthritis.Methods: Patients with gout (n=86), rheumatoid arthritis (n=7), osteoarthritis (n=9), and healthy controls (n=40) were enrolled. γδT cell frequency, chemokine receptor expression and production of pro-inflammatory cytokines in cells from peripheral blood and synovial fluid samples were quantified by flow cytometry. The chemotaxis ability of Vδ 2 T cells was determined by transwell migration assay. The levels of chemokines were also detected by enzyme-linked immunosorbent assay.Results: Peripheral Vδ 2 T cells had significantly lower frequencies in acute gout patients than that in healthy controls (P< 0.001). These peripheral Vδ 2 T cells were negatively correlated with inflammatory markers. Vδ 2 T cells from acute gout patients accumulated in synovial fluid, as evidenced by a higher abundance of Vδ 2 T cells in it than that in the serum (P< 0.01). And Vδ 2 T cells expressed a high level of C-X-C chemokine receptor 3 (P=0.035), and its corresponding chemokine C-X-C motif chemokine ligand 10 showed a high concentration in synovial fluid (P< 0.05). Vδ 2 T cells from synovial fluid of acute gout patients produced a high level of interleukin-17 (P=0.033).Conclusion: The up-regulated expression of C-X-C chemokine receptor 3 on Vδ 2 T cells potentially facilitates their infiltration into synovial fluid during acute gouty arthritis. Further production of interleukin-17 by Vδ 2 T cells may contribute to the pathogenesis of gout. This study sheds new light on developing novel Vδ 2 T cells-based therapeutic strategies for gout treatment. Keywords: acute gouty arthritis, γδT cells, Vδ 2 T cells, Interleukin-17, CXCR3, CXCL10

Xiujuan Han,1,2,&ast; Chunai Gong,3,&ast; Qingru Yang,1,2 Kaile Zheng,1 Zhuo Wang,1,2 Wei Zhang4 1Department of Pharmacy, First Affiliated Hospital of Naval Medical University (Shanghai Changhai Hospital), Shanghai, 200433, People’s Republic of China; 2School of Life Sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China; 3Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 201999, People’s Republic of China; 4Department of Pharmacy, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhuo Wang, Department of Pharmacy, First Affiliated Hospital of Naval Medical University (Shanghai Changhai Hospital), Shanghai, 200433, People’s Republic of China, Email wztgyx223@163.com Wei Zhang, Department of Pharmacy, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China, Email jydzw1981@163.comAbstract: With the development of nanotechnology, nanoparticles (NPs) have shown broad prospects as drug delivery vehicles. However, they exhibit certain limitations, including low biocompatibility, poor physiological stability, rapid clearance from the body, and nonspecific targeting, which have hampered their clinical application. Therefore, the development of novel drug delivery systems with improved biocompatibility and high target specificity remains a major challenge. In recent years, biofilm mediated biomimetic nano-drug delivery system (BNDDS) has become a research hotspot focus in the field of life sciences. This new biomimetic platform uses bio-nanotechnology to encapsulate synthetic NPswithin biomimetic membrane, organically integrating the low immunogenicity, low toxicity, high tumor targeting, good biocompatibility of the biofilm with the adjustability and versatility of the nanocarrier, and shows promising applications in the field of precision tumor therapy. In this review, we systematically summarize the new progress in BNDDS used for optimizing drug delivery, providing a theoretical reference for optimizing drug delivery and designing safe and efficient treatment strategies to improve tumor treatment outcomes.Keywords: nanoparticles, cell membrane, targeted therapy

Xingling He,1– 4,&ast; Yanhui Jiang,1,&ast; Sijing Li,1– 4,&ast; Donghua Liu,1– 4 Ziru Li,1– 4 Xiaowei Han,1– 4 Xiaojiao Zhang,1– 4 Xiaoming Dong,1 Haohui Liu,1 Jie Huang,1 Xiaojing Wang,5 Wenjie Long,1 Shihao Ni,1– 4 Zhongqi Yang,1 Taochun Ye1 1Department of Geriatrics, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou, Guangdong Province, People’s Republic of China; 4Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5Clinical Medical Center, Tasly Pharmaceutical Group Co. Ltd., Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Taochun Ye; Zhongqi Yang, Email yetaochun@163.com; yang_zhongqi@163.comBackground: Heart failure (HF) is a serious and terminal stage of various cardiac diseases and the most common complication of coronary heart disease (CHD). Previous clinical studies have shown that Qishen Yiqi dropping pills (QSYQ) have the effect of treating chronic heart failure. This study aims to evaluate the clinical efficacy, safety and optimal effective dose of QSYQ in treating CHD complicating chronic HF with reduced ejection fraction (HFrEF).Methods: We will conduct a randomized, double-blind, placebo controlled, multicenter clinical trial. A total of 228 individuals from 16 hospitals in China will be randomly assigned to the low-dose, high-dose, and placebo groups in a ratio of 1:1:1. The trial consists of a screening period (standard medical treatment for at least 2 weeks) and a 12-week treatment period. After randomization, follow-up will be conducted at the 4th, 8th and 12th week. The primary outcomes will be the 6-Minute Walk Test (6MWT) at Week 12. Secondary outcomes will include 6MWT distance at Week 4 and 8, New York Heart Association (NYHA) functional classification, Traditional Chinese Medicine (TCM) Syndrome score, echocardiography indices, N-terminal pro-B-type natriuretic peptide (NT-proBNP), oxyhemoglobin saturation, Minnesota living with heart failure questionnaire (MLHFQ) score, grasp strength body mass index test and cardiovascular adverse events (AE).Ethics and Dissemination: This trial has been approved by the Research Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, China (approval number: ZYYEC [2021]005). Written informed consent will be obtained from all participants. The results of this trial will be publicly shared through academic conferences and peer-reviewed journals.Study Registration: Clinical Trials Registry (NCT04983043, Date: 07/08/2021, https://clinicaltrials.gov/ct2/show/NCT04983043).Keywords: heart failure, coronary heart disease, Chinese medicine, QiShen YiQi Dripping Pill, syndrome of Qi deficiency with blood stasis

Peikun Teng,1 Xingyu Zhang,2 Hong Wang,3 Xiudi Han,4 Xuedong Liu4 1General Medicine Dapartment, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 2Human Resources Department, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 3Hospital-Acquired Infection Control Department, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of ChinaCorrespondence: Xuedong Liu; Xiudi Han, Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China, Email xuedongliu@263.net; hanxiudi@163.comPurpose: The aim of this study was to investigate the level of serum tumor suppressor factor (Oncostatin-M, OSM) in patients with community-acquired pneumonia (CAP) and evaluate its predictive value for the severity and prognosis of pneumonia, so as to improve the ability to identify the risk of death in CAP patients.Patients and Methods: A total of 110 patients with CAP admitted to the hospital from November 2020 to November 2021 were enrolled in this prospective study. Clinical data of all patients were collected. According to the 2016 edition of “Guidelines for the Diagnosis and Treatment of Community-acquired Pneumonia in Chinese Adults”, the patients were divided into non-severe CAP (NSCAP)(n=55) and severe CAP (SCAP)(n=55). At the same time, they were divided into a survival group (n=96) and a death group (n=14) by tracking the survival of patients in the hospital. The OSM concentration of CAP patients on the first day after admission was determined by enzyme-linked immunosorbent assay. All clinical data were statistically and graphed using SPSS V23.0 and Grahpad Prim 8.Results: Compared with NSCAP, patients with SCAP had higher serum OSM concentration on the day of admission, which was negatively correlated with LYM and positively correlated with WBC, NEU, CRP, IL-6, IL-8, IL-10, CURB-65 score, and PSI score. The level of OSM in the dead patient group was significantly higher than that in the surviving patient group. OSM and PSI scores were independent risk factors for in-hospital mortality in CAP patients. Kaplan-Meier survival curve showed that OSM≥ 76pg/mL was more advantageous in predicting mortality in patients with CAP.Conclusion: The level of the OSM is closely related to the severity and prognosis of CAP and may be a new biomarker for the prognosis of CAP patients.Keywords: community-acquired pneumonia, severity of disease, oncostatin-M, mortality

Zhongxin Hou,1,&ast; Yang Chen,1,2,&ast; Yunrui Sun,1 Chongwei Song,1 Haoyuan Deng,3 Nan Cheng,4 Xiaoyu Han,2 Jianghui Zhang,5 Qian Wang,1 Yi Li,1 Jianzhong Yin,1,6 Qiong Meng1 1School of Public Health, Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 2Institute for Acute Communicable Disease Prevention and Control, Yunnan Provincial Center for Disease Control and Prevention, Kunming, Yunnan, People’s Republic of China; 3Medical Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 4Department of Hospital Infection, Wuhan Mental Health Center, Wuhan, Hubei, People’s Republic of China; 5AIDS Care Center, Yunnan Provincial Hospital of Infectious Disease, Anning, Yunnan, People’s Republic of China; 6Baoshan College of Traditional Chinese Medicine, Baoshan, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiong Meng, School of Public Health, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, Yunnan, 650500, People’s Republic of China, Tel +8615559789771, Email mengqiong2006@163.com Jianzhong Yin, Baoshan College of Traditional Chinese Medicine, Baoshan Longyang District Qingyang District Vocational Education Park, Baoshan, Yunnan, 678000, People’s Republic of China, Tel +8613987645337, Email yinjianzhong2005@sina.comPurpose: Depression and anxiety are two highly prevalent mental disorders that commonly coexist. However, little is known about the association between sleep and comorbid depressive and anxiety symptoms (CDAS). Therefore, this study aims to explore the relationship between sleep duration, insomnia and CDAS.Methods: This is a cross-sectional study of 22,004 community adults who participated in the China Multi-Ethnic Cohort (CMEC) study. Chinese version of Patient Health Questionnaire-2 and Generalized Anxiety Disorder-2 were used to screen CDAS in community adults. A positive score on each scale was considered indicative of CDAS. All participants received face-to-face interviews, medical examinations, and biochemical examinations to assess sleep duration and insomnia and collect covariates. The self-reported sleep duration was divided into three groups: < 7 hr, 7– 9 hr and > 9 hr groups. Logistic regression was used to analyze the association between sleep duration, insomnia and CDAS. A restricted cubic spline (RCS) was used to explore the dose–response relationship between sleep duration and CDAS. Stratified analysis based on gender and age was conducted.Results: Overall, 2.8% (95% CI 2.6%~3.0%) of participants reported having CDAS. After adjusting the potential covariates, sleep duration < 7 hr (OR=1.635, 95% CI=1.335~2.004) was significantly associated with CDAS, compared with sleep 7– 9 hr. After RCS analysis, there was a nonlinear relationship between sleep duration and CDAS. The increase in the number of types of insomnia, the greater the likelihood of CDAS (p for trend< 0.05). In sensitivity analysis, it was found that the results were consistent with those of the main analysis. After stratification by gender and age, the association between sleep duration and CDAS was only observed in female and young and middle-aged adults, not in men and older adults.Conclusion: Both insufficient sleep duration and insomnia are associated with a higher prevalence of CDAS in Chinese adults.Keywords: sleep duration1, insomnia2, comorbid depressive and anxiety symptoms3, adults4, cross-sectional study5

Zhimei Zhao,1,&ast; Xiang Han,1,&ast; Yunhong You,1 Jiankang Zhang,2 Keke Nie,1 Youxin Ji1 1Department of Oncology, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao City, People’s Republic of China; 2Department of Medicine, Qingdao Medical College, Qingdao University, Qingdao City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Keke Nie; Youxin Ji, Department of Oncology, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, 127 Si Liu South Road, Shibei District, Qingdao City, 266042, People’s Republic of China, Tel + (86)532-6866-5078, Fax + (86)532-8486-3506, Email niekekeqd@163.com; mdji001@gmail.comBackground: We study the characteristics and outcomes in lung cancer patients with COVID-19 Omicron variant infection.Methods: Hospitalized lung cancer patients with advanced-stage disease and laboratory-confirmed COVID-19 Omicron infection were included. Pneumonitis involving at least 25% of lung parenchyma on CT scans, accompanied by symptoms and oxygen saturation below 93%, were criteria for enrollment. Pneumonitis severity was graded using CTCAE v5.0. Treatment included Paxlovid, prednisolone, anticoagulation, and ventilation. Initial data, radiographic findings, and outcomes were compared. Logistic regression was employed to determine risk factors for in-hospital mortality.Results: Fifteen patients (median age: 65 years; 80.0% males) were included. 73.3% improved and were discharged, 20.0% died, and 6.7% remained intubated. Initial symptoms included cough (100.0%), fever (73.3%), and shortness of breath (53.3%). Symptoms resolved in discharged patients. Median fever duration was 3.5 days, and respiratory symptom recovery took 26 days. Three patients died due to respiratory failure from Omicron pneumonia. Lower oxygen saturation, reduced lymphocyte/neutrophil ratio on day 7, and diffuse bilateral lung lesions were poor prognostic factors.Conclusion: This study underscores the importance of prompt intervention and early diagnosis for lung cancer patients infected with the COVID-19 Omicron variant. Lower oxygen saturation, decreased lymphocyte/neutrophil ratio on day 7, and diffuse lung lesions on CT scans were associated with worse outcomes. Clinicians should prioritize timely and comprehensive management to improve survival rates in this population.Keywords: COVID-19 omicronvariant, lung cancer, oxygen saturation, lymphocyte and neutrophils ratio, chest CT scan

Lingyan Sun,1– 3,&ast; Yan Chen,4– 6,&ast; Tingting Qu,7,8 Keren Shi,4– 6 Xinhong Han,4– 6 Wenhao Wu,7,8 Yan Jiang,4– 6 Yunsong Yu4– 6 1Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Key Laboratory of Clinical in Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, People’s Republic of China; 3Institute of Laboratory Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 5Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, People’s Republic of China; 6Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 7State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 8Infection Control Department, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunsong Yu, Tel +86 138 0579 0432, Email yvys119@zju.edu.cnPurpose: We aimed to characterize a novel blaNDM-5 and blaKPC-2 co-carrying hybrid plasmid from a clinical carbapenem-resistant Klebsiella pneumoniae (CRKP) strain.Methods: Antimicrobial susceptibility was determined by the broth microdilution method. Plasmid size and localization were estimated using S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting. Plasmid transfer ability was evaluated by conjugation experiments. Whole genome sequencing (WGS) was performed using Illumina NovaSeq6000 and Oxford Nanopore MinION platforms. Genomic characteristics were analyzed using bioinformatics methods.Results: Strain ZY27320 was a multidrug-resistant (MDR) clinical ST11 K. pneumoniae strain that confers high-level resistance to carbapenems (meropenem, MIC 128 mg/L; imipenem, MIC 64 mg/L) and ceftazidime/avibactam (MIC > 128/4 mg/L). Both S1-PFGE–Southern blotting and whole genome sequencing revealed that the carbapenemase genes blaKPC-2 and blaNDM-5 were carried by the same IncFIIpHN7A8:IncR:IncN hybrid plasmid (pKPC2_NDM5). Conjugation experiments indicated that pKPC2_NDM5 was a non-conjugative plasmid.Conclusion: This is the first report of a hybrid plasmid carrying both carbapenemase genes blaNDM-5 and blaKPC-2 in a clinical K. pneumoniae ST11 isolate that confers resistance to both ceftazidime/avibactam and carbapenems, thereby presenting a serious threat to treatment in clinical practice.Keywords: blaNDM-5, blaKPC-2, Klebsiella pneumoniae, hybrid plasmid, IS 26

Jie Liu,1 Xiaoxia Han,1 Jia Zhou,1 Yufang Leng1,2 1The First School of Clinical Medicine, Lanzhou University, Lanzhou, People’s Republic of China; 2Department of Anesthesiology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of ChinaCorrespondence: Yufang Leng, Email lengyf@lzu.edu.cnAbstract: Ferroptosis is a novel way of regulating cell death, which occurs in a process that is closely linked to intracellular iron metabolism, lipid metabolism, amino acid metabolism, and multiple signaling pathways. The latest research shows that ferroptosis plays a key role in the pathogenesis of acute kidney injury (AKI). Ferroptosis may be an important target for treating AKI caused by various reasons, such as ischemia-reperfusion injury, rhabdomyolysis syndrome, sepsis, and nephrotoxic drugs. This paper provides a review on the regulatory mechanisms of ferroptosis and its role in AKI, which may help to provide new research ideas for the treatment of AKI and future research.Keywords: ferroptosis, iron, lipid peroxidation, molecular mechanism, acute kidney injury

Xiao Han,1 Qianjuan Zhang,2 Chengcheng Wang,3 Bingjuan Han4 1Department of Pediatrics, Jining First People’s Hospital, Jining, Shandong, 272011, People’s Republic of China; 2Department of Children’s Medical Rehabilitation Center, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250001, People’s Republic of China; 3Department of Pediatric Surgery, Jining First People’s Hospital, Jining, Shandong, 272011, People’s Republic of China; 4Department of Children’s Health Prevention, The Second Children & Women’s Healthcare of Jinan City, Jinan, Shandong, 271100, People’s Republic of ChinaCorrespondence: Bingjuan Han, Email hbj208@163.comPurpose: Mowat-Wilson syndrome (MWS) is an autosomal dominant disease caused by a pathogenic variant of the ZEB2 gene. The main clinical manifestations include special facial features, Hirschsprung disease (HSCR), global developmental delay and other congenital malformations. Here, we summarize the clinical characteristics and genetic mutation analysis of three Chinese patients with MWS.Patients and Methods: The clinical characteristics of the patients were monitored and the treatment effect was followed up. DNA was extracted from peripheral blood and analyzed by sequencing. Whole exome sequencing was then performed.Results: Three novel ZEB2 gene mutations were identified in 3 patients (c.1147_1150dupGAAC, p.Q384Rfs&ast;7, c.1137_1146del TAGTATGTCT, p.S380Nfs &ast;13 and c.2718delT, p.A907Lfs&ast;23). They all had special facial features, intellectual disability, developmental delay, microcephaly, structural brain abnormalities and other symptoms. After long-term regular rehabilitation treatment, the development quotient of each functional area of the patient was slightly improved.Conclusion: Our study expanded the mutation spectrum of ZEB2 and enriched our understanding of the clinical features of MWS. It also shows that long-term standardized treatment is of great significance for the prognosis of patients.Keywords: Mowat-Wilson syndrome, ZEB2, gene mutation, rehabilitation treatment, long-term follow-up

Yue Zhang,1,&ast; Xue Han,1,&ast; Ke Wang,1 Da Liu,1 Xiaoyun Ding,2 Zhiqiang Hu,2 Jing Wang1,3 1School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 2Oncology Hospital, General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 3Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education, Yinchuan, 750004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiqiang Hu, Oncology Hospital, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, 750004, People’s Republic of China, Tel/Fax +86 951 674 3771, Email hzqpty@163.com Jing Wang, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, People’s Republic of China, Tel/Fax +86 951 408 1046, Email jingwang_2023@nxmu.edu.cnPurpose: Immune checkpoint inhibitors (ICI) have received the most attention for triple negative breast cancer (TNBC), while the response rate to ICI remains limited due to insufficient T cell infiltration. It is therefore essential that alternative strategies are developed to improve the therapeutic outcomes of ICI in non-responsive TNBC cases. The efficacy of pH-responsive nanomicelles (P/A/B@NM) co-loaded with paclitaxel (PTX), CXCR4 antagonist AMD3100, and PD-1/PD-L1 inhibitor BMS-1 activating the T cell-mediated antitumor immune response were evaluated using a 4T1 antiPD-1-resistance breast tumor model.Methods: In vitro, pH-responsive antitumor effect of P/A/B@NM was investigated by assessing cell viability, migration and invasion. In vivo, the distribution of P/A/B@NM was visualized in 4T1 orthotopic TNBC model using an IVIS spectrum imaging instrument. The efficacy of the co-delivery nanocarriers was evaluated by monitoring mouse survival, tumor growth and metastasis, cancer-associated fibroblasts (CAFs)-mediated tumor stroma and immunosuppressive microenvironment components, and the recruitment and infiltration of CD8+ T cells.Results: The prepared P/A/B@NM in acid microenvironment demonstrates remarkable cytotoxicity against MDA-MB-231 cells, with an IC50 of 105 μg/mL. Additionally, it exhibits substantial inhibition of tumor cell migration and invasion. The P/A/B@NM based on co-delivery nanocarriers efficiently accumulate at the tumor site and release the drugs in a pH-responsive controlled manner. The nanomedicine-PTX, AMD3100, and BMS-1 formulation significantly inhibits tumor growth and lung/liver metastasis by inducing antitumor immune responses via CXCL12/CXCR4 axis blockade, and immunogenic cell death to reprogramme both tumor stroma and immunosuppressive microenvironment. As a result, CD8+ T cell infiltration is triggered into the tumor site, boosting the efficacy of ICI therapy synergistically.Conclusion: These results demonstrate that combination therapy using P/A/B@NM reshapes CAFs-mediated tumor stroma and immunosuppressive microenvironment, which can enhance the infiltration of CD8+ T cells, thereby reactivating anti-tumor immunity for non-responsive TNBC cases.Keywords: TNBC, immunotherapy, co-delivery nanomicelles, CAFs, immunosuppressive microenvironment

Xuqi Sun,1,&ast; Yangyang Wang,2,3,&ast; Hongbin Ge,2,3 Cao Chen,2,3 Xu Han,2,3 Ke Sun,4 Meng Wang,4 Xiaobao Wei,2,3 Mao Ye,2,3 Qi Zhang,2,3,5,6 Tingbo Liang2,3,5,6 1Department of Medical Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 5Zhejiang University Cancer Center, Hangzhou, People’s Republic of China; 6Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tingbo Liang; Qi Zhang, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel/Fax +86-0571-87236601, Email liangtingbo@zju.edu.cn; qi.zhang@zju.edu.cnBackground: The heterogeneity of hepatocellular carcinoma (HCC) leads to the unsatisfying predictive performance of current staging systems. HCC patients with pathological tumor micronecrosis have an immunosuppressive microenvironment. We aimed to develop novel prognostic models by integrating micronecrosis to predict the survival of HCC patients after hepatectomy more precisely.Methods: We enrolled 765 HCC patients receiving curative hepatic resection. They were randomly divided into a training cohort (n= 536) and a validation cohort (n = 229). We developed two prognostic models for postoperative recurrence-free survival (RFS) and overall survival (OS) based on independent factors identified through multivariate Cox regression analyses. The predictive performance was assessed using the Harrell concordance index (C-index) and the time-dependent area under the receiver operating characteristic curve, compared with six conventional staging systems.Results: The RFS and OS nomograms were developed based on tumor micronecrosis, tumor size, albumin-bilirubin grade, tumor number and prothrombin time. The C-indexes for the RFS nomogram and OS nomogram were respectively 0.66 (95% CI, 0.62– 0.69) and 0.74 (95% CI, 0.69– 0.79) in the training cohort, which was significantly better than those of the six common staging systems (0.52– 0.61 for RFS and 0.53– 0.63 for OS). The results were further confirmed in the validation group, with the C-indexes being 0.66 and 0.77 for the RFS and OS nomograms, respectively.Conclusion: The two nomograms could more accurately predict RFS and OS in HCC patients receiving curative hepatic resection, thereby aiding in formulating personalized postoperative follow-up plans.Keywords: hepatocellular carcinoma, micronecrosis, postoperative survival

Xiaoyu Zhu,1 Ran Li,1 Yu Zhu,1 Jia Zhou,1 Junchao Huang,1 Yanfang Zhou,1 Jinghui Tong,1 Ping Zhang,1 Xingguang Luo,2 Song Chen,1 Yanli Li,1 Baopeng Tian,1 Shu-Ping Tan,1 Zhiren Wang,1 Xiaole Han,1 Li Tian,3 Chiang-Shan R Li,2 Yun-Long Tan1 1Psychosomatic Department, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China; 2Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; 3Institute of Biomedicine and Translational Medicine, Department of Physiology, Faculty of Medicine, University of Tartu, Tartu, EstoniaCorrespondence: Yun-Long Tan, Psychosomatic Department, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China, Tel +86-10-83024319, Fax +86-10-62710156, Email yltan21@126.comObjective: Accumulating evidence suggested that immune system activation might be involved in the pathophysiology of schizophrenia. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) can measure inflammation. This study aimed to investigate the inflammatory state in patients with schizophrenia by using these indicators.Methods: In this study, the complete blood count data for 187 continuing hospitalized patients with schizophrenia and 187 age- and sex-matched healthy participants was collected annually from 2017 to 2019. Platelet (PLT), lymphocyte (LYM), monocyte (MON) and neutrophil (NEU) counts were aggregated and NLR, MLR, PLR, and SII were calculated. Using a generalized linear mixed model, we assessed the impact of age, sex, diagnosis, and sampling year on the above indicators and evaluated the interaction between the factors.Results: According to the estimation results of the generalized linear mixed model, the NLR increased by 0.319 (p = 0.004), the MLR increased by 0.037 (p < 0.001), and the SII increased by 57.858 (p = 0.018) in patients with schizophrenia. Data after two years of continuous antipsychotic treatment showed that the NLR and MLR were higher in patients with schizophrenia than those in healthy controls, while the PLT and LYM counts were decreased in patients with schizophrenia. The schizophrenia diagnosis was correlated to the MON and LYM count, NLR, MLR, and SII (p < 0.05).Conclusion: The differences in these markers were stable and cannot be eliminated by a full course of treatment. This study provides impetus for the inflammatory hypothesis of schizophrenia.Keywords: schizophrenia, systemic immune-inflammation index, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, platelet/lymphocyte ratio

