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Bin Liu,* Bingtian Zhao,* Yan Yin, Yan Jiang, Xue Feng, Lei Wang, Liang Zhai, Guangxin Liu, Dongsheng Shi, Jianwen Qin Department of Respiratory and Critical Medicine, Tianjin Chest Hospital, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongsheng Shi; Jianwen Qin, Tianjin Chest Hospital, No. 261, Taierzhuang South Road, Jinnan District, Tianjin, 300051, People’s Republic of China, Email shi_ds@126.com; qinjianwen2005@aliyun.com; 5020200603@nankai.edu.cnPurpose: DNA methylation plays a regulatory role in the oncogenesis and tumor progression and is valuable in the diagnosis and prognosis of cancer. While circulating tumor DNA (ctDNA) is widely used in the detection of oncogenic mutations and the guidance of treatment in advanced non-small cell lung cancer (NSCLC), studies of ctDNA methylation remains insufficient. We aim to investigate the methylation profiles of ctDNA in patients with advanced NSCLC undergoing EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and to discover novel biomarkers with predictive or prognostic value.Patients and Methods: We recruited 49 patients with EGFR-mutated advanced NSCLC undergoing EGFR-TKI as first-line treatment. Utilizing next-generation sequencing, we examined the somatic mutations and methylation signatures within the tumor-associated genomic regions of ctDNA from pre-treatment blood. Subsequently, we explored the association of these molecular features with the patients’ response to therapy and their progression-free survival (PFS).Results: Genomic mutation profiling revealed no significant association of PFS or best overall response (BOR) and ctDNA status. Evaluation of ctDNA methylation showed a negative correlation between the methylation of small nucleolar RNA (snoRNA) genes and PFS (R=− 0.31, P=0.043). Furthermore, high-level methylation of SNORD3F was associated with poorer PFS (mPFS 346d vs 243d, HR 0.49, 95% CI 0.24– 0.93, P=0.029).Conclusion: Our study explored the prognostic value of ctDNA methylation in patients with advanced NSCLC undergoing targeted therapies and first revealed the predictive role of SNORD3F.Keywords: ctDNA, EGFR, DNA methylation, lung cancer, snoRNA, SNORD3F

Yichen Wang,1,&ast; Yibo Zhang,1,&ast; Qun Wang,1 Wenhui Li,1 Dake Shi,1 Yumin Xu1,2 1Department of Hospital Infection Management, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yumin Xu, Email xym121@163.comPurpose: Hospital-acquired infections (HAIs) caused by multidrug-resistant organisms (MDROs) pose a significant challenge to healthcare systems. The present study aimed to evaluate the impact of the infection policy to COVID-19 on the incidence of HAIs caused by MDROs.Methods: We conducted an eight-years retrospective analysis at a hospital in Shanghai, China. Bloodstream, sputum, and urinary tract cultures of MDROs obtained 48h after admission were collected monthly from January 2016 to Dec 2023. Occupied bed days (OBDs) were used to generate monthly HAI incidences per 10,000 OBDs. The study period was divided into pre-control, in-control, and post-control cohorts, in January 2020 and January 2022. The incidence was compared using interrupted time-series regression.Results: In total, 6763 MDRO cultures were identified, comprising 1058 bloodstream, 4581 sputum, and 1124 urine cultures derived from 4549 patients. The incidence rates of all HAIs were 8.68 per 10,000 OBDs in the pre-control cohort, 9.76 per 10,000 OBDs in the in-control cohort and 12.58 per 10,000 OBDs in the post-control cohorts, respectively. A downward trend in the incidence of HAI was observed in the post-control cohort (p< 0.05).Conclusion: This study demonstrates that while the COVID-19 pandemic poses a significant challenge to infection control within hospitals, it provides a unique opportunity to enhance infection control measures and evaluate their effectiveness. In addition, these findings highlight the need for more targeted prevention and control strategies against different pathogens in future epidemics.Keywords: hospital required infection, multidrug-resistant organism, infection control, policy, Covid-19, surveillance

Zhaoyong Li,1,&ast; Yanping Lin,1,&ast; Ting Qiu,2,&ast; Junsheng Liang,1 Yintao Lan,3 Fan Meng,4 Chaohao Liang,4 Yiqing Zhang,4 Qingyun Wang,1 Da Shi,1 Changli Zhang,1 Yanan Shi,1 Liujun Liu,1 Yanlan Yang,1 Jian Zhang4,5 1Department of Radiology, DongGuan Tungwah Hospital, Dongguan Key Laboratory of Radiology and Molecular Imaging, DongGuan, Guangdong, 523000, People’s Republic of China; 2Department of Radiology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, Guangdong, 519000, People’s Republic of China; 3Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, Guangdong, 510030, People’s Republic of China; 4School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, 511436, People’s Republic of China; 5Department of Oncology, the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, 511500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Zhang; Zhaoyong Li, Email jianzhang@gzhmu.edu.cn; lizhaoyong2003@163.comBackground: Photothermal therapy (PTT) guided by photoacoustic imaging (PAI) using nanoplatforms has emerged as a promising strategy for cancer treatment due to its efficiency and accuracy. This study aimed to develop and synthesize novel second near-infrared region (NIR-II) absorption-conjugated polymer acceptor acrylate-substituted thiadiazoloquinoxaline-diketopyrrolopyrrole polymers (PATQ-DPP) designed specifically as photothermal and imaging contrast agents for nasopharyngeal carcinoma (NPC).Methods: The PATQ-DPP nanoparticles were synthesized and characterized for their optical properties, including low optical band gaps. Their potential as PTT agents and imaging contrast agents for NPC was evaluated both in vitro and in vivo. The accumulation of nanoparticles at tumor sites was assessed post-injection, and the efficacy of PTT under near-infrared laser irradiation was investigated in a mouse model of NPC.Results: Experimental results indicated that the PATQ-DPP nanoparticles exhibited significant photoacoustic contrast enhancement and favorable PTT performance. Safety and non-toxicity evaluations confirmed the biocompatibility of these nanoparticles. In vivo studies showed that PATQ-DPP nanoparticles effectively accumulated at NPC tumor sites and demonstrated excellent tumor growth inhibition upon exposure to near-infrared laser irradiation. Notably, complete elimination of nasopharyngeal tumors was observed within 18 days following PTT.Discussion: The findings suggest that PATQ-DPP nanoparticles are a promising theranostic agent for NIR-II PAI and PTT of tumors. This innovative approach utilizing PATQ-DPP nanoparticles provides a powerful tool for the early diagnosis and precise treatment of NPC, offering a new avenue in the management of this challenging malignancy.Keywords: nasopharyngeal carcinoma, photoacoustic imaging, photothermal therapy, PATQ-DPP nanoparticles

Yanjun Li,1,&ast; Xiaoyu Zhang,1,&ast; Jiaying Zhang,1 Tianhang Li,2 Dongmei Shi3 1School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, People’s Republic of China; 2Department of Dermatology, Jining No. 1 People’s Hospital, Jining, Shandong, People’s Republic of China; 3Department of Dermatology and Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, Jining, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongmei Shi, Department of Dermatology and Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, No. 6 Jiankang Road, Jining, Shandong Province, 272000, People’s Republic of China, Tel +86 537-6051008, Email shidongmei28@163.comAbstract: Onychomycosis in infants is a rare fungal infection. The condition is frequently linked to congenital or secondary immunodeficiency, as well as exposure to contaminated environments. In this report, we present a case of infant onychomycosis, likely infected during birth delivery from the mother with vaginal candidiasis. However, both the infant and the mother recovered spontaneously without any treatment over several months.Keywords: Candida albicans, infant, neonatal candidiasis, onychomycosis, self-healing

Yanan Li,1 Yahui Feng,2 Dongmei Li,3 Dongmei Shi,2,4 Guanzhi Chen1 1Department of Dermatology, Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2The Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, Jining, Shandong, People’s Republic of China; 3Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA; 4Department of Dermatology, Jining No.1 People’s Hospital, Jining, Shandong, People’s Republic of ChinaCorrespondence: Guanzhi Chen, Department of Dermatology, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266000, People’s Republic of China, Email chenguanzhiqd@hotmail.comObjective: The increasing incidence of chronic skin infections caused by Mycobacterium marinum, coupled with the time-consuming and low detection rates nature of traditional culture and histological-based diagnostic methods, underscores the need for an expedited approach. The study aims to develop a rapid and efficient method for detecting M. marinum with PCR technology.Methods: We designed four pairs of primers based on DNA sequences from GeneBank and prior studies, we utilized both PCR and Real-time PCR to identify M. marinum. Specificity and sensitivity assessments were conducted in vitro by DNAs extracted from M. marinum and other bacterial or fungal cultures. Further validation was performed through the implementation of a mouse skin infection model to optimize and confirm the efficacy of the detection method in both fresh and paraffin-embedded skin tissues. The same PCR testing system was further confirmed with paraffin-embedded skin tissues samples from patients as well.Results: The results of the study indicate promising outcomes for the four-pair primers system. It demonstrated 100% sensitivity in detecting M. marinum from purified cultures, including typical strains and nine clinical isolates, while achieving a specificity of 100%. This specificity was evidenced by the absence of PCR products from 12 bacterial species, 12 fungi species, and six other non-tuberculous mycobacterium (NTM) species. In the animal model, the PCR assay exhibited high detection efficacy for both infected fresh tissues and paraffin-embedded tissues, with a slight superiority observed in fresh tissues. However, the PCR assay exhibited high detection efficacy for clinical paraffin-embedded tissues. These findings collectively underscore the robust detection capabilities of our four-pair primers in both in vitro and in vivo settings.Conclusion: A sensitive and highly specific rapid detection system has been successfully developed that can be used to detect M. marinum in both infected fresh tissues and paraffin-embedded tissues.Keywords: Mycobacterium marinum, bacteria, infected tissue, paraffin-embedded tissue, PCR technique

Leyao Shi,1,&ast; Juanjuan Li,2,&ast; Weida Liu,3 Dongmei Shi4,5 1The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 2Department of First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People’s Republic of China; 3Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, 210042, People’s Republic of China; 4Department of Dermatology, Jining No. 1 People’s Hospital, Jining, Shandong, 272067, People’s Republic of China; 5Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, Jining, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongmei Shi, Department of Dermatology, Jining No. 1 People’s Hospital, No. 6 Jiankang Road, Jining, Shandong Province, 272000, People’s Republic of China, Tel +86 537-6051008, Email shidongmei28@163.comAbstract: Tinea capitis, primarily caused by dermatophytes such as Trichophyton and Microsporum species, is a superficial fungal infection affecting the scalp and hair, commonly observed in prepubertal children but rare in adults. Here we report a unique case of an adult female with tinea capitis presenting as diffused alopecia and erythema inflammation on the scalp’s apex, mimicking seborrheic dermatitis. Examination of the hair and scalp using fluorescence microscopy and fungal culture identified the presence of hyphae from Malassezia globosa, Malassezia furfur and Microsporum canis. The patient underwent with oral antifungal treatment for 3 months, resulting in the resolution of the rash and subsequent hair regrowth, with no recurrence during 6-month follow-up. In vitro co-culture experiments of Microsporum canis and Malassezia (both Malassezia globose and Malassezia furfur) revealed that Malassezia appears to facilitate Microsporum canis growth, while the reverse was not observed. This data suggests that Malassezia’s use of long-chain fatty acids by might reduce its antibacterial effect, potentially aiding adult tinea capitis development caused by Microsporum canis.Keywords: Microsporum canis, Malassezia, tinea capitis, coinfection

Yixin Liu,1 Feifei Ren,1 Shan Li,1 Xiangchen Li,1 Dongyan Shi,2 Zhiqing Zhang1 1Department of Pharmacy, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Clinical Laboratory, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Zhiqing Zhang, Department of pharmacy, the Second Hospital of Hebei Medical University, 215, Heping Road, Xinhua District, Shijiazhuang, Hebei, People’s Republic of China, Email 26500007@hebmu.edu.cn Dongyan Shi, Department of clinical laboratory, the Second Hospital of Hebei Medical University, 215, Heping Road, Xinhua District, Shijiazhuang, Hebei, People’s Republic of China, Email shidongyan73@126.comObjective: To define the antifungal activity of n-butylphthalide alone or in combination with fluconazole in Candida glabrata and Candida tropicalis.Methods: The antifungal activity of n-butylphthalide alone and in combination with fluconazole was investigated by the classical broth microdilution method and the time-killing curve method. The QRT-PCR method was used to determine gene expressions changes of mitochondrial respiratory chain enzymes, drug efflux pumps and drug target enzymes in Candida glabrata and Candida tropicalis after n-butylphthalide treatment.Results: The MIC values of n-butylphthalide against Candida glabrata and Candida tropicalis ranged from 16 to 64 μg·mL-1. The FICI value of the combination of n-butylphthalide and fluconazole against drug-resistant Candida glabrata and Candida tropicalis ranged from 0.5001 to 0.5315 with partial synergism. Time-killing curves showed that 256 μg·mL-1 n-butylphthalide significantly inhibited the growth of drug-resistant colonies of Candida glabrata and Candida tropicalis, and 128 μg·mL-1 n-butylphthalide combined with 1 μg·mL-1 fluconazole had an additive effect. N-butylphthalide could alter the expression of mitochondrial respiratory chain enzymes COX1, COX2, COX3, and CYTB genes in Candida glabrata and Candida tropicalis (P< 0.05) and downregulate the expression of the drug efflux pump genes CDR1 and CDR2 in drug-resistant Candida glabrata to 3.36% and 3.65%, respectively (P< 0.001), but did not affect the drug target enzyme ERG11 in drug-resistant Candida tropicalis.Conclusion: N-butylphthalide had antifungal activity against Candida glabrata and Candida tropicalis. N-butylphthalide improved the activity of fluconazole against drug-resistant Candida glabrata by affecting the expression of mitochondrial respiratory chain enzyme genes and reversing the high expression of drug efflux pump genes CDR1 and CDR2.Keywords: n-butylphthalide, fluconazole, drug resistance, Candida glabrata, Candida tropicalis, potentiation

