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Vladislav Berdunov,1 Gebra Cuyun Carter,2 Ewan Laws,1 Roger Luo,2 Christy A Russell,2 Sara Campbell,2 Yara Abdou,3 Jeremy Force4 1Putnam, London, UK; 2Exact Sciences, Madison, WI, USA; 3School of Medicine, UNC, Chapel Hill, NC, USA; 4School of Medicine, Duke University, Durham, NC, USACorrespondence: Vladislav Berdunov, Putnam, 22-24 Torrington Place, Fitzrovia, London, WC1E 7HJ, UK, Tel +44 7542947557, Email vlad.berdunov@putassoc.comBackground and Objectives: The 21-gene assay (the Oncotype DX Breast Recurrence Score® test) estimates the 10-year risk of distant recurrence in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) early-stage breast cancer to inform adjuvant chemotherapy decisions. The cost-effectiveness of the 21-gene assay compared against standard clinical-pathological risk tools alone for HR+/HER2- early-stage breast cancer was assessed using an economic model informed by evidence from randomized controlled trials.Materials and Methods: A cost-effectiveness model consisted of a decision-tree to stratify patients according to their Recurrence Score (RS) results and the use of adjuvant chemotherapy, followed by a Markov component to estimate the long-term costs and outcomes of the chosen treatment. Distributions of patients and distant recurrence probabilities were derived from the TAILORx (N0) and RxPONDER (N1) trials. The model was evaluated from a healthcare payer and societal perspective. Endocrine therapy and chemotherapy use were informed using clinical expert opinion to reflect US clinical practice and were combined with Medicare drug costs (2021) to estimate the cost of treatment. Societal costs included lost productivity and patient out-of-pocket costs obtained from literature.Results: The Oncotype DX test generated more quality-adjusted life-years (QALYs) (N0: 0.25; N1: 0.08) at a lower cost (N0: -$13,395; N1: -$2526) compared to clinical-pathological risk alone from a societal cost perspective. The overall conclusions from the model did not change when considering a payer perspective. The main cost drivers were avoidance of distant recurrence for N0 (-$12,578), and the cost of adjuvant chemotherapy for N1 (-$2133). Lost productivity had a major impact in the societal perspective analysis (N0: -$4607; N1: -$1586).Conclusion: Adjuvant chemotherapy decisions based on the RS result led to more life year gains and lower healthcare costs (dominant) compared to using clinical-pathological risk factors alone among patients with HR+/HER2- N0 and N1 early-stage breast cancer.Keywords: cost-effectiveness, tumour profiling test, breast cancer, chemotherapy, the Oncotype DX test

Zhengqin Tian,1,* Qihang Man,1,* Yixin Yang,1,* Xiaomei Zhang,2,* Hexian Guan,1 Wenjing Gu,2 Ying Wang,1 Dandan Song,2 Rongmu Luo,1,2 Jingbo Wang1 1Department of Hematology, Aerospace Center Hospital, Beijing, People’s Republic of China; 2Department of Hematology, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongmu Luo; Jingbo Wang, Email luorongmu@163.com; wangjingbo721@126.comAbstract: Engraftment syndrome (ES) is an early complication of hematopoietic stem cell transplantation (HSCT) characterized by fever and additional clinical manifestations including rash, diarrhea, lung infiltrates, weight gain, and neurological symptoms. Steroid-resistant ES following HSCT significantly affects the efficacy of transplantation and may even result in patient mortality. As ES essentially represents a cytokine storm induced by engrafted donor cells with interferon-gamma (IFN-γ) playing a central role, we hypothesized that emapalumab (an anti-IFN-γ monoclonal antibody) may be an effective approach to treat steroid-resistant ES. Here, we present a case report of a 14-year-old female patient who received a second haploidentical HSCT due to a relapse of acute myeloid leukemia. Nine days after the transplantation, the patient developed a fever and exhibited a poor response to antimicrobials (ceftazidime/avibactam). A few days later, the patient presented with a new-onset rash, weight gain, and impaired liver function, leading to a diagnosis of ES. Initial immunosuppressive (tacrolimus and mycophenolate mofetil) treatment failed to control the disease. On day 16 post-transplantation, the patient received two infusions of 50 mg of emapalumab. Following the initiation of emapalumab treatment, the patient’s fever returned to normal and ES was effectively controlled. This case report demonstrated that emapalumab had a possible efficacy for steroid-resistant ES and provided a novel therapeutic strategy to treat this clinical complication.Keywords: haploidentical hematopoietic stem cell transplantation, engraftment syndrome, emapalumab, acute myeloid leukemia