Jun Li,1,&ast; Yangyang Yang,2,&ast; Xiumin Han,3,&ast; Jing Li,2 Mengxiao Tian,1 Wenjing Qi,1 Huniu An,3 Chuanchuan Wu,1 Yao Zhang,1 Shuai Han,4 Liping Duan,4 Weisi Wang,4 Wenbao Zhang1 1State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China; 3Qinghai Provincial People’s Hospital, Xining, Qinghai, People’s Republic of China; 4NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenbao Zhang; Weisi Wang, Tel +86 991 4366319 ; +86 21 64377008, Email wenbaozhang2013@163.com; wangws@nipd.chinacdc.cnBackground: Alveolar echinococcosis (AE) is a lethal parasitic disease caused by infection with the metacestode of the dog/fox tapeworm Echinococcus multilocularis, which primarily affects the liver. Although continued efforts have been made to find new drugs against this orphan and neglected disease, the current treatment options remain limited, with drug delivery considered a likely barrier for successful treatment.Methods: Nanoparticles (NPs) have gained much attention in the field of drug delivery due to their potential to improve delivery efficiency and targetability. In this study, biocompatible PLGA nanoparticles encapsulating a novel carbazole aminoalcohol anti-AE agent (H1402) were prepared to promote the delivery of the parent drug to liver tissue for treating hepatic AE.Results: H1402-loaded nanoparticles (H1402-NPs) had a uniform spherical shape and a mean particle size of 55 nm. Compound H1402 was efficiently encapsulated into PLGA NPs with a maximal encapsulation efficiency of 82.1% and drug loading content of 8.2%. An in vitro uptake assay demonstrated that H1402-NPs rapidly penetrated the in vitro cultured pre-cyst wall and extensively accumulated in the pre-cysts of E. multilocularis within only 1 h. The biodistribution profile of H1402-NPs determined through ex vivo fluorescence imaging revealed significantly enhanced liver distribution compared to unencapsulated H1402, which translated to improved therapeutic efficacy and reduced systemic toxicity (especially hepatotoxicity and cytotoxicity) in a hepatic AE murine model. Following a 30-day oral regimen (100 mg/kg/day), H1402-NPs significantly reduced the parasitic burden in both the parasite mass (liver and metacestode total weight, 8.8%) and average metacestode size (89.9%) compared to unmedicated infected mice (both p-values < 0.05); the treatment outcome was more effective than those of albendazole- and free H1402-treated individuals.Conclusion: Our findings demonstrate the advantages of encapsulating H1402 into PLGA nanoparticles and highlight the potential of H1402-NPs as a promising liver-targeting therapeutic strategy for hepatic AE.Graphical Abstract: Keywords: alveolar echinococcosis, Echinococcus multilocularis, PLGA, nanoparticles, liver targeting, oral administration

Kang Yu,&ast; Zhigang Ding,&ast; Jiaojiao Yang, Xue Han, Tianzuo Li, Huihui Miao Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huihui Miao, Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, 10th Tieyi Road, Haidian District, Beijing, 100038, People’s Republic of China, Email iverymhh@hotmail.comBackground: Maternal pain during labor is one of the most important factors contributing to increased cesarean delivery rates and poor pregnancy outcomes, and this pain can be managed by labor analgesia. Many studies exist on labor analgesia, and the quantity and quality of these studies have not been reported. Therefore, we aimed to perform a bibliometric analysis of studies from 2002 to 2021.Methods: We used the Web of Science database to obtain publications related to labor analgesia from January 2002 to December 2021. Various bibliographic information was collected, including country; author; journal; grant; discipline; institution and research hotspot. A total of 4536 papers were included.Results: A total of 4536 articles were included in the study. The country with the most published articles on labor analgesia and the country of the funding agency was the United States. Most articles were published in the disciplines Anesthesiology and Obstetrics & Gynecology. The journal that published the most articles in this category was International Journal of Obstetric Anesthesia. In addition, we found different research hotspots for labor analgesia in the United States, Japan, and China.Conclusion: This paper provides a bibliometric analysis of research on labor analgesia and highlights the differences in research hotspots for labor analgesia between countries.Keywords: labor analgesia, bibliometric analysis, hotspots

Yuting Liu,1,&ast; Jie Tang,1,&ast; Xiaolan Qiu,1,&ast; Lucy A Teng,2 Mukesh K Sriwastva,2 Xuedong Han,1 Zhi Li,1 Minmin Liu,1 Shuangyue Liu,1 Dongzhu Da,1 Zhi Li,1 Linlin Zhen,1 Yi Ren1 1Department of Breast and Thyroid Surgery, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China; 2Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, USA&ast;These authors contributed equally to this workCorrespondence: Yi Ren; Linlin Zhen, Department of Breast and Thyroid Surgery, The Affiliated Huai’an No. 1 People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China, Email only_renyi@163.com; simu1027@sina.comBackground: Recent therapeutic approaches have improved survival rate for women with breast cancer, but the survival rate for metastatic breast cancer is still low. Exosomes released by various cells are involved in all steps of breast cancer development.Methods: We established the multimodal imaging report expression in breast cancer cells with lentivirus vectors pGluc and pBirA to investigate the secreted exosomes. Comparative microRNA (miRNA) analysis was performed with miRNA qPCR array in mice with breast cancer lung metastasis. The co-immunoprecipitation and chromatin immunoprecipitation assays were used to identify the mechanism of miRNA sorting to exosomes. The potential therapeutic strategy using an anti-sorting antibody was used to investigate breast cancer lung metastasis.Results: We identified 26 high- and 32 low-expression level miRNAs in exosomes from metastasis compared to those from primary tumors and normal tissues. The tumor suppressors, including miR-200c and let-7a, were reduced in tumor tissues and metastasis but increased in the respective exosomes compared to normal tissues. Furthermore, the Ras-related protein (Rab1A) facilitated miR-200c sorting to exosomes circumventing the influence of tumor suppressor miR-200c on tumor cells, while the metastatic exosome cargo miR-200c inhibited F4/80+ macrophage immune response. Administration of anti-Rab1A antibody significantly repressed the trafficking of miR-200c to exosomes and breast cancer lung metastasis.Conclusion: Our study has identified a novel molecular mechanism for breast cancer lung metastasis mediated by exosome cargo miRNAs and provided a new therapeutic strategy for cancer immunotherapy.Graphical Abstract: Keywords: extracellular vehicles, exosomes, breast cancer lung metastasis, miR-200c, Rab1A, miRNA sorting

Rui Wang,1,&ast; Yijing Yao,1,2,&ast; Yihui Gao,1 Mengyao Liu,1 Qian Yu,3 Xuejiao Song,4 Xiao Han,5 Dechao Niu,6 Lixin Jiang1,2 1Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People’s Republic of China; 2Shanghai Institute of Ultrasound in Medicine, Shanghai, 200233, People’s Republic of China; 3Department of Ultrasonography, Shanghai Jiao Tong University Affiliated No. 6 Hospital, Shanghai, 200233, People’s Republic of China; 4School of Physical and Mathematical Sciences, Nanjing Tech University (NanjingTech), Nanjing, 211800, People’s Republic of China; 5Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu, 215123, People’s Republic of China; 6Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lixin Jiang; Dechao Niu, Email jinger_28@sina.com; dcniu@ecust.edu.cnBackground: Pancreatic cancer is regarded as one of the most lethal types of tumor in the world, and optional way to treat the tumor are urgently needed. Cancer stem cells (CSCs) play a key role in the occurrence and development of pancreatic tumors. CD133 is a specific antigen for targeting the pancreatic CSCs subpopulation. Previous studies have shown that CSC-targeted therapy is effective in inhibiting tumorigenesis and transmission. However, CD133 targeted therapy combined with HIFU for pancreatic cancer is absent.Purpose: To improve therapeutic efficiency and minimize side effects, we carry a potent combination of CSCs antibody with synergist by an effective and visualized delivery nanocarrier to pancreatic cancer.Materials and Methods: Multifunctional CD133-targeted nanovesicles (CD133-grafted Cy5.5/PFOB@P-HVs) with encapsulated perfluorooctyl bromide (PFOB) in a 3-mercaptopropyltrimethoxysilane (MPTMS) shell modified with poly ethylene glycol (PEG) and superficially modified with CD133 and Cy 5.5 were constructed following the prescribed order. The nanovesicles were characterized for the biological and chemical characteristics feature. We explored the specific targeting capacity in vitro and the therapeutic effect in vivo.Results: The in vitro targeting experiment and in vivo FL and ultrasonic experiments showed the aggregation of CD133-grafted Cy5.5/PFOB@P-HVs around CSCs. In vivo FL imaging experiments demonstrated that the nanovesicles assemble for the highest concentration in the tumor at 24 h after administration. Under HIFU irradiation, the synergistic efficacy of the combination of the CD133-targeting carrier and HIFU for tumor treatment was obvious.Conclusion: CD133-grafted Cy5.5/PFOB@P-HVs combined with HIFU irradiation could enhance the tumor treatment effect not only by improving the delivery of nanovesicles but also by enhancing the HIFU thermal and mechanical effects in the tumor microenvironment, which is a highly effective targeted therapy for treating pancreatic cancer.Keywords: multifunctional nanovesicles, cancer stem cells, high-intensity focused ultrasound, in vivo fluorescent imaging, ultrasonic imaging