Guocheng Qian,1 Jiaying Zhang,2 Leyao Shi,1 Dongmei Li,3 Biao Yang,4,5 Biao Chen,4 Dongmei Shi4,5 1The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 2School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, People’s Republic of China; 3Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA; 4Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, Jining, Shandong Province, People’s Republic of China; 5Department of Dermatology, Jining No. 1 People’s Hospital, Jining, Shandong Province, People’s Republic of ChinaCorrespondence: Biao Chen; Dongmei Shi, Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, No. 6, Jiankang Road, Jining, Shandong Province, 272067, People’s Republic of China, Email cbjn@mail.jnmc.edu.cn; shidongmei28@163.comAbstract: Chronic Mucocutaneous Candidiasis (CMC) is a rare immunodeficiency disease characterized by chronic or recurrent superficial Candida infections on the skin, nail, and mucous membranes. Here, we present four Chinese patients with CMC who manifested oral mucosal leukoplakia and nail thickening during early childhood, all displaying fissured tongue lines. The causative pathogens isolated from their oral mucosa and nails were identified as C. albicans and C. parapsilosis through morphology and molecular sequencing. Notably, among the four patients, one presented with vitiligo, while another had hypothyroidism. We have also conducted a review of reported cases of CMC in China and worldwide over the last five years, highlighting potential approaches for diagnosis and treatment. The current molecular evidence in the literature suggests potential for the development of early diagnosis methods, such as screening genetic variables on STAT1 and STAT3. Additionally, potential treatment avenues, including gene-targeted analogues and GM-CSF analogues, could be explored in conjunction with traditional antifungal therapy.Keywords: chronic mucocutaneous candidiasis, Candida spp., diagnosis, treatment

Xingping Zhou,1,&ast; Jinjin Luo,1,&ast; Xi Liang,1,2 Peng Li,1 Keke Ren,1 Dongyan Shi,1,2 Jiaojiao Xin,1,2 Jing Jiang,1,2 Jiaxian Chen,1 Lulu He,1 Hui Yang,1 Shiwen Ma,1 Bingqi Li,1 Jun Li1,2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China; 2Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel/Fax +86-571-87236425, Email lijun2009@zju.edu.cnBackground and Aim: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complicated syndrome with high short-term mortality. Effective biomarkers are required for its early diagnosis and prognosis. This study aimed to determine the diagnostic and prognostic value of thrombomodulin (TM) in patients with HBV-ACLF.Methods: The expression of TM during disease progression was evaluated through transcriptomics analysis. The plasma TM concentrations of 393 subjects with HBV-ACLF (n=213), acute-on-chronic hepatic dysfunction (ACHD, n=50), liver cirrhosis (LC, n=50) or chronic hepatitis B (CHB, n=50), and normal controls (NC, n=30) from a prospective multicenter cohort, were measured to verify the diagnostic and prognostic significance of plasma TM for HBV-ACLF patients by enzyme-linked immunosorbent assay (ELISA).Results: TM mRNA was highly expressed in the HBV-ACLF group compared with the ACHD group (AUROC=0.710). High expression of TM predicted poor prognosis for HBV-ACLF patients at 28/90 days (AUROCs=0.823/0.788). Functional analysis showed that TM was significantly associated with complement activation and the inflammatory signaling pathway. External validation confirmed its high diagnostic accuracy for HBV-ACLF patients (AUROC=0.796). Plasma TM concentrations were correlated with organ failure, including coagulation and kidney failure. Plasma TM concentrations showed a potential prognostic value for 28-day mortality rates (AUROC=0.702). Risk stratification specifically identified HBV-ACLF patients with a high risk of death as having a plasma TM concentration of ≥ 8.4 ng/mL.Conclusion: This study reveals that the plasma TM can be a candidate biomarker for early diagnosis and prognosis of HBV-ACLF, and might play a vital role in coagulation and inflammation.Keywords: thrombomodulin, HBV-ACLF, biomarker, organ failure

Jing Yang,1,&ast; Dixia Hu,2,&ast; Kaige Yin,3 Fang Li,4 Dongyan Shi5 1Hebei Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Clinical Lab, Zhangjiakou First Hospital, Zhangjiakou, People’s Republic of China; 3Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 4Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 5Department of Clinical Lab, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongyan Shi, Email shidongyan73@126.comBackground: Nocardia farcinica, a pathogen known for its strong pathogenicity, is frequently implicated in skin, central nervous system, and lung infections among immunosuppressed hosts, while intestinal nocardiosis is rare. We report the case of infectious diarrhea caused by N. farcinica in a child.Case Presentation: A 19-month-old female child was admitted to the hospital with fever and diarrhea after the consumption of oranges. The etiological agent responsible for the diarrhea was identified through the examination of fecal smears using weak acid-fast staining and conducting fecal cultures. Whole-genome sequencing was employed to analyze the causative gene. Subsequent to a 5-day treatment regimen with amoxicillin-clavulanate at a dosage of 30 mg/kg every 12 hours, the child’s condition improved significantly, leading to an uncomplicated discharge.Conclusion: This case illustrates the presence of intestine virulence factors in N. farcinica capable of causing diarrhea. The utilization of weak acid-fast staining in the examination of fecal smears is crucial for the accurate diagnosis of infectious diarrhea caused by Nocardia spp.Keywords: Nocardia farcinica, diarrhea, virulence factors

Leyao Shi,1 Yahui Feng,2 Dongmei Shi2,3 1The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 2The Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, Jining, Shandong, People’s Republic of China; 3Department of Dermatology, Jining No. 1 People’s Hospital, Jining, Shandong, People’s Republic of ChinaCorrespondence: Dongmei Shi, Department of Dermatology, Jining No. 1 People’s Hospital, No. 6 Jiankang Road, Jining, Shandong Province, 272000, People’s Republic of China, Tel +86 537-6051008, Email shidongmei28@163.comAbstract: The clinical manifestation of superficial candidiasis varies depending on the infectious sites and causative Candida species that brings a great challenge to diagnose or treat without mycological or pathological evidence in clinical settings. Oral mucosal candidiasis and onychomycosis are most common types of superficial candidiasis. Typically, oral mucosal candidiasis manifests as white or erythematous thrush coated on the tongue and other interior oral cavity; and onychomycosis caused by Candida spp. presents with thick, fragile, or cracked fingernails or toenails in yellow or white discoloration. Here, we report one case of patient with a black hairy tongue caused by Candida tropicalis and one case of greenish discolored onychomycosis caused by Candida parapsilosis. The cases of superficial candidiasis with the same discolored lesions were searched in literature and compared with our cases in clinical manifestation, causative pathogen and treatment. These cases highlight the importance of mycological diagnosis for identifying non-Candida albicans Candida species (NCAC) in superficial infections to guide an effective therapy.Keywords: Candida tropicalis, Candida parapsilosis, onychomycosis, black hairy tongue, nail discoloration

Xin Su,1,&ast; Hengqiong Gu,1,&ast; Fajun Li,2 Donglei Shi,3 Zhaojun Wang3 1Department of Respiratory, Hainan Hospital of PLA General Hospital, Sanya, People’s Republic of China; 2Department of Critical Care Medicine, The First People’s Hospital of Kunshan, Kunshan, People’s Republic of China; 3Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Donglei Shi; Zhaojun Wang, Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, 518107, People’s Republic of China, Tel/Fax +86-755-81206874, Email shidlei@mail.sysu.edu.cn; wangzhj55@mail.sysu.edu.cnBackground: A study aimed to estimate the burden of Chronic obstructive pulmonary disease (COPD) caused by occupational exposure to particulate matter, gases, and fumes in 204 countries from 1990 to 2019.Methods: Data on the deaths number, age-standardized mortality rates (ASMR), and age-standardized disability-adjusted life years (DALYs) rates (ASDR) of COPD attributable to occupational particulate matter, gases, and fumes were collected from the GBD study 2019. We also investigated the association between the ASDR and SDI.Results: There were 517.7 thousand deaths [95% UI: 413.9 to 634.5] in 2019. The number of deaths increased from 1990 to 2019. The ASMR and ASDR were 6.61 (5.24 to 8.17) and 143.02 (118.56 to 168.69) in 2019, respectively, representing a 46% and 44.5% decrease since 1990. China had the highest number of deaths [200,748.4 (151,897.6 to 260,703.9)], while Nepal had the highest ASMR [39 (27.7 to 50)] and ASDR [724.5 (549 to 894.2)]. Males and females 75– 79 and 80– 84 years old had the highest number of COPD deaths. A negative correlation was observed when SDI > 0.4, whereas a positive correlation was found when SDI < 0.4.Conclusion: From 1990 to 2019, there was an increase in the number of deaths, but a decline in ASMR and ASDR globally. Besides, there was a heterogeneous burden of COPD attributable to occupational particulate matter, gases, and fumes across regions and countries. It is important to develop and implement strategies to prevent and reduce the burden of COPD attributable to occupational particulate matter, gases, and fumes.Keywords: chronic obstructive pulmonary disease, occupational particulate matter, gases, fumes, global burden of disease, deaths number, age-standardized rates

Kailin Xing,1,&ast; Xinyu Bian,2,&ast; Dongmin Shi,3,&ast; Shuangshuang Dong,1 Hongxin Zhou,1 Shuxiu Xiao,4 Jinjin Bai,4 Weizhong Wu1,4 1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Shanghai, 200032, People’s Republic of China; 2Department of Radiation Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210000, People’s Republic of China; 3Department of Medical Oncology, Shanghai Changzheng Hospital, Shanghai, 200072, People’s Republic of China; 4Clinical Center for Biotherapy, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weizhong Wu, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, People’s Republic of China, Tel +86-21-60268628, Fax +86-21-64037181, Email wu.weizhong@zs-hospital.sh.cnBackground: MicroRNA-612 (miR-612) has been proven to suppress the formation of invadopodia and inhibit hepatocellular carcinoma (HCC) metastasis by hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA)-mediated lipid reprogramming. However, its biological roles in HCC cell ferroptosis remain unclear.Methods and Results: In this study, we found that HCC cells with high metastatic potential were more resistant to ferroptosis, indicating that ferroptosis is related to HCC metastasis. The levels of lipid reactive oxygen species (ROS) were found to be much lower in HCC cells with high metastatic potential by flow cytometry (FCM). We used HCC cells with miR-612 overexpression/knockout and HADHA overexpression/knockdown to test cell viability after stimulation with RSL3. HCC cells overexpressing miR-612 were more sensitive to ferroptosis, and miR-612 could increase lipid ROS levels. Furthermore, colony formation assays and Transwell assays showed that miR-612 could inhibit the proliferation and metastasis of HCC cells by promoting ferroptosis. We next confirmed that miR-612 influenced HCC cell ferroptosis by regulating HADHA. HADHA could upregulate the expression of key enzymes in the mevalonate (MVA) pathway. HADHA overexpression upregulated the expression of CoQ10 and decreased polyunsaturated fatty acid (PUFA) levels and lipid peroxide abundance. miR-612 also suppressed HCC cell proliferation and metastasis by enhancing RSL3- and lovastatin-induced ferroptosis in vivo.Conclusion: Overall, miR-612 promotes ferroptosis in HCC cells and affects HCC proliferation and metastasis by downregulating CoQ10 and increasing cellular PUFA levels and lipid peroxides via the HADHA-mediated MVA pathway.Keywords: HCC, Ferroptosis, miR-612, HADHA, MVA pathway