Siyi Zhang,1,2,* Yue Zhou,1,* Jinghui Wang,2 Qingan Fu,1 Tianzhou Shen,2 Guanrui Pan,2 Renfei Luo,1 Xinlei Yang,3 Long Jiang,1 Hui Hu4 1Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 2Department of Clinical Medicine, Queen Mary School of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 3Department of Biobank Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 4Department of Medical Big Data Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Long Jiang, Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China, Tel +86-13767026990, Email skyiadx@hotmail.com Hui Hu, Department of Medical Big Data Center, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China, Tel +86-13576978125, Email huhuillz@sina.comBackground: Lipoprotein(a) [Lp(a)] is a well-established risk factor for ischaemic stroke (IS). It is unclear whether Lp(a) is associated with IS in patients with atrial fibrillation (AF). The aim of this study is to explore the association between the concentration of Lp(a) and the risk of IS in AF patients, hope to find the potential risk factor for the IS in AF patients.Methods: This study is a retrospective cohort study. The screened AF patients between January 2017 and July 2021 were matched at 1:1 by the propensity score matching (PSM) method in the Second Affiliated Hospital of Nanchang University. Associations between Lp(a) and ischaemic stroke were analysed using logistic regression models, stratified analysis and sensitivity analysis. Statistical analyses were conducted using IBM SPSS software.Results: The number of enrolled participates is 2258, which contains 1129 non-AF patients and 1129 AF patients. Among IS patients, the median Lp(a) concentration was higher than that of controls (17.03 vs. 15.36 mg/dL, P = 0.032). The Spearman rank-order correlation coefficients revealed significant positive relationships between IS and Lp(a) (P = 0.032). In addition, a significant increase in IS risk was associated with Lp(a) levels > 30.00 mg/dL in unadjusted model [OR:1.263, 95% CI(1.046– 1.523), P = 0.015], model 1 [OR:1.284, 95% CI(1.062,1.552), P = 0.010], model 2 [OR: 1.297, 95% CI(1.07,1.573). P = 0.008], and model 3 [OR: 1.290, 95% CI (1.064, 1.562). P = 0.009]. The stratified analysis indicated that this correlation was not affected by female sex [1.484 (1.117, 1.972), P = 0.006], age ≤ 60 [1.864 (1.067-3.254), P=0.029], hypertension [1.359 (1.074, 1.721), P = 0.011], or non-coronary heart disease (CHD) [1.388 (1.108, 1.738), P = 0.004].Conclusion: High levels of Lp(a) were significantly related to IS in AF patients and may be a potential risk factor in the onset of an IS in AF patients. Keywords: ischaemic stroke, Lipoprotein(a), atrial fibrillation, risk factor, retrospective cohort study

Wenjie Wei,* Renrui Luo,* Zhikui Chen, Jianbin He Department of Respiratory and Critical Care Medicine, Hunan University of Medicine General Hospital, Huaihua, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianbin He, Department of Respiratory and Critical Care Medicine, Hunan University of Medicine General Hospital, Jinxi South Road 144, Hecheng District, Huaihua, 418000, People’s Republic of China, Email hjb0919@aliyun.comAbstract: In the available reports on clinical medicine, the infection sites of Mycobacterium porcinum include wounds, bone marrow, respiratory tract, and catheters. A 61-year-old woman was admitted to our hospital; her hilar and mediastinal lymph nodes were found to be enlarged during health examination, but there was no specific discomfort. Initially, she had undergone a mediastinal lymph node biopsy and pathology, but the diagnosis was not confirmed. However, 16S rRNA gene sequencing revealed M. porcinum infection of hilar and mediastinal lymph nodes. Subsequently, she was treated with clarithromycin, amikacin, imipenem, and tigecycline. After 2 months, chest computed tomography showed a significant reduction in lymph nodes. M. porcinum infection was considered to be the cause of disease.Keywords: Mycobacterium porcinum, hilar, mediastinal, lymph nodes, infection

