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Jia Zhou,1,* Wenwen Wang,1,* Qiyu Zhang,1,* Hanlin Zhang,1 Keyun Tang,1 Chenhui Mao,2 Mingli Li,3 Jun Li1 1Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, People’s Republic of China; 2Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Li, Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Disease, No. 1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86-010-69151500, Fax +86-010-69151502, Email lijun35@hotmail.comPurpose: Syphilis, caused by Treponema pallidum, presents a diagnostic challenge due to its diverse clinical manifestations. Neurosyphilis has seen a resurgence in recent years, particularly among men who have sex with men and those living with HIV. Diagnosis of neurosyphilis in emergency settings is challenging due to its varied neurological presentations. This study aims to serve as a reference for dermatologists and neurologists in diagnosing and treating neurosyphilis.Patients and Methods: This retrospective study analyzed patients who presented with neuropsychiatric symptoms and were ultimately diagnosed with neurosyphilis. These patients were collected from the emergency department in Peking Union Medical College Hospital between January 2018 and November 2023. The medical history, clinical symptoms, laboratory examinations, cranial MRI characteristics, and treatment regimens of these patients were investigated.Results: Among the included 12 neurosyphilis patients, memory deterioration was observed in 8 out of the 12 neurosyphilis patients. Diagnosis often resulted in delays, with misdiagnoses mainly including Alzheimer’s disease, stroke, and epilepsy. Neuroimaging revealed various abnormalities, predominantly affecting ventricular and temporal regions. Treatment with penicillin-based regimens varied in compliance, with only a minority of patients adhering to guidelines. Treatment outcomes were inconsistent, with some patients experiencing irreversible neurological damage and fluctuating serum rapid plasma reagin (RPR) titers.Conclusion: Diagnosis of neurosyphilis in the emergency department remains challenging, necessitating awareness of its varied neurological presentations. Enhanced diagnostic strategies are imperative to accelerate treatment initiation and improve outcomes for affected individuals.Keywords: neurosyphilis, emergency department, neuropsychiatric symptoms, cerebrospinal fluid, serologic tests

Xinkai Luo,1,* Ying Wang,2,* Yufei Mao,3,* Xiaowei Xu,1,4 Weifeng Gu,1 Wen Li,1 Chaoming Mao,1 Tingting Zheng,1 Liyang Dong1 1Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of China; 2Department of Respiratory Diseases, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, People’s Republic of China; 3Department of Ultrasound Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of China; 4Department of Laboratory Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liyang Dong; Tingting Zheng, Email liyangdong@ujs.edu.cn; tingtingzheng@ujs.edu.cnBackground: Nebulization of hypoxic human umbilical cord mesenchymal stem cell-derived extracellular vesicles (Hypo-EVs) can suppress airway inflammation and remodeling in a chronic asthmatic mouse; however, the exact mechanism remains unclear. Recently, airway epithelial barrier defects have been regarded as crucial therapeutic targets in asthma. The aim of this study was to investigate whether and how Hypo-EVs protect against the disruption of the airway epithelial barrier under asthmatic conditions.Methods: The therapeutic effects of Hypo-EVs on airway epithelial barrier defects were evaluated in ovalbumin (OVA)-induced asthmatic mice and in IL-4 and IL-13-induced HBE135-E6E7 cell models by detecting cell monolayer leakage and junctional protein expression. The protein levels in Hypo-EVs were determined by Western blotting, and a gene knockdown approach was used to investigate the biofactors in Hypo-EVs.Results: Nebulization of Hypo-EVs directly alleviated airway epithelial barrier defects in asthmatic mice, as evidenced by colocalization with bronchial epithelial cells, decreased albumin concentration, and increased ZO-1 and E-cadherin expression. In vitro, Hypo-EV treatment dramatically rescued the increase in airway cell permeability, and upregulated the ZO-1 and E-cadherin protein expressions. Based on WB analysis, we found that caveolin-1 (CAV-1) was strongly enriched in Hypo-EVs. The knockdown of CAV-1 protein levels in Hypo-EVs significantly impaired Hypo-EV-mediated barrier protection in vitro and in vivo. Moreover, CAV-1 knockdown significantly abolished the beneficial effects of Hypo-EVs on airway inflammation and remodeling in asthmatic mice. In addition, we showed that IL-4/IL-13-induced airway epithelial barrier defects were mainly related to activation of STAT6 phosphorylation (p-STAT6), and overexpression of CAV-1 or Hypo-EV treatment inhibited the levels of p-STAT6 in IL-4/IL-13-induced HBE135-E6E7 cells.Conclusion: Nebulization of Hypo-EVs can attenuate airway epithelial barrier defects in asthma by delivering CAV-1 to inhibit p-STAT6 expression and may be used to treat other barrier defect diseases.Keywords: nebulization, Hypo-EVs, asthma, airway epithelial barrier, caveolin-1