Xiaoyu Zhang,1 Yahui Feng,2 Dongmei Li,3 Jingjian Han,4 Dongmei Shi2,5 1School of Clinical Medicine, Weifang Medical University, Weifang, People’s Republic of China; 2Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, Jining, People’s Republic of China; 3Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, USA; 4Department of Medical Cosmetology, Jining No. 1 People’s Hospital, Jining, People’s Republic of China; 5Department of Dermatology, Jining No. 1 People’s Hospital, Jining, People’s Republic of ChinaCorrespondence: Dongmei Shi, Laboratory of Medical Mycology & Department of Dermatology, Jining No. 1 People’s Hospital, No. 6 Jiankang Road, Jining, Shandong Province, 272067, People’s Republic of China, Tel +8618678769757, Email shidongmei28@163.com Jingjian Han, Department of Medical Cosmetology, Jining No. 1 People’s Hospital, No. 6 Jiankang Road, Jining, Shandong Province, 272067, People’s Republic of China, Email hjj_1983@163.comAbstract: Mycobacterium abscessus (M. abscessus) is a fast-growing, non-tuberculous mycobacterium (NTM) that can cause human infections varying from superficial infection to pulmonary or even systemic infections. The latter is more commonly appeared in immunocompromised patients. The skin infection caused by M. abscessus often appears after trauma or surgical procedure. It is often manifested by subcutaneous nodules, papules, erythema, tender erythematous or violaceous plaques, cellulitis, abscesses, ulcerations, and draining sinuses. Herein, we present a non-typical cutaneous manifestation of M. abscessus infection in a 46-year-old woman who presented with alopecia on the scalp with no itching or pain. The pathogen was isolated and identified as M. abscessus by morphology and DNA sequencing. To our best knowledge, there was no report that this organism could cause skin lesions mimicking patchy alopecia. After 3 months of antibacterial treatment, the cutaneous lesion disappeared, and new growth of hair occurred in this patient.Keywords: Mycobacterium abscessus, alopecia, non-tuberculous mycobacteria

Donglei Shi,&ast; Li Wei,&ast; Hongsen Liang, Dongqing Yan, Junhang Zhang, Zhaojun Wang Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhaojun Wang, Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China, Email wangzhj55@mail.sysu.edu.cnBackground: Malaria remains a substantial concern in the realm of public health on a worldwide level. Using information from the global burden of disease (GBD) 2019 for 204 countries and territories between 1990 and 2019, we assessed the burden of malaria.Methods: Data on malaria were derived from the GBD 2019 study between 1990 and 2019. We evaluated the number of incidence, deaths, disability-adjusted life years (DALYs), age-standardized incidence rates (ASIR), age-standardized mortality rates (ASMR), and age-standardized DALY rates (ASDR), examining them across variables such as age, year, gender, country, region, and socio-demographic index (SDI).Results: The burden of malaria decreased globally between 1990 and 2019. There were 2313.57× 105 incident cases and 6.43× 105 deaths in 2019, contributing to 464.38× 105 DALYs. Largest incident cases were observed in Western Sub-Saharan Africa [1151.72 (95% UI: 890.01– 1527.17)] × 105 in 2019. The only region where deaths increased between 1990 and 2019 was Western Sub-Saharan Africa. ASRs of malaria are distributed heterogeneously in different regions. The highest ASIR was observed in Central Sub-Saharan Africa [21,557.65 (95% UI: 16,639.4– 27,491.48)] in 2019. From 1990 to 2019, the ASMR of malaria declined. Compared to other age cohorts, the ASIR, ASMR, and ASDR for children aged between 1 to 4 years were found to be higher. Worst-affected regions by malaria infection were the low-middle SDI region and low SDI region.Conclusion: Malaria threatens global public health, especially in Central Sub-Saharan Africa and Western Sub-Saharan Africa. Children 1– 4 years old continue to bear the most significant burden of malaria. The study’s results will guide efforts to reduce malaria’s impact on the global population.Keywords: malaria, global burden of disease, ASIR, ASMR, ASDR

Yibo Zhang,1,&ast; Yichen Wang,1,&ast; Zike Sheng,2,&ast; Qun Wang,1 Dake Shi,1 Shirui Xu,3 Yaping Ai,4 Erzhen Chen,5 Yumin Xu1,2 1Department of Hospital Infection Management, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Clinical Laboratory Medicine, Shanghai Fenglin Clinical Laboratory Co. Ltd, Shanghai, People’s Republic of China; 4Health Economics and Outcome Research, Becton & Dickinson Medical Device (Shanghai) Ltd, Shanghai, People’s Republic of China; 5Department of Emergency Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Erzhen Chen, Department of Emergency Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Tel +86 021-64370045-665599, Email chenerzhen@hotmail.com Yumin Xu, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Tel +86 021-64370045-600653, Email xym121@163.comPurpose: Indwelling central venous catheters (CVCs) can cause catheter related bloodstream infection (CRBSI). CRBSI occurring in intensive care unit (ICU) patients may lead to the worse outcomes and extra medical costs. The present study aimed to assess the incidence and incidence density, pathogens and economic burden of CRBSI in ICU patients.Patients and Methods: A case-control study was retrospectively carried out in six ICUs of one hospital between July 2013 and June 2018. The Department of Infection Control performed routinely surveillance for CRBSI on these different ICUs. Data of the clinical and microbiological characteristics of patients with CRBSI, the incidence and incidence density of CRBSI in ICUs, the attributable length of stay (LOS), and the costs among patients with CRBSI in ICU were collected and assessed.Results: A total of 82 ICU patients with CRBSI were included into the study. The CRBSI incidence density was 1.27 per 1000 CVC-days in all ICUs, in which the highest was 3.52 per 1000 CVC-days in hematology ICU and the lowest was 0.14 per 1000 CVC-days in Special Procurement ICU. The most common pathogen causing CRBSI was Klebsiella pneumoniae (15/82, 16.67%), in which 12 (80%) were carbapenem resistant. Fifty-one patients were successfully matched with control patients. The average costs in the CRBSI group were &dollar; 67,923, which were significantly higher (P < 0.001) than the average costs in the control group. The total average costs attributable to CRBSI were &dollar;33, 696.Conclusion: The medical costs of ICU patients were closely related to the incidence of CRBSI. Imperative measures are needed to reduce CRBSI in ICU patients.Keywords: CRBSI, prolonged length of stay, cost, CRKP, ICU

Rui Liu, Dandan Shi, Lu Guo, Shan Xiao, Mengmeng Shang, Xiao Sun, Dong Meng, Yading Zhao, Xiaoxuan Wang, Jie Li Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of ChinaCorrespondence: Jie Li, Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China, Email jieli@email.sdu.edu.cnIntroduction: Triple-negative breast cancer (TNBC) is known to be the most aggressive form of breast cancer. Due to its high recurrence and mortality rates, the treatment of TNBC is a significant challenge for the medical community. Besides, ferroptosis is an emerging regulatory cell death that may provide new insights into the treatment of TNBC. As a central inhibitor of the ferroptosis process, the selenoenzyme glutathione peroxidase 4 (GPX4) is its classical therapeutic target. However, inhibition of GPX4 expression is quite detrimental to normal tissues. Ultrasound contrast agents, as an emerging visualization precision treatment, may provide a solution to the existing problem.Methods: In this study, nanodroplets (NDs) carrying simvastatin (SIM) were constructed using the homogeneous/emulsification method. Then, the characterization of SIM-NDs was systematically evaluated. Meanwhile, in this study, the ability of SIM-NDs combined with ultrasound-targeted microbubble disruption (UTMD) to initiate ferroptosis and its respective mechanisms of ferroptosis induction were verified. Finally, the antitumor activity of SIM-NDs was investigated in vitro and in vivo using MDA-MB-231 cells and TNBC animal models.Results: SIM-NDs exhibited excellent pH- and ultrasound-responsive drug release and noticeable ultrasonographic imaging ability, also showing good biocompatibility and biosafety. UTMD could promote increased intracellular reactive oxygen species and consume intracellular glutathione. However, SIM-NDs were efficiently internalized into cells under ultrasound irradiation, followed by the rapid release of SIM, which inhibited intracellular mevalonate production, and synergistically downregulated GPX4 expression, thereby promoting ferroptosis. Moreover, this combined treatment demonstrated strong antitumor ability in vitro and in vivo.Conclusion: The combination of UTMD and SIM-NDs presents a promising avenue for harnessing ferroptosis in the treatment of malignant tumors.Graphical Abstract: Keywords: ultrasound-targeted microbubble disruption, nanodroplets, ferroptosis, glutathione peroxidase 4, theranostics, lipid peroxidation

Huan Zhang,1,2 Xiaojiao Tan,1 Zhen Zhang,1 Xuewei Yang,1 Lijie Wang,1 Meiqian Li,1 Dan Shi,1 Yao Li,1 Jianbo Li,1 Zhen Li,3 Xuelian Liao1,4 1Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Critical Care Medicine, The Third People’s Hospital of Chengdu, Chengdu, People’s Republic of China; 3Clinical Research Unit, First Maternity and Infant Hospital of Shanghai, Shanghai, People’s Republic of China; 4Department of Critical Care Medicine, West China Tianfu Hospital of Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Xuelian Liao, Department of Critical Care Medicine, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Wuhou district, Chengdu, People’s Republic of China, Tel +8613541023033, Email liaoxuelian@scu.edu.cnPurpose: To assess the impact of targeted antibiotic therapy on clinical outcomes of patients with lower respiratory tract (LRT) infection with Corynebacterium striatum (C. striatum).Methods: A new propensity score-inverse probability of treatment weighting (IPTW) cohort study was conducted by using 10-year data. The study included LRT infection patients with respiratory secretions cultured positive for C. striatum simultaneously. The primary outcome was all-cause hospital mortality; the secondary outcomes included hospital stay, ICU stay and ventilation time. The safety outcomes were drug-related serum creatinine (Cr) increase and thrombocytopenia.Results: A total of 339 patients were included in the cohort, and 84 (24.78%) initiated vancomycin or linezolid therapy. In the new IPTW cohort, targeted antibiotic therapy did not improve all-cause hospital mortality (P=0.632), and the OR (95% CI) was 0.879 (0.519– 1.488). Moreover, targeted antibiotic therapy was not associated with hospital stay (P=0.415), ICU stay (P=0.945) or ventilation time (P=0.885). The side effects of drug-related higher serum Cr (P=0.044) and thrombocytopenic levels (P=0.038) cannot be ignored.Conclusion: Clinical benefits by vancomycin or linezolid targeted against LRT infection with C. striatum were limited and with drug-related side effects. A prospectively designed study is needed to further confirm the results.Keywords: Corynebacterium striatum, lower respiratory tract infection, vancomycin, linezolid, all-cause mortality

Fatemeh Kohram,1– 3 Zicheng Deng,1– 4 Yufang Zhang,1– 3 Abid A Al Reza,1– 3 Enhong Li,1– 3 Olena A Kolesnichenko,1– 3 Samriddhi Shukla,1– 3 Vladimir Ustiyan,1– 3 Jose Gomez-Arroyo,1– 3 Anusha Acharya,1– 3 Donglu Shi,4 Vladimir Kalinichenko,1– 3 Alan P Kenny1,2,5,6 1Department of Pediatrics, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 3Center for Lung Regenerative Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 4The Materials Science and Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, USA; 5Division of Neonatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USACorrespondence: Alan P Kenny, Divisions of Pulmonary Biology and Neonatology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, Tel +1 513-803-2224, Email Alan.Kenny@cchmc.orgIntroduction: Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins (ACDMPV) is a fatal congenital disease resulting from a pulmonary vascular endothelial deficiency of FOXF1, producing abnormal morphogenesis of alveolar capillaries, malpositioned pulmonary veins and disordered development of lung lobes. Affected neonates suffer from cyanosis, severe breathing insufficiency, pulmonary hypertension, and death typically within days to weeks after birth. Currently, no treatment exists for ACDMPV, although recent murine research in the Kalinichenko lab demonstrates nanoparticle delivery improves survival and reconstitutes normal alveolar-capillary architecture. The aim of the present study is to investigate the safety of intravenous administration of FOXF1-expressing PEI-PEG nanoparticles (npFOXF1), our pioneering treatment for ACDMPV.Methods: npFOXF1 was constructed, validated, and subsequently administered in a single dose to postnatal day 14 (P14) mice via retro-orbital injection. Biochemical, serologic, and histologic safety were monitored at postnatal day 16 (P16) and postnatal day 21 (P21).Results: With treatment we observed no lethality, and the general condition of mice revealed no obvious abnormalities. Serum chemistry, whole blood, and histologic toxicity was assayed on P16 and P21 and revealed no abnormality.Discussion: In conclusion, npFOXF1 has a very good safety profile and combined with preceding studies showing therapeutic efficacy, npFOXF1 can be considered as a good candidate therapy for ACDMPV in human neonates.Keywords: nanoparticle, FOXF1, ACDMPV, mouse, toxicity, safety