Chunxiang He,1,2 Ze Li,1,2 Miao Yang,1,2 Wenjing Yu,1,2 Rongsiqing Luo,1,2 Jinyong Zhou,1,2 Jiawei He,1,2 Qi Chen,1,2 Zhenyan Song,1,2 Shaowu Cheng1,2 1School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 2Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Zhenyan Song; Shaowu Cheng, Tel +86 073188458257, Email songzhenyan2013@hnucm.edu.cn; scheng@hnucm.edu.cnAbstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by complex pathophysiological features. Amyloid plaques resulting from extracellular amyloid deposition and neurofibrillary tangles formed by intracellular hyperphosphorylated tau accumulation serve as primary neuropathological criteria for AD diagnosis. The activation of microglia has been closely associated with these pathological manifestations. Non-coding RNA (ncRNA), a versatile molecule involved in various cellular functions such as genetic information storage and transport, as well as catalysis of biochemical reactions, plays a crucial role in microglial activation. This review aims to investigate the regulatory role of ncRNAs in protein expression by directly targeting genes, proteins, and interactions. Furthermore, it explores the ability of ncRNAs to modulate inflammatory pathways, influence the expression of inflammatory factors, and regulate microglia activation, all of which contribute to neuroinflammation and AD. However, there are still significant controversies surrounding microglial activation and polarization. The categorization into M1 and M2 phenotypes may oversimplify the intricate and multifaceted regulatory processes in microglial response to neuroinflammation. Limited research has been conducted on the role of ncRNAs in regulating microglial activation and inducing distinct polarization states in the context of neuroinflammation. Moreover, the regulatory mechanisms through which ncRNAs govern microglial function continue to be refined. The current understanding of ncRNA regulatory pathways involved in microglial activation remains incomplete and may be influenced by spatial, temporal, and tissue-specific factors. Therefore, further in-depth investigations are warranted. In conclusion, there are ongoing debates and uncertainties regarding the activation and polarization of microglial cells, particularly concerning the categorization into M1 and M2 phenotypes. The study of ncRNA regulation in microglial activation and polarization, as well as its mechanisms, is still in its early stages and requires further investigation. However, this review offers new insights and opportunities for therapeutic approaches in AD. The development of ncRNA-based drugs may hold promise as a new direction in AD treatment.Keywords: Alzheimer’s disease, non-coding RNA, neuroinflammation, microglia activation, miRNA, circRNA, lncRNA

Jiasheng Cai,1,&ast; Mingxuan Li,2,&ast; Wei Wang,1,&ast; Rong Luo,1 Zheng Zhang,1 Haibo Liu1 1Department of Cardiology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, 201700, People’s Republic of China; 2Department of Cardiology, Shanghai Medical College Fudan University, Huadong Hospital, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haibo Liu; Zheng Zhang, Department of Cardiology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Park, Shanghai, 201700, People’s Republic of China, Email haiboliu13@fudan.edu.cn; zhangzheng@qphospital.comBackgrounds and Aims: Atrial fibrillation (AF) is the most common cardiac arrhythmia among the older patients (≥ 80 years) in clinical practice. The index of neutrophil percentage-to-albumin ratio (NPAR) is a reliable predictor of adverse outcomes in cardiovascular diseases. There is scarce evidence regarding the association between NPAR and mortality among the older patients with AF.Methods: The research was conducted among 1141 patients with AF between January 2015 and June 2020, hospitalized at Huadong Hospital affiliated with Fudan University. The primary outcome were 28-day all-cause and cardiovascular mortality. Cox regression analysis and Kaplan-Meier survival curves were used to explore the correlation between NPAR and 28-day all-cause or cardiovascular mortality. Receiver operating characteristic (ROC) curve and the area under the curve (AUC) were performed for the predictive values of NPAR on prognosis.Results: The 28-day death rate from cardiovascular disease and all-causes were 3.3% and 8.7%, respectively. Continuous NPAR levels were positively associated with all-cause (HR 1.13, 95% CI 1.09, 1.16) and cardiovascular (HR 1.16, 95% CI 1.10, 1.23) mortality after adjustment for confounding variables. Relative to patients in the T1 group, those in higher NPAR tertiles also exhibit elevated risks of all-cause (P < 0.001) and cardiovascular mortality (P < 0.001). Furthermore, both all-cause and cardiovascular mortality rates rose with increasing NPAR in all analyzed subgroups.Conclusion: NPAR values are consistently positively related to 28-day all-cause and cardiovascular mortality rates in patients ≥ 80 years of age with AF.Keywords: cardiovascular disease, neutrophil, atrial fibrillation, mortality, older