Bo Zhang,1,2 Minmin Guo,2 Ting Dong,2 Huajuan Yang,2 Qiujuan Zhang,2 Quanxin Yang,2 Xiaoqian Zhou,2 Cuiping Mao,2 Ming Zhang1 1Department of Medical Imaging, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China; 2Department of Medical Imaging, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of ChinaCorrespondence: Ming Zhang, Department of Medical Imaging, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China, Email zmmri@163.comPurpose: Chronic low back pain (cLBP) is a recurring and intractable disease that is often accompanied by emotional and cognitive disorders such as depression and anxiety. The nucleus accumbens (NAc) plays an important role in mediating emotional and cognitive processes and analgesia. This study investigated the resting-state functional connectivity (rsFC) and effective connectivity (EC) of NAc and its subregions in cLBP.Methods: Thirty-four cLBP patients and 34 age- and sex-matched healthy controls (HC) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Seed-based rsFC and Dynamic Causal Modelling (DCM) were used to examine the alteration of the rsFC and EC of the NAc.Results: Our results showed that the cLBP group had increased rsFC of the bilateral NAc-left superior frontal cortex (SFC), orbital frontal cortex (OFC), left angular gyrus, the left NAc-bilateral middle temporal gyrus, as well as decreased rsFC of left NAc-left supramarginal gyrus, right precentral gyrus, left cerebellum, brainstem (medulla oblongata), and right insula pathways compared with the HC; the results of the subregions were largely consistent with the whole NAc. In addition, the rsFC of the left NAc-left SFC was negatively correlated with Hamilton’s Depression Scale (HAMD) scores (r = − 0.402, p = 0.018), and the rsFC of left NAc-OFC was positively correlated with present pain intensity scores (r = 0.406, p = 0.017) in the cLBP group. DCM showed that the cLBP group showed significantly increased EC from the left cerebellum to the right NAc (p = 0.012) as compared with HC.Conclusion: Overall, our findings demonstrate aberrant rsFC and EC between NAc and regions that are associated with emotional regulation and cognitive processing in individuals with cLBP, underscoring the pivotal roles of emotion and cognition in cLBP.Keywords: low back pain, nucleus accumbens, resting-state functional connectivity, dynamic causal modelling

Shiying Li,1 Jin Tong,2 Hu Li,1 Chenxue Mao,3 Wei Shen,1 Yu Lei,1 Peng Hu1 1Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Respiratory Medicine, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Laboratory Diagnosis, ChongQing KingMed Center for Clinical Laboratory Co., Ltd, Chongqing, 400050, People’s Republic of ChinaCorrespondence: Peng Hu, Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74# Linjiang Road, Chongqing, 400010, People’s Republic of China, Email hp_cq@163.com; hupengcq@hospital.cqmu.edu.cnAbstract: We report a case of a 34-year-old lady with multiple joint pain. Autoimmune diseases were considered first with a positive result of anti-Ro antibody and her right knee joint cavity effusion. Later, bilateral interstitial changes in her lungs and mediastinal lymphadenopathy were found after chest CT scanning. Empirical quinolone therapy was given although pathological examinations of blood, sputum and bronchoalveolar lavage fluid (BALF) did not find anything. Finally, Legionella pneumophila was identified by target next-generation sequencing (tNGS) detection. This case highlighted the timely use of tNGS, a new tool with fast speed, high accuracy and effective cost, could help to identify atypical infection and start an early therapy.Keywords: case report, Legionella pneumophila, targeted next-generation sequencing, tNGS, precision treatment, levofloxacin

Congying Zheng,* Chengliang Mao,* Kai Tang, Hang Shu Department of Neurosurgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou City, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hang Shu, Department of Neurosurgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No. 106, Zhongshan Er Road, Guangzhou City, Guangdong Province, 510080, People’s Republic of China, Tel +86- 13902204543, Email zhengcongying@gdph.org.cnBackground: Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. VSIG4 has been identified to be associated with GBM. We aimed to determine the downstream regulatory mechanisms of VSIG4 in GBM.Methods: Differential expression of VSIG4 was analysed using GEPIA. The expression of VSIG4 was assessed by RT-qPCR and its downstream genes were screened by transcriptome sequencing. The expression of pyroptosis-related proteins and the JAK2/STAT3 pathway was measured by Western blotting. GBM cell viability, migration, and invasion were detected using CCK-8, scratch, and Transwell assays. The levels of pyroptosis-related factors were measured using ELISA. The effect of VSIG4 on GBM tumour growth in vivo was explored by constructing a xenograft tumour model.Results: VSIG4 expression was upregulated in GBM. Functionally, silencing of VSIG4 inhibited proliferation, invasion, and migration of U251 and LN229 cells, and promoted pyroptosis. Mechanically, transcriptome sequencing revealed that the JAK2/STAT3 pathway might be a downstream regulator of VSIG4. Further studies proved that silencing of VSIG4 enhanced the expression of p-JAK2 and p-STAT3, and the JAK2/STAT3 pathway inhibitor relieved the suppression of VSIG4 silencing on GBM cell viability, invasion, and migration. Furthermore, in vivo experiments further validated that knockdown of VSIG4 inhibited the growth of GBM tumors.Conclusion: In GBM, silencing VSIG4 promoted pyroptosis and inhibited tumor progression by regulating the JAK2/STAT3 signaling pathway.Keywords: glioblastoma, VSIG4, JAK2/STAT3 pathway, pyroptosis