Lijuan Zhou,1,2,&ast; Dan Shi,2 Liyuan Zhang,2,&ast; Qian Wang,2 Li Chen,2 Honglin Chen3 1Medical School, Nantong University, Nantong, People’s Republic of China; 2Nursing Department, Taizhou People’s Hospital, Taizhou, People’s Republic of China; 3School of Public Health, Nantong University, Nantong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Honglin Chen, Email honglinyjs@126.comBackground: Maintenance hemodialysis(MHD) patients often suffer from fatigue and are recommended to undertake physical activities. The optimal format of exercise rehabilitation for MHD patients remains uncertain despite demonstrated health benefits. This study aimed to evaluate the effectiveness of an intradialytic group exercise programme for MHD patients.Methods: This was a single-centre, single-group repeated-measures design study. The 12-week, three times per-week intradialytic group exercise programme was conducted for around 30 min during the first 2 hours of each dialysis session. Patient-reported outcomes including fatigue, anxiety, depression and health-related quality of life, laboratory parameters including haemoglobin, albumin, pre-albumin and hypersensitive C-reactive protein, and anthropometric parameters including triceps skinfold thickness, mid-upper arm circumference, mid-arm muscle circumference and handgrip strength, were measured at baseline, immediately post-intervention and 12-weeks post-intervention. The repeated-measures analysis of variance and Friedman test were used to compare the parametric and non‐parametric data across time points, respectively.Results: Ninety patients were enrolled and 75 completed. Participants reported significant improvements across time points in fatigue (F = 10.19, p < 0.01), depression (F = 19.20, p < 0.001), health-related quality of life (F = 5.36, p = 0.006), haemoglobin (F = 3.43, p = 0.047), albumin (F = 4.42, p = 0.032), hypersensitive C-reactive protein (χ2 = 50.39, p < 0.001), pre-albumin (χ2 = 11.85, p = 0.003), triceps skinfold thickness (F = 25.03, p < 0.001), mid-upper arm circumference (F = 6.32, p = 0.005), mid-arm muscle circumference (F = 4.89, p = 0.02), and handgrip strength (F = 13.59, p < 0.001). Although the mean anxiety score tended to reduce, the difference across time points was nonsignificant (F = 1.33, p = 0.27).Conclusion: The findings suggested that the intradialytic group exercise programme could improve MHD patients’ fatigue, depression, health-related quality of life, nutritional status, and inflammation.Trial Registration: Chinese Clinical Trial Registry ChiCTR2000034394 (04/07/2020).Keywords: maintenance hemodialysis, group exercise, aerobic exercise, resistance exercise nutrition, quality of life

Xin Su,1,&ast; Haifeng Li,2,&ast; Fajun Li,3 Hongsen Liang,4 Li Wei,4 Donglei Shi,4 Junhang Zhang,4 Zhaojun Wang4 1Department of Respiratory, Hainan Hospital of PLA General Hospital, Sanya, People’s Republic of China; 2Department of Anesthesiology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 3Department of Critical Care Medicine, The First People’s Hospital of Kunshan, Kunshan, People’s Republic of China; 4Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junhang Zhang; Zhaojun Wang, Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, No. 628, Zhenyuan Road, Guangming (New) Dist, Shenzhen, 518107, People’s Republic of China, Email zhangjh33@mail.sysu.edu.cn; wangzhj55@mail.sysu.edu.cnObjective: Exposure to ambient particulate matter (PM2.5) is the leading risk factor for developing chronic obstructive pulmonary disease (COPD) in China. The present study aimed to investigate the trends in COPD mortality attributable to ambient PM2.5 exposure in China from 1990 to 2019.Methods: Data on COPD burden attributable to ambient PM2.5 exposure in China were extracted from the Global Burden of Disease (GBD) study 2019. The estimated annual percentage change (EAPC) was used to assess COPD mortality from 1990 to 2019. The APC model was used to analyze the temporal trends in the rate of COPD mortality attributable to ambient PM2.5 exposure according to age, period, and cohort.Results: Exposure to ambient PM2.5 contributed to 192.4 thousand deaths in 1990 and 263.6 thousand deaths in 2019. The age-standardized mortality rate (ASMR) and the age-standardized disability-adjusted life year rate (ASDR) due to ambient PM2.5 exposure showed a gradual downward trend, the ASMR and ASDR in 2019 decreased to 16.6 per 100,000 with an EAPC of − 2.82 (95% CI: − 8.61 to 3.34) and 278.6 per 100,000 with an EAPC of − 2.02 (95% CI: − 7.85 to 4.19), compared to those in 1990, respectively. The relative risk (RR) of COPD increased with age in females, while in males, mortality significantly increased from the levels among those in the 60– 64 age group to that among those in the 90– 94 age group. In the period group, the RR of COPD in males remained above 1.0 from the 2000 to 2004 period, but it gradually decreased in females. The cohort effect showed an overall downward trend.Conclusion: Although the ASMR and ASDR are decreasing in Chinese patients with COPD, the number of deaths due to COPD is increasing. Ambient PM2.5 exposure is more harmful in males and older people above 60 years of age.Keywords: chronic obstructive pulmonary disease, PM2.5, age-period-cohort model

Zhiya Yang,1,&ast; Fangfang Zhang,2,&ast; Dongmei Li,3 Sisi Wang,1 Zhiping Pang,1 Liu Chen,1 Renzhe Li,4 Dongmei Shi1,5 1The Laboratory of Medical Mycology, Jining No.1 People’s Hospital, Jining, Shandong, 272111, People’s Republic of China; 2Department of Dermatology, Jining Dermatosis Prevention and Treatment Hospital, Jining, Shandong, 272000, People’s Republic of China; 3Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, 20057 USA; 4The Laboratory of Clinical Medicine, Jining No.1 People’s Hospital, Jining, Shandong, 272111, People’s Republic of China; 5Department of Dermatology, Jining No.1 People’s Hospital, Jining, Shandong, 272001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongmei Shi, The Laboratory of Medical Mycology and Dermatology Department of Jining No.1 People’s Hospital, Shandong, 272011, China, Tel +86 537-6051008, Email shidongmei28@163.com Renzhe Li, Clinical Laboratory of Jining No.1 People’s Hospital, 272111, People’s Republic of China, Tel +86 13563704987, Email 552080646@qq.comPurpose: This article aims to provide a theoretical basis for new or adjuvant strategies to facilitate the early diagnosis and treatment of candidiasis and to determine if drug-resistant Candida would affect virulence.Patients and Methods: Our strains were collected from patients diagnosed with candidiasis in our hospital. The strains were identified by MALDI-TOF system and ITS sequencing. Antifungal sensitivity testing in vitro was performed to evaluate susceptibility of these isolates to current widely used antifungal drugs. The Galleria mellonella larvae model infected by Candida spp. was used to compare the virulence of drug-resistant and susceptible Candida spp.Results: A total of 206 Candida strains were collected from clinical specimens. Candida albicans was the most common species among them, and was predominantly isolated from male patients aged over 40 years in ICU environments suffering from pulmonary and/or cerebral conditions. The accuracy rate of MALDI TOF-MS identification was 92.72% when compared with ITS sequencing as the standard method. Most Candida species, except for C. tropicalis which showed high resistance to micafungin, showed high susceptibilities to voriconazole, itraconazole, amphotericin B and micafungin but were highly resistant to terbinafine. For each specific Candida species, the G. mellonella larvae model revealed that the virulence of drug-resistant Candida isolates did not markedly differ from that of the drug-susceptible isolates, however, the virulence was dose-dependent on inoculated fungal cells in this model.Conclusion: The possibility of Candida infection should not be neglected in patients at critical care hospital settings and C. albicans is the most common causative agent. MALDI-TOF MS has the advantages of rapidity and high accuracy, and should be a preferred method for identification of Candida spp. in a clinical laboratory. Voriconazole, itraconazole, amphotericin B and micafungin can still be recommended as the first line antifungals to treat candidiasis.Keywords: Candida, antifungal susceptibility testing, fungal infection, MALDI-TOF MS

Yulian Gao,1,&ast; Hongxia Lin,1,&ast; Yumin Xu,2,&ast; Yijin Yao,1,&ast; Dake Shi,1 Junjie Li,1 Haixing Zhu,1 Hanssa Dwarka Summah,3 Lei Ni,1 Yun Feng1 1Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Hospital Infection Management, Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Respiratory, Poudre D’Or Chest Hospital, Rivière du Rempart, Mauritius&ast;These authors contributed equally to this workCorrespondence: Yun Feng; Lei Ni, Email fy01057@163.com; nilei625@139.comPurpose: Carbapenem-resistant Gram-negative bacteria bloodstream infection (CRGNB-BSI) has gradually become a major threat worldwide due to its treatment difficulty and high mortality. This study aimed to determine the risk factors for CRGNB-BSI in immunosuppressed patients.Patients and Methods: A total of 427 immunosuppressed patients with CRGNB-BSI were retrospectively investigated from 2015 to 2021. Both univariate and multivariate logistic regression analyses were applied to evaluate independent risk factors for CRGNB-BSI.Results: The most common etiology was Klebsiella Pneumoniae (50.59%; 216/427), while the Acinetobacillus baumannii infection was associated with the highest mortality (58.25%) among all etiologies. The 60-day mortality of immunosuppressed patients with CRGNB-BSI was 52.48% (224/427). Procalcitonin (PCT) > 0.5 μg/L (OR = 2.32, 95% CI: 1.28– 4.19, P = 0.005) and age > 55 years (OR = 2.06, 95% CI: 1.17– 3.64, P = 0.012) were found to be predictors of 60-day mortality of CRGNB-BSI, and tigecycline regimen (OR = 3.20, 95% CI: 1.81– 5.67, P < 0.001) was associated with higher mortality. Multivariate analysis also revealed that patients who developed acute kidney injury (AKI) (OR = 2.19, 95% CI: 1.11– 4.30, P = 0.023), gastrointestinal bleeding (OR = 3.18, 95% CI: 1.10– 9.16, P = 0.032), multiple organ dysfunction syndrome (MODS) (OR = 12.11, 95% CI: 2.61– 56.19, P = 0.001), and septic shock (OR = 3.24, 95% CI: 1.77– 5.94, P < 0.001) showed worse outcomes. The risk factors were also significantly associated with mortality in the different subgroups.Conclusion: This study demonstrated that PCT > 0.5 μg/L, age > 55 years, and the tigecycline regimen were significantly associated with higher 60-day mortality among immunosuppressed patients with CRGNB- BSI. Patients developing MODS, septic shock, or AKI had worse clinical outcomes.&#x2003Keywords: bloodstream infection, carbapenem-resistant, immunosuppressed patients, subgroups, prognosis

Dawei Shi,1,&ast; Qiulong Zhou,2,&ast; Sihong Xu,1 Yumei Zhu,3 Hui Li,4 Ye Xu2 1National Institutes for Food and Drug Control, Institute of Pathogen Biology at the Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, State Key Laboratory of Cellular Stress Biology, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China; 3Shenzhen Center for Chronic Disease Control, Shenzhen, People’s Republic of China; 4Tuberculosis Reference Laboratory, Henan Provincial Centers for Disease Control and Prevention, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Li, Tuberculosis Reference Laboratory, Henan Provincial Centers for Disease Control and Prevention, Zhengzhou, People’s Republic of China, Tel/Fax +86 371-68089049, Email lihui2005yan@126.com Ye Xu, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, State Key Laboratory of Cellular Stress Biology, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen, People’s Republic of China, Tel +86 592 2187992, Fax +86 592 2187363, Email xuye@xmu.edu.cnPurpose: Pyrazinamide (PZA) is a critical component of standardized chemotherapy for tuberculosis (TB) and is recommended for the treatment of multidrug-resistant (MDR) TB. We aimed to characterize mutations in pncA of M. tuberculosis and evaluate their diagnostic accuracy for PZA susceptibility in China. We also combined genotypic methods with phenotypic susceptibility testing and pyrazinamidase (PZAse) activity to confirm PZA-resistant M. tuberculosis isolates.Results: An evaluation of 82 MDR M. tuberculosis strains revealed that 28.0% (23/82) were phenotypically resistant to 100 mg/L PZA and 15.9% (13/82) showed resistance to 300 mg/L PZA. Mutations in pncA were detected at 33 unique sites, and the majority were point mutations. No evident mutation hotspots or mutations affecting multiple amino acids were found, but the association between pncA mutations and PZA resistance was significant under 100 and 300 mg/L. The sensitivity of pncA mutation detection for predicting PZA susceptibility was 82.6% (19/23), and the specificity was 61.0% (36/59), based on 100 mg/L PZA, whereas the sensitivity was 84.6% (11/13) and the specificity was 55.1% (38/69), based on 300 mg/L PZA. All mutations identified in the highly PZA-resistant (300 mg/L) strains had an 80% loss relative to PZAse activity. No evident PZAse activity loss was observed in one synonymous mutation strain and the loss exceed 60% in all other strains.Conclusion: The association between pncA mutation and PZA resistance was significant. Relatively, the molecular method have shown better reliability than the phenotypic method for the detection of PZA resistance. This provides a theoretical basis for the clinical diagnosis of drug-resistant TB.Keywords: MDR, PZA, pncA, DST, Beijing genotype, enzymatic activity