Hui Li,1,2,&ast; Tao Liu,1,2,&ast; Jingjing Sun,1,2 Shuai Zhao,1,2 Xin Wang,1,2 Wei Luo,1,2 Ruyi Luo,1,2 Weiyun Shen,1,2 Cong Luo,1,2 Di Fu3 1Department of Anesthesiology, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University, Changsha, People’s Republic of China; 3Department of Anesthesiology, the XiangYa Hospital, Central South University, ChangSha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Di Fu, Department of Anesthesiology, the XiangYa Hospital, Central South University, Xiangya Road No. 86, Changsha, Hunan Province, 410011, People’s Republic of China, Tel/Fax +86 85295987, Email xyyyfudi@csu.edu.cnBackground: The spinal cord expresses brain-derived neurotrophic factor precursor (proBDNF) and its receptor pan neurotrophin receptor 75 (p75NTR). However, the role of spinal proBDNF signaling in the pathogenesis of inflammatory pain remains unknown.Methods: Rats were locally injected with complete Freund’s adjuvant (CFA) to induce inflammatory pain. The proBDNF signal expression was detected by double-labeled immunofluorescence. ProBDNF protein, p75NTR extracellular domain (p75NTR-ECD), or monoclonal anti-proBDNF (McAb-proB) were administrated by intrathecal injection to investigate their effects on pain behavior. Paw withdrawal thermal latency (PWL) and paw withdrawal mechanical threshold (PWT) were performed to evaluate pain behavior. Immunoblotting, immunohistochemistry, and immunofluorescence were used to assess inflammation-induced biochemical changes.Results: CFA induced a rapid increase in proBDNF in the ipsilateral spinal cord, and immunofluorescence revealed that CFA-enhanced proBDNF was expressed in NeuN positive neurons and GFAP positive astrocytes. The administration of furin cleavage-resistant proBDNF via intrathecal injection (I.t.) significantly decreased the PWT and PWL, whereas McAb-proB by I.t. alleviated CFA-induced pain-like hypersensitivity in rats. Meanwhile, CFA administration triggered the activation of p75NTR and its downstream signaling extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor (NF)-kappaB p65 in the spinal cord. I.t. administration of p75NTR-ECD suppressed CFA-induced pain and neuroinflammation, including the expression of p-ERK1/2, p-p65, and the gene expression of tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6).Conclusion: Our study reveals that the activated proBDNF/p75NTRsignaling in the spinal cord contributes to the development of CFA-induced inflammatory pain. McAb-proB and p75NTR-ECD appear to be promising therapeutic agents for inflammatory pain.Keywords: brain-derived neurotrophic factor precursor, inflammatory pain, spinal cord, neuron, pan neurotrophin receptor 75

Fast radio bursts (FRBs) are millisecond-duration radio transients.sup.1,2 of unknown origin. Two possible mechanisms that could generate extremely coherent emission from FRBs invoke neutron star magnetospheres.sup.3-5 or relativistic shocks far from the central energy source.sup.6-8. Detailed polarization observations may help us to understand the emission mechanism. However, the available FRB polarization data have been perplexing, because they show a host of polarimetric properties, including either a constant polarization angle during each burst for some repeaters.sup.9,10 or variable polarization angles in some other apparently one-off events.sup.11,12. Here we report observations of 15 bursts from FRB 180301 and find various polarization angle swings in seven of them. The diversity of the polarization angle features of these bursts is consistent with a magnetospheric origin of the radio emission, and disfavours the radiation models invoking relativistic shocks. Polarization observations of the fast radio burst FRB 180301 with the FAST radio telescope show diverse polarization angle swings, consistent with a magnetospheric origin of the emission., Author(s): R. Luo [sup.1] [sup.2] [sup.3] , B. J. Wang [sup.1] [sup.2] , Y. P. Men [sup.1] [sup.2] , C. F. Zhang [sup.1] [sup.2] , J. C. Jiang [sup.1] [sup.2] [...]