Fengli Huang,1,&ast; Qun Zhang,2,&ast; Jie Xiao,3,&ast; Xin Zhang,1 Xingzhi Han,3 Xiao Shi,3 Jing Hu,2 Li Li,2 Xiaoping Qian1,2 1Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Oncology, Nanjing Drum Tower Hospital, Nanjing, People’s Republic of China; 3Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoping Qian, Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Tel +86-13951743162, Fax +86-25-68182342, Email xiaopingqian@nju.edu.cnPurpose: Recent studies have shown that traditional Chinese medicine (TCM), such as gambogic acid (GA), is involved in the regulation of tumor immune microenvironment and can be combined with other anti-tumor treatment strategies. Here, we used GA as an adjuvant to construct a nano-vaccine to improve the anti-tumor immune response of colorectal cancer (CRC).Materials and Methods: We used a previously reported two-step emulsification method to obtain poly (lactic-co-glycolic acid) /GA nanoparticles (PLGA/GA NPs), and then CT26 colon cancer cell membrane (CCM) was used to obtain CCM-PLGA/GA NPs. This novel nano-vaccine, CCM-PLGA/GA NPs, was co-synthesized with GA as an adjuvant and neoantigen provided by CT26 CCM. We further confirmed the stability, tumor targeting, and cytotoxicity of CCM-PLGA/GA NPs. The regulatory effect on the tumor immune microenvironment, the anti-tumor efficacy, and the combined anti-tumor efficacy with anti-PD-1 monoclonal Antibodies (mAbs) of this novel nano-vaccine was also detected in vivo.Results: We successfully constructed the CCM-PLGA/GA NPs. In vitro and in vivo tests showed low biological toxicity, as well as the high tumor-targeting ability of the CCM-PLGA/GA NPs. Besides, we revealed a remarkable effect of CCM-PLGA/GA NPs to activate the maturation of dendritic cells (DCs) and the formation of a positive anti-tumor immune microenvironment.Conclusion: This novel nano-vaccine constructed with GA as the adjuvant and CCM providing the tumor antigen can not only directly kill tumors by enhancing the ability of GA to target tumors, but also indirectly kill tumors by regulating tumor immune microenvironment, providing a new strategy for immunotherapy of CRC.Keywords: cancer immunotherapy, gambogic acid, nano-vaccine, tumor immune microenvironment, colorectal cancer

Shenghan Gao,1,2 Xinyu Zhang,1,2 Jie Liu,3 Fuqing Ji,2 Zhihao Zhang,2 Qingjie Meng,2 Qi Zhang,1 Xiaogang Han,2 He Wu,2 Yulong Yin,2 Yonggang Lv,2 Wenzhen Shi3 1The College of Life Sciences, Northwest University, Xi’an, 710069 People’s Republic of China; 2Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China; 3Clinical Medical Center, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of ChinaCorrespondence: Yonggang Lv, Department of Thyroid Breast Surgery, Xi’an NO.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China, Email lvygwytt@163.com Wenzhen Shi, Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, School of Life Sciences and Medicine, Northwest University, Xi’an, People’s Republic of China, Tel +8615037916770, Email shiwenzhen736@163.comBackground: Breast cancer is a common cancer worldwide. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by a poor prognosis. Icariin (ICA) is a flavonoid glycoside purified from the natural product Epimedium, which is reported to exert an inhibitory effect on a variety of cancers. However, molecular mechanisms behind ICA suppressed TNBC remain elusive.Methods: The curative effects of ICA on TNBC cells and potential targets were predicted by network pharmacology and molecular biology methods screening, and the mechanism of inhibition was explained through in vitro experiments such as cell function determination, Western blot analysis, molecular docking verification, etc.Results: This study showed that ICA inhibits TNBC cell functions such as proliferation, migration, and invasion in a dose-dependent manner. ICA could induce redox‐induced apoptosis in TNBC cell, as shown by ROS upregulation. As a result of network pharmacology, ICA was predicted to be able to inhibit the MAPK signaling pathway. ICA treatment inhibited the expression of JNK and c-Jun and downregulated the antiapoptotic gene cIAP-2. Our results suggested that ICA could induce apoptosis by inducing an excessive accumulation of ROS in cells and suppress TNBC cell invasion via the JNK/c-Jun signaling pathway.Conclusion: We demonstrated that ICA can effectively inhibit cell proliferation and induced apoptosis of TNBC cells. In addition, ICA could inhibit TNBC cell invasion through the JNK/c-Jun signaling pathway. The above suggests that ICA may become a potential drug for TNBC.Keywords: triple-negative breast cancer, icariin, JNK/c-Jun, apoptosis, ROS, invasion

Na Wang,1,&ast; Minghua Zhan,2,&ast; Teng Wang,3 Jinlu Liu,1 Caiqing Li,1 Baoliang Li,1 Xuying Han,1 Huiying Li,4 Shuting Liu,5 Jing Cao,1 Xinran Zhong,1 Chunmei Lei,1 Wei Zhang,1 Zhihua Zhang6 1Microbiology Department, The First Affiliated Hospital of Hebei North University, Zhangjiakou, People’s Republic of China; 2Clinical Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, People’s Republic of China; 3Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, People’s Republic of China; 4Obstetrics and Gynecology Department, The First Affiliated Hospital of Hebei North University, Zhangjiakou, People’s Republic of China; 5Hemodialysis Department, The First Affiliated Hospital of Hebei North University, Zhangjiakou, People’s Republic of China; 6Respiratory and Critical Care Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Zhang; Zhihua Zhang, Respiratory and Critical Care Medicine, The First Affiliated Hospital of Hebei North University, No. 14, Changqing Road, Zhangjiakou City, Hebei Province, 075000, People’s Republic of China, Tel +86-03138043503, Fax +86-1088326317, Email 15369318318@163.com; zzh19641229@163.comPurpose: Through long-term and large sample size statistical analysis, we revealed the pattern of Klebsiella pneumoniae (KP) infection and drug resistance and provided epidemiological data for the treatment and prevention and control of multidrug-resistant bacterial infection in our hospital.Patients and Methods: Strains were identified using the BD PhoenixTM 100 system, minimal inhibitory concentration of antibiotics were determined by the broth method, and data were statistically analyzed using WHONET 5.6 and SPSS27.0.Results: The isolation rate of KP from Enterobacteriaceae (26.2%, 4547/17358) in our hospital showed an increasing annual trend, ranking second only to Escherichia coli. Carbapenem-resistant KP (CRKP) accounted for the highest proportion of carbapenem-resistant Enterobacteriaceae (72.2%, 431/597), showing an upward trend. Infected patients had a male-to-female ratio of approximately 2:1 and were mainly > 60 years of age (66.2%), with intensive care units being the most commonly distributed department. Sputum was the most common specimen type (74.0%). Compared with spring and summer, autumn and winter were the main epidemic seasons for KP and extended-spectrum β-lactamase KP (ESBL-KP). The resistance rate of KP to common antibiotics was low, but all showed an increasing trend each year. ESBL-KP was > 90% resistant to piperacillin, amoxicillin/clavulanic acid, and cefotaxime and less resistant to other common antibiotics, but showed an increasing trend in resistance to most antibiotics. CRKP resistance to common antibiotics was high, with resistance rates > 90%, excluding amikacin (64.1%), gentamicin (87.4%), cotrimoxazole (44.3%), chloramphenicol (13.6%), and tetracycline (30.5%).Conclusion: KP in our hospital mainly caused pulmonary infection in older men, which occurred frequently in autumn and winter, and the isolation and drug resistance rates showed an increasing trend. Age over 70 years, admission to intensive care unit, and urinary tract infection were found to be the risk factors for CRKP and ESBL-KP-resistance.Keywords: Klebsiella pneumoniae, antibacterial drugs, resistance trends, carbapenem-resistant, extended-spectrum β-lactamase, antimicrobial susceptibility surveillance

Jie Zhao,1,2 Teng Zhang,2,3 Zhe Deng,1,2 Xia Han,1,2 Tao Ma,2,3,&ast; Keliang Xie1,2,&ast; 1Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Ma, Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, People’s Republic of China, Tel +86 13702172328, Email taoma@tmu.edu.cn Keliang Xie, Department of Critical Care Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, People’s Republic of China, Tel +86 15332112099, Email xiekeliang2009@hotmail.comPurpose: Intra-abdominal infection is considered the second most common cause of sepsis and results in localized or diffused inflammation of the peritoneum. The main treatment for abdominal sepsis is an emergency laparotomy for source control. However, surgical trauma also causes inflammation, and patients become susceptible to postoperative complications. Therefore, it is necessary to identify biomarkers that can be used to distinguish sepsis from abdominal infection. This prospective study investigated whether cytokine levels in the peritoneum could predict complications and indicate severity of sepsis following emergency laparotomy.Methods: We prospectively observed 97 patients with abdominal infection admitted to the Intensive Care Unit (ICU). After emergency laparotomy,SEPSIS-3 criteria were used for the diagnosis of sepsis or septic shock. Blood and peritoneal fluid samples were drawn at postoperative admission to the ICU and cytokine concentrations were measured by flow cytometry.Results: Fifty-eight postoperative patients were enrolled. We found significant elevations in the peritoneal concentrations of IL-1β, IL-6, TNF-α, IL-17, and IL-2 in patients with sepsis or septic shock compared to the patients without sepsis after surgery. Positive correlations between levels of these peritoneal cytokines with APACHE II scores were found: IL-6, in particular, had the highest correlation coefficient of 0.833. Meanwhile, IL-10 in blood, MCP-1 and IL-8 in both blood and peritoneum were simultaneously increased in patients with sepsis and septic shock, and also positively correlated with disease severity.Conclusion: The cytokine storm that occurs in the abdominal cavity after emergency laparotomy may be the main mechanism leading to sepsis. It may be valuable to measure IL-1β, IL-6, TNF-α,IL-17, IL-2, MCP-1, and IL-8 in the peritoneal fluid, combined with serum IL-10, MCP-1 and IL-8, in a panel of cytokines, to assess the severity of sepsis and predict mortality from abdominal infection after emergency laparotomy.Keywords: abdominal infection, emergency laparotomy, peritoneal cytokine, cytokine storm