Haifeng Li,1,&ast; Hongsen Liang,2,&ast; Li Wei,2 Donglei Shi,2 Xin Su,3 Fajun Li,4 Junhang Zhang,2 Zhaojun Wang2 1Department of Anesthesiology, Guangdong Provincial People’s Hospitall, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 2Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China; 3Department of Respiratory, Hainan Hospital of PLA General Hospital, Sanya, People’s Republic of China; 4Department of Critical Care Medicine, The First People’s Hospital of Kunshan, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junhang Zhang; Zhaojun Wang, Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, 628 Zhenyuan Road, Shenzhen, People’s Republic of China, Tel/Fax +86-755-81206874, Email zhangjh33@mail.sysu.edu.cn; wangzhj55@gmail.sysu.edu.cnBackground: This study assessed health inequality in the global burden of chronic obstructive pulmonary disease (COPD) between 1990 and 2019 using data extracted from the Global Burden of Diseases (GBD 2019) study.Methods: Data were extracted from the GBD 2019 study. A series of comparative and descriptive analyses of the disease burden between women and men in countries with different socioeconomic development (SDI) status were performed. The slope index of inequality (SII), relative index of inequality (RII), and concentration index (CI) were calculated to measure the socioeconomic-related cross-national health inequity between 1990 and 2019.Results: The global health burden caused by COPD increased by 25.7% in terms of disability-adjusted life years (DALY) from 59.2 million years in 1990 to 74.4 million years in 2019. Global age-standardized DALY rate (ASDR) associated with COPD decreased by 40.0%, from 1537.7 per 100,000 population in 1990 to 926.1 per 100,000 population in 2019. The highest sex-specific DALY number was at age 70– 74 in male and female, and female is lower than male. However, after controlling for population size, the burden of COPD is more concentrated in the population living in low SDI countries, relative health inequality indicators (RII and CI) supported this conclusion.Conclusion: The health inequalities caused by the disparity of socioeconomic status are increasing, and the increasing concentration of wealth worldwide is likely to aggravate health inequalities associated with COPD.Keywords: chronic obstructive pulmonary disease, disease burden, health inequality

Fangfang Zhang,1,2 Yahui Feng,1 Sisi Wang,3 Dongmei Li,4 Dongmei Shi3,5 1College of Clinical Medicine, Jining Medical University, Jining, 272000, People’s Republic of China; 2Department of Dermatology, Jining Dermatosis Prevention and Treatment Hospital, Jining, 272000, People’s Republic of China; 3Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, Jining, 272000, People’s Republic of China; 4Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, 20057, USA; 5Department of Dermatology, Jining No. 1 People’s Hospital, Jining, 272000, People’s Republic of ChinaCorrespondence: Dongmei Shi, Laboratory of Medical Mycology, Jining No. 1 People’s Hospital, Jining, 272000, People’s Republic of China, Tel +86 537-6051008, Email shidongmei28@163.comAbstract: Impetigo, commonly caused by bacteria, is characterized by lesions of pustules, bullae or golden yellow crusts; it is seldom caused by fungi. Here, we report one case of a 17-year-old female patient with a 1-month history of erythematous pustules on her left cheek. She was clinically diagnosed with “impetigo”, but did not respond to 1 week of treatment with topical mupirocin cream (antibacterial agent). We then saw that a fungal colony grew on the culture, which was identified as T. mentagrophytes based on the morphological and molecular characteristics. The patient was then diagnosed with tinea faciei and was topically treated with 0.2% ketoconazole cream twice per day for 7 days. Through a literature review, we found another 18 cases of impetigo-like tinea faciei with similar clinical manifestations and pathogenic characteristics. Among these, the most common causative agent was T. mentagrophytes complex, which frequently occurs in children and adolescents and exhibits no gender preferences. Systemic and topical antifungals such as terbinafine or itraconazole are effective for impetigo-like tinea faciei caused by T. mentagrophytes complex. However, prolonged course of impetigo in more than 50% cases highlights the importance of mycological examination when dealing with apparent antibiotic-resistant impetigo cases in clinical settings.Keywords: tinea faciei, impetigo, Trichophyton mentagrophytes

Xiaonan Zhou,1,2,&ast; Kai Zhu,1,2,&ast; Yiqiu Zhang,3– 5,&ast; Yang Ming,1,2 Dai Shi,3– 5 Hui Tan,3– 5 Bitao Xiang,1,2 Shichao Zhu,1,2 Dengfeng Cheng,3– 5 Hao Lai,1,2 Chunsheng Wang,1,2 Guobing Liu3– 5 1Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, People’s Republic of China; 3Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 4Institute of Nuclear Medicine, Fudan University, Shanghai, 200032, People’s Republic of China; 5Shanghai Institute of Medical Imaging, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guobing Liu, Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, No. 180 in Fenglin Road, Shanghai, 200032, People’s Republic of China, Tel +8618317086732, Fax +86-21-62489191, Email liu.guobing@zs-hospital.sh.cn Chunsheng Wang, Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, No. 180 in Fenglin Road, Shanghai, 200032, People’s Republic of China, Email wangchunsheng@fudan.edu.cnPurpose: To investigate the feasibility of a pre-targeted imaging strategy based on the cycloaddition between 1,2,4,5-terazine (Tz) and trans-cyclooctene (TCO) for evaluating CD11b expression in inflammatory aortic aneurysm (AA) using single photon emission computed tomography/computed tomography (SPECT/CT).Methods: C57BL/6J mice were fed β-aminopropionitrile (1 g/kg/day) for 4 weeks to establish AA models. Anti-CD11b-TCO was synthesized and 99mTc-HYNIC-PEG11-Tz was designed for pre-targeted SPECT/CT. The affinity and specificity of the probe for the inflammatory cell line Raw-264.7 were investigated. Then, anti-CD11b-TCO pre-targeted and 99mTc-HYNIC-PEG11-Tz based SPECT/CT were performed to detect in vivo inflammation in AA. Finally, ex vivo aortic breast-specific gamma imaging (BSGI), Western blot assays, and immunohistochemical CD11b staining were performed to confirm the in vivo findings of SPECT/CT.Results: In the AA models, 65.22% (15/23) had aortic lesions, including 43.48% (10/23) AA lesions. The anti-CD11b-TCO presented with a high TCO coupling ratio (7.43), and the 99mTc-HYNIC-PEG11-Tz showed high radio-purity (> 95%), good in vitro stability and a rapid clearance rate. Additionally, anti-CD11b-TCO and 99mTc-HYNIC-PEG11-Tz presented high click rate (∼ 89%). The in vitro clicked compound, 99mTc-HYNIC-PEG11-Tz/TCO-anti-CD11b, showed high affinity and specificity for Raw-264.7 cells. 99mTc-HYNIC-PEG11-Tz/TCO-anti-CD11b pre-targeting SPECT/CT successfully demonstrated inflammatory AA with a high AA-to-background ratio in AA mice, compared to AA mice that were injected with 99mTc-HYNIC-Tz/TCO-IgG (8.13 versus 3.71, P < 0.001) and control mice injected with 99mTc-HYNIC-Tz/TCO-anti-CD11b (8.13 versus 3.66, P < 0.001). This result was confirmed by ex vivo BSGI performed immediately after SPECT/CT and immunohistochemical CD11b staining.Conclusion: SPECT/CT imaging using the anti-CD11b-TCO/Tz-PEG11-HYNIC-99mTc based pre-targeting imaging strategy allows for the detection of inflammation in progressive AA.Keywords: aortic aneurysm, inflammation, SPECT/CT, CD11b, macrophage

Longxian Lv,1,&ast; Ling Peng,2,&ast; Ding Shi,1 Li Shao,3,&ast; Huiyong Jiang,1 Ren Yan1 1State Key Laboratory for the 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, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Respiratory Disease, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 3Institute of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huiyong Jiang; Ren Yan, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, Zhejiang, 310003, People’s Republic Of China, Tel/Fax +86-571-87236453, Email jianghuiyong@zju.edu.cn; 1514090@zju.edu.cnBackground: Streptococcus pneumoniae (SP) is the most common cause of bacterial pneumonia, especially for people with immature or compromised immune systems. In addition to vaccination and antibiotics, immune regulation through microbial intervention has emerged in recent anti-SP infection research. This study investigated the therapeutic effect of a combination of live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus (CBLEB), a widely used probiotic drug, on SP infection in rats.Methods: An immunocompromised SP-infection rat model was established by intraperitoneal injection of cyclophosphamide and nasal administration of SP strain ATCC49619. Samples from SP-infected, SP-infected and CBLEB-treated, and healthy rats were collected to determine blood indicators, serum cytokines, gut microbiota, faecal and serum metabolomes, lung- and colon-gene transcriptions, and histopathological features.Results: CBLEB treatment alleviated weight loss, inflammation, organ damage, increase in basophil percentage, red cell distribution width, and RANTES levels and decrease in total protein and albumin levels of immunocompromised SP-infection rats. Furthermore, CBLEB treatment alleviated dysbiosis in gut microbiota, including altered microbial composition and the aberrant abundance of opportunistic pathogenic bacterial taxa such as Eggerthellaceae, and disorders in gut and serum metabolism, including altered metabolomic profiles and differentially enriched metabolites such as 2,4-di-tert-butylphenol in faeces and L-tyrosine in serum. The transcriptome analysis results indicated that the underlying mechanism by which CBLEB fights SP infection is mainly attributed to its regulation of immune-related pathways such as TLR and NLR signalling in the lungs and infection-, inflammation- or metabolism-related pathways such as TCR signalling in the colon.Conclusion: The present study shows a potential value of CBLEB in the treatment of SP infection.Keywords: Streptococcus pneumonia infection, probiotics, microbiota, metabolism, transcriptome

Ning Yu, Xuefang Liu, Dandan Shi, Long Bai, Tianfu Niu, Ya Liu Department of Anaesthesiology and Intensive Care, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050004, People’s Republic of ChinaCorrespondence: Ya Liu, Department of Anaesthesiology and Intensive Care, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050004, People’s Republic of China, Email md2006liuya@aliyun.com; liuya6660707@163.comBackground: The molecular mechanism of septic shock is unknown. We studied the pathogenesis of septic shock and provide a novel strategy for treating and improving the prognosis of septic shock.Methods: Gluten-Sensitive Enteropathy (GSE) 131761, GSE119217, GSE26378 datasets were downloaded from the Gene Expression Omnibus (GEO) database. The three datasets included 204 septic shock samples and 48 normal samples. The R packages “affy” and “limma” were employed to identify the differently expressed genes (DEGs) between septic shock and normal samples. Weighted gene co-expression network analysis (WGCNA) was performed to search for modules that play an important role in septic shock. Functional annotation of DEGs and construction and analysis of hub genes were used to explore the pathomechanism of septic shock. The receiver operating characteristic (ROC) curves were obtained using MedCalc software. The drug molecules that could regulate hub genes associated with septic shock were searched for in the CMap database. An animal model of septic shock was constructed to analyze the role of these hub genes.Results: The merged series contained 321 up-regulated and 255 down-regulated genes. WGCNA showed the brown module had the highest correlation with the status of septic shock. GO and KEGG enrichment analysis results of the brown module genes showed they were mainly enriched in “leukocyte differentiation”, “Ras-proximate-1 (Rap1) signaling pathway”, and “cytokine–cytokine receptor interaction”. Through construction and analysis of a protein–protein interaction (PPI) network, cluster of differentiation 63 (CD63) and complement component 3a receptor 1 (C3AR1) were identified as hub genes of septic shock. The area under curve (AUC) of C3AR1 for the septic shock is 0.772 (P< 0.001), and the AUC of CD63 for the septic shock is 0.871 (P< 0.001). Small molecule drugs were filtered by the number of instances (n> 3) and P-values < 0.05, including “monensin”, “verteporfin”, “ikarugamycin”, “tetrahydroalstonine”, “cefamandole”, “etoposide”. In the animal model, the relative expression levels of interleukin-6 (IL-6), Tumor Necrosis Factor-? (TNF-?), and lactic acid were significantly higher in the septic shock group compared with the control group. Results of Real Time Quantitative PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) analysis for CD63 and C3AR1 showed that their relative expression levels were significantly lower in the septic shock group compared with the control group (P< 0.05).Conclusion: CD63 and C3AR1 are significant hub genes of septic shock and may represent potential molecular targets for future studies of septic shock.Keywords: septic shock, CD63, C3AR1, hub genes, animal model