Xianli Wei,1,* Junzi Ke,2,3,* Haonan Huang,2,3,* Shikun Zhou,2,3 Ao Guo,4 Kun Wang,2,3 Yujuan Zhan,2,3 Cong Mai,5 Weizhen Ao,3 Fuda Xie,6,7 Rongping Luo,8 Jianyong Xiao,2 Hang Wei,4 Bonan Chen2,3 1Department of Medical Instruments, Guangdong Food and Drug Vocational College, Guangzhou 510520, People’s Republic of China; 2Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 3Research Center of Integrative Medicine, School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 4School of Medical Information Engineering, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5Department of Abdominal Surgery, Cancer Center of Guangzhou Medical University, Guangzhou 510095, People’s Republic of China; 6The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 7Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, People’s Republic of China; 8School of Foreign Language, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bonan Chen; Hang Wei Email 20171104455@stu.gzucm.edu.cn; crwei@gzucm.edu.cnIntroduction: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Up to now, many genes associated with HCC have not yet been identified. In this study, we screened the HCC-related genes through the integrated analysis of the TCGA database, of which the potential biomarkers were also further validated by clinical specimens. The discovery of potential biomarkers for HCC provides more opportunities for diagnostic indicators or gene-targeted therapies.Methods: Cancer-related genes in The Cancer Genome Atlas (TCGA) HCC database were screened by a random forest (RF) classifier based on the RF algorithm. Proteins encoded by the candidate genes and other associated proteins obtained via protein–protein interaction (PPI) analysis were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The newly identified genes were further validated in the HCC cell lines and clinical tissue specimens by Western blotting, immunofluorescence, and immunohistochemistry (IHC). Survival analysis verified the clinical value of genes.Results: Ten genes with the best feature importance in the RF classifier were screened as candidate genes. By comprehensive analysis of PPI, GO and KEGG, these genes were confirmed to be closely related to HCC tumors. Representative NOX4 and FLVCR1 were selected for further validation by biochemical analysis which showed upregulation in both cancer cell lines and clinical tumor tissues. High expression of NOX4 or FLVCR1 in cancer cells predicts low survival.Conclusion: Herein, we report that NOX4 and FLVCR1 are promising biomarkers for HCC that may be used as diagnostic indicators or therapeutic targets.Keywords: hepatocellular carcinoma, biomarkers, TCGA database, NOX4, FLVCR1

Peng Li,1 Ruihua Luo,1 Lanwei Guo,2 Wenlu Li,3 Jinxing Qi1 1Department of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Office for Cancer Control and Research, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Oral and Maxillofacial Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Peng LiDepartment of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, 127 Dongming Road, Jinshui District, Zhengzhou 450008, Henan, People’s Republic of ChinaEmail zlyylipeng2383@zzu.edu.cnObjective: To investigate the effects of different values of the body mass index (BMI) on postoperative hemorrhage (PH) in thyroid cancer (TC) and its clinical management.Methods: This retrospective cohort study selected 43 patients with hemorrhage after TC surgery in 7413 cases. Patients were divided based on the BMI (kg/m2) into normal (24), overweight group (24 ≤BMl< 28) and obese (≥ 28) groups. Clinical and pathologic data, bleeding cause, bleeding site, treatment and prognosis were assessed.Results: BMI (P=0.038) is an independent risk factor for PH of TC, related to hypertension (P=0.004) and coronary heart disease (P=0.001) in the three groups. Preoperative weight loss was not noted (P=0.477). Hemorrhage in 60.47% of patients occurred between 4 h and 8 h after surgery. The higher the BMI, the longer was the operative time (≥ 1 h, 65.12%) (P=0.017), which resulted in greater intraoperative blood loss (≥ 20 mL, 74.42%) (P=0.025), postoperative hypoparathyroidism (P=0.015) and the probability of injury to the recurrent laryngeal nerve (P=0.026). The main causes of bleeding were incomplete vascular ligation (30.23%), severe postoperative cervical activity (16.28%) and long-term use of anticoagulant drugs (11.63%). Overall survival at 5 years in the obese group was poor (P=0.015). Forty patients (93.02%) underwent surgical exploration and hemostasis and two patients (4.65%) underwent tracheotomy. All PH complications disappeared completely after active postoperative treatment, and all patients were discharged from hospital.Conclusion: Obesity is closely associated with PH in TC patients. Therefore, in obese patients, active prevention preoperatively, complete hemostasis intraoperatively, early detection and timely treatment postoperatively are the key factors to reduce PH risk.Keywords: body mass index, thyroid cancer, hemorrhage