Jian Peng,1– 3,* Yue Wang,3,* Zhaoyin Wu,3 Chengju Mao,3 Lu Li,1,2 Huijun Cao,4 Zhilang Qiu,3 Guo Guo,3,5 Guiyou Liang,4,5 Feng Shen1,2 1Department of Intensive Care Unit, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, People’s Republic of China; 2Guizhou Institute of Precision Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, People’s Republic of China; 3Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Cellular Immunotherapy Engineering Research Center of Guizhou Province, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 550025, People’s Republic of China; 4Department of Cardiac Surgery, the affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, People’s Republic of China; 5Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, 550025, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng Shen; Guiyou Liang, Email doctorshenfeng@163.com; guiyou515@163.comIntroduction: Acinetobacter baumannii has become a major difficulty in the treatment of bacteria-associated infection. The previously reported antimicrobial peptide Cec4 exhibited good and stable activity against A. baumannii in vitro, but the mechanisms and effects in vivo are elusive.Methods: The effects of Cec4 on bacterial membrane permeability, membrane potential and bacterial reactive oxygen species were measured. The cell membrane localization of antimicrobial peptides was studied by fluorescence labelling. The ability of bacteria to develop resistance to antimicrobial peptides was studied by continuous induction, and transcriptome difference was analysed. The in vivo toxicity of Cec4 against nematodes and mice was studied, and the in vivo therapeutic potential of Cec4 against A. baumannii was assessed.Results: Cec4 effectively cleared multidrug-resistant A. baumannii by altering bacterial cell membrane permeability, changing bacterial cell membrane polarity, and increasing bacterial intracellular reactive oxygen species. Cec4 affected the expression of the secretion system, outer membrane, and efflux pump genes of A. baumannii. In addition, the bacteria did not acquire stable drug-resistant ability. Cec4 at 1.024 mg/mL did not affect the proliferation of HeLa and HepG2 cells, and Cec4 at 45 mg/kg had little effect on the mortality of Caenorhabditis elegans, even the liver and kidney tissues of mouse. Most importantly, Cec4 could effectively improve the survival rates and reduce the bacterial load of various tissues in the mouse model of infection.Conclusion: In conclusion, Cec4 can damage the cell membrane of bacteria, and the bacteria is not easy to produce resistance to Cec4. Besides, Cec4 has good potential for the treatment of multidrug-resistant A. baumannii infections.Keywords: antimicrobial peptide, A. baumannii, sepsis, skin infection, drug safety

Science DMZs are specialized networks that enable large-scale distributed scientific research, providing efficient and guaranteed performance while transferring large amounts of data at high rates. The high-speed performance of a Science DMZ is made viable via data transfer nodes (DTNs), therefore they are a critical point of failure. DTNs are usually monitored with network intrusion detection systems (NIDS). However, NIDS do not consider system performance data, such as network I/O interrupts and context switches, which can also be useful in revealing anomalous system performance potentially arising due to external network based attacks or insider attacks. In this paper, we demonstrate how system performance metrics can be applied towards securing a DTN in a Science DMZ network. Specifically, we evaluate the effectiveness of system performance data in detecting TCP-SYN flood attacks on a DTN using DBSCAN (a density-based clustering algorithm) for anomaly detection. Our results demonstrate that system interrupts and context switches can be used to successfully detect TCP-SYN floods, suggesting that system performance data could be effective in detecting a variety of attacks not easily detected through network monitoring alone.

Yaru Zou,1,2 Wei Gao,3 Huizhen Jin,2 Chenmei Mao,2 Yi Zhang,1 Xiaoling Wang,1 Dong Mei,1 Libo Zhao1,4 1Department of Pharmacy, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of China; 2Department of Pharmacy, Children’s Hospital of Soochow University, Suzhou, Jiangsu, 215025, People’s Republic of China; 3Department of Pharmaceutical Sciences, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA; 4Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, People’s Republic of ChinaCorrespondence: Dong Mei; Libo Zhao, Email meidong11290926@126.com; libozhao2011@163.comBackground: Nanomedicines have significant advantages in enhancing the oral bioavailability of drugs, but a deeper understanding of the underlying mechanisms remains to be interpreted. Hence, the present study aims to explain the uptake and trafficking mechanism for 6-MP nanomedicines we previously constructed.Methods: 6-MP loaded poly(lactide-co-glycolide) (PLGA) nanomedicines (6-MPNs) were prepared by the multiple emulsion method. The transcytosis mechanism of 6-MPNs was investigated in Caco-2 cells, Caco-2 monolayers, follicle associated epithelium (FAE) monolayers and rats, including transmembrane pathway, intracellular trafficking, paracellular transport and the involvement of transporter.Results: Pharmacokinetics in rats showed that the area under the curve (AUC) of 6-MP in the 6-MPNs group (147.3 ± 42.89 μg/L·h) was significantly higher than that in the 6-MP suspensions (6-MPCs) group (70.31 ± 18.24 μg/L·h). The uptake of 6-MPNs in Caco-2 cells was time-, concentration- and energy-dependent. The endocytosis of intact 6-MPNs was mediated mainly through caveolae/lipid raft, caveolin and micropinocytosis. The intracellular trafficking of 6-MPNs was affected by endoplasmic reticulum (ER)-Golgi complexes, late endosome-lysosome and microtubules. The multidrug resistance associated protein 4 (MRP4) transporter-mediated transport of free 6-MP played a vital role on the transmembrane of 6-MPNs. The trafficking of 6-MPNs from the apical (AP) side to the basolateral (BL) side in Caco-2 monolayers was obviously improved. Besides, 6-MPNs affected the distribution and expression of zona occludens-1 (ZO-1). The transport of 6-MPNs in FAE monolayers was concentration- and energy-dependent, while reaching saturation over time. 6-MPNs improved the absorption of the intestinal Peyer’s patches (PPs) in rats.Conclusion: 6-MPNs improve the oral bioavailability through multiple pathways, including active transport, paracellular transport, lymphatic delivery and MRP4 transporter. The findings of current study may shed light on the cellular uptake and transcellular trafficking mechanism of oral nanomedicines.Keywords: nanomedicines, oral bioavailability, cellular uptake, transport mechanism

Dongjiu Li,1,* Jiayin You,2,* Chengyu Mao,1,* En Zhou,1,* Zhihua Han,1 Junfeng Zhang,1 Tiantian Zhang,1 Changqian Wang1 1Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China; 2Department of Emergency, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tiantian Zhang; Changqian Wang, Email ZhangTT2022Dr@163.com; wangcqdr17@163.comObjective: Cardiomyocyte apoptosis critically contributes to ischemia reperfusion injury (IRI), which lacks effective therapeutic strategies. Circular RNAs (circRNAs) serve as novel diagnostic and therapeutic targets in various cardiovascular diseases. CircRNA Fbxl5 is one of the abundantly expressed circRNAs in the heart and its role in myocardial IRI remains elusive.Materials and Methods: Wild-type (WT) mice and neonatal mice ventricular myocytes (NMVMs) were used and subjected to myocardial IRI and anoxia reoxygenation (AR), respectively. Molecular and histological analyses and echocardiography were used to determine the extent of apoptosis, infarct size, and cardiac function.Results: We found that circRNA Fbxl5 was significantly upregulated in the myocardium, as well as in NMVMs subjected to AR. Knockdown of circRNA Fbxl5 ameliorated cardiomyocyte apoptosis, thereby decreasing infarct size and preserving cardiac function. Additionally, in vitro knockdown of circRNA Fbxl5 in NMVMs subjected to AR recapitulated the in vivo findings. Mechanistically, we identified that circRNA Fbxl5 directly sponged and suppressed the endogenous microRNA-146a (miR-146a), thereby weakening its inhibitory effect on MED1, which could further promote the apoptosis of cardiomyocytes.Conclusion: Our findings revealed a novel and critical role for circRNA Fbxl5 in regulating cardiomyocyte apoptosis, and added additional insight into circRNAs mediated during myocardial IRI. The underlying miR-146a-MED1 signaling serves as an important cascade in regulating the apoptosis of cardiomyocytes.Keywords: myocardial ischemia reperfusion injury, circular RNA, microRNA-146a, cardiomyocyte apoptosis

Ajay S Kasi,1 Hong Li,2 Kelli-Lee Harford,1 Humphrey V Lam,3 Chad Mao,4 April M Landry,5 Sarah G Mitchell,6 Matthew S Clifton,7 Roberta M Leu1 1Department of Pediatrics, Division of Pediatric Pulmonology and Sleep Medicine, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 2Department of Human Genetics, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 3Division of Pediatric Anesthesiology, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 4Department of Pediatrics, Division of Pediatric Cardiology, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 5Division of Pediatric Otorhinolaryngology, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 6Department of Pediatrics, Division of Pediatric Hematology and Oncology, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA, USA; 7Division of Pediatric Surgery, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA, USACorrespondence: Ajay S Kasi, Department of Pediatrics, Division of Pediatric Pulmonology and Sleep Medicine, Emory University, Children’s Healthcare of Atlanta, 1400 Tullie Road NE, Atlanta, GA, 30329, USA, Tel +1 404 785 5437, Fax +1 404 785 9087, Email ajay.kasi@emory.eduAbstract: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder affecting respiratory control and autonomic nervous system function caused by variants in the paired-like homeobox 2B (PHOX2B) gene. Although most patients are diagnosed in the newborn period, an increasing number of patients are presenting later in childhood, adolescence, and adulthood. Despite hypoxemia and hypercapnia, patients do not manifest clinical features of respiratory distress during sleep and wakefulness. CCHS is a lifelong disorder. Patients require assisted ventilation throughout their life delivered by positive pressure ventilation via tracheostomy, noninvasive positive pressure ventilation, and/or diaphragm pacing. At different ages, patients may prefer to change their modality of assisted ventilation. This requires an individualized and coordinated multidisciplinary approach. Additional clinical features of CCHS that may present at different ages and require periodic evaluations or interventions include Hirschsprung’s disease, gastrointestinal dysmotility, neural crest tumors, cardiac arrhythmias, and neurodevelopmental delays. Despite an established PHOX2B genotype and phenotype correlation, patients have variable and heterogeneous clinical manifestations requiring the formulation of an individualized plan of care based on collaboration between the pulmonologist, otolaryngologist, cardiologist, anesthesiologist, gastroenterologist, sleep medicine physician, geneticist, surgeon, oncologist, and respiratory therapist. A comprehensive multidisciplinary approach may optimize care and improve patient outcomes. With advances in CCHS management strategies, there is prolongation of survival necessitating high-quality multidisciplinary care for adults with CCHS.Keywords: congenital central hypoventilation syndrome, multidisciplinary care, diaphragm pacing, tracheostomy, noninvasive ventilation, CCHS

Changlin Mao,1 Wei Dong,2 Jiaju Lu,3 Zhao Zhang,4 Hongliang Wu,5 Armin Ghavamian,1 Dongbin Bi,3 Pei Gao,1 Zhao Liu,5 Sentai Ding1,3 1Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People’s Republic of China; 2Department of Urology, Shandong Provincial Hospital West Branch, Jinan, Shandong, 250000, People’s Republic of China; 3Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 4Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China; 5Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of ChinaCorrespondence: Zhao LiuDepartment of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of ChinaEmail zhao.liu@sdu.edu.cnSentai DingDepartment of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of ChinaEmail dingsentai@126.comObjective: Prostate cancer (PCa) ranks as the second common malignancy in males worldwide. Although conspicuous progressions in diagnosis and treatment have been achieved in the past decades, the prognosis expectation of PCa remains unsatisfied yet. To improve the prognosis prediction of PCa, more specific biomarkers are needed. In this retrospective research, we focused on βKlotho and ETS-like transcription factor 4 (ELK4), aiming to identify potential prognostic biomarkers for PCa.Methods: Western blotting was used to determine the expression of βKlotho, ELK4, and PARP in C4-2B and PC3 PCa cell lines. CCK-8 assay and colony formation assay were applied to examine the roles of βKlotho and ELK4 in the proliferation of PCa cells. The expression of βKlotho and ELK4 in PCa tissue samples was determined by immunochemistry. Pearson’s χ 2 test and Fisher’s exact test were performed to investigate the associations among βKlotho, ELK4 and various clinical factors. Kaplan–Meier curves and Cox regression model were established to reveal the correlation among βKlotho, ELK4 expression and the prognosis of patients.Results: βKlotho overexpression down-regulated the ELK4 expression, induced apoptosis and inhibited cell proliferation in both C4-2B and PC3 cells, which were reversed by ELK4 overexpression. βKlotho expression in PCa tissue samples had negative correlation with the ELK4 expression, and higher βKlotho expression was associated with lower Gleason score, absent distant metastasis and lower prostate-specific antigen (PSA) level. On the contrast, higher ELK4 expression was correlated with distant metastasis and higher PSA level. Moreover, βKlotho and ELK4 were both recognized as independent factors for the prognosis of patients with PCa.Conclusion: βKlotho inhibits proliferation of prostate cancer cells by downregulating ELK4. Both βKlotho and ELK4 expressions correlate with the prognosis of PCa, which may serve as potential biomarkers for follow-up surveillance and prognostic assessments.Keywords: FGFR, biomarker, prostate cancer, survival

Mengjie Wu,1 Yu Hu,1 Anjing Ren,2 Xiaojing Peng,1 Qian Ma,1 Cuilian Mao,1 Jing Hang,1 Ao Li1 1Department of Ultrasound, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, People’s Republic of China; 2Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, People’s Republic of ChinaCorrespondence: Ao LiThe First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, People’s Republic of ChinaTel +86-15205159458Email cqh2liao@163.comPurpose: The objective of this study was to establish a predictive nomogram based on ultrasound (US) and clinical features for patients with soft tissue tumors (STTs).Patients and Methods: A total of 260 patients with STTs were enrolled in this retrospective study and were divided into a training cohort (n=200, including 110 malignant and 90 benign masses) and a validation cohort (n=60, including 30 malignant and 30 benign masses). Multivariate analysis was performed by binary logistic regression analysis to determine the significant factors predictive of malignancy. A simple nomogram was established based on these independent risk factors including US and clinical features. The predictive accuracy and discriminative ability of the nomogram were measured by the calibration curve and the concordance index (C-index).Results: The nomogram, comprising US features (maximum diameter, margin and vascular density) and clinical features (sex, age, and duration of disease), showed a favorable performance for predicting malignancy, with a sensitivity of 88.2% and a specificity of 78.7%. The calibration curve for malignancy probability in the training cohort showed good agreement between the nomogram predictions and actual observations. The C-indexes of the training cohort and validation cohort for predicting malignancy were 0.89 (95% CI: 0.85– 0.94) and 0.83 (95% CI: 0.73– 0.94), respectively.Conclusion: The nomogram based on US and clinical features could be a simple, intuitive and reliable tool to individually predict malignancy in patients with STTs.Keywords: soft tissue tumors, ultrasonography, malignancy, predictive model, nomogram

Dongjiu Li,1,* Chengyu Mao,1,* En Zhou,1,* Jiayin You,2,* Erhe Gao,3 Zhihua Han,1 Yuqi Fan,1 Qing He,1 Changqian Wang1 1Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 2Department of Emergency, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 3Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA*These authors contributed equally to this workCorrespondence: Changqian Wang Email wangcqdr17@163.comObjective: Post myocardial infarction (MI) fibrosis has been identified as an important factor in the progression of heart failure. Previous studies have revealed that microRNA-21 (miR-21) plays an important role in the pathogenesis of fibrosis. The purpose of this study was to explore the role of miR-21 in post-MI cardiac fibrosis.Material and Methods: MI was established in wild-type (WT) and miR-21 knockout (KO) mice. Primary mice cardiac fibroblasts (CFs) were isolated from WT and miR-21 KO mice and were treated with angiotensin II (Ang II) or Sprouty1 (Spry1) siRNA. Histological analysis and echocardiography were used to determine the extent of fibrosis and cardiac function.Results: Compared with WT mice, miR-21 KO mice displayed smaller fibrotic areas and decreased expression of fibrotic markers and inflammatory cytokines. In parallel, Ang II-induced myofibroblasts transformation was partially inhibited upon miR-21 KO in primary CFs. Mechanistically, we found that the expression of Spry1, a previously reported target of miR-21, was markedly increased in miR-21 KO mice post MI, further inhibiting ERK1/2 activation. In vitro studies showed that Ang II activated ERK1/2/TGF-β/Smad2/3 pathway. Phosphorylated Smad2/3 further enhanced the expression of α-SMA and FAP and may promote the maturation of miR-21, thereby downregulating Spry1. Additionally, these effects of miR-21 KO on fibrosis were reversed by siRNA-mediated knockdown of Spry1.Conclusion: Our findings suggest that miR-21 promotes post-MI fibrosis by targeting Spry1. Furthermore, it mediates a positive feedback on Ang II, thereby inducing the ERK/TGF-β/Smad pathway. Therefore, targeting the miR-21–Spry1 axis may be a promising therapeutic option for ameliorating post-MI cardiac fibrosis.Keywords: cardiac fibrosis, myocardial infarction, microRNA-21, Sprouty1, ERK/TGF-β/Smad signaling pathway

He Huang,1,* Xinxin Yang,2,* Jing Sun,2,* Ce Zhu,2 Xiang Wang,2 Yunpeng Zeng,2 Jingxuan Xu,2 Chenchen Mao,2 Xian Shen2,3 1Department of General Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Gastrointestinal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chenchen Mao; Xian ShenDepartment of Gastrointestinal Surgery, The Second Affiliated Hospital, Wenzhou Medical University, No. 109 West College Road, Wenzhou, Zhejiang Province, People’s Republic of ChinaTel +86 577 8800 2709Email 578117567@qq.com; shenxian5166@gmain.comPurpose: Although peritoneal metastasis (PM) is associated with poor prognosis in gastric cancer (GC) patients, it is difficult to discriminate preoperatively. Our previous study has demonstrated visceral fat area (VFA) is a better obesity index than body mass index (BMI) in predicting abdominal metastasis. This study aimed to further explore the relationship between obesity and PM.Patients and Methods: VFA was retrieved for 859 consecutive patients undergoing radical gastrectomy between January 1, 2009, and December 31, 2013. A receiver operating characteristic curve analysis was used to determine the BMI-specific cutoff values for VFA. Univariate and multivariate analyses evaluating the risk factors for PM at different BMI levels were performed.Results: The optimal cutoff values for VFA were 67.28, 88.03, and 175.32 cm2 for low, normal, and high BMI patients, respectively, and 18 (15.52%), 220 (40.15%), and 61 (31.28%) patients were classified as having high VFA in each group. Univariate logistic regression revealed that the association between high VFA and PM was not dependent on BMI (odds ratio [OR]=9.048, P=0.007 for low BMI, OR=3.827, P< 0.001 for normal BMI, and OR=2.460, P=0.049 for high BMI). In multivariate logistic regression analysis, high VFA (OR=3.816, P< 0.001) and vascular invasion (OR=1.951, P=0.039) were independent risk factors for PM only in the normal BMI group.Conclusion: VFA only effectively predicted PM for GC patients with normal BMI, rather than those with low and high BMI. More attentions should be paid to those GC patients with high VFA and normal BMI.Keywords: gastric cancer, peritoneal metastasis, obesity, visceral fat area, body mass index

We used baseline data from a study of Black MSM/MSMW in 6 US cities to examine the association of female partnership types with disease prevalence and sexual behaviors among the 555 MSMW participants. MSMW reported more than three times as many total and unprotected sex acts with each primary as they did with each non-primary female partner. We compared MSMW whose recent female partners were: (1) all primary ("PF only", n = 156), (2) both primary and non-primary ("PF & NPF", n = 186), and (3) all non-primary ("NPF only", n = 213). HIV/STI prevalence did not differ significantly across groups but sexual behaviors did. The PF only group had the fewest male partners and was the most likely to have only primary male partners; the PF & NPF group was the most likely to have transgender partners. PF & NPF men reported the most sex acts (total and unprotected) with females; NPF only men reported the fewest. Implications for HIV risk and prevention are discussed.