Yunqi Bao,1 Wei Zhang,1 Dandan Shi,2 Weili Bai,1 Dongdong He,1 Dan Wang1 1Department of Rheumatology, Xi’an Fifth Hospital, Xian, 710000, Shaanxi, People’s Republic of China; 2Department of Radiology, Xi’an Fifth Hospital, Xian, 710000, Shaanxi, People’s Republic of ChinaCorrespondence: Dan WangDepartment of Rheumatology, Xi’an Fifth Hospital, 112 Xiguanzheng Street, Lianhu District, Xian, 710000, Shaanxi, People’s Republic of ChinaEmail wdtougao2021@163.comObjective: The main aims of this study were to explore the relationships between serum tumor markers and connective tissue disease-related interstitial lung disease (CTD-ILD) and to evaluate the clinical value of tumor markers for investigating interstitial lung disease (ILD) in patients with connective tissue disease (CTD).Methods: The study included 235 patients with CTD (90 CTD without ILDs, 145 CTD-ILD). Clinical information and the levels of inflammatory and tumor markers, including carbohydrate antigen (CA) 19– 9, CA125, carcinoembryonic antigen (CEA), CA153, and cytokeratin 19 fragments (CYFRA21-1), were obtained in all the patients.Results: A significant difference between CTD with or without ILD and higher levels of tumor markers was observed in the CTD-ILD group, including CA19-9 (p< 0.001), CEA (p< 0.001), CA153 (p< 0.001), and CYFRA21-1 (p< 0.001). There was no significant difference in serum tumor marker levels in the various types of CTD (rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, inflammatory myositis, systemic sclerosis, and mixed connective tissue disease). The levels of CA153 [odds ratio (OR)=1.159] and CYFRA21-1 (OR=2.269) were clearly related to the risk of CTD-ILD. The diagnostic value of CA153 [area under receiver operating characteristic curve (AUC)=0.736] and CYFRA21-1 (AUC=0.718) was confirmed for ILDs in CTD patients, at cut-off values of 9.45 U/mL and 2.13 ng/mL, respectively.Conclusion: There is a positive correlation between serum tumor marker levels and CTD-ILD. Higher levels of CA153 and CYFRA21-1 suggest an increased risk of developing ILD and may therefore be useful as biomarkers for detecting CTD-ILD in the clinical setting.Keywords: connective tissue disease, tumor markers, interstitial lung disease

Dan Shi,1 Huiyun Li,2 Junge Zhang,3 Yadong Li1 1Department of Oral Medicine Centre, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Anesthesiology, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 3Department of Ophthalmology, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Yadong LiDepartment of Oral Medicine Centre, Henan Provincial People’s Hospital, No. 7 Wei-Wu Road, Zhengzhou City, 450000 Henan Province, People’s Republic of ChinaTel +86-186-38723618Email liyadongjibao2009@163.comBackground: Aberrant expression of circular RNA (circRNA) is involved in the occurrence and development of multifarious cancers, including oral squamous cell carcinoma (OSCC). However, the biological role of circGDI2 and the action mechanism in OSCC remain largely unclear.Methods: The expression levels of circGDI2, miR-454-3p and forkhead box F2 (FOXF2) were examined by quantitative real-time PCR (qRT-PCR) or Western blot. The stability of circGDI2 was confirmed by Ribonuclease R (RNase R) assay. Cell Counting Kit 8 (CCK8) assay, colony formation and transwell assay were used to detect cell proliferation, migration or invasion. Cell apoptosis was tested by flow cytometry. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to verify the interaction between miR-454-3p and circGDI2 or FOXF2. Moreover, xenograft mouse models were constructed to assess tumor growth in vivo.Results: CircGDI2 was a stable circRNA and was low expressed in OSCC tissues and cells. CircGDI2 overexpression could effectively inhibit the proliferation, migration, invasion and promote apoptosis in OSCC cells, and suppress OSCC tumor growth in nude mice in vivo. MiR-454-3p could be sponged by circGDI2, and its overexpression could mitigate the suppressive effects of circGDI2 overexpression on OSCC progression. In addition, FOXF2 was a target of miR-454-3p, and miR-454-3p silence could impede the cell growth of OSCC cells by enhancing FOXF2 expression. Meanwhile, circGDI2 positively regulated FOXF2 expression by targeting miR-454-3p.Conclusion: CircGDI2 served as a repressor to restrain OSCC malignancy via miR-454-3p/FOXF2 axis, which might be a novel biomarker for targeted OSCC therapy.Keywords: OSCC, circGDI2, miR-454-3p, FOXF2

Jia Li,1,2,* Da Shi,1,2,* Zijian Hua,1,2 Linfeng Wang1,2 1Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, People’s Republic of China; 2The Key Laboratory of Orthopedic Biomechanics of Hebei Province, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, People’s Republic of China*These authors contributed equally to this workCorrespondence: Linfeng Wang No. 139, Ziqiang Road, Shijiazhuang, Hebei, People’s Republic of ChinaTel +86-311-88602016Fax +86-311-88602015Email jzwlf1899@163.comBackground: There are few reports describing the imaging features of traumatic central cord syndrome (TCCS) in kinematic magnetic resonance imaging (kMRI) scans. The current study aimed to assess and characterize dynamic spinal cord impingement (DSCI) using kMRI and evaluate the risk factors for poor outcomes in patients with TCCS after surgery.Methods: This retrospective study included 63 patients with TCCS who underwent surgery in the authors’ hospital. The American Spinal Injury Association impairment scale grade and Japanese Orthopedic Association (JOA) score were collected preoperatively and at the final follow-up to assess neurological function. Patients were divided into two groups based on the JOA score (> or < 50%), and clinical and radiographic evaluations were compared. The metrics examined included age at the time of surgery, gender, type of trauma, the interval from injury to surgery, surgical approach, pathological signs, range of motion, DSCI and the length of intramedullary hyperintensity signal (LIHS).Results: There were statistical differences in the LIHS, DSCI and preoperative JOA score between good (JOA > 50%; n = 50) and poor (JOA < 50%, n =13) recovery patient groups (P< 0.05). Logistic regression, with poor outcomes as the dependent variable, suggested independent risk associations with preoperative JOA score (P< 0.05), DSCI (P< 0.05) and LIHS (P< 0.05).Conclusion: kMRI can be effective for decision-making in the treatment of TCCS. The lower preoperative JOA score, longer high signal cord and higher dynamic spinal cord impingement were risk factors for poor outcomes in patients with TCCS after surgery.Keywords: dynamic spinal cord impingement, traumatic central cord syndrome kinematic magnetic resonance imaging, risk factor

Xinxin Liu, Dandan Shi, Lu Guo, Xiaoying Zhou, Mengmeng Shang, Xiao Sun, Dong Meng, Yading Zhao, Jie Li Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Jie LiDepartment of Ultrasound, Qilu Hospital of Shandong University, Wenhua Western Road, Jinan 107#, People’s Republic of ChinaTel/Fax +86-531-82166101Email jieli301@163.comPurpose: To synthesize echogenic chitosan/perfluorohexane nanodroplets (CNDs) for DKK-2 gene delivering in a spatiotemporally controlled manner in vitro.Methods: The characteristics, contrast-enhanced ultrasound imaging, DNA binding and DNase protection capacity, DKK-2 gene transfection and effects on LNCaP cells of these CNDs were investigated.Results: The obtained CNDs showed positive surface charges and could attract the genetic cargo with negative surface charges to form nanocomplexes. Agarose gel electrophoresis confirmed binding of the CNDs and pDNA. DKK-2 pDNA-loaded CNDs, in combination with ultrasound, ruptured and released DKK-2 pDNA, entering LNCaP cells through nano-scale pores in the cell membrane, which further reduced the proliferation of LNCaP cells.Conclusion: These stable and safe CNDs may be a promising choice to achieve efficient ultrasound-mediated gene delivery to specific tissues in a spatiotemporally controlled manner.Keywords: nanodroplets, chitosan, DKK-2, ultrasonic gene transfer, prostate cancer

Dazun Shi, Yu Zhang, Yan Tian Department of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of ChinaCorrespondence: Yan TianDepartment of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of ChinaEmail tianyxycsu@163.comObjective: The acquisition of chemoresistance to methotrexate (MTX) still remains one of the major challenges for choriocarcinoma treatment. Herein, we aimed to evaluate the potential role of Signaling Lymphocytic Activation Molecule Family Member 1 (SLAMF1) as a possible regulator of chemoresistance to MTX in choriocarcinoma.Material and Methods: MTX-resistant JEG3 and JAR sublines (JEG3/MTX, JAR/MTX) were used to study SLAMF1 function. CCK8 assay and soft agar assay were conducted to measure the cell viability and clonogenesis of choriocarcinoma cells, respectively; MDC incorporation assay was conducted for the quantification of intracellular autophagy; BrdU labeling was used to assess the proliferative potential of choriocarcinoma cells; SLAMF1 protein expression was analyzed by Western blotting.Results: Upregulation of SLAMF1 expression was observed in MTX-resistant JEG3/MTX and JAR/MTX sublines compared to their parental JEG3 and JAR cell lines, respectively. Knockdown of SLAMF1 markedly attenuated cell viability and soft agar clonogenesis after incubation with MTX in JEG3/MTX and JAR/MTX cells. In contrast, constitutive expression of SLAMF1 rescued cell survival soft agar clonogenesis in JEG3 and JAR cells treated with MTX. Moreover, autophagy is apparently activated in MTX-resistant JEG3/MTX and JAR/MTX sublines compared to their parental cell lines. Autophagy inhibitor 3-methyladenine and bafilomycin A1 enhanced MTX-induced cytotoxicity in MTX-resistant JEG3 and JAR sublines. Further, SLAMF1 might activate autophagy-related mechanism to promote resistance to MTX in choriocarcinoma cells. Depletion of SLAMF1 suppressed autophagy and induced apoptosis in MTX-treated JEG3/MTX and JAR/MTX cells.Conclusion: SLAMF1 might promote MTX resistance via activating protective autophagy in choriocarcinoma cell lines. Targeting SLAMF1 might be a useful therapeutic strategy to sensitize choriocarcinoma cells to MTX-based regimens.Keywords: choriocarcinoma, methotrexate, drug resistance, SLAMF1, autophagy

Buyankhishig Dorjsuren,1,* Birendra Chaurasiya,2,* Zixuan Ye,1 Yanyan Liu,1 Wei Li,3 Chaoyang Wang,1 Di Shi,4 Colin E Evans,2 Thomas J Webster,4 Yan Shen1 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People’s Republic of China; 2Department of Pediatrics, Critical Care Division, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou 225002, People’s Republic of China; 4Department of Chemical Engineering, Northeastern University, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Yan Shen; Thomas J Webster Tel +86 (025) 83271305; Tel +86 (025) 83271305; Email shenyan@cpu.edu.cn; th.webster@northeastern.eduBackground: One major limitation of cancer chemotherapy is a failure to specifically target a tumor, potentially leading to side effects such as systemic cytotoxicity. In this case, we have generated a cancer cell-targeting nanoparticle-liposome drug delivery system that can be activated by near-infrared laser light to enable local photo-thermal therapy and the release of chemotherapeutic agents, which could achieve combined therapeutic efficiency.Methods: To exploit the magnetic potential of iron oxide, we prepared and characterized citric acid-coated iron oxide magnetic nanoparticles (CMNPs) and encapsulated them into thermo-sensitive liposomes (TSLs). The chemotherapeutic drug, doxorubicin (DOX), was then loaded into the CMNP-TSLs, which were coated with an antibody against the epidermal growth factor receptor (EGFR), cetuximab (CET), to target EGFR-expressing breast cancer cells in vitro and in vivo studies in mouse model.Results: The resulting CET-DOX-CMNP–TSLs were stable with an average diameter of approximately 120 nm. First, the uptake of TSLs into breast cancer cells increased by the addition of the CET coating. Next, the viability of breast cancer cells treated with CET-CMNP-TSLs and CET-DOX-CMNP-TSLs was reduced by the addition of photo-thermal therapy using near-infrared (NIR) laser irradiation. What is more, the viability of breast cancer cells treated with CMNP-TSLs plus NIR was reduced by the addition of DOX to the CMNP-TSLs. Finally, photo-thermal therapy studies on tumor-bearing mice subjected to NIR laser irradiation showed that treatment with CMNP-TSLs or CET-CMNP-TSLs led to an increase in tumor surface temperature to 44.7°C and 48.7°C, respectively, compared with saline-treated mice body temperature ie, 35.2°C. Further, the hemolysis study shows that these nanocarriers are safe for systemic delivery.Conclusion: Our studies revealed that a combined therapy of photo-thermal therapy and targeted chemotherapy in thermo-sensitive nano-carriers represents a promising therapeutic strategy against breast cancer.Keywords: breast cancer, cetuximab, doxorubicin, iron oxide magnetic nanoparticles, epidermal growth factor receptors, combined therapy