Ruina Zhang,1,&ast; Yizhen Zhang,1,&ast; Wenjing Xu,2 Xiaomin Han,2 Junying Zhao1 1Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Key Laboratory of Food Safety Risk Assessment, Ministry of Health, China National Center for Food Safety Risk Assessment, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaomin Han, Key Laboratory of Food Safety Risk Assessment, Ministry of Health, China National Center for Food Safety Risk Assessment, Beijing, People’s Republic of China, Tel +8613488894538, Email hanxiaomin@cfsa.net.cn Junying Zhao, Department of dermatology, Beijing friendship hospital, capital medical university, 95 Yongan Road, Xicheng District, Beijing, People’s Republic of China, Tel +8613621098570, Email zjy63014411@aliyun.comBackground: Aspergillosis is an uncommon fungal infection in which primary cutaneous sites are very rare, and most cases occur in patients with immunocompromised status. Although primary cutaneous aspergillosis is usually encountered in immunocompromised patients, it also occurs in immunocompetent individuals.Case Presentation: We report a case of primary cutaneous aspergillosis in a 46-year-old immunocompetent woman with diabetes mellitus after tattooing. She presented with erythematous papules, papulopustules and a plaque on the right lower limb of more than two years duration which had failed to respond to antihistamine treatment. Histological examination of a skin biopsy sample showed oval spores in the corneous layer, a slightly thickened epidermis, and infiltrating lymphocytes and neutrophils around the blood vessels in the superficial dermis. Aspergillus fumigatus was isolated and identified in cultures. Clinical and biological examinations did not reveal any systemic localization of aspergillosis, ruling out a hypothesis of blood dissemination. Lesions resolved completely after systemic antifungal treatment with itraconazole.Conclusion: Clinical lesions of primary cutaneous aspergillosis are nonspecific and usually present as a variety of lesions, including macules, papules, nodules, plaques, purpura, blood blisters, and pustules. The nonspecific features and variety of lesions can lead to misdiagnosis and delayed treatment. Direct microscopy, microbiological culture, and histopathological examination are helpful for diagnosing primary cutaneous aspergillosis. Moreover, the physicians should be aware of the possibility of Aspergillus infection in tattooed cases.Keywords: Aspergillosis, primary cutaneous aspergillosis, Aspergillus fumigatus

Zhiqiang Liu,1,&ast; Xiaoli Gao,1,&ast; Lirong Liang,2 Xuan Zhou,1 Xiaozhe Han,3 Ting Yang,4– 7 Kewu Huang,8 Yingxiang Lin,8 Shu Deng,9 Zuomin Wang,1 Chen Wang4– 7,10 1Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Clinical Epidemiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Oral Science and Translational Research, Nova Southeastern University College of Dental Medicine, Fort Lauderdale, FL, USA; 4Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 5National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 6Institute of Respiratory Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 7Department of Respiratory Medicine, Capital Medical University, Beijing, People’s Republic of China; 8Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Beijing, People’s Republic of China; 9Department of Immunology and Infectious Diseases, The Forsyth Institute, Harvard School of Dental Medicine Affiliate, Cambridge, MA, USA; 10WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zuomin Wang, Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongti South Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86 10 85231492, Email wzuomin@sina.cn Chen Wang, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, 2 Yinghuayuan Dongjie, Chaoyang District, Beijing, 100029, People’s Republic of China, Tel +86 10 65105565, Email wangchen@pumc.edu.cnPurpose: There is insufficient information about the prevalence and risk factors of gastroesophageal reflux disease (GERD) in the Chinese adult population. We aimed to assess the prevalence and identify the risk factors of GERD in China.Methods: We collected data from a nationally representative sample (50,991 subjects) of Chinese adults from a large nation-wide cross-sectional survey. GERD was diagnosed by a standardized Chinese-language GERD questionnaire with a score of ≥ 8. The demographic characteristics, comorbidities and periodontal factors of all participants were collected.Results: Fifty-thousands-one-hundred-eighty-three participants were finally included in this study. The overall prevalence of GERD was 5.6% (95% CI, 5.4– 5.8%) among the general Chinese population aged 20 years or older. Women, smokers, and people with older age, BMI ≥ 25.0 kg/m2, urban residence, lower education level or comorbidities were more prevalent with GERD (p < 0.001). Symptoms of severe periodontitis (OR = 1.40, 95% CI 1.28– 1.52, p < 0.001) and lower frequency of tooth brushing (OR = 2.01, 95% CI 1.76– 2.29, p < 0.001) were significantly associated with risk of GERD.Conclusion: Symptom-based GERD is highly prevalent in the Chinese population. Overweight and smoking are major preventable risk factors for GERD. Periodontal factors are novel potential risk factors for GERD and should be given more attention in GERD prevention.Keywords: gastroesophageal reflux disease, prevalence, risk factor, periodontitis, epidemiology

Zihui Yan,1 Mengjie Cai,1 Xu Han,2 Qingguang Chen,2 Hao Lu1,2 1Department of Endocrinology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Diabetes Research Institute, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of ChinaCorrespondence: Qingguang Chen; Hao Lu, Email ruiqi3721@163.com; tangniaobing107@163.comObjective: This study aimed to investigate the interaction between age groups and risk factors for diabetes and prediabetes in Shanghai communities and to identify the effect of age on other risk factors for diabetes and prediabetes.Methods: This study recruited 3540 participants with undiagnosed diabetes or prediabetes in 14 communities in Shanghai from February to August 2019. All participants underwent a comprehensive examination, including filling out a detailed questionnaire, physical examination, 75 g oral glucose tolerance test, and blood sample collection. In addition, logistic regression was used to analyze the interaction between age and risk factors for prediabetes and diabetes.Results: The statistical analysis included 2776 people. In this study, the prevalence of diabetes and prediabetes were 15.1% and 52.3%, respectively. The prevalence of diabetes and prediabetes is higher in the elderly than in the middle-aged group. Among the risk factors for diabetes, overweight was associated with higher age (P-interaction 0.028). In addition, among the risk factors for prediabetes, a high level of education was associated with higher age (P-interaction 0.039) and elevated serum cholesterol level was associated with lower age (P-interaction 0.019).Conclusion: This study confirmed an interaction between age and other influencing factors, which may be important in explaining differences in risk factors for diabetes and prediabetes in the middle-aged and elderly populations. Community health facilities can provide health guidance to people of different age groups to prevent and control prediabetes and diabetes.Keywords: diabetes, prediabetes, risk factors, age, interaction

Jie Hu,1,&ast; Huihui Li,1,&ast; Yingshan Zhao,1 Yuancheng Ke,1 Ilva D Rupenthal,2 Hanyu Liu,1 Jinghua Ye,1 Xinyue Han,1 Fan Yang,1 Wei Li,3 Huaqing Lin,1 Dongzhi Hou1 1Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems and Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, People’s Republic of China; 2Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand; 3Guangzhou Institute for Drug Control, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huaqing Lin; Dongzhi Hou, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, 280 Wai Huan Dong Road, Guangzhou, People’s Republic of China, Tel +86 180 2631 2508, Fax +86 20 3935 2117, Email huaqing_@163.net; houdongzhi406@163.comIntroduction: Glaucoma is a chronic disease that requires long-term adherence to treatment. Topical application of conventional eye drops results in substantial drug loss due to rapid tear turnover, with poor drug bioavailability being a major challenge for efficient glaucoma treatment. We aimed to prepare the anti-glaucoma drug betaxolol hydrochloride (BH) as a novel nano-delivery system that prolonged the retention time at the ocular surface and improved bioavailability.Methods: We constructed multifunctional nanoparticles (MMt-BH-HA/CS-ED NPs) by ion cross-linking-solvent evaporation method. The particle size, zeta potential, encapsulation efficiency and drug loading of MMt-BH-HA/CS-ED NPs were physicochemically characterized. The structure of the preparations was characterized by microscopic techniques of SEM, TEM, XPS, XRD, FTIR and TGA, and evaluated for their in vitro release performance as well as adhesion properties. Its safety was investigated using irritation assays of hemolysis experiment, Draize test and histopathology examination. Precorneal retention was examined by in vivo fluorescence tracer method and pharmacokinetics in tear fluid was studied. A model of high IOP successfully induced by injection of compound carbomer solution was used to assess the IOP-lowering efficacy of the formulation, and it was proposed that micro-interactions between the formulation and the tear film would be used to analyze the behavior at the ocular surface.Results: The positively charged MMt-BH-HA/CS-ED NPs were successfully prepared with good two-step release properties, higher viscosity, and slower pre-corneal diffusion rate along with longer precorneal retention time compared to BH solution. The micro-interactions between nanoparticles and tear film converted the drug clearance from being controlled by fast aqueous layer turnover to slow mucin layer turnover, resulting in higher drug concentration on the ocular surface, providing more durable and stable IOP-lowering efficacy.Conclusion: The novel multifunctional MMt-BH-HA/CS-ED NPs can effectively reduce IOP and are suitable for the treatment of chronic disease glaucoma.Graphical Abstract: Keywords: glaucoma, nanoparticles, betaxolol hydrochloride, BH, precorneal retention, micro-interactions

