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Min Lei,1,2,&ast; Zheng Jiang,1,2,&ast; Peng Xu,1,2 Zhenglin Chang,1– 3 Yuyan Zhang,4 Shike Zhang,1,2 Lingyue An,1,2,5 Shujue Li,2,3 Tao Zeng,2,3 Hans-Göran Tiselius,6 Yuhao Zhou,1,2 Guohua Zeng,2,3 Wenqi Wu1,2 1Department of Urology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 2Guangdong Key Laboratory of Urology, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 3Department of Urology, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 4Guangzhou Institute of Dermatology, Guangzhou, Guangdong, 510095, People’s Republic of China; 5Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China; 6Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, 14186, Sweden&ast;These authors contributed equally to this workCorrespondence: Wenqi Wu; Guohua Zeng, Email 2009681012@gzhmu.edu.cn; gzgyzgh@vip.sina.comBackground: The purpose of this study was to identify bacterial differences between urine cultures (UC) and stone cultures (SC) in patients with complex kidney stones and to determine any correlation with post-percutaneous nephrolithotomy Systemic Inflammatory Response Syndrome (SIRS).Methods: Perioperative data of 1055 patients with complex kidney stones treated with first-stage Percutaneous Nephrolithotomy (PCNL) from September 2016 until September 2021 were included. Preoperative mid-stream urine samples and surgically obtained stone material were subjected to bacterial culture and antibiotic sensitivity tests. Preoperatively, antibiotic usage was determined by the UC or local bacterial resistance patterns. After PCNL treatment, antibiotic selection was guided by stone bacterial culture result and clinical symptