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Jinlu Huang,1,* Jiugeng Chen,2,* Le Ma,3,* Xieyi Zhu,4 Lili Wan,1 Xinyan Li,4 Cheng Guo1 1Department of Pharmacy, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai Mental Health Center, Shanghai, People’s Republic of China; 4College of Pharmacy, Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinyan Li; Cheng Guo, Email lixy@sjtu.edu.cn; guopharm@126.comBackground: Ionomics is used to study levels of ionome in different states of organisms and their correlations. Bone cancer pain (BCP) severely reduces quality of life of patients or their lifespan. However, the relationship between BCP and ionome remains unclear.Methods: The BCP rat model was constructed through inoculation of Walker 256 cells into the left tibia. Von Frey test, whole-cell patch-clamp recording and inductively coupled plasma mass spectrometry (ICP-MS) technologies were conducted for measuring tactile hypersensitivity, the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) of neurons of spinal slices, and ionome of spinal cord samples, respectively. Principal component analysis (PCA) was used to explore ionomic patterns of the spinal cord.Results: The BCP rat model was successfully constructed through implantation of Walker 256 cells into the left tibia. The frequency and amplitude of mEPSCs of neurons in the spinal cord slices from the BCP model rats were notably greater than those in the sham control. In terms of ionomics, the spinal cord levels of two macroelements (Ca and S), four microelements (Fe, Mn, Li and Sr) and the toxic element Ti in the BCP group of rats were significantly increased by inoculation of Walker 256 cancer cells, compared to the sham control. In addition, the correlation patterns between the elements were greatly changed between the sham control and BCP groups. PCA showed that inoculation of Walker 256 cells into the tibia altered the overall ionomic profiles of the spinal cord. There was a significant separation trend between the two groups.Conclusion: Taken together, inoculation of Walker 256 cells into the left tibia contributes to BCP, which could be closely correlated by some elements. The findings provided novel information on the relationship between the ionome and BCP.Keywords: bone cancer pain, spinal cord, micronutrient, ionomic profile

Xiaojing Liu,&ast; You Song,&ast; Limin Wan, Rong Du Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rong Du, Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email dudurong2003@126.comBackground: This study aims to investigate the knowledge, attitudes, and practices (KAP) among patients with systemic lupus erythematosus (SLE) toward disease management and biologic therapy.Methods: This cross-sectional study was conducted between April 20, 2023, and May 5, 2023, among patients with SLE at Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology. A self-designed questionnaire was developed to collect demographic information of SLE patients and assess their KAP.Results: A total of 463 SLE patients participated. The mean scores for knowledge, attitudes, and practices were 8.52 ± 2.36 (possible range: 0– 11), 39.40 ± 3.38 (possible range: 11– 55), and 27.10 ± 6.29 (possible range: 8– 40), respectively. The path analysis demonstrated a significant and positive association between knowledge and attitudes, as indicated by a path coefficient of 0.455 (p < 0.001), and a significant and positive relationship between knowledge and practices, with a path coefficient of 0.709 (p < 0.001).Conclusion: Patients with SLE exhibited insufficient knowledge, negative attitudes, and poor practices.Keywords: knowledge, attitudes, practices, systemic lupus erythematosus, biologic therapy, cross-sectional study

Bijia Song, Xiuliang Li, Jiguang Yang, Wenjing Li, Lei Wan Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of ChinaCorrespondence: Lei Wan, Email wanleimz@sina.comIntroduction: Seeking effective multimodal analgesia and anesthetic regimen is the basis for the success of ERAS. Opioid-free anesthesia (OFA) is a multimodal anesthesia associating hypnotics, N-methyl-D-aspartate (NMDA) antagonists, local anesthetics, anti-inflammatory drugs and α-2 agonists. Although previous studies have confirmed that OFA is safe and feasible for VATS surgery, there is great heterogeneity in how to select and combine anti-harm drugs to replace opioids. We hypothesized that the reduced opioid use during and after surgery allowed by OFA compared with standard of care will be associated with a reduction of postoperative opioid-related adverse events and an improvement in the quality of rehabilitation of patients after partial VATS lung resection.Methods/Analysis: The TEDOFA Study is a prospective double-blind, randomized, controlled clinical trial with a concealed allocation of patients scheduled to undergo elective partial VATS pneumonectomy 1:1 to receive either a standard anesthesia protocol or an OFA. A total of 146 patients were recruited in the study. Primary endpoint was the 15-item recovery quality scale (QoR-15) at 24 hours after surgery.Ethics and Dissemination: This trial has been approved by the Institutional Review Board of Beijing Friendship Hospital of China Capital University. The TEDOFA trial study protocol was approved on 27 February 2023. The trial started recruiting patients after registered on the Chinese Clinical Trial Registry.Trial Registration Number: ChiCTR2300069210; Pre-results.Keywords: opioid-free anesthesia, thoracoscopic surgery, postoperative recovery, chronic pain

Yuedi Hu,1,2 Jian Liu,1,3,4 Ling Xin,3,4 Lei Wan,1,3,4 Yajun Qi,1 Yang Li,1 Yiming Chen1 1Department of Rheumatology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, People’s Republic of China; 2College of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, People’s Republic of China; 3Institute of Rheumatology, Anhui University of Chinese Medicine, Hefei, Anhui, People’s Republic of China; 4Department of Internal Medicine Application Foundation Research and Development, Anhui Province—Key Laboratory of Modern Chinese Medicine, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Jian Liu, Department of Rheumatology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, People’s Republic of China, Tel +86 13955109537, Email liujianahzy@126.comPurpose: The therapeutic effects of Huangqin Qingre Chubi (HQC) in rheumatoid arthritis (RA) have been documented. However, there is a lack of real-world clinical evidence supporting its efficacy.Methods: Patients diagnosed with RA were recruited from the First Affiliated Hospital of the Anhui University of Chinese Medicine. Patient information was obtained from the hospital’s database. Propensity score matching (PSM), Kaplan–Meier curve, and Cox proportional hazards model were used to control confounding factors and analyze the factors influencing readmission. Association rule analysis and random walk evaluation models were used to evaluate the correlations among HQC treatment, inflammation indicators, and self-perception of patients (SPP) scale.Results: After PSM, 3423 patients were enrolled, with 1142 in the HQC group and 2281 in the non-HQC group. The readmission risk of the HQC group was significantly lower than that of the non-HQC group. Combined univariate and multivariate analysis results revealed that risk factors for readmission were age > 60 years, female sex, hypertension, chronic gastritis, and elevated levels of laboratory indices, including anticyclic citrullinated peptide and complement component 3 (C3) and C4. HQC, disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and glucocorticoid therapy were protective factors for readmission. HQC treatment was closely associated with improvements in many factors, including erythrocyte sedimentation rate, C-reactive protein, C3, rheumatoid factor levels, visual analog scale, depression self-assessment scale, and patient-reported activity index scores with RA.Conclusion: HQC treatment can reduce the risk of readmission and significantly improve immune inflammatory indicators and SPP in patients with RA, with no risk of hepatorenal toxicity.Keywords: Huangqin Qingre Chubi capsule, traditional Chinese medicine, rheumatoid arthritis, readmission

Liujiazi Shao,1 Yang Liu,2 Junqiang Hao,1 Jiayi Li,1 Hongyu Wang,1 Fu-Shan Xue,1 Bijia Song,1 Lei Wan1 1Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China; 2Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of ChinaCorrespondence: Bijia Song, Email songbijia@163.comObjective: Our study aimed to demonstrate that the combination of sevoflurane inhalation with continuous intravenous anesthesia can effectively reduce the dosage of muscle relaxants, shorten extubation time under anesthesia while meeting the requirements of laparoscopic deep neuromuscular block (dNMB) in obese patients. Additionally, we sought to assess the potential reduction in postoperative residual muscle relaxants.Methods: Fifty-nine patients were randomly assigned. Anesthesia-related variables, such as anesthetics dosages, muscle relaxant effective time, clinical muscle relaxant time, muscle relaxant in vivo action time, muscle relaxant recovery time, body movement times, and extubation duration were recorded. Surgery-related variables (the Leiden-Surgical Rating Scale (L-SRS), duration of the procedure) were recorded. Pain was measured using the visual analog scale (VAS) score before leaving the PACU. The duration of the PACU stay and patients’ satisfaction levels in the PACU were also recorded.Results: Patients who inhaled sevoflurane during the operation required a lower dosage of muscle relaxant to achieve the same deep neuromuscular block (dNMB) effect. The time from stopping the rocuronium pump to T1 recovery of 90% was shorter, and the time for T1 to recover from 25% to 75% was faster among patients who inhaled sevoflurane during the operation. Furthermore, the sevoflurane combined with continuous intravenous anesthesia group exhibited a shorter extubation time for obese patients undergoing laparoscopic bariatric surgery, along with a reduced risk of experiencing hypoxemia and a shorter observation time in the PACU.Conclusion: Inhaling sevoflurane combined with continuous intravenous anesthesia during the operation effectively reduces the dosage of muscle relaxant required to achieve the same deep neuromuscular block (dNMB) effect. Additionally, this approach significantly shortens the extubation time for obese patients undergoing laparoscopic bariatric surgery and reduces the risk of experiencing hypoxemia, along with reducing the observation time in the PACU.Keywords: obese, laparoscopy bariatric surgery, rocuronium, sevoflurane, deep neuromuscular block

Shasha Zhang,1,&ast; Jinchun Li,2,&ast; Li Wan,1 Jing Yu,2 Sumei Chen,2 Zhengjiang Jin3 1Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People’s Republic of China; 2Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People’s Republic of China; 3Department of Clinical Laboratory, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengjiang Jin, Department of Clinical Laboratory, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People’s Republic of China, Email king199735@126.comPurpose: To determine the clinical features, laboratory findings, antibiotic treatment, and outcomes of neonatal listeriosis in a specialized tertiary hospital in Wuhan, China.Patients and Methods: We retrospectively analyzed the medical records of patients diagnosed with neonatal listeriosis at Maternal and Child Health Hospital of Hubei Province from January 2015 to December 2022. Listeriosis was indicated by positive culture for Listeria monocytogenes (LM).Results: A total of 11 cases were included in our study. The incidence rate of neonatal listeriosis was 2.06 per 100,000 live births. Seventy-three percent of the cases were born prematurely, caused early onset sepsis. Respiratory distress (100%) was the most common and earliest symptom, followed by fever (64%) and rashes (27%). The levels of C-reactive protein (CRP) and procalcitonin (PCT) were elevated in 100% of the cases. The median time-to-positivity (TTP) of the culture was 15 hours (range 9– 28hours). Of the 11 neonates, 6 were cured, 2 showed improvement, and 3 died, with a mortality rate of 27%. There were statistically significant differences in Apgar score at 5 minutes (p=0.037) and CRP (p=0.025) between the survival group and fatality group. Ampicillin was sensitive to LM isolates and effective for therapy if initiated early.Conclusion: Neonatal listeriosis is a rare but severe infection with a high mortality rate. Early identification and appropriate use of effective antibiotics are particularly critical for achieving positive outcomes. Apgar score and CRP are relevant indices for prognosis. Ampicillin is the first-line therapy and can be empirically administered to neonates suspected of having listeriosis.Keywords: neonatal listeriosis, Listeria monocytogenes, clinical features, antibiotic treatment, Apgar score, C-reactive protein

Hui Zhao,1 Yan Li,1,2 Luyuan Wan,1,3 Ke Li1 1Faculty of Education, Henan Normal University, Xinxiang, People’s Republic of China; 2Sanzhang Primary School, Nanyang, People’s Republic of China; 3Central School of Huolong Town, Xuchang, People’s Republic of ChinaCorrespondence: Yan Li; Hui Zhao, Faculty of Education, Henan Normal University, Jianshe Road, Muye District, Xinxiang, Henan Province, People’s Republic of China, Email lee_yaner@163.com; zhaohui@htu.edu.cnPurpose: With a growth mindset, individuals focus on the process of growth, actively seek challenges, recognise and accept failures, and apply more effort and monitor themselves to overcome difficulties. Doing so translates into excellent academic performance. However, it has not yet been fully clarified how growth mindset affects academic delay of gratification (ADG) and the mechanisms underlying their interactions. In this study, grit and academic self-efficacy were tested as mediating mechanisms between growth mindset and the ADG using a serial mediation effect model based on self-determination theory (SDT).Methods: A cross-sectional design was conducted with 759 Chinese junior high school students using the following tools: Growth Mindset Scale, Short Grit Scale, Academic Self-efficacy Scale, and Academic Delay of Gratification Scale. Hypotheses were tested using structural equation modeling.Results: The results showed that: (1) by gender and grade control, growth mindset indicated a positive significance in the prediction of ADG; (2) grit and academic self-efficacy played a mediating role in the influence of a growth mindset on the ADG. Grit and academic self-efficacy also have a serial mediation effect between growth mindset and ADG.Conclusion: The results showed that a growth mindset does not only directly affect the ADG but also indirectly affects it through grit and academic self-efficacy. Based on SDT, this study further revealed the potential mechanism of a growth mindset affecting the ADG. Furthermore, it provides practical guidance for the cultivation of ADG for junior high school students.Keywords: junior high school students, academic delay of gratification, growth mindset, grit, academic self-efficacy

Abstract A growing body of research associates the oral microbiome and oral cancer. Well-characterized clinical samples with outcome data are required to establish relevant associations between the microbiota and disease. The objective of this study was to characterize the community variations and the functional implications of the microbiome in low-grade oral epithelial dysplasia (OED) using 16S rRNA gene sequencing from annotated archival swabs in progressing (P) and non-progressing (NP) OED. We characterised the microbial community in 90 OED samples — 30 swabs from low-grade OED that progressed to cancer (cases) and 60 swabs from low-grade OED that did not progress after a minimum of 5 years of follow up (matched control subjects). There were small but significant differences between P and NP samples in terms of alpha diversity as well as beta diversity in conjunction with other clinical factors such as age and smoking status for both taxa and functional predictions. Across all samples, the most abundant genus was Streptococcus, followed by Haemophilus, Rothia, and Neisseria. Taxa and predicted functions were identified that were significantly differentially abundant with progression status (all Ps and NPs), when samples were grouped broadly by the number of years between sampling and progression or in specific time to progression for Ps only. However, these differentially abundant features were typically present only at low abundances. For example, Campylobacter was present in slightly higher abundance in Ps (1.72%) than NPs (1.41%) and this difference was significant when Ps were grouped by time to progression. Furthermore, several of the significantly differentially abundant functions were linked to the Campylobacteraceae family in Ps and may justify further investigation. Larger cohort studies to further explore the microbiome as a potential biomarker of risk in OED are warranted.

The growth and metastasis of solid tumours is known to be facilitated by the tumour microenvironment (TME), which is composed of a highly diverse collection of cell types that interact and communicate with one another extensively. Many of these interactions involve the immune cell population within the TME, referred to as the tumour immune microenvironment (TIME). These non-cell autonomous interactions exert substantial influence over cell behaviour and contribute to the reprogramming of immune and stromal cells into numerous pro-tumourigenic phenotypes. The study of some of these interactions, such as the PD-1/PD-L1 axis that induces CD8+ T cell exhaustion, has led to the development of breakthrough therapeutic advances. Yet many common analyses of the TME either do not retain the spatial data necessary to assess cell-cell interactions, or interrogate few (

Juanyong Zhao, Haiyang Liu, Ming Xia, Qian Chen, Lili Wan, Bin Leng, Chengyuan Tang, Guochun Chen, Yu Liu, Lei Zhang, Hong Liu Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Hong Liu; Lei Zhang, Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China, Tel +86-13973116951 ; +86-18673174522, Email liuhong618@csu.edu.cn; zhanglei_xp@163.comPurpose: Accumulating clinical evidence showed that Tripterygium hypoglaucum (Lév.) Hutch (THH) is effective against IgA nephropathy (IgAN), but the mechanism is still unclear. This study is to evaluate the renal protective effect and molecular mechanism of THH against IgAN via network pharmacology, molecular docking strategy and experimental validation.Methods: Several databases were used for obtaining the active ingredients of THH, the corresponding targets, as well as the IgAN-related genes. The critical active ingredients, functional pathways, and potential for the combination of the hub genes and their corresponding active components were determined through bioinformatics analysis and molecular docking. The IgAN mouse model was treated with celastrol (1 mg/kg/d) for 21 days, and the aggregated IgA1-induced human mesangial cell (HMC) was treated with various concentrations of celastrol (25, 50 or 75 nM) for 48 h. The immunohistochemistry and Western blot techniques were applied to evaluate the protein expression of the predicted target. The cell counting kit 8 (CCK8) was used to detect HMC proliferation.Results: A total of 17 active ingredients from THH were screened, covering 165 IgAN-related targets. The PPI network identified ten hub targets, including PTEN. The binding affinity between the celastrol and PTEN was the highest (− 8.69 kJ/mol). The immunohistochemistry showed that celastrol promoted the expression of PTEN in the glomerulus of IgAN mice. Furthermore, the Western blot techniques showed that celastrol significantly elevated the expression of PTEN and inhibited PCNA and Cyclin D1 in vitro and in vivo. The CCK8 assay determined that celastrol decreased HMC proliferation in a concentration-dependent manner.Conclusion: This study suggests that activating PTEN by celastrol may play a pivotal role in THH alleviating IgAN renal injury.Keywords: IgA nephropathy, Tripterygium hypoglaucum (Lév.) Hutch, network pharmacology, molecular docking, celastrol, PTEN

Kaiwen Zhang, Meihong Li, Wenlong Yao, Li Wan Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Li Wan, Department of Anaesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email wanli0604@163.comBackground: Local anesthetics are commonly used in surgical procedures to control pain in patients. Whilst the cardiotoxicity and neurotoxicity of local anesthetics have received much attention, the cytotoxicity they exert against bone, joint, and muscle tissues has yet to be well recognized.Objective: This review aimed to raise awareness regarding how local anesthetics may cause tissue damage and provide a deeper understanding of the mechanisms of local anesthetic-induced cytotoxicity. We summarized the latest progress on the cytotoxicity of local anesthetics and the underlying mechanisms and discussed potential strategies to reduce it.Findings: We found that the toxic effects of local anesthetics on bone, joint, and muscle tissues were time- and concentration-dependent in vitro. Local anesthetics induced apoptosis, necrosis, and autophagy through specific cellular pathways. Altogether, this review indicates that toxicity of local anesthetics may be avoided by rationally selecting the appropriate anesthetic, limiting the total amount, and determining the lowest effective concentration and duration.Keywords: local anesthetics, cytotoxicity, myotoxicity, chondrotoxicity, cell death mechanism

Lung adenocarcinoma (LUAD) is a highly prevalent and lethal form of lung cancer, comprising approximately half of all cases. It is often diagnosed at advanced stages with brain metastasis (BM), resulting in high mortality rates. Current BM management involves complex interventions and conventional therapies that offer limited survival benefits with neurotoxic side effects. The tumor microenvironment (TME) is a complex system where cancer cells interact with various elements, significantly influencing tumor behavior. Immunotherapies, particularly immune checkpoint inhibitors, target the TME for cancer treatment. Despite their effectiveness, it is crucial to understand metastatic lung cancer and the specific characteristics of the TME, including cell–cell communication mechanisms, to refine treatments. Herein, we investigated the tumor microenvironment of brain metastasis from lung adenocarcinoma (LUAD-BM) and primary tumors across various stages (I, II, III, and IV) using single-cell RNA sequencing (scRNA-seq) from publicly available datasets. Our analysis included exploring the immune and non-immune cell composition and the expression profiles and functions of cell type-specific genes, and investigating the interactions between different cells within the TME. Our results showed that T cells constitute the majority of immune cells present in primary tumors, whereas microglia represent the most dominant immune cell type in BM. Interestingly, microglia exhibit a significant increase in the COX pathway. Moreover, we have shown that microglia primarily interact with oligodendrocytes and endothelial cells. One significant interaction was identified between DLL4 and NOTCH4, which demonstrated a relevant association between endothelial cells and microglia and between microglia and oligodendrocytes. Finally, we observed that several genes within the HLA complex are suppressed in BM tissue. Our study reveals the complex molecular and cellular dynamics of BM-LUAD, providing a path for improved patient outcomes with personalized treatments and immunotherapies.

Haibin Lu,1,2,* Lei Wan,2,* Xiaoling Li,2 Mu Zhang,2 Adnan Shakoor,3 Wenqiang Li,4 Xueyang Zhang1,2 1Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, 528308, People’s Republic of China; 2Stomatological Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 3Department of Control and Instrumentation Engineering, King Fahd University of Petroleum & Minerals, Dhahran, Kingdom of Saudi Arabia; 4Engineering Technology Research Center for Sports Assistive Devices of Guangdong, Guangzhou Sport University, Guangzhou, 510000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenqiang Li, Engineering Technology Research Center for Sports Assistive Devices of Guangdong, Guangzhou Sport University, Guangzhou, 510000, People’s Republic of China, Tel +8602038025086, Fax +02038025086, Email liwq@gzsport.edu.cn Xueyang Zhang, Email zhangxueyang666@126.comIntroduction: Kochiae Fructus has been widely used in Chinese Herbal medicine to treat various diseases. We report a rapid and eco-friendly approach for cerium oxide (CeO2) nanoparticles (NPs) synthesis using the extract of medicinally important plant “Kochiae Fructus”, and the synthesized NPs were named KF-CeO2 NPs.Methods: Various spectroscopic approaches such as transmission electron microscope (TEM), powder X-ray diffraction (XRD), and energy-dispersive X-Ray (EDX) were used to characterize the KF-CeO2 NPs effectively. The antibacterial and biofilm inhibition activity of KF-CeO2 NPs against Gram-positive and Gram-negative multi-drug resistant (MDR) bacteria was determined using the serial dilution method and XTT assay. KF-CeO2 NPs were assessed for anticancer activity against HeLa cancer cells using an MTT assay. Cytobiocompatibility was determined in two normal cell lines (3T3 and hMSC).Results and Discussion: The average size of the KF-CeO2 NPs was 11.3 ± 3.9 nm with spherical morphology. KF-CeO2 NPs demonstrated a greater than 95% bactericidal efficacy against MDR microorganisms. In addition, KF-CeO2 NPs strongly suppressed (more than 79%) the biofilms of MDR bacteria, indicating their potential for addressing antibiotic resistance issues. Compared to Kochiae Fructus extract and CH-CeO2 NPs, they exhibited significant cytotoxic effects (35.60% cell viability) on HeLa cancer cells. In addition, the KF-CeO2 NPs were shown to be highly biocompatible with hMSC and 3T3 cell lines (85.13% and 81.17% cell viability, respectively), suggesting that they may be employed in biological systems.Conclusion: These data indicate that KF-CeO2 NPs synthesized using Kochiae Fructus extract are promising alternative treatments for MDR. In addition, this study will give the potential for the sustained development of biocompatible NPs with enhanced biological capabilities derived from vital pharmaceutical plants.Graphical Abstract: Keywords: green synthesis, CeO2 NPs, Kochiae Fructus, antimicrobial, cytobiocompatibility

Fan Zhang,1 Yi-Nuo Yang,2 Jin-Di Feng,2 Jing-Hui Zhao,1 Li Wan,1 Jing Che,1 Ying Yan,1 Ning-Ning Guo,1 Jia-Yu Zhang1 1Hair Medical Research Center, Department of Dermatology and Venereology, Beijing Jishuitan Hospital, Beijing, People’s Republic of China; 2School of Clinical Medicine, Peking University School of Medicine, Beijing, People’s Republic of ChinaCorrespondence: Fan Zhang, Hair Medical Research Center, Department of Dermatology and Venereology, Beijing Jishuitan Hospital, No. 31 of Xinjiekou East Street, Xicheng District, Beijing, 100035, People’s Republic of China, Tel +86 10 58516688, Email zhangfanzf63z@126.comObjective: To evaluate the effectiveness and safety of a combined treatment for moderate and severe androgenetic alopecia (AGA) involving the use of electric microneedles.Methods: A total of 83 patients with moderate to severe AGA in the Department of Dermatology at Beijing Jishuitan Hospital were included in this study. The male patients were administered finasteride orally and 5% minoxidil for external use, while the female patients were given spironolactone orally or Diane-35 and 2% minoxidil for external use. All the patients were then treated via electric microneedle therapy alongside the YUFA ®medical care package (Foshan, China) once a week for 1– 28 weeks. The seven-point method and root hair measurement using a hair mirror were adopted to evaluate the efficacy and any adverse reactions of the combined treatment.Results: Eleven patients were treated for 1– 3 weeks, 60 for 4– 12 weeks, and 12 for more than 12 weeks. The efficacy evaluation using the seven-point method for 12 weeks of treatment indicated a 100% response rate, specifically, a 42.1% mild improvement rate, a 38.6% moderate improvement rate, and a 19.3% marked improvement rate. Besides, the efficacy assessment was also completed with root hair count method and the number of hair roots measured at fixed points were 148.67± 11.15, 158.13± 5.11 and 169.75± 2.06 after treatment time at 16, 20 and 24 weeks, respectively. Of note, a statistical difference in the number of hair roots could be observed during the period of week 20–week 24 (P < 0.01).Conclusion: The combined treatment of moderate to severe AGA using the electric microneedle technique has a clear effect and can effectively increase the hair density. With a simple operation and mild side effects, the technique has wide application prospects.Keywords: electric microneedles, androgenic alopecia, combined therapy, efficacy observation

Wenhao Liao,1,&ast; Yuchen Li,1,2,&ast; Jing Wang,3,&ast; Maoyuan Zhao,1 Nianzhi Chen,1 Qiao Zheng,1 Lina Wan,1 Yu Mou,1 Jianyuan Tang,1,4 Zhilei Wang1,4 1Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3Department of Obstetrics and Gynecology, Bishan Hospital of Traditional Chinese Medicine, Chongqing, People’s Republic of China; 4TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianyuan Tang; Zhilei Wang, Email tangjy@cdutcm.edu.cn; wangzl1993@outlook.comAbstract: Cancer stem cells (CSCs) lead to the occurrence and progression of cancer due to their strong tumorigenic, self-renewal, and multidirectional differentiation abilities. Existing cancer treatment methods cannot effectively kill or inhibit CSCs but instead enrich them and produce stronger proliferation, invasion, and metastasis capabilities, resulting in cancer recurrence and treatment resistance, which has become a difficult problem in clinical treatment. Therefore, targeting CSCs may be the most promising approach for comprehensive cancer therapy in the future. A variety of natural products (NP) have significant antitumor effects and have been identified to target and inhibit CSCs. However, pharmacokinetic defects and off-target effects have greatly hindered their clinical translation. NP-based nanoformulations (NPNs) have tremendous potential to overcome the disadvantages of NP against CSCs through site-specific delivery and by improving their pharmacokinetic parameters. In this review, we summarize the recent progress of NPNs targeting CSCs in cancer therapy, looking forward to transforming preclinical research results into clinical applications and bringing new prospects for cancer treatment.Keywords: cancer, cancer stem cells, nanoformulations, natural products, targeted therapy

Yiting Kong,1,&ast; Chuan Liu,2,&ast; Chenyu Zhang,1 Wo Wang,2 Yalan Li,2 Haitang Qiu,1 Gaomao Wang,2 Daqi Li,2 Xiaorong Chen,2 Zhen Lv,2 Dongdong Zhou,2 Liyang Wan,2 Ming Ai,1 Jianmei Chen,1 Liuyi Ran,2,&ast; Li Kuang1,2,&ast; 1Department of Psychiatry, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liuyi Ran, Mental Health Center, University-Town Hospital of Chongqing Medical University, Shapingba District, Chongqing, 401331, People’s Republic of China, Tel/Fax +86-023-65714061, Email ranliuyi@163.com Li Kuang, Department of Psychiatry, the First Affiliated Hospital of Chongqing Medical University, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel/Fax +86-023-89012696, Email kuangli0308@163.comPurpose: Uric acid (UA) is thought to exert neuroprotective roles. The purpose of this study was to examine the association of serum UA with suicide attempts (SA) in adolescents and young adults with major depressive disorder (MDD).Patients and Methods: We retrospectively recruited 533 participants with MDD aged 13 to 25 years, of which 168 had a history of SA in the past three months and 365 did not have a history of SA. Serum UA levels were measured using the uricase-peroxidase coupling method. In addition to overall serum UA level comparison in MDD individuals with and without SA, a stratified analysis by biological sex was carried out.Results: Compared to MDD individuals without a history of SA, serum UA levels were significantly lower in MDD individuals with SA (P < 0.001). Female MDD, but not male MDD individuals, with SA exhibited lower levels of UA than those without SA (P < 0.01). Importantly, serum UA remained significantly associated with SA in MDD individuals (OR = 0.996, 95% CI: 0.993∼ 0.999, P < 0.01) when controlling for possible confounding variables.Conclusion: This research identifies a relationship between serum UA levels and SA in adolescents and young adults with MDD. UA may represent a biological risk marker for SA, in particular for female MDD individuals.Keywords: suicide, MDD, uric acid, antioxidant, oxidative stress, biomarker

In recent years, there has been a growing interest in the relationship between microorganisms in the surrounding environment and cancer cells. While the tumor microenvironment predominantly comprises cancer cells, stromal cells, and immune cells, emerging research highlights the significant contributions of microbial cells to tumor development and progression. Although the impact of the gut microbiome on treatment response in lung cancer is well established, recent investigations indicate complex roles of lung microbiota in lung cancer. This article focuses on recent findings on the human lung microbiome and its impacts in cancer development and progression. We delve into the characteristics of the lung microbiome and its influence on lung cancer development. Additionally, we explore the characteristics of the intratumoral microbiome, the metabolic interactions between lung tumor cells, and how microorganism-produced metabolites can contribute to cancer progression. Furthermore, we provide a comprehensive review of the current literature on the lung microbiome and its implications for the metastatic potential of tumor cells. Additionally, this review discusses the potential for therapeutic modulation of the microbiome to establish lung cancer prevention strategies and optimize lung cancer treatment.

Deregulated miRNAs are associated with colorectal cancer (CRC), with alterations depending on the tumor location. Novel tissue-specific miRNAs have been identified in different tumors and are associated with cancer. We used miRMaster to identify novel miRNAs in CRC from the TCGA and GEO data (discovery and validation groups). We used TCGA data from five tissues to analyze miRNA tissue specificity. miRDB was used to predict miRNA targets, and the UCSC Xena Browser was used to evaluate target expression. After successive analyses, we identified 15 novel miRNAs with the same expression patterns in CRC in both the discovery and validation groups. Four molecules (nov-miR-13844-5p, nov-miR-7154-5p, nov-miR-5035-3p, and nov-miR-590-5p) were differentially expressed in proximal and distal CRC. The nov-miR-3345-5p and nov-miR-13172-3p, which are upregulated in tumors, are only expressed in colorectal tissues. These molecules have been linked to a worse prognosis in right-sided colon and rectal carcinomas. An analysis revealed an association between eight novel miRNAs and 81 targets, mostly cancer-related genes, with varying expression based on tumor location. These findings provide new miRNAs with potential biological relevance, molecular biomarkers, and therapeutic targets for CRC treatment.

Rao X, Wan L, Jie Z, Zhu X, Yin J, Cao H. Onco Targets Ther. 2019;12:11241–11254. We, the Editors and Publisher of OncoTargets and Therapy, have retracted the published article. Since publication, concerns have been raised about the integrity of the data in the article. When approached for an explanation, the authors did not respond to our queries, nor did they provide original data for their study. As verifying the validity of the published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Qing Liu,1,2 Lei Wan,1,2 Jinyan Zhou,1,2 Yusen Huang1,2 1Qingdao Eye Hospital of Shandong First Medical University, Qingdao, People’s Republic of China; 2State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, People’s Republic of ChinaCorrespondence: Yusen Huang, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, People’s Republic of China, Tel +86 13791802251, Email huang_yusen@126.comPurpose: To describe the etiology and spectrum of isolated pathogens in endophthalmitis over 10 years from an ophthalmic hospital in North China and report their antimicrobial susceptibilities.Patients and Methods: The data covered the patients with endophthalmitis treated at Qingdao Eye Hospital from January 2011 to December 2020. Patients’ medical history, pathogenic factors, bacterial and fungal culture results of intraocular specimens, and in vitro drug sensitivity test results were assessed.Results: A total of 524 cases were counted in this study. Exogenous endophthalmitis was the main component, accounting for 94.66%, of which 49.62% of eyes had a history of ophthalmic trauma, intraocular surgery in 26.72% and suppurative keratitis in 17.37%. By comparison, endogenous endophthalmitis was found in only 5.34% of eyes. Among the 292 strains of pathogenic organisms obtained by co-culture, gram-positive bacteria accounted for 64.04%, with Staphylococcus epidermidis as the predominant pathogen (29.45%). Gram-positive cocci were identified in 76.77% of eyes with traumatic endophthalmitis, while 53.70% of keratitis-associated endophthalmitis was caused by fungi. The high susceptibility of bacteria to vancomycin (77.78%∼ 98.33%) supported its continued use as empirical treatment. Among the fluoroquinolones, gram-positive cocci showed a higher susceptibility to gatifloxacin (94.83%), while there was a significant decrease to levofloxacin (51.67%). Gram-negative bacteria were less sensitive to cephalosporins (45.95%∼ 66.67%) than fluoroquinolones (68.42%∼ 78.05%) and aminoglycosides (75.00%∼ 78.05%). Fungal susceptibilities to voriconazole and amphotericin B were 90.16% and 70.31% respectively. More than half of the 11 antibiotics were observed to exhibit a trend of reduced susceptibility.Conclusion: Ophthalmic trauma was the primary pathogenic factor of endophthalmitis. Gram-positive cocci were the most common pathogens of traumatic and postoperative endophthalmitis, while suppurative keratitis-associated endophthalmitis often resulted from fungal pathogens. Levofloxacin as the preferred antibiotic in the perioperative period and cephalosporin as the first-line drug for the treatment of empiric endophthalmitis need to be vigilant.Keywords: endophthalmitis, epidemiology, antibiotic sensitivity, microbiology

Abstract Background Asthma, lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are three respiratory diseases characterized by complex mechanisms underlying and genetic predispositions, with asthma having the highest calculated heritability. Despite efforts deployed in the last decades, only a small part of its heritability has been elucidated. It was hypothesized that shared genetic factors by these three diseases could help identify new asthma loci. Methods GWAS-nominated LC and COPD loci were selected among studies performed in Caucasian cohorts using the GWAS Catalog. Genetic analyses were carried out for these loci in the Saguenay–Lac-Saint-Jean (SLSJ) asthma familial cohort and then replicated in two independent cohorts (the Canadian Cohort Obstructive Lung Disease [CanCOLD] and the Epidemiological Study of the Genetics and Environment of Asthma [EGEA]). Results Analyses in the SLSJ cohort identified 2851 and 4702 genetic variants to be replicated in the CanCOLD and EGEA cohorts for LC and COPD loci respectively. Replication and meta-analyses allowed the association of one new locus with asthma, 2p24.3, from COPD studies. None was associated from LC studies reported. Conclusions The approach used in this study contributed to better understand the heritability of asthma with shared genetic backgrounds of respiratory diseases.

Abstract Resident microbial populations have been detected across solid tumors of diverse origins. Sequencing of the airway microbiota represents an opportunity for establishing a novel omics approach to early detection of lung cancer, as well as risk prediction of cancer development. We hypothesize that bacterial shifts in the pre-malignant lung may be detected in non-cancerous airway liquid biopsies collected during bronchoscopy. We analyzed the airway microbiome profile of near 400 patients: epithelial brushing samples from those with lung cancer, those who developed an incident cancer, and those who do not develop cancer after 10-year follow-up. Using linear discriminate analysis, we define and validate a microbial-based classifier that is able to predict incident cancer in patients before diagnosis with no clinical signs of cancer. Our results demonstrate the potential of using lung microbiome profiling as a method for early detection of lung cancer.

Lu Wan,1,2 Wenchao Zhang,1,2 Zhongyue Liu,1,2 Zhimin Yang,1,2 Chao Tu,1,2 Zhihong Li1,2 1Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Chao Tu; Zhihong Li, Tel +86 15974290117; +86 13975112458, Email tuchao@csu.edu.cn; lizhihong@csu.edu.cnPurpose: Metabolic reprogramming, as one of the hallmarks of cancer, shows promising translational potential for cancer diagnosis, treatment and prognostic prediction. This study aims to construct and validate a prognostic prediction model for osteosarcoma based on glutamine metabolism-related genes.Materials and Methods: A group of glutamine metabolism-related genes was identified from a public database and intersected with a list of osteosarcoma survival-related genes, and a risk score model based on sixteen glutamine metabolism-related genes was developed by using LASSO penalized Cox regression analysis.Results: The prognosis of patients in the high-risk group was significantly worse than that of patients in the low-risk group in the training dataset (high- vs low-risk, 5-year overall survival: 11% vs 88%, p < 0.0001) and in two other external validation cohorts (high- vs low-risk, 5-year overall survival: 39% vs 81%, p = 0.015; 50% vs 94%, p = 0.011).In addition, a novel nomogram was constructed by integrating the risk score and clinical characteristics, including age, sex, metastasis status and chemotherapy response. This nomogram had superior predictive power compared with a nomogram composed of only conventional factors. Gene set enrichment analysis indicated that several well-known malignancy-associated gene sets, including MYC targets V1, DNA repair, and unfolded protein response, were enriched in the high-risk subgroup.Conclusion: A novel glutamine metabolism-related prognostic prediction model and nomogram for osteosarcoma was developed and validated in the present study, which could predict the survival of patients with osteosarcoma and may facilitate individualized clinical decision-making for patients.Keywords: bone tumor, survivorship, amino acid metabolism, nomogram

Nasopharyngeal carcinoma (NPC) is unique among head and neck cancers for its strong causative association with Epstein Barr-Virus and high levels of immune infiltration that play a role in pathogenesis. As such, immunotherapy for the treatment of NPC is a promising area of research in the pursuit of improving patient outcomes. Understanding the tumour immune microenvironment (TIME) of NPC is the key to developing targeted immunotherapies and stratifying patients to determine optimal treatment regimens. Recent research has uncovered distinct characteristics of the TIME in NPC as well as important differences between the different disease subtypes; however, reviewing the state of the field reveals a further need for the application of novel techniques like multiplexed hyperspectral imaging and mass cytometry. These techniques can be used to identify spatial, compositional, and functional aspects of the TIME in NPC such as immune cell sociology, novel immune populations, and differences in immune-related signalling pathways in NPC in order to identify clinically relevant characteristics for targeted immunotherapy development and biomarker discovery.

Lung tumors frequently metastasize to the brain. Brain metastasis (BM) is common in advanced cases, and a major cause of patient morbidity and mortality. The precise molecular mechanisms governing BM are still unclear, in part attributed to the rarity of BM specimens. In this work, we compile a unique transcriptomic dataset encompassing RNA-seq, microarray, and single-cell analyses from BM samples obtained from patients with lung adenocarcinoma (LUAD). By integrating this comprehensive dataset, we aimed to enhance understanding of the molecular landscape of BM, thereby facilitating the identification of novel and efficient treatment strategies. We identified 102 genes with significantly deregulated expression levels in BM tissues, and discovered transcriptional alterations affecting the key driver ‘hub’ genes CD69 (a type II C-lectin receptor) and GZMA (Granzyme A), indicating an important role of the immune system in the development of BM from primary LUAD. Our study demonstrated a BM-specific gene expression pattern and revealed the presence of dendritic cells and neutrophils in BM, suggesting an immunosuppressive tumor microenvironment. These findings highlight key drivers of LUAD-BM that may yield therapeutic targets to improve patient outcomes.

Lin Wan, Jing Wei Department of Psychological Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Jing WeiDepartment of Psychological Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Shuaifuyuan 1, Dongcheng District, Beijing, People’s Republic of ChinaTel +86-10-61956061Email weijing@pumch.cnBackground: Patients with early-onset schizophrenia usually exhibit more severe symptoms, revealing a potentially distinctive disease phenotype. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate conversion and methylation modification associated with the disease. We aimed to investigate the potential effects of MTHFR polymorphisms and related methylation patterns in patients with early-onset schizophrenia, which implies special phenotypes of schizophrenia.Methods: In 177 patients with schizophrenia, MTHFR polymorphism at three sites (C677T, A1298C, and G1793A) and the Positive and Negative Syndrome Scale (PANSS) were tested. Differential methylation positions (DMPs) and enrichment of genes and related pathways were analyzed by testing the genomic methylation level. Catechol-O-methyltransferase (COMT), solute carrier family 6 member 4 (SLC6A4), neuregulin1 (NRG1), and brain-derived neurotrophic factor (BDNF) were selected to evaluate the methylation levels of specific CpG regions by pyrosequencing.Results: Higher levels of symptom severity and MTHFR polymorphisms and lower levels of global DNA methylation in patients with early-onset schizophrenia were observed in this study. SLC6A4 was hypermethylated, and BDNF was hypomethylated in specific regions of patients with early-onset schizophrenia.Conclusion: Aggravating symptoms, increased MTHFR polymorphisms, and reduced genomic methylation levels may be characteristics and underlying mechanisms of early-onset schizophrenia, which implies a special disease phenotype. Beyond that, specific genes and biological pathways may imply the potential phenotype of schizophrenia.Keywords: schizophrenia, phenotype, onset age, MTHFR, polymorphism, methylation

Qin Zhang,1 Juan Tan,1 Li Wan,1 Chao Chen,1 Bin Wu,2 Xijian Ke,1 Rongxue Wu,3 Xiao Ran4 1Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 2Laboratory of Platelet and Endothelium Biology, Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 3Department of Biological Sciences Division/ Cardiology, University of Chicago, Chicago, IL, 60637, USA; 4Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of ChinaCorrespondence: Xiao Ran Email ranxiao1001@tjh.tjmu.edu.cnAim: Disruption of the blood–brain barrier (BBB) is a critical pathological feature after stroke. Although tissue kallikrein (TK) has used in the treatment of stroke in China, the role of TK in modulating BBB permeability is not clear.Methods: We investigated the effect of different doses of TK on BBB by in vivo assessments of Evans blue (EB) and sodium-fluorescein isothiocyanate (FITC) leakage and in vitro assessments of the integrity of BBB and monolayers of microvascular endothelial cells (BMVECs). The expression of zonula occludens-1 (ZO-1) and bradykinin receptor-mediated signaling in BMVECs was detected.Results: A significant increase in BBB permeability was observed in the mice treated with high dose of TK. However, standard and medium doses of TK could only enable sodium-FITC to enter the brain. The result of in vitro study indicated that high-doses of TK, but not standard and medium-dose of TK, reduced normal BBB integrity accompanied by a decreased expression of zonula occludens-1 (ZO-1), upregulated the mRNA levels of bradykinin 2 receptor (B2R) and endothelial nitric oxide synthase (eNOS) and the abundance of B2R. Moreover, standard-dose of TK exacerbated lipopolysaccharide-induced BBB hyperpermeability, upregulated the mRNA levels of bradykinin 1 receptor (B1R) and inducible nitric oxide synthase (iNOS), increased the abundance of B1R and reduced the abundance of ZO-1; these effects were inhibited by TK inhibitor.Conclusion: TK can disrupt tight junctions and increase normal BBB permeability via B2R-dependent eNOS signaling pathway, aggravate impairment of BBB via B1R-dependent iNOS signaling pathway, and consequently serve as a useful adjunctive treatment for enhancing the efficacy of other neurotherapeutics.Keywords: tissue kallikrein, blood–brain barrier, bradykinin, permeability

Robert N Jamison,1 Robert R Edwards,1 Samantha Curran,1 Limeng Wan,1 Edgar L Ross,1 Christopher J Gilligan,1 Shai N Gozani2 1Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Brigham & Women’s Hospital, Chestnut Hill, MA, USA; 2NeuroMetrix, Inc., Woburn, MA, USACorrespondence: Shai N GozaniNeuroMetrix, Inc., 4b Gill St., Woburn, MA, 01801, USATel +1 781 314 2789Fax +1 781 890 1556Email gozani@neurometrix.comPurpose: Fibromyalgia is a chronic condition characterized by widespread pain and interference with daily activities. The aim of this study is to assess the benefit of transcutaneous electrical nerve stimulation (TENS) for persons diagnosed with fibromyalgia.Patients and Methods: Adults meeting diagnostic criteria for fibromyalgia were randomized in a double-blind trial to receive either an active (n=62) or sham (n=57) wearable TENS device for 3-months. Subjects were classified as having lower or higher pain sensitivity by Quantitative Sensory Testing (QST). Patient Global Impression of Change (PGIC, primary outcome) and secondary efficacy measures including Fibromyalgia Impact Questionnaire (FIQR), Brief Pain Inventory (BPI) and painDETECT questionnaire (PDQ) were assessed at baseline, 6-weeks and 3-months. Treatment effects were determined by a mixed model for repeated measures (MMRM) analysis of the intention-to-treat (ITT) population (N=119). A pre-specified subgroup analysis of pain sensitivity was conducted using an interaction term in the model.Results: No differences were found between active and sham treatment on PGIC scores at 3-months (0.34, 95% CI [− 0.37, 1.04], p=0.351) in the ITT population. However, in subjects with higher pain sensitivity (n=60), PGIC was significantly greater for active treatment compared to sham (1.19, 95% CI [0.24, 2.13], p=0.014). FIQR total score (− 7.47, 95% CI [− 12.46, − 2.48], p=0.003), FIQR pain item (− 0.62, 95% CI [− 1.17, − 0.06], p=0.029), BPI Interference (− 0.70, 95% CI [− 1.30, − 0.11], p=0.021) and PDQ (− 1.69, 95% CI [− 3.20, − 0.18], p=0.028) exhibited significant improvements for active treatment compared to sham in the ITT population. Analgesics use was stable and comparable in both groups.Conclusion: This study demonstrated modest treatment effects of reduced disease impact, pain and functional impairment from wearable TENS in individuals with fibromyalgia. Subjects with higher pain sensitivity exhibited larger treatment effects than those with lower pain sensitivity. Wearable TENS may be a safe treatment option for people with fibromyalgia.Clinicaltrials.gov Registration: NCT03714425.Keywords: fibromyalgia, wearable, transcutaneous electrical nerve stimulation, neuromodulation, non-pharmacological treatment, clinical trial