Xuhua Duan,&ast; Wenze Xu,&ast; Hao Li, Manzhou Wang, Wenhui Wang, Huibin Lu, Yancang Zhang, Xinwei Han Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yancang Zhang; Xinwei Han, Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, No. 1, East Jian She Road, People’s Republic of China, 450052, Tel +86-371-66278081, Email zhangyancang2016@126.com; zzudxh@yeah.netPurpose: Chemoresistance is a major factor contributing to the failure of cancer treatment. The conventional chemotherapy agent 5-fluorouracil (5-FU) has been used for cancer treatment for decades. However, its use is limited in the treatment of hepatocellular carcinoma (HCC) due to acquired resistance. Nrf2 (NF-E2-related factor 2) is known to be associated with drug resistance across a wide range of cancer types. Also, since arsenic trioxide (As2O3) showed antitumor effects on HCC, the purpose of this study was to determine whether As2O3 and Nrf2-siRNA could inhibit HCC synergistically.Methods: We generated two separate 5-FU-resistant HCC cell lines (SNU-387/5-FU and Hep3B/5-FU). Western blotting was used to determine protein levels. An efficient lentiviral delivery system was used to establish stable knockdown or overexpression of Nrf2 and HIF-1α. In vitro and in vivo analyses of the effects of Nrf2 gene knockdown and As2O3 on 5-FU-resistant HCC cells were conducted.Results: The expression of Nrf2 was higher in the 5-FU-resistant HCC cell lines than in the parental cell lines. When coupled with Nrf2 knockdown, As2O3 treatment significantly decreased 5-FU-resistant SNU-387 and Hep3B cell viability, migration, and invasion, inactivated HIF-1α/HSP70 signaling, inhibited anti-apoptotic B-cell lymphoma (Bcl-2) activity, and increased the expression of pro-apoptotic Bcl-2-associated X protein (BAX) along with caspase-3. The synergistic effect was also confirmed using a 5-FU-resistant Hep3B mouse xenograft model in vivo.Conclusion: Nrf2 knockdown could improve the effect of As2O3 on reversing drug resistance in 5-FU-resistant HCC cells.Keywords: arsenic trioxide, 5-fluorouracil, chemoresistance, hepatocellular carcinoma, Nrf2, HIF-1&#x03B1

Xue Han,1,&ast; Yakun Yang,1,&ast; Muqing Zhang,2,3 Li Li,4 Yucong Xue,2 Qingzhong Jia,4 Xiangting Wang,2,5 Shengjiang Guan3,6 1School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, People’s Republic of China; 2College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, People’s Republic of China; 3Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang, People’s Republic of China; 4School of Pharmacy, Hebei Medical University, Shijiazhuang, People’s Republic of China; 5Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang, People’s Republic of China; 6School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangting Wang, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China, Email wangxiangting@hebcm.edu.cn Shengjiang Guan, Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, People’s Republic of China, Email guanshengjiang123@126.comPurpose: Despite significant advances in interventional treatment, myocardial infarction (MI) and subsequent cardiac fibrosis remain major causes of high mortality worldwide. Liquiritin (LQ) is a flavonoid extract from licorice that possesses a variety of pharmacological properties. However, to our knowledge, the effects of LQ on myocardial fibrosis after MI have not been reported in detail. The aim of our research was to explore the potential role and mechanism of LQ in MI-induced myocardial damage.Methods: The MI models were established by ligating the left anterior descending branch of the coronary artery. Next, rats were orally administered LQ once a day for 14 days. Biochemical assays, histopathological observations, ELISA, and Western blotting analyses were then conducted.Results: LQ improved the heart appearance and ECG, decreased cardiac weight index and reduced levels of cardiac-specific markers such as CK, CK-MB, LDH, cTnI and BNP. Meanwhile, LQ reduced myocardial infarct size and improved hemodynamic parameters such as LVEDP, LVSP and ±dp/dtmax. Moreover, H&E staining showed that LQ attenuated the pathological damage caused by MI. Masson staining showed that LQ alleviated myocardial cell disorder and fibrosis while reducing collagen deposition. LQ also decreased the levels of oxidative stress and inflammation. Western blotting demonstrated that LQ significantly down-regulated the expressions of Collagen I, Collagen III, TGF-β 1, MMP-9, α-SMA, CCL5, and p-NF-κB.Conclusion: LQ protected against myocardial fibrosis following MI by improving cardiac function, and attenuating oxidative damage and inflammatory response, which may be associated with inhibition of CCL5 expression and the NF-κB pathway.Keywords: liquiritin, cardiac fibrosis, myocardial infarction, CCL5 expression, NF-κB signaling pathway

Han X, Liu J, Liu Y, Mou L, Li C. Cancer Manag Res. 2021;13:4393–4401. We, the Editors and Publisher of Cancer Management and Research, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figure 3 with images from other unrelated articles. Specifically, Images for Figure 3E and 3F have been duplicated with images in Figures 4A and 4B from Xu L, Ni N, Gao H, Hu P. MicroRNA‑1301‑3p promotes the progression of non‑small cell lung cancer by targeting Thy‑1 and predicts poor prognosis of patients. Oncology Letters. 2021;21:327. https://doi.org/10.3892/ol.2021.12589; Figure 4B from Wang C, Wang J, Zhang J, et al. MicroRNA‑623 inhibits tumor progression and is a predictor of poor prognosis of breast cancer. Oncology Letters. 2020;20:386. https://doi.org/10.3892/ol.2020.12249; and Figure 4B from Lu Y, Zhang X, Zhang H, Zhu Z. Prognosis and Biological Function of miR-3195 in Non-Small Cell Lung Cancer. Cancer Manag Res. 2022;14:169-176. https://doi.org/10.2147/CMAR.S345618. The authors did not respond to our queries and were unable to provide an explanation for the duplicated images or provide data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

HM Adnan Hameed1– 4&ast;, Cuiting Fang1– 4&ast;, Zhiyong Liu,1– 3 Yanan Ju,1– 3 Xingli Han,1– 4 Yamin Gao,1– 4 Shuai Wang,1– 3,5 Gift Chiwala,1– 4 Yaoju Tan,6 Ping Guan,6 Jinxing Hu,6 Xiaoli Xiong,1– 3 Jiacong Peng,3,7 Yongping Lin,3,7 Muzammal Hussain,4 Nanshan Zhong,3,7,8 Dmitry A Maslov,9 Gregory M Cook,10,11 Jianxiong Liu,6 Tianyu Zhang1– 4 1State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, People’s Republic of China; 2China-New Zealand Joint Laboratory of Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, People’s Republic of China; 3Guangdong-Hong Kong-Macau Joint Laboratory of Respiratory Infectious Diseases, Guangzhou, People’s Republic of China; 4University of Chinese Academy of Sciences (UCAS), Beijing, People’s Republic of China; 5National Clinical Research Center for Infectious Diseases, Guangdong Provincial Clinical Research Center for Tuberculosis, Shenzhen Third People’s Hospital, Shenzhen, People’s Republic of China; 6State Key Laboratory of Respiratory Disease, Guangzhou Chest Hospital, Guangzhou, People’s Republic of China; 7State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 8Guangzhou National Laboratory, Guangzhou, People’s Republic of China; 9Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia; 10Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; 11Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand&ast;These authors contributed equally to this workCorrespondence: Tianyu Zhang, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Room A207, 190 Kaiyuan Ave, Science Park, Huangpu District, Guangzhou, 510530, People’s Republic of China, Tel +86-2032015270, Email zhang_tianyu@gibh.ac.cn Jianxiong Liu, Guangzhou Chest Hospital, 62 Hengzhigang Road, Yuexiu District, Guangzhou, People’s Republic of China, Tel +86-2083595977, Email ljxer64@qq.comObjective: Rifampicin (RIF)-resistance, a surrogate marker for multidrug-resistant tuberculosis (TB), is mediated by mutations in the rpoB gene. We aimed to investigate the prevalence of mutations pattern in the entire rpoB gene of Mycobacterium tuberculosis clinical isolates and their association with resistance level to RIF.Methods: Among 465 clinical isolates collected from the Guangzhou Chest Hospital, drug-susceptibility of 175 confirmed Mtb strains was performed via the proportion method and Bactec MGIT 960 system. GeneXpert MTB/RIF and sanger sequencing facilitated in genetic characterization, whereas the MICs of RIF were determined by Alamar blue assay.Results: We found 150/175 (85.71%) RIF-resistant strains (MIC: 4 to > 64 μg/mL) of which 57 were MDR and 81 pre-XDR TB. Genetic analysis identified 17 types of mutations 146/150 (97.33%) within RRDR (codons 426– 452) of rpoB, mainly at L430 (P), D435 (V, E, G, N), H445 (N, D, Y, R, L), S450 (L, F) and L452 (P). D435V 12/146 (8.2%), H445N 16/146 (10.9%), and S450L 70/146 (47.94%) were the most frequently encountered mutations. Mutations Q432K, M434V, and N437D are rarely identified in RRDR. Deletions at (1284– 1289 CCAGCT), (1295– 1303 AATTCATGG), and insertion at (1300– 1302 TTC) were detected within RRDR of three RIFR strains for the first time. We detected 47 types of mutations and insertions/deletions (indels) outside the RRDR. Four RIFR strains were detected with only novel mutations/indels outside the RRDR. Two of the four had (K274Q + C897 del + I491M) and (A286V + L494P), respectively. The other two had (G1687del + P454L) and (TT1835-6 ins + I491L) individually. Compared with phenotypic characterization, diagnostic sensitivities of GeneXpert MTB/RIF and sequencing analysis were 95.33% (143/150), and 100% (150/150) respectively.Conclusion: Our findings underscore the key role of RRDR mutations and the contribution of non-RRDR mutations in rapid molecular diagnosis of RIFR clinical isolates. Such insights will support early detection of disease and recommend the appropriate anti-TB regimens in high-burden settings.Keywords: rifampicin-resistance, Mycobacterium tuberculosis, rpoB, GeneXpert MTB/RIF, resistance-determining region

Muqing Zhang,1,2,&ast; Jian Chen,3,4,&ast; Yanwei Wang,2 Guobin Kang,2 Yixin Zhang,3,4 Xue Han3,4 1College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, People’s Republic of China; 2Affiliated Hospital, Hebei University of Chinese Medicine, Shijiazhuang, People’s Republic of China; 3School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, People’s Republic of China; 4International Joint Research Center on Resource Utilization and Quality Evaluation of Traditional Chinese Medicine, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yixin Zhang; Xue Han, Tel +86 311 89926316, Fax +86 311 89926316, Email hbzyx123@163.com; hanxuecc@126.comPurpose: The network pharmacology approach and validation experiment were performed to investigate the potential mechanisms of Agrimonia pilosa Ledeb. (APL) extract against acute myocardial infarction (AMI).Methods: The primary compounds of APL extract were identified by High-Performance Liquid Chromatography (HPLC) analysis. The intersecting targets of active compounds and AMI were determined via network pharmacology analysis. A mouse model of AMI was established by subcutaneous injection of isoproterenol (Iso). Mice were treated with APL extract by intragastric administration. We assessed the effects of APL extract on the electrocardiography (ECG), cardiac representative markers, representative indicators of oxidative stress, pathological changes, and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, as well as apoptosis-related indicators in the mice.Results: Five candidate compounds were identified in APL extract. Enrichment analyses indicated that APL extract could exert myocardial protective effects via the PI3K/Akt pathway. ST segment elevation and increased heart rate were obviously reversed in APL extract groups compared to Iso group. We also detected significant decreases in lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase MB (CK-MB), malondialdehyde (MDA), and reactive oxygen species (ROS), as well as a significant increase in superoxide dismutase activities (SOD) after APL extract treatment. In addition, APL extract markedly decreased the number of apoptotic cardiomyocytes after AMI. In the APL extract groups of AMI mice, there were increased expression levels of p-PI3K, p-Akt, and B-cell lymphoma-2 (Bcl-2) protein, and there were decreases in Bcl-2-associated X (Bax), cysteinyl aspartate-specific proteases-3 (caspase-3), and cleaved-caspase-3 protein expression levels, as well as the Bax/Bcl-2 ratio.Conclusion: APL extract had a protective effect against Iso-induced AMI. APL extract could ameliorate AMI through antioxidant and anti-apoptosis actions which may be associated with the activation of the PI3K/Akt signaling pathway.Keywords: acute myocardial infarction, APL extract, isoproterenol, oxidative stress, apoptosis, PI3K/Akt

Miaomiao Li,1,&ast; Yue Yuan,1,&ast; Xue Han,2 Xinjuan Liu,1 Weizhen Zhang,2 Jianyu Hao1 1Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianyu Hao, Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, South Road of Workers Stadium, Chaoyang District, Beijing, 100020, Email haojianyu@ccmu.edu.cn Weizhen Zhang, Department of Physiology and Pathophysiology, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing, 100191, Email weizhenzhang@bjmu.edu.cnBackground: Chronic pancreatitis (CP) is a long-term inflammatory disease of the pancreas that can be caused by various pathogenic factors. Oxidative stress (OS), which is associated with several pancreatic diseases, can induce pancreatic stellate cell (PSC) activation, leading to pancreatic fibrosis. Given the inefficacy of existing treatments for CP, in this study, our objective was to evaluate the therapeutic effect of the antioxidant, mitoquinone (MitoQ).Methods: First, in vivo, we established a CP mouse model via the repeated injection of cerulein. Mice in the MitoQ group simultaneously received MitoQ daily. After 4 weeks of cerulein injection, pancreatic tissues from mice were evaluated by morphological changes and the expression of fibrosis markers. Further, OS in the collected pancreatic tissue samples was evaluated by determining the level of malondialdehyde (MDA) as well as the expression levels and activities of antioxidants. Furthermore, in vitro, the effect of MitoQ on human PSCs (hPSCs) was evaluated based on PSC activation markers and fibrotic phenotypes, and OS in these treated hPSCs was evaluated by measuring reactive oxygen species (ROS), MDA, and antioxidant levels.Results: In vivo, MitoQ alleviated pancreatic fibrosis and inhibited OS in the cerulein-induced murine CP model. In vitro, it inhibited PSC activation as well as the subsequent development of the profibrogenic phenotypes by balancing out the levels of free radicals and the intracellular antioxidant system.Conclusion: MitoQ is a potential candidate for CP treatment.Keywords: chronic pancreatitis, pancreatic stellate cells, pancreatic fibrosis, oxidative stress, mitochondria-specific antioxidant, MitoQ, superoxide dismutase

Xiaosong Yuan, Xiaoya Han, Chenbo Jia, Wenbo Zhou, Bin Yu Department of Medical Genetics, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, People’s Republic of ChinaCorrespondence: Bin Yu, Email binyu@njmu.edu.cnObjective: To examine the association between low fetal fraction (FF) of cell free DNA determined at non-invasive prenatal screening (NIPS) and the subsequent risk of preterm birth in uncomplicated singleton pregnancy.Methods: We retrospectively interrogated NIPS System and hospitalization records from April 2018 to August 2019 and obtained results from 1521 consecutive and uncomplicated women with singleton pregnancy in which plasma FF of cell free DNA at NIPS had been investigated together with birth outcomes. We examined the association between FF and preterm birth (PTB) by regression analysis.Results: The incidence of preterm birth, low birthweight, and macrosomia in the study population was 5.06%, 2.89%, and 7.17%, respectively. FF at NIPS in the second to fourth quartiles (8.40– 11.07, 11.08– 13.70, and > 13.70%, respectively) was associated with higher gestational age at delivery relative to the lowest quartile (< 8.40%), with estimated mean increases of 0.27 weeks (95% CI: 0.05– 0.49), 0.29 weeks (95% CI: 0.06– 0.51), and 0.28 weeks (95% CI: 0.05– 0.51), respectively (P for trend = 0.027). Low FF (< the 5th percentile) was associated with an increased risk of PTB (adjusted OR: 2.23, 95% CI: 1.01– 4.98, P = 0.047) compared to normal FF (≥ the 5th and ≤ the 95th percentiles). In addition, when compared to women with normal FF and body mass index (BMI) < 25 at NIPS, the risk of early PTB (< 34 weeks gestation) was remarkably significantly higher among those with low FF and BMI ≥ 25 (adjusted OR: 6.29, 95% CI: 1.71– 23.15, P = 0.006).Conclusion: Our study supports the association of low FF at NIPS with PTB (especially early PTB) for uncomplicated singleton pregnancy.Keywords: preterm birth, cell-free fetal DNA, fetal fraction, non-invasive prenatal screening, birth outcomes