Xiaodong Chen,1,* Yunpeng Zeng,1,* Yunshi Huang,2 Jingxuan Xu,1 Weiyang Meng,3 Xiang Wang,1 Ce Zhu,2 Guanbao Zhu,2 Chenchen Mao,1 Xian Shen1,21Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Gastrointestinal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Emergency Medical, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Chenchen Mao; Xian ShenDepartment of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 West College Road, Wenzhou, Zhejiang Province, People’s Republic of ChinaTel +86 05 778 800 2709Email 578117567@qq.com; shenxian5166@gmail.com*These authors contributed equally to this workBackground: Cachexia affects nearly 50–80% of cancer patients, and most studies have only focused on elderly patients. We investigated preoperative cachexia in gastric cancer (GC) patients by age group and comprehensively analyzed the impact of preoperative cachexia on the prognosis of GC patients in all age groups.Methods: In total, 575 patients were prospectively analyzed. The effect of preoperative cachexia on overall survival (OS) in all the patients and in patients with different age groups were investigated using log-rank test and Cox proportional hazards regression, respectively.Results: In total, 35.8% (206 of 575) individuals were diagnosed with cachexia. The median survival of cachexia patients (29.2 months) was shorter than that of non-cachexia patients (35.7 months). Cachexia (HR =1.976, P

Xiaodong Chen,1,* Weisheng Chen,2,* Yunshi Huang,2 Jingxuan Xu,1 Yunpeng Zeng,1 Mingming Shi,2 Libin Xu,2 Weiteng Zhang,2 Guanbao Zhu,2 Chenchen Mao,1 Xian Shen1,21Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Gastrointestinal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this work Background: Peritoneal metastases of gastric cancer are usually detected using imaging, However, the results of imaging modalities are not always reliable; therefore, the prediction of prognosis based on these findings is therefore inaccurate. As visceral obesity has been identified as a potential risk factor for cancer, the present study aimed to evaluate the predictive value of visceral fat area (VFA), a representative marker of visceral obesity, for peritoneal metastasis in patients with gastric cancer and to construct a reliable preoperative prediction system for peritoneal metastasis.Patients and methods: We enrolled 859 patients with gastric cancer. The VFA and other objective clinical tumor characteristics were evaluated using receiver operating characteristic (ROC) curves. Independent predictors of peritoneal metastasis were determined using logistic regression analysis; a prediction system was also evaluated using ROC curves.Results: The ROC curves indicated a VFA cutoff value of 91.00 cm2 as predictive of peritoneal metastasis. On logistic regression, visceral obesity (VFA ≥91.00 cm2) was identified as an independent predictor of peritoneal metastasis, with an area under the ROC curve of 0.659; the platelet-to-lymphocyte ratio (PLR), invasion depth, and vascular invasion were also identified as independent predictors. On integrating these predictors into a single prediction system, peritoneal metastases were more reliably predicted (area under the ROC curve=0.779).Conclusions: Visceral obesity, as defined by the VFA, effectively predicted peritoneal metastases in our cohort. Our scoring system may be a reliable instrument for identifying patients with peritoneal metastasis.Keywords: gastric cancer, peritoneal metastasis, visceral fat area, risk-scoring system

Liang Zhang,1 Mengxia Li,1 Bo Deng,2 Nan Dai,1 Yan Feng,1 Jinlu Shan,1 Yuxin Yang,1 Chengyi Mao,3 Ping Huang,1 Chengxiong Xu,1 Dong Wang11Cancer Center of Daping Hospital, Third Military Medical University, Chongqing 400042, People’s Republic of China; 2Thoracic Surgery Department of Daping Hospital, Third Military Medical University, Chongqing 400042, People’s Republic of China; 3Pathology Department of Daping Hospital, Third Military Medical University, Chongqing 400042, People’s Republic of ChinaBackground: Postoperative recurrence is the main cause of a poor prognosis in early-stage lung adenocarcinoma (LUAD). Factors that can predict recurrence risk are critically needed.Materials and methods: In this study, we designed a screening procedure based on gene profile data and performed validation using TCGA and Daping hospital’s cohorts. Differentially expressed genes (DEGs) between patients with recurrence-free survival (RFS) 3 years were identified, overlapping genes among these DEGs were selected as candidate biomarkers. A Cox proportional hazards model, immunohistochemistry and Kaplan-Meier survival analysis were performed to validate these biomarkers in two distinct validation sets.Results: SFTPB, SFTPD, SFTA1P, HLA-DQB1, ITGB8, ANLN, and LRRN1 were overlapped both in TCGA and Daping discovery sets. The Cox proportional hazards model analysis of the TCGA validation set showed that HLA-DQB1 was an independent prognostic factor for RFS (HR=0.686, 95% CI, 0.542–0.868). Immunohistochemistry and Kaplan-Meier analysis in Daping validation sets confirmed HLA-DQB1 expression on tumor cells (not interstitial cells) to be an effective predictor of postoperative recurrence. Further examination revealed that the level of HLA-DQB1 expression on tumor cells was positively correlated with CD4- and CD8-positive lymphocyte infiltration into the tumor.Conclusion: All results indicate that high expression of HLA-DQB1 on tumor cells is a good prognostic marker in early-stage LUAD, and the mechanism may be related to anti-tumor immune activity.Keywords: HLA-DQB1, lung adenocarcinoma, tumor recurrence, prognostic factor

Shuai Dong,1,2 Hongxi Shi,1 Xintong Zhang,1,2 Xi Chen,1 Donghui Cao,2 Chuanbin Mao,3,4 Xiang Gao,1 Li Wang1 1Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, 2First Hospital of Jilin University, Changchun, Jilin, 3School of Materials Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, China; 4Department of Chemistry and Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, Norman, OK, USA Background: Candida albicans is the most prevalent fungal pathogen of the human microbiota, causing infections ranging from superficial infections of the skin to life-threatening systemic infections. Due to the increasing occurrence of antibiotic-resistant C. albicans strains, new approaches to control this pathogen are needed. Photodynamic inactivation is an emerging alternative to treat infections based on the interactions between visible light and photosensitisers, in which pheophorbide a (PPA) is a chlorophyll-based photosensitizer that could induce cell death after light irradiation. Due to PPA’s phototoxicity and low efficiency, the main challenge is to implement photosensitizer cell targeting and attacking. Methods: In this study, PPA was conjugated with JM-phage by EDC/NHS crosslinking. UV-Vis spectra was used to determine the optimum conjugation percentages of PPA and JM-phage complex for photodynamic inactivation. After photodynamic inactivation, the efficacy of PPA-JM-phage was assessed by performing in vitro experiments, such as MTS assay, scanning electron microscopy, measurement of dysfunctional mitochondria, ROS accumulation, S cell arrest and apoptotic pathway.Results: A single-chain variable-fragment phage (JM) with high affinity to MP65 was screened from human single-fold single-chain variable-fragment libraries and designed as a binding target for C. albicans cells. Subsequently, PPa was integrated into JM phage to generate a combined nanoscale material, which was called PPA-JM-phage. After photodynamic inactivation, the growth of C. albicans was inhibited by PPA-JM-phage and apoptosis was observed. Scanning electron microscopy analysis revealed shrinking and rupturing of C. albicans. We also found that depolarization of mitochondrial membrane potential was decreased and intracellular reactive oxygen species levels were elevated significantly in C. albicans inhibited by PPA-JM-phage. Additionally, PPA-JM-phage also lead to S-phase arrest, and metacaspase activation resulting from mitochondrial dysfunction was also found to be involved in C. albicans apoptosis. Conclusion: PPa-JM-phage may induce C. albicans apoptosis through a caspase-dependent pathway and the results herein shed light on the potential application of phtototherapeutic nanostructures in fungal inactivation. Keywords: PPA, phage, photodynamic therapy, apoptosis, metacaspase

OBJECTIVE: We aimed to explore the effectiveness of the modified tubularized incised plate urethroplasty (Snodgrass Technique) in hypospadias surgery. PATIENTS AND METHODS: A study was conducted on 50 pediatric patients with hypospadias treated in our hospital from May 2020 to May 2023. The patients were divided into two groups based on the condition of their urethral plate; 22 patients were included in the study group and 28 patients were included in the control group. The control group underwent the traditional Snodgrass technique, while the study group received the modified Snodgrass technique. The two groups were compared in terms of treatment efficacy, preoperative and postoperative 6-month Hypospadias Objective Scoring Evaluation (HOSE) scores, surgical data, and postoperative complications. RESULTS: The operation time for the study group was longer than that of the control group, and the intraoperative blood loss was less, but the differences were not statistically significant (p > 0.05). The success rate of surgery in the study group was 95.45% (21/22), compared to 71.43% (20/28) in the control group, showing a statistically significant difference (p < 0.05). The maximum urinary flow rate at 3 and 6 months postoperatively was significantly higher in the study group than in the control group (p < 0.05). The time to maximum flow (TQmax) and postvoid residual (PVR) at 3 and 6 months postoperatively were significantly lower in the study group (p < 0.05). A total of 3 patients in the cohort developed urethral fistulas, all between 0.10 cm x 0.10 cm and 0.15 cm x 0.15 cm in size. By instructing the patients to apply pressure to the fistula during urination, all fistulas closed between 3 and 6 months postoperatively. The incidence of postoperative complications was 4.55% in the study group and 28.57% in the control group, a difference that was statistically significant (p < 0.05). CONCLUSIONS: The modified Snodgrass technique shows significant therapeutic effectiveness in hypospadias surgery, substantially increasing the success rate and reducing postoperative complications in pediatric patients, making it suitable for widespread application. [ABSTRACT FROM AUTHOR]