Ru-Yin Hu,1–3,* Xiao-Bin Tian,3,* Bo Li,3 Rui Luo,3 Bin Zhang,3 Jin-Min Zhao1 1Department of Orthopaedics, Guangxi Medical University, Nanning 530021, People’s Republic of China; 2Department of Orthopaedics, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, People’s Republic of China; 3Department of Orthopaedics, Guizhou Provincial People’s Hospital, Guiyang 550002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jin-Min ZhaoDepartment of Orthopaedics, Guangxi Medical University, No. 22 Shuangyong Road, Nanning, Guangxi 530021, People’s Republic of ChinaTel +86 771 13985048001Email zhao948586007@126.comBackground: Existing drugs are far from enough for investigators and patients to administrate the therapy of rheumatoid arthritis. Drug repositioning has drawn broad attention by reusing marketed drugs and clinical candidates for new uses.Purpose: This study attempted to predict candidate drugs for rheumatoid arthritis treatment by mining the similarities of pathway aberrance induced by disease and various drugs, on a personalized or customized basis.Methods: We firstly measured the individualized pathway aberrance induced by rheumatoid arthritis based on the microarray data and various drugs from CMap database, respectively. Then, the similarities of pathway aberrances between RA and various drugs were calculated using a Kolmogorov–Smirnov weighted enrichment score algorithm.Results: Using this method, we identified 4 crucial pathways involved in rheumatoid arthritis development and predicted 9 underlying candidate drugs for rheumatoid arthritis treatment. Some candidates with current indications to treat other diseases might be repurposed to treat rheumatoid arthritis and complement the drug group for rheumatoid arthritis.Conclusion: This study predicts candidate drugs for rheumatoid arthritis treatment through mining the similarities of pathway aberrance induced by disease and various drugs, on a personalized or customized basis. Our framework will provide novel insights in personalized drug discovery for rheumatoid arthritis and contribute to the future application of custom therapeutic decisions.Keywords: rheumatoid arthritis, drug repositioning, individualized pathway aberrance, differential pathway

Ke Li,1 Dengyang Fang,1 Zuming Xiong,1 Runlan Luo21Department of General Surgery, Fuling Central Hospital of Chongqing City, Chongqing, People’s Republic of China; 2Department of Ultrasound, Fuling Central Hospital of Chongqing City, Chongqing, People’s Republic of ChinaCorrespondence: Runlan LuoDepartment of Ultrasound, Fuling Central Hospital of Chongqing City, Chongqing 408000, People’s Republic of ChinaEmail 156460145@qq.comAbstract: Itraconazole (ITZ) is an anti-fungal drug that has been used in clinical practice for nearly 35 years. Recently, numerous experiments have shown that ITZ possesses anti-cancer properties. The Hedgehog (Hh) pathway plays a pivotal role in fundamental processes, including embryogenesis, structure, morphology and proliferation in various species. This pathway is typically silent in adult cells, and inappropriate activity is linked to various tumor types. The most important mechanism of ITZ in the treatment of cancer is inhibition of the Hh pathway through the inhibition of smoothened receptors (SMO), glioma-associated oncogene homologs (GLI), and their downstream targets. In this review, we discuss the mechanisms of ITZ in the treatment of cancer through inhibition of the Hh pathway, which includes anti-inflammation, prevention of tumor growth, induction of cell cycle arrest, induction of apoptosis and autophagy, prevention of angiogenesis, and drug resistance. We also discuss the clinical use of ITZ in many types of cancers. We hope this review will provide more information to support future studies on ITZ in the treatment of various cancers.Keywords: Itraconazole, cancer, hedgehog pathway, apoptosis, autophagy

As the sample size of repeating fast radio bursts (FRBs) has grown, an increasing diversity of phenomenology has emerged. Through long-term multi-epoch studies of repeating FRBs, it is possible to assess which phenomena are common to the population and which are unique to individual sources. We present a multi-epoch monitoring campaign of the repeating FRB source 20180301A using the ultra-wideband low (UWL) receiver observations with Murriyang , the Parkes 64-m radio telescope. The observations covered a wide frequency band spanning approximately 0.7–4 GHz, and yielded the detection of 46 bursts. None of the repeat bursts displayed radio emission in the range of 1.8–4 GHz, while the burst emission peaked at 1.1 GHz. We discover evidence for secular trends in the burst dispersion measure, indicating a decline at a rate of |$-2.7\pm 0.2\, {\rm pc\, cm^{-3}\, yr^{-1}}$|⁠. We also found significant variation in the Faraday rotation measure of the bursts across the follow-up period, including evidence of a sign reversal. While a majority of bursts did not exhibit any polarization, those that did show a decrease in the linear polarization fraction as a function of frequency, consistent with spectral depolarization due to scattering, as observed in other repeating FRB sources. Surprisingly, no significant variation in the polarization position angles was found, which is in contrast with earlier measurements reported for the FRB source. We measure the burst rate and sub-pulse drift rate variation and compare them with the previous results. These novel observations, along with the extreme polarization properties observed in other repeating FRBs, suggest that a sub-sample of FRB progenitors possess highly dynamic magneto-ionic environments. [ABSTRACT FROM AUTHOR]

We report five new fast radio bursts (FRBs) discovered from the Galactic Plane Pulsar Snapshot (GPPS) survey by the Five-hundred-meter Aperture Spherical radio Telescope (FAST): FRB 20210126, FRB 20210208, FRB 20210705, FRB 20211005, and FRB 20220306. To date, no repeating bursts from these FRB sources have been detected in the follow-up monitoring observations, leading to their classification as potential one-off events. We obtain the basic parameters for these bursts, including position, dispersion measure, pulse width, spectral index, scattering time-scale, etc. The fluences and flux densities are generally lower in comparison to the values observed in one-off bursts discovered by other telescopes. Among the observed bursts, polarization data for four bursts were recorded during observations. Consequently, we obtain polarization profiles and Faraday rotation measures for these bursts. [ABSTRACT FROM AUTHOR]

Junhui Su,1–3,* Cui Chang,3,* Qi Xiang,1,2 Zhi-Wei Zhou,4 Rong Luo,5 Lun Yang,6 Zhi-Xu He,7 Hongtu Yang,2,3 Jianan Li,1 Yu Bei,1 Jinmei Xu,1,2 Minjing Zhang,1 Qihao Zhang,1 Zhijian Su,1 Yadong Huang,1 Jiyan Pang,5 Shu-Feng Zhou4,7 1Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, 2Department of Pharmacy, Jinan University, Guangzhou, 3The People’s Hospital of Shenzhen City, Shenzhen, People’s Republic of China; 4Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, FL, USA; 5School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, 6Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 7Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, People’s Republic of China *These two authors contributed equally to this work Abstract: Natural compounds are becoming popular for the treatment of illnesses and health promotion, but the mechanisms of action and safety profiles are often unknown. Xyloketal B (XKB) is a novel marine compound isolated from the mangrove fungus Xylaria sp., with potent antioxidative, neuroprotective, and cardioprotective effects. However, its molecular targets and effects on drug-metabolizing enzymes are unknown. This study aimed to investigate the potential molecular targets of XKB using bioinformatic approaches and to examine the effect of XKB on the expression and activity of rat cytochrome P450 3a (Cyp3a) subfamily members using midazolam as a model probe. DDI-CPI, a server that can predict drug–drug interactions via the chemical–protein interactome, was employed to predict the targets of XKB, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to analyze the pathways of the predicted targets of XKB. Homology modeling was performed using the Discovery Studio program 3.1. The activity and expression of rat hepatic Cyp3a were examined after the rats were treated with XKB at 7 and 14 mg/kg for 8 consecutive days. Rat plasma concentrations of midazolam and its metabolite 1'-OH-midazolam were determined using a validated high-performance liquid chromatographic method. Bioinformatic analysis showed that there were over 324 functional proteins and 61 related signaling pathways that were potentially regulated by XKB. A molecular docking study showed that XKB bound to the active site of human cytochrome P450 3A4 and rat Cyp3a2 homology model via the formation of hydrogen bonds. The in vivo study showed that oral administration of XKB at 14 mg/kg to rats for 8 days significantly increased the area under the plasma concentration-time curve (AUC) of midazolam, with a concomitant decrease in the plasma clearance and AUC ratio of 1'-OH-midazolam over midazolam. Further, oral administration of 14 mg/kg XKB for 8 days markedly reduced the activity and expression of hepatic Cyp3a in rats. Taken together, the results show that XKB could regulate networks of molecular proteins and related signaling pathways and that XKB downregulated hepatic Cyp3a in rats. XKB might cause drug interactions through modulation of the activity and expression of Cyp3a members. More studies are warranted to confirm the mechanisms of action of XKB and to investigate the underlying mechanism for the regulating effect of XKB on Cyp3a subfamily members. Keywords: Xyloketal B, molecular target, cytochrome P450 3A, DDI-CPI tool, DAVID, midazolam, pharmacokinetics, rat, bioinformatics

1. In this study, transcriptomics and metabolomics were used to analyse changes in gene expression and metabolites in the liver of 70-d-old mule ducks after 10 and 20 d of continuous overfeeding. 2. In the free-feeding group, 995 differentially expressed genes and 51 metabolites (VIP >1, P < 0.05) were detected in the early stage, and 3,448 differentially expressed genes and 55 metabolites (VIP >1, P < 0.05) were detected in the later stage. There were 775 differentially expressed genes and 47 metabolites (VIP >1, P < 0.05) detected in the early stage of the overfeeding group, and 6,719 differentially expressed genes and 57 metabolites (VIP >1, P < 0.05) detected in the later stage. 3. There were no significant differences between the early stage in the overfeeding and free-feeding groups at the transcriptional and metabolic levels. Oleic acid and palmitic acid synthesis increased in the early stage of the overfeeding and free-feeding groups, however, these were inhibited in the late stage. Fatty acid oxidation and β-oxidation pathways were inhibited and insulin resistance was enhanced significantly in the late overfeeding stage. 4. In the early stage, the digestion and absorption of fat in the overfeeding and free-feeding groups were enhanced. In the later stage, the ability to store triglyceride in the overfeeding group was greater than in the free-feeding group. 5. The expression of nuclear factor κB (NFκB), a key inflammatory factor, was inhibited in the late stage of overfeeding, while arachidonic acid (AA), a metabolite with anti-inflammatory properties, increased in the late stage of overfeeding to inhibit the inflammatory effects caused by excessive lipid accumulation. These results add to the understanding of the mechanism of production of fatty liver in mule ducks and facilitate the development of treatments for non-alcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

1. This study aimed to study the preventive and therapeutic effects of andrographolide (Andro) during Mycoplasma gallisepticum HS strain (MG) infection in ArborAcres (AA) broilers. 2. The minimum inhibitory concentration (MIC) of Andro against MG was measured. Broiler body weight, feed efficiency, morbidity, cure rate and mortality were recorded during the experiment. Air sac lesion scores and immune organ index were calculated. Expression of pMGA1.2 in lung tissue and serum biochemical indices were examined. Histopathological examinations of immune organs, liver, trachea and lung tissue were conducted by Haematoxylin and Eosin stain. 3. MIC was 3.75 μg/mL and Andro significantly inhibited the expression of pMGA1.2 (P ≤ 0.05). Compared with control MG-infected group, Andro low-dose and high-dose prevention reduced the morbidity of chronic respiratory disease in 40.00% and 50.00%, respectively. Mortality of C, D and E group was 16.67%, 10.00% and 6.67%, respectively. Cure rate of E, F, G and H group was 92.00%, 92.86%, 93.33% and 100.0%, respectively. Compared with control MG-infected group, Andro treatment significantly increased average weight gain (AWG), relative weight gain rate (RWG) and feed conversion rate (FCR) at 18 to 24 days (P ≤ 0.05). Compared with control group, Andro alone treatment significantly increased AWG in broilers (P ≤ 0.05). 4. Compared with control MG-infected group, Andro significantly attenuated MG-induced air sac lesion, immune organs, liver, trachea and lung damage in broilers. Andro alone treatment did not induce abnormal morphological changes in these organs in healthy broilers. Serum biochemical analysis results showed, comparing with control MG-infected group, Andro significantly decreased the content of total protein, albumin, globulin, alanine aminotransferase, aspartate aminotransferase, total bilirubin, urea, creatinine, uric acid, total cholesterol, and increased the albumin/globulin ratio and content of alkaline phosphatase, apolipoprotein B and apolipoprotein A-I in a dose-dependent manner (P ≤ 0.05). 5. Andro could act as a potential agent against MG infection in broilers. [ABSTRACT FROM AUTHOR]