Ya Gao, Xinyi Wu, Yunhao Li, Yifei Li, Qingyu Zhou, Qiongqiong Wang, Chaoyi Wei, Deli Shi, Congying Xie, Huanle Pan Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Congying Xie; Huanle PanDepartment of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Street, Wenzhou, Zhejiang 325000, People’s Republic of ChinaTel +86 138 6771 1881; +8615088980299Fax +86 577 8806 9372Email wzxiecongying@163.com; phlphh@163.comPurpose: To evaluate the predictive value of blood lymphocyte, monocyte to lymphocyte ratio (MLR), and neutrophil to lymphocyte ratio (NLR) for radiation pneumonia (RP) in patients with thoracic tumors receiving radiotherapy.Patients and Methods: The clinical data of 65 patients with thoracic tumor (esophageal cancer, lung cancer) treated by radiotherapy in our hospital were retrospectively analyzed. Patients were divided into the RP group and the non-RP group according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Data on blood cell counts, including lymphocytes, monocytes, and neutrophils, were collected before (0 weeks) and after 1, 2, and 4 weeks of radiotherapy.Results: Of the 65 patients enrolled, 27 developed radiation pneumonia and 38 did not. Patients’ clinical factors, including age, TNM stage, tumor type, underlying lung disease, and history of smoking, had no correlation with RP. ANOVA of repeated measurement data showed that the changes of MLR in the group with RP during radiotherapy were significantly different from those in the non-RP group (P< 0.05). The RP prediction model based on the identified risk factors was established using receiver operator characteristic curves. The results showed that the area under the curve for the monocyte to lymphocyte ratio was 0.755 (95% CI, 0.63– 0.87, P=0.000), and the best cutoff point for MLR was 0.426.Conclusion: MLR could predict radiation pneumonia in patients with thoracic tumor radiotherapy and achieve early monitoring, early prevention, and treatment.Keywords: cancer, radiotherapy, radiation pneumonitis, monocyte to lymphocyte ratio

Xiao Sun,1 Lu Guo,1 Mengmeng Shang,1 Dandan Shi,1 Ping Liang,2 Xuanxuan Jing,1 Dong Meng,1 Xinxin Liu,1 Xiaoying Zhou,1 Yading Zhao,1 Jie Li1 1Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jie LiDepartment of Ultrasound, Qilu Hospital of Shandong University, Wenhua Western Road, 107#, Jinan Tel/Fax +86-531-82166101Email jieli301@163.comPurpose: To synthesize and evaluate a novel folate-conjugated ultrasonic nanobubble (HA-FOL-NB) loading low-molecular-weight hyaluronic acid (LMW-HA) for specific tumor-associated macrophages (TAMs) targeting and reeducation.Methods: The characteristics, cytotoxicity, contrast-enhanced ultrasound imaging (CEUS), and targeting ability to TAMs of HA-FOL-NBs were investigated. The TAMs reprogramming function of HA-FOL-NBs combining ultrasound targeted nanobubble destruction was assessed as well.Results: HA-FOL-NBs (about 342 nm) showed remarkable contrast enhancement images, and higher targeting ability due to the folate to folate receptor interactions. Combined with ultrasound targeted nanobubble destruction, HA-FOL-NBs could specifically deliver LMW-HA into TAMs, thus exhibited stronger reeducation effect compared with free LMW-HA.Conclusion: These folate-conjugated and LMW-HA-loaded nanobubbles, with targeted CEUS imaging and TAMs reeducation, are expected to be a potential approach for tumor therapy based on TAMs, especially folate receptor-positive ones.Keywords: ultrasound contrast agent, ultrasonic nanobubble, tumor-associated macrophage, tumor microenvironment, contrast-enhanced ultrasound imaging

Yunxiang Zhang,1,2,* Yu Zheng,1,2,* Fangyi Dong,1,2,* Handong Ma,3 Liping Zhu,1 Dake Shi,4 Xiaoyang Li,1,2 Junmin Li,1,2 Jiong Hu1,2 1Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3John Hopcroft Center for Computer Science, Department of Computer Science and Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Clinical Microbiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junmin Li; Jiong Hu Tel +86 21 6437 0045 665 258Fax +86-21-64374756Email drlijunmin@126.com; hj10709@rjh.com.cnBackground: The epidemiology of Gram-negative bacteria in patients with febrile neutropenia (FN) and their susceptibility to initial empirical antibiotic therapy is key to successful treatment during the treatment of hematologic malignancies.Methods: A retrospective study was conducted. Patients with FN and confirmed laboratory results of Gram-negative bacteria infections were included. If no direct sensitivity of the identified pathogen to the initially prescribed antibiotic regimen was confirmed, it was defined as inappropriate initial antibiotic treatment (IIAT).Results: A total of 247 patients with FN were proven to be infected with Gram-negative bacteria, and 200 were diagnosed with acute leukemia. The most commonly detected bacteria were Escherichia coli (40%), Klebsiella pneumoniae (20%), and Pseudomonas aeruginosa (11%). In sum, 176 patients were classified as IIAT. The mortality rate in the IIAT group was significantly higher (37.7% vs 23.9%, P=0.038). With monotherapy as empirical treatment, high possibility of IIAT with fluoroquinolones (52%) and cephalosporins (35%) was detected, while more sensitivity to carbapenems (16%) and glycopeptides antibiotics (19%) was noticed. With combined treatment, cephalosporins/carbapenems had with the lowest percentage of IIAT (18%).Conclusion: In conclusion, inappropriate initial empirical antibiotic treatments were associated with higher mortality in patients with hematologic malignancies. The current empirical antibiotic regimen needs to be further optimized.Keywords: febrile neutropenia, Gram-negative bacteria, hematologic malignancy, empirical antibiotic treatment, inappropriate initial antibiotic treatment

Mengmeng Shang,1 Xiao Sun,1 Lu Guo,1 Dandan Shi,1 Ping Liang,2 Dong Meng,1 Xiaoying Zhou,1 Xinxin Liu,1 Yading Zhao,1 Jie Li1 1Department of Ultrasound, Qilu Hospital of Shandong University, Jinan 250012, People’s Republic of China; 2Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing 100853, People’s Republic of ChinaCorrespondence: Jie LiDepartment of Ultrasound, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan 250012, People’s Republic of ChinaTel +86-531-82166101Fax +86-531-86927544Email jieli301@163.comBackground: Synergistic chemoradiotherapy (CRT) has become a primary effective curative approach for many solid cancers. However, CRT is still associated with several obstacles, including the increases in side effects and systemic toxicity. Incorporating nanocarriers into CRT is a new and exciting approach to solve these obstacles. The purpose of the present study was to design a unique pH- and ultrasound-responsive perfluoropentane-encapsulated, paclitaxel (PTX)-loaded carboxymethyl chitosan nanodroplets (NDs) for combined imaging and synergistic CRT.Materials and Methods: The NDs were prepared by a homogenization/emulsion method. Their physicochemical properties, echogenicity and biocompatibility were evaluated. PTX-loaded NDs with a high loading efficiency and encapsulation efficiency were prepared and their pH-responsive drug release profile was determined by dialysis sack method. Then, PC3 cells were exposed to (1) PTX (4 μg/mL), (2) NDs (30 μg/mL), (3) PTX-loaded NDs (34 μg/mL), (4) RT (6 Gy), (5) RT (10 Gy), (6) combination of PTX (4 μg/mL), ultrasound (0.5 W/cm2, 30 s) and RT (6 Gy), (7) combination of NDs (30 μg/mL), ultrasound (0.5 W/cm2, 30 s) and RT (6Gy), (8) combination of PTX-loaded NDs (30 μg/mL), ultrasound (0.5 W/cm2, 30 s) and RT (6 Gy). 24 hrs later, CCK-8 assay, flow cytometry and migration assay were carried out to evaluate their therapeutic effects in CRT.Results: The desired NDs were successfully prepared, which were with round, spherical shapes, relatively smooth surfaces, core-shell structures and uniform in sizes (< 300 nm with PDI< 0.3 when at pH≧6.0). The NDs exhibited good abilities in pH-dependent charge conversion, biocompatibility and ultrasound contrast echogenicity. The in vitro drug release from PTX-loaded NDs (the highest loading efficiency and encapsulation efficiency were 20.35% and 91.58%) was pH dependent and exhibited an initial burst followed by a sustained drug release. The results of the CCK-8 assay, flow cytometry and migration assay all showed PTX-loaded NDs combined ultrasound and RT significantly enhanced cell responses in CRT.Conclusion: The pH- and ultrasound-responsive PTX-loaded NDs, which exhibited a high echogenicity, drug delivery ability and radiosensitization ability, could be a feasible option for combined imaging and novel enhancing approach in synergistic CRT.Keywords: nanodroplets, ultrasound contrast agents, chemoradiotherapy, radiosensitizer, paclitaxel, chitosan

Yang Bao,1,* Yijun Zhu,1,* Guangbao He,1 Hongwei Ni,1 Chenxia Liu,1 Limin Ma,1 Lifeng Zhang,2 Dongping Shi1 1Department of Anesthesiology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai 201800, People’s Republic of China; 2Department of Anesthesiology, Jiading Maternal and Child Health Hospital, Shanghai 201821, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongping ShiDepartment of Anesthesiology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, No.1 Chengbei Road, Jiading District, Shanghai, Shanghai 201800, People’s Republic of ChinaEmail dongpingshi@yandex.com Lifeng ZhangDepartment of Anesthesiology, Jiading Maternal and Child Health Hospital, No 1216 Gaotai Road, Jiading District, Shanghai, Shanghai 201821, People’s Republic of ChinaEmail zhanglifeng2019@126.comBackground: Dexmedetomidine (Dex) was reported to exhibit anti-inflammatory effect in the nervous system. However, the mechanism by which Dex exhibits anti-inflammation effects on LPS-stimulated BV2 microglia cells remains unclear. Thus, this study aimed to investigate the role of Dex in LPS-stimulated BV2 cells.Methods: The BV2 cells were stimulated by lipopolysaccharides (LPS). BV2 cells were infected with short-hairpin RNAs targeting NF-κB (NF-κB-shRNAs) and NF-κB overexpression lentivirus, respectively. In addition, miR-340 mimics or miR-340 inhibitor was transfected into BV2 cells, respectively. Meanwhile, the dual-luciferase reporter system assay was used to explore the interaction of miR-340 and NF-κB in BV2 cells. CCK-8 was used to detect the viability of BV2 cells. In addition, Western blotting was used to detect the level of NF-κB in LPS-stimulated BV2 cells. The levels of TNF-α, IL-6, IL-1β, IL-2, IL-12, IL-10 and MCP-1 in LPS-stimulated BV2 cells were measured with ELISA.Results: The level of miR-340 was significantly upregulated in Dex-treated BV2 cells. Meanwhile, the level of NF-κB was significantly increased in BV2 cells following infection with lenti-NF-κB, which was markedly reversed by Dex. LPS markedly increased the expression of NF-κB and proinflammatory cytokines in BV2 cells, which were reversed in the presence of Dex. Moreover, miR-340 mimics enhanced the anti-inflammatory effects of Dex in LPS-stimulated BV2 cells via inhibiting NF-κB and proinflammatory cytokines. Furthermore, Dex obviously inhibited LPS-induced phagocytosis in BV2 cells.Conclusion: Taken together, our results suggested that Dex might exert anti-inflammatory effects in LPS-stimulated BV2 cells via upregulation of miR-340. Therefore, Dex might serve as a potential agent for the treatment of neuroinflammation.Keywords: NF-κB, dexmedetomidine, BV2 microglia cells, postoperative cognitive dysfunction

Xiaoyan Hu,1 Jiangshan Wan,2,3 Xiaole Peng,2,3 Hao Zhao,1,3 Dingwen Shi,1,3 Liyi Mai,2 Hai Yang,1 Yanbing Zhao,1,3 Xiangliang Yang1 1National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, People’s Republic of China; 2Institute of Consun Co. For Chinese Medicine in Kidney Diseases, C. Consum Pharmaceutical Group, Shenzhen 518000, People’s Republic of China; 3Shenzhen Institute of Huazhong University of Science and Technology, Shenzhen 518057, People’s Republic of ChinaCorrespondence: Hai YangNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, People’s Republic of ChinaEmail yanghai@hust.edu.cnYanbing ZhaoNational Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, People’s Republic of ChinaEmail zhaoyb@hust.edu.cnBackground: Lateral flow assays (LFA) play an increasingly important role in the rapid detection of various pathogens, pollutants, and toxins.Purpose: To overcome the drawbacks of low sensitivity and poor quantification in LFA, we developed a new calorimetric LFA (CLFA) using gold nanocages (GNCs) due to their high photothermal conversion efficiency, good stability of photophysical properties, and stronger penetrating ability of NIR light.Methods: Thiol-polyethylene glycol-succinyl imide ester (HS-PEG-NHS) was modified onto GNCs, and the complex was conjugated with an antibody. Subsequently, the antibody-conjugated GNCs were analyzed by UV/Vis spectrophotometer, transmission electron microscope, high-resolution transmission electron microscope with energy dispersive spectrometer, dynamic light scattering instrument, and Atom force microscope. The GNC-based CLFA of alpha-fetoprotein (AFP) and zearalenone (ZEN), a food toxin, required nitrocellulose strips, a NIR laser source, and an infrared camera.Results: The GNC-labeled CLFA platform technique exhibited detection sensitivity, qualitative specificity, and quantitative accuracy. The superior performance of the technique was evident both in sandwich format detection of biomacromolecules (eg, AFP protein) or competitive format detection of small molecules (eg, ZEN). After optimizing various test parameters, GNC-labeled CLFA provided ca. 5-6-fold enhanced sensitivity, higher correlativity (R2>0.99), and more favorable recovery (82–115%) when compared with visual LFA.Conclusion: GNC-labeled CLFA may be a promising detection platform with high sensitivity, specificity, and precision.Keywords: lateral flow assays, LFA, gold nanocages, photothermal effect, alpha-fetoprotein, AFP, zearalenone, ZEN