Xiao Ran,1 Qin Zhang,2 Shaoping Li,1 Zhen Yu,1 Li Wan,2 Bin Wu,3 Rongxue Wu,4 Shusheng Li1 1Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 2Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 3Laboratory of Platelet and Endothelium Biology, Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 4Department of Biological Sciences Division/Cardiology, University of Chicago, Chicago, IL, 60637, USACorrespondence: Qin Zhang Email qzhang8@tjh.tjmu.cnShusheng Li Email Shushengli16@sina.comAim: Sepsis, an acute, life-threatening dysregulated response to infection, affects practically all aspects of endothelial function. Tissue kallikrein (TK) is a key enzyme in the kallikrein–kinin system (KKS) which has been implicated in endothelial permeability. Thus, we aimed to establish a potentially novel association among TK, endothelial permeability, and sepsis demonstrated by clinical investigation and in vitro studies.Methods: We performed a clinical investigation with the participation of a total of 76 controls, 42 systemic inflammatory response syndrome (SIRS) patients, and 150 patients with sepsis, who were followed-up for 28 days. Circulating TK levels were measured with an enzyme-linked immunosorbent assay. Then, the effect of TK on sepsis-induced endothelial hyperpermeability was evaluated by in vitro study.Results: Data showed a gradual increase in TK level among controls and the patients with SIRS, sepsis, and septic shock (0.288± 0.097 mg/l vs 0.335± 0.149 vs 0.495± 0.170 vs 0.531± 0.188 mg/l, respectively, P < 0.001). Further analysis revealed that plasma TK level was positively associated with the severity and mortality of sepsis and negatively associated with event-free survival during 28 days of follow-up (relative risk, 3.333; 95% CI, 2.255– 4.925; p < 0.001). With a septic model of TK and kallistatin in vitro, we found that TK exacerbated sepsis-induced endothelial hyperpermeability by downregulating zonula occluden-1 (ZO-1) and vascular endothelial (VE)-cadherin, and these could be reversed by kallistatin, an inhibitor of TK.Conclusion: TK can be used in the diagnosis of sepsis and assessment of severity and prognosis of disease. Inhibition of TK may be a novel therapeutic target for sepsis through increasing ZO-1 and VE-cadherin, as well as downregulating endothelial permeability.Keywords: tissue kallikrein, sepsis, mortality, endothelial permeability, junction protein

Abstract The placenta is vital to embryonic development and requires a finely-tuned pattern of gene expression, achieved in part by its unique epigenetic landscape. Piwi-interacting RNAs (piRNAs) are a class of small-non-coding RNA with established roles as epigenetic regulators of gene expression, largely via methylation of targeted DNA sequences. The expression of piRNAs have mainly been described in germ cells, but a fraction have been shown to retain expression in adult somatic tissues. To aid in understanding the contribution of these regulators in the placenta, we provide the first description of the piRNA transcriptome in human placentas. We find 297 piRNAs to be preferentially expressed in the human placenta, a subset of which are expressed at higher levels relative to testes samples. We also observed a large proportion of placental piRNAs to be expressed from a single locus, as distinct from canonical cluster locations associated with transposable element silencing. Finally, we find that 15 of the highest-expressed placental piRNAs maps to the DLK1-DIO3 locus, suggesting a link to placental biology. Our findings suggest that piRNAs could contribute to the molecular networks defining placental function in humans, and a biological impact of piRNA expression beyond germ cells.

Measurement(s) small non-coding RNA Technology Type(s) small RNA sequencing assay Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14233229

BackgroundCOVID-19 vaccination significantly reduces the risk of infection and its associated morbidity and mortality. However, poor uptake of the COVID-19 vaccination was reported among the high-risk group of older people amidst emerging variants of concern. This community case study reports an outreach program in Singapore, COVE (COVID-19 Vaccination for the Elderly) initiated by healthcare workers in a cluster of primary care clinics. They assessed the vaccine hesitancy among these older persons, addressed their concerns and facilitated their vaccination appointment during a brief phone conversation.MethodTwenty one thousand six hundred and sixty three unvaccinated adults aged ≥60 years were contacted by healthcare worker volunteers over two phases from June to October 2021. In phase I, they contacted adults aged above 70 years over 2 weeks. Adults who were uncontactable in phase I and those aged 60–69 years were sent SMS in phase II. Data were analyzed via descriptive data analysis.ResultsAfter phase 1, 65.5% (n = 5,646/8,617) of older adults had received at least one dose of the COVID-19 vaccine. The respondents expressed intention to vaccinate (39%, n = 3,390), requested to seek further information (25%, n = 2,138), reported access barrier (8%, n = 715), or were concerned of the vaccine adverse effects (3%, n = 288). Vaccination was refused by 24% (n = 2,086) of the respondents. Eventually 60.4% (n = 13,082/21,663) of them were vaccinated 3 months after COVE implementation.ConclusionThe COVE program increased the COVID-19 vaccination uptake of older adults from 84.6 to 96.3%. A person-centric proactive approach by healthcare workers addressed vaccine hesitancy and optimized vaccination. The outreach scheduling of vaccination appointments is key in promoting vaccination uptake among older adults.

Liquid biopsies have emerged as a promising tool for the detection of metastases as well as local and regional recurrence in lung cancer. Liquid biopsy tests involve analyzing a patient’s blood, urine, or other body fluids for the detection of biomarkers, including circulating tumor cells or tumor-derived DNA/RNA that have been shed into the bloodstream. Studies have shown that liquid biopsies can detect lung cancer metastases with high accuracy and sensitivity, even before they are visible on imaging scans. Such tests are valuable for early intervention and personalized treatment, aiming to improve patient outcomes. Liquid biopsies are also minimally invasive compared to traditional tissue biopsies, which require the removal of a sample of the tumor for further analysis. This makes liquid biopsies a more convenient and less risky option for patients, particularly those who are not good candidates for invasive procedures due to other medical conditions. While liquid biopsies for lung cancer metastases and relapse are still being developed and validated, they hold great promise for improving the detection and treatment of this deadly disease. Herein, we summarize available and novel approaches to liquid biopsy tests for lung cancer metastases and recurrence detection and describe their applications in clinical practice.

Lung cancer detection and monitoring are hampered by a lack of sensitive biomarkers, which results in diagnosis at late stages and difficulty in tracking response to treatment. Recent developments have established liquid biopsies as promising non-invasive methods for detecting biomarkers in lung cancer patients. With concurrent advances in high-throughput sequencing technologies and bioinformatics tools, new approaches for biomarker discovery have emerged. In this article, we survey established and emerging biomarker discovery methods using nucleic acid materials derived from bodily fluids in the context of lung cancer. We introduce nucleic acid biomarkers extracted from liquid biopsies and outline biological sources and methods of isolation. We discuss next-generation sequencing (NGS) platforms commonly used to identify novel biomarkers and describe how these have been applied to liquid biopsy. We highlight emerging biomarker discovery methods, including applications of long-read sequencing, fragmentomics, whole-genome amplification methods for single-cell analysis, and whole-genome methylation assays. Finally, we discuss advanced bioinformatics tools, describing methods for processing NGS data, as well as recently developed software tailored for liquid biopsy biomarker detection, which holds promise for early diagnosis of lung cancer.