Rehman M, Ihsan A, Madni A, et al. Int J Nanomedicine. 2021;16:5187. The authors have advised Figure 3 on page 5187 is incorrect. An error was made in the labelling of the scale bar for figure part 3B. The correct Figure 3 is shown in Download Article. The authors apologize for this error. Read the original articlePrevious corrigendum has been published

Nadine Abdallah,1 Misako Nagasaka,2,3 Eman Abdulfatah,4 Dongping Shi,4 Antoinette J Wozniak,2 Ammar Sukari2 1Department of Internal Medicine, Wayne State University, Detroit, MI 48201, USA; 2Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA; 3Department of Advanced Medical Innovation, St. Marianna University Graduate School of Medicine, Kawasaki, Kanagawa, Japan; 4Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA Introduction: Histologic transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a well-recognized mechanism of resistance in EGFR-mutant adenocarcinoma upon treatment with TKIs, but rarely reported with programmed death1 (PD-1) inhibitors. We report two cases of potential transformation during treatment with PD-1 inhibitors.Case presentations: Case 1, a 65-year-old man was diagnosed with stage IVa lung adenocarcinoma on pleural fluid cytology. He received six cycles of carboplatin and pemetrexed, then maintained on pemetrexed. He had disease progression after nine cycles of pemetrexed and was switched to nivolumab. He progressed after five cycles of nivolumab. Core biopsy of the lung mass revealed SCLC. Case 2, a 68-year-old man was diagnosed with two primary NSCLCs and underwent resection. He had recurrence after several months and was treated with four cycles of carboplatin, paclitaxel, and pembrolizumab on clinical trial, with partial response. He was continued on pembrolizumab and had disease progression after 30 cycles. Biopsy of the new lesions showed SCLC.Discussion: Histologic transformation from NSCLC to SCLC can be explained by the presence of a common cell precursor. Proposed molecular mechanisms include loss of RB1, TP53 mutations, and MYC amplification. The distinction between transformation and mixed histology tumors is challenging, especially when pathologic material used for the initial diagnosis is limited. The possibility of a second metachronous primary lung cancer cannot be excluded in our cases.Conclusion: Histologic transformation with PD-1 inhibitors could be under-recognized. Disease progression should prompt re-biopsy to uncover new histology and change in treatment. Future studies are needed to elucidate mechanisms and predictors of transformation. Keywords: transformation, small cell lung cancer, non-small cell lung cancer, PD-1 inhibitor, resistance, checkpoint inhibitor

Chaogang Yang,1–3,* Dongdong Shi,1–3,* Shuyi Wang,1–3 Chen Wei,1–3 Chunxiao Zhang,1–3 Bin Xiong1–3 1Department of Gastrointestinal Surgery and Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Hubei Key Laboratory of Tumor Biological Behaviors, Hubei, People’s Republic of China; 3Hubei Cancer Clinical Study Center, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Background: Circulating tumor cells (CTCs) have been regarded as a promising biomarker for colorectal cancer (CRC); however, the prognostic value of post-operative (op) CTCs is still unclear. This study aimed to compare the recurrence prediction value of pre- and post-op CTCs in CRC patients treated with curative resection.Patients and methods: Consecutive CRC patients treated with curative resection from January 2014 to March 2015 were identified. CTCs from 2.5 mL peripheral blood were enumerated with an ISETdevice-CTCBIOPSY® before and after surgery. Based on the status of pre- and post-op CTCs, the included patients were grouped into four cohorts: pre- and post-op CTCs−, pre-op CTCs− but post-op CTCs+, pre-op CTCs+ but post-op CTCs−, and pre- and post-op CTCs+. The 3-year recurrence-free survival (RFS) rate of patients was analyzed.Results: A total of 138 patients (79 [57.2%] male; median age=62 [43–75] years) were enrolled. Patients with pre-op CTCs− had a 19.2% higher 3-year RFS rate (86.2%) than the combined cohorts with pre-op CTCs+ (67.0%) (P=0.038). Patients with post-op CTCs+ had aa 25.6% lower 3-year RFS rate (57.1%) than the combined cohorts with post-op CTCs− (82.7%) (P=0.001). Moreover, patients with pre- and post-op CTCs+ had a 25.1% lower 3-year RFS rate (53.8%) than patients with pre-op CTCs+ but post-op CTCs− (78.9%) (P=0.004). Multivariate analyses confirmed that post-op CTCs+ (HR=2.82, 95% CI=1.39–5.75, P=0.004), but not but pre-op CTCs+ (HR=2.17, 95% CI=0.75–6.31, P=0.153), was independently associated with shorter 3-year RFS rate.Conclusion: Post-op CTCs+, but not pre-op CTCs+, is an independent indicator of poor prognosis for CRC patients treated with curative resection. Patients with post-op CTCs+ have a higher risk of recurrence those with pre-op CTCs+. Evaluation of post-op, rather than pre-op, CTCs is warranted. Keywords: circulating tumor cells, colorectal cancer, preoperative, postoperative, recurrence

Xiaofei Zhu,* Fuqi Li,* Dongchen Shi,* Xiaoping Ju,* Yangsen Cao, Yuxin Shen, Fei Cao, Shuiwang Qing, Fang Fang, Zhen Jia, Huojun Zhang Department of Radiation Oncology, Changhai Hospital Affiliated to Navy Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: To compare the effects of gemcitabine and nab-paclitaxel (GT) plus stereotactic body radiation therapy (SBRT) or gemcitabine and S-1 (GS) plus SBRT on health-related quality of life (HRQOL) of metastatic pancreatic cancer. Methods: Patients with biopsy-proven and radiographically metastatic pancreatic cancer were included. HRQOL was assessed using the Chinese version of Brief Pain Inventory (BPI) and 5-level European quality of life 5-dimensions (EQ-5D-5L). Data were analyzed with Spearman’s rank correlation, ordinal regression, and propensity score-matched analysis. Results: A total of 75 and 89 patients received GT and GS, respectively. The median biological effective dose of GT group and GS group was 59.5 Gy (range 48–85.5 Gy) and 64.4 Gy (range 52.48–85.5 Gy) in 5–8 fractions, respectively. More patients in the GS group had improvement in BPI and EQ-5D-5L compared with those in the GT group (n=38 vs n=15, P

Xiaofei Zhu,1,* Fuqi Li,1,* Wenyu Liu,2,* Dongchen Shi,1,* Xiaoping Ju,1 Yangsen Cao,1 Yuxin Shen,1 Fei Cao,1 Shuiwang Qing,1 Fang Fang,1 Zhen Jia,1 Huojun Zhang1 1Departmant of Radiation Oncology, Changhai Hospital affiliated to Navy Medical University, Shanghai, China; 2Departmant of Surgery, Changhai Hospital affiliated to Navy Medical University, Shanghai, China *These authors contributed equally to this article Background: To evaluate and compare the efficacy and safety of stereotactic body radiation therapy (SBRT) plus induction chemotherapy and SBRT plus adjuvant therapy. Methods: Patients with radiographically resectable, biopsy-proven pancreatic cancer were enrolled. Data were prospectively collected from 2012 to 2016. Cox proportional hazards regression was used to identify factors predictive of survival. Propensity score matching analysis was performed to assess the efficacy of SBRT combined with different timing of chemotherapy. Results: One hundred patients were enrolled with 48 receiving induction chemotherapy and 52 undergoing adjuvant chemotherapy. The median overall survival (OS) and progression-free survival (PFS) were 17.5 months (95% CI: 15.8–19.2 months) and 13.7 months (95% CI: 12.3–15.1 months), respectively. Patients with adjuvant chemotherapy (P

Xin Huang,1,* Chengqi Fan,2,* Huanhuan Zhu,1 Wenjun Le,1 Shaobin Cui,1 Xin Chen,3 Wei Li,4 Fulei Zhang,4 Yong Huang,4 Donglu Shi,1,5 Zheng Cui,1,6 Chengwei Shao,2 Bingdi Chen1 1The Institute for Translational Nanomedicine, Shanghai East Hospital, The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai, China; 2Radiology Department of Changhai Hospital, The Second Military Medical University, Shanghai, China; 3Department of Thyroid Surgery, The First Bethune Hospital of Jilin University, Jilin, China; 4International Joint Cancer Institute, The Second Military Medical University, Shanghai, China; 5The Materials Science & Engineering Program, Department of Mechanical & Materials Engineering, College of Engineering & Applied Science, University of Cincinnati, OH, USA; 6Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA *These authors contributed equally to this work Introduction: Pancreatic cancer (PC) has a poor prognosis with high mortality, due to the lack of effective early diagnostic and prognostic tools. Materials and methods: In order to target and diagnose PC, we developed a dual-modal imaging probe using Glypican-1 (GPC-1) antibody conjugated with Gd–Au nanoclusters (NCs; Gd-Au-NC-GPC-1). GPC-1 is a type of cell surface heparan sulfate proteoglycan, which is often highly expressed in PC. The probe was successfully prepared with a hydrodynamic diameter ranging from 13.5 to 24.4 nm. Results: Spectral characteristics showed absorption at 280 nm and prominent emission at 650 nm. Confocal microscopic imaging showed effective detection of GPC-1 highly expressed PC cells by Gd-Au-NC-GPC-1, which was consistent with flow cytometry results. In vitro relaxivity characterization demonstrated that the r1 value of the probe was 17.722 s−1 mM−1 Gd, which was almost 4 times higher compared with that of Gd-diethylenetriaminepentacetate (DTPA; r1 value =4.6 s−1 mM−1 Gd). Gd-Au-NC-GPC-1 exhibited similar magnetic resonance (MR) signals when compared to Gd-DTPA even at lower Gd concentrations. Much higher MR signals were registered in PC cells (COLO-357) compared with normal cells (293T). Furthermore, Gd-Au-NC-GPC-1 could effectively detect PC cells in vivo by dual-modal fluorescence imaging/magnetic resonance imaging (FI/MRI) at 30 minutes postinjection. In addition, Gd-Au-NC-GPC-1 did not show significant biotoxicity to normal cells at tested concentrations both in vitro and in vivo. Conclusion: Gd-Au-NC-GPC-1 has demonstrated to be a promising dual-modal FI/MRI contrast agent for targeted diagnosis of PC. Keywords: pancreatic cancer, Glypican-1, fluorescence imaging, magnetic resonance imaging, Gd–Au NCs

Lijun Shen,1,2* Miao Mo,2,3* Leon Jia,4 Huixun Jia,2,3 Qingguo Li,2,5 Lei Liang,2,5 Debing Shi,2,5 Zhen Zhang,1,2 Sanjun Cai,2,5 Xinxiang Li,2,5 Ji Zhu1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; 3Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, China; 4Virginia Commonwealth University, Richmond, VA, USA; 5Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China *These authors contributed equally to this work Purpose: To investigate the association of age and sex on survival in non-metastatic colorectal cancer (CRC) patients and to identify groups at high risk for poor outcomes.Materials and methods: We performed a retrospective analysis of 5,047 non-metastatic CRC patients from 2008 to 2013. Data regarding age at diagnosis; gender; tumor site; tumor stage; differentiation; lymphatic, neural or vascular invasion; and survival outcomes were collected. Patients were stratified into 10-year age groups (≤35, 36–45, 46–55, 56–65, 66–75, >75) and then further analyzed in three age groups (≤35, 36–75, >75). Disease-free survival (DFS) and overall survival (OS) were evaluated using univariate and multivariate Cox regression models.Results: Of the 5,047 eligible patients, 41.3% were female. The tumor stages were balanced between the genders. In the female patients, the tumor stages were similarly distributed among the different age groups, while younger male patients were diagnosed with more advanced disease (P75 had shorter DFS than patients between 36 and 75 years old (HR=1.57 [1.03–2.38] and HR=1.51 [1.11–2.05, respectively]), while there was no difference in DFS between females ≤35 and those >75. For male patients, older age was associated with poorer OS after the same adjustment.Conclusion: Young female CRC patients (≤35 years old) had the poorest DFS and quite poor OS compared to the other age groups. This emphasizes the need for health care providers to have a heightened awareness and to conduct further research when caring for young female CRC patients. Keywords: colorectal cancer, young female, prognosis, China