Meifang Liu, Jie Yang, Lagen Wan, Rui Zhao Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of ChinaCorrespondence: Lagen Wan; Rui ZhaoDepartment of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of ChinaTel +86 79188693136Fax +86 79188692272Email WLGME196412@126.com; zhaoruisc@163.comPurpose: The objective of our study was to assess the association between lymphocyte percentage (LY%), fibrinogen (FIB), fibrinogen-to-lymphocyte percentage ratio (FLR) and the tumor staging and the clinical outcome role in non-small cell lung cancer (NSCLC) patients with chemotherapy or surgery combined with chemotherapy.Patients and Methods: Between August 2013 and October 2020, 375 patients initially diagnosed with NSCLC and 201 healthy subjects were enrolled in the retrospective study. The concentrations of LY%, FIB, and FLR were compared between the case group and the control group by using the Mann–Whitney U-test or Kruskal–Wallis test, and then these biomarkers were compared in terms of the tumor category and PTNM stage of the test group, etc. The cutoffs of LY%, FIB, and FLR were determined using X-tile software. The prognostic roles of LY%, FIB, and FLR were identified by the Kaplan–Meier curve and Cox regression model. The biological markers on overall survival (OS) were analyzed.Results: The study showed that the concentration levels of LY%, FIB, and FLR in the stage III–IV group were significant difference from those in the stage I–II group (P< 0.001), indicating that three biomarkers (LY%, FIB, and FLR) were significantly correlated with tumor staging. Pretreatment high FIB and FLR and low LY% indicated an increased risk of death in NSCLC patients. Also, it was found that the clinical outcome of low FLR patients with chemotherapy or chemotherapy combined with surgery was superior to high FLR patients.Conclusion: Our findings demonstrated that FLR could be used to predict NSCLC staging and was an independent prognosis factor within NSCLC patients receiving chemotherapy or chemotherapy combined with surgery.Keywords: fibrinogen-to-lymphocyte percentage ratio, lymphocyte percentage, fibrinogen, non-small-cell lung cancer, overall survival

Yu Tan,1,&ast; Feng Zhou,2,&ast; Dejiang Yang,1 Xiaowei Zhang,1 Meihong Zeng,1 Lei Wan1 1Department of Neurology, The Third Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, 330008, People’s Republic of China; 2Department of Neurology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai City, Guangdong Province, 519000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu TanDepartment of Neurology, The Third Affiliated Hospital of Nanchang University, No. 128 Xiangshan Road, Nanchang City, Jiangxi Province, 330008, People’s Republic of ChinaEmail YuTanhospital@163.comBackground: Ischemic stroke is a destructive cerebrovascular disorder related to oxidative stress; NOX2 is a major source for ROS production; and miR-126a-5p is involved in several diseases, such as abdominal aortic aneurysm. We investigated the role of miR-126a-5p in regulating NOX2 in ischemic stroke.Methods: MiR-126a-5p and NOX2 were examined in the brains of rats subjected to cerebral ischemia/reperfusion (I/R) by RT-PCR and Western blot. MiR-126a-5p agomir was delivered to examine the effects of miR-126a-5p on I/R injury. The neurological deficit, infarct volume, and brain water content were evaluated. NOX activity, ROS production, and MDA and SOD levels were detected to assess oxidative stress. H&E staining was used to examine cell state. Apoptosis was evaluated by TUNEL, caspase-3 activity, and cleaved-caspase-3 protein level. The relationship between miR-126a-5p and NOX2 was analyzed by bioinformatics and luciferase reporter assay. MiR-126a-5p mimic, miR-126a-5p inhibitor, or pcDNA-NOX2 were transfected in SH-SY5Y cells to further assess the effects of miR-126a-5p on OGD/R-induced cells injury.Results: NOX2 was upregulated and miR-126a-5p was down-regulated in the brains of I/R rats. MiR-126a-5p agomir obviously reduced the neurological deficit, infarct volume, brain water content, oxidative stress, and apoptosis in I/R rats. MiR-126a-5p targeted NOX2 directly and regulated NOX2 negatively. Moreover, miR-126a-5p mimic elevated cell viability and inhibited oxidative stress and apoptosis in OGD/R-treated SH-SY5Y cells, while miR-126a-5p inhibitor had the opposite effects. NOX2 overexpression antagonized the protective effects of miR-126a-5p mimic on OGD/R-induced cell injury.Conclusion: MiR-126a-5p is a novel potential target for ischemic stroke therapy due to its protection against cerebral I/R injury via directly targeting NOX2.Keywords: oxidative stress, NOX2, miR-126a-5p, cerebral ischemia/reperfusion

Dysregulation of ubiquitin-proteasome pathway genes through copy number alteration, promoter hypomethylation, and miRNA deregulation is involved in cancer development and progression. Further characterizing alterations in these genes may uncover novel drug targets across a range of diseases in which druggable alterations are uncommon, including hepatocellular carcinoma (HCC). We analyzed 377 HCC and 59 adjacent non-malignant liver tissue samples, focusing on alterations to component genes of the widely studied CRL2pVHL E3 ubiquitin ligase complex. mRNA upregulation of the component genes was common, and was correlated with DNA hypomethylation and copy number increase, but many tumours displayed overexpression that was not explained by either mechanism. Interestingly, we found 66 miRNAs, including 39 previously unannotated miRNAs, that were downregulated in HCC and predicted to target one or more CRL2pVHL components. Several miRNAs, including hsa-miR-101-3p and hsa-miR-139-5p, were negatively correlated with multiple component genes, suggesting that miRNA deregulation may contribute to CRL2pVHL overexpression. Combining miRNA and mRNA expression, DNA copy number, and methylation status into one multidimensional survival analysis, we found a significant association between greater numbers of alterations and poorer overall survival for multiple component genes. While the intricacies of CRL2pVHL complex gene regulation require additional research, it is evident that multiple causes for the deregulation of these genes must be considered in HCC, including non-traditional mechanisms.

Mengpei Zhu,1 Lisong Dai,2 Lei Wan,3 Shuling Zhang,1 Hongxing Peng1 1Department of Respiratory Medicine, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Radiology Department, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Department of Cardiovascular Medicine, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Hongxing PengDepartment of Respiratory Medicine, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of ChinaEmail penghx2008@126.comPurpose: Studies have demonstrated that red blood cell distribution width (RDW) is closely associated with the prognosis of patients with chronic obstructive pulmonary disease (COPD). In addition, the dynamic changes in RDW appear to play an important role. Thus, we aimed to investigate the relationship between dynamic changes in RDW and 30-day all-cause readmission of patients with acute exacerbation of COPD (AECOPD).Methods: In this retrospective cohort study, we enrolled patients with AECOPD hospitalized in the Department of Respiratory Medicine in Liyuan Hospital (Wuhan China), a tertiary, university-affiliated, public hospital. Patients with AECOPD were divided into three groups based on their RDW values after the first and fourth days of admission. The normal range for RDW is 10– 15%. Patients with normal RDW values were included in the normal group. Patients with an RDW value > 15% on the first day, which subsequently decreased by > 2% on the fourth day was included in the decreased group. The increased group was comprised of patients with an RDW value > 15% on the first day which continued to increase, or those with a normal RDW value on the first day which increased > 15% on the fourth day.Results: A total of 239 patients (age: 72 years [range: 64– 81 years]; male: n=199 [83.3%]) were included. There were 108, 72, and 59 patients in the RDW normal, decreased, and increased groups, respectively; the 30-day all-cause readmission rate was 9.3%, 9.7%, 27.1%, respectively; (p=0.003), being noticeably higher in the RDW increased group. Dynamic increase of RDW (OR:3.45, 95% CI: 1.39– 8.58, p=  0.008) was independently correlated with 30-day all-cause readmission of patients with AECOPD.Conclusion: The dynamic increase of RDW is an independent prognostic factor of 30-day all-cause readmission of patients with AECOPD.Keywords: RDW, chronic obstructive pulmonary disease, hospitalization, readmission, prognosis

Hui Ye,1,* Xiaoying Chu,1,* Zhensheng Cao,2,* Xuanxuan Hu,1,* Zihan Wang,2 Meiqi Li,1 Leyu Wan,2 Yongping Li,3 Yongge Cao,4 Zhanqiu Diao,2 Fengting Peng,2 Jinsong Liu,2 Lihua Xu5 1School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 2School of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 3Department of Surgery, Chengdu Shuangliu District Maternal and Child Health Hospital, ChengDu, Sichuan, 610200, People’s Republic of China; 4Department of Stomatology, Haiyuan College, Kunming, Yunnan, 650106, People’s Republic of China; 5Department of General Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui YeSchool of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of ChinaEmail wmcyh@wmu.edu.cnLihua XuDepartment of General Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, ChinaEmail lihuaxu@wmu.edu.cnBackground: This study was aimed to prepare a novel magnetic thermosensitive cationic liposome drug carrier for the codelivery of Oxaliplatin (OXA) and antisense lncRNA of MDC1 (MDC1-AS) to Cervical cancer cells and evaluate the efficiency of this drug carrier and its antitumor effects on Cervical cancer.Methods: Thermosensitive magnetic cationic liposomes were prepared using thin-film hydration method. The OXA and MDC1-AS vectors were loaded into the codelivery system, and the in vitro OXA thermosensitive release activity, efficiency of MDC1-AS regulating MDC1, in vitro cytotoxicity, and in vivo antitumor activity were determined.Results: The codelivery system had desirable targeted delivery efficacy, OXA thermosensitive release, and MDC1-AS regulating MDC1. Codelivery of OXA and MDC1-AS enhanced the inhibition of cervical cancer cell growth in vitro and in vivo, compared with single drug delivery.Conclusion: The novel codelivery of OXA and MDC1-AS magnetic thermosensitive cationic liposome drug carrier can be applied in the combined chemotherapy and gene therapy for cervical cancer.Keywords: magnetic thermosensitive cationic liposome, oxaliplatin, antisense lncRNA of MDC1, targeted therapy, cervical cancer

Chen Li1 12 2,* Long Wan1 12 2,* Jie Luo1 12 2, Mingyan Jiang1 12 2, Keke Wang1 12 2 1Department of Pharmacy, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, People’s Republic of China; 2School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Keke WangDepartment of Pharmacy, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning, People’s Republic of ChinaTel +86-24-83282662Email wkkcc@163.comAbstract: Diabetes mellitus is a major threat to human health. Both its incidence and prevalence have been rising steadily over the past few decades. Biomacromolecular agents such as insulin and glucagon-like peptide 1 receptor agonists are commonly used hypoglycemic drugs that play important roles in the treatment of diabetes. However, their traditional frequent administration may cause numerous side effects, such as pain, infection or local tissue necrosis. To address these issues, many novel subcutaneous delivery systems have been developed in recent years. In this review, we survey recent developments in subcutaneous delivery systems of biomacromolecular hypoglycemic drugs, including sustained-release delivery systems and stimuli-responsive delivery systems, and summarize the advantages and limitations of these systems. Future opportunities and challenges are discussed as well.Keywords: diabetes mellitus, subcutaneous injection, insulin, glucagon-like peptide 1 receptor agonists, sustained-release, stimuli-responsive

Abstract Pathological links between neurodegenerative disease and cancer are emerging. LRRK2 overactivity contributes to Parkinson’s disease, whereas our previous analyses of public cancer patient data revealed that decreased LRRK2 expression is associated with lung adenocarcinoma (LUAD). The clinical and functional relevance of LRRK2 repression in LUAD is unknown. Here, we investigated associations between LRRK2 expression and clinicopathological variables in LUAD patient data and asked whether LRRK2 knockout promotes murine lung tumorigenesis. In patients, reduced LRRK2 was significantly associated with ongoing smoking and worse survival, as well as signatures of less differentiated LUAD, altered surfactant metabolism and immunosuppression. We identified shared transcriptional signals between LRRK2-low LUAD and postnatal alveolarization in mice, suggesting aberrant activation of a developmental program of alveolar growth and differentiation in these tumors. In a carcinogen-induced murine lung cancer model, multiplex IHC confirmed that LRRK2 was expressed in alveolar type II (AT2) cells, a main LUAD cell-of-origin, while its loss perturbed AT2 cell morphology. LRRK2 knockout in this model significantly increased tumor initiation and size, demonstrating that loss of LRRK2, a key Parkinson’s gene, promotes lung tumorigenesis.

The importance of gut microbiome to cancer therapy and response cannot be overstated, however the contribution of the bacterial population to the local solid tumour ecosystem is often overlooked. Seminal studies of tumour-resident microbiomes have shown that relative abundances of specific bacteria in the tumour correlate with survival metrics, implicating the microbiome in patient outcome. Similarly, patterns of microbiome community shifts between tumour-bearing and unaffected organs suggests a role for the tumour microbiome niche in contributing to tumour biology and behaviour. Recent reports of the detection of bacteria in solid tumours of diverse human organs have provided a strong rationale for deciphering the role of the solid-tumour microbiome across all human-host anatomic and physiologic niches, as the microbiome is ubiquitously present throughout the human body. Here, we review the role of the human microbiome in mediating response to therapies, as well as the differences between tumour and non-malignant-resident communities. We discuss the ability of the tumour microbiome to interact with the host, thereby influencing host cell behaviour and cancer-associated processes. Further, we evaluate recent technological advances that allow us to actively quantify these populations and the relationships between cell types. Finally, we suggest how these dynamic interactions can be harnessed for therapeutic benefit in the treatment of cancer.

Lung cancer and chronic obstructive pulmonary disease (COPD) often co-occur, and individuals with COPD are at a higher risk of developing lung cancer. While the underlying mechanism for this risk is not well understood, its major contributing factors have been proposed to include genomic, immune, and microenvironment dysregulation. Here, we review the evidence and significant studies that explore the mechanisms underlying the heightened lung cancer risk in people with COPD. Genetic and epigenetic changes, as well as the aberrant expression of non-coding RNAs, predispose the lung epithelium to carcinogenesis by altering the expression of cancer- and immune-related genes. Oxidative stress generated by tobacco smoking plays a role in reducing genomic integrity, promoting epithelial-mesenchymal-transition, and generating a chronic inflammatory environment. This leads to abnormal immune responses that promote cancer development, though not all smokers develop lung cancer. Sex differences in the metabolism of tobacco smoke predispose females to developing COPD and accumulating damage from oxidative stress that poses a risk for the development of lung cancer. Dysregulation of the lung microenvironment and microbiome contributes to chronic inflammation, which is observed in COPD and known to facilitate cancer initiation in various tumor types. Further, there is a need to better characterize and identify the proportion of individuals with COPD who are at a high risk for developing lung cancer. We evaluate possible novel and individualized screening strategies, including biomarkers identified in genetic studies and exhaled breath condensate analysis. We also discuss the use of corticosteroids and statins as chemopreventive agents to prevent lung cancer. It is crucial that we optimize the current methods for the early detection and management of lung cancer and COPD in order to improve the health outcomes for a large affected population.

Lung cancer is one of the most frequent tumors that metastasize to the brain. Brain metastasis (BM) is common in advanced cases, being the major cause of patient morbidity and mortality. BMs are thought to arise via the seeding of circulating tumor cells into the brain microvasculature. In brain tissue, the interaction with immune cells promotes a microenvironment favorable to the growth of cancer cells. Despite multimodal treatments and advances in systemic therapies, lung cancer patients still have poor prognoses. Therefore, there is an urgent need to identify the molecular drivers of BM and clinically applicable biomarkers in order to improve disease outcomes and patient survival. The goal of this review is to summarize the current state of knowledge on the mechanisms of the metastatic spread of lung cancer to the brain and how the metastatic spread is influenced by the brain microenvironment, and to elucidate the molecular determinants of brain metastasis regarding the role of genomic and transcriptomic changes, including coding and non-coding RNAs. We also present an overview of the current therapeutics and novel treatment strategies for patients diagnosed with BM from NSCLC.

Guilian Li,1,* Qian Guo,1,2,* Haican Liu,1 Li Wan,1 Yi Jiang,1 Machao Li,1 Li-li Zhao,1 Xiuqin Zhao,1 Zhiguang Liu,1 Kanglin Wan1 1State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, People’s Republic of China; 2Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kanglin Wan Email wankanglin@icdc.cnBackground: Reliable and timely determination of second-line drug resistance is essential for early initiation effective anti-tubercular treatment among multi-drug resistant (MDR) patients and blocking the spread of MDR and extensively drug-resistant tuberculosis. Molecular methods have the potency to provide accurate and rapid drug susceptibility results. We aimed to establish and evaluate the accuracy of a reverse dot blot hybridization (RDBH) assay to simultaneously detect the resistance of fluoroquinolones (FQs), kanamycin (KN), amikacin (AMK), capreomycin (CPM) and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis.Methods: We established and evaluated the accuracy of the RDBH assay by comparing to the phenotypic drug susceptibility testing (DST) and sequencing in 170 M. tuberculosis, of which 94 and 27 were respectively resistant to ofloxacin (OFX) and SLIDs.Results: The results show that, compared to phenotypic DST, the sensitivity and specificity of the RDBH assay for resistance detection were 63.8% and 100.0% for OFX, 60.0% and 100.0% for KN, 61.5% and 98.1% for AMK, 50.0% and 99.3% for CPM, and 55.6% and 100% for SLIDs, respectively; compared to sequencing, the sensitivity and specificity of the RDBH assay were 95.2% and 100.0% for OFX, 93.8% and 100.0% for SLIDs or KN (both based on mutations in rrs 1400 region and eis promoter), and 91.6% and 100.0% for AMK or CPM (both based on mutations in rrs 1400 region), respectively. The turnaround time of the RDBH assay was 7 h for testing 42 samples.Conclusion: Our data suggested that compared to sequencing, the RDBH assay could serve as a rapid and reliable method for testing the resistance of M. tuberculosis against OFX and SLIDs, enabling early administration of appropriate treatment regimens among MDR tuberculosis patients.Keywords: Mycobacterium tuberculosis, drug resistance, reverse dot blot hybridization, fluoroquinolones, second-line injectable drugs, ofloxacin, kanamycin, amikacin, capreomycin

The placenta is a vital organ formed during pregnancy, and being the interface between the mother and fetus, it is paramount that placental functioning is strictly controlled. Gene expression in the placenta is finely tuned—with aberrant expression causing placental pathologies and inducing stress on both mother and fetus. Gene regulation is brought upon by several mechanisms, and small non-coding RNAs (sncRNAs) have recently been appreciated for their contribution in gene repression. Their dysregulation has been implicated in a range of somatic and inherited disorders, highlighting their importance in maintaining healthy organ function. Their specific roles within the placenta, however, are not well understood, and require further exploration. To this end, we summarize the mechanisms of microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), and transfer RNAs (tRNAs), their known contributions to human placental health and disease, the relevance of sncRNAs as promising biomarkers throughout pregnancy, and the current challenges faced by placental sncRNA studies.

Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumor-derived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRASG12V or EGFRL858R expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (Tregs), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high CCL5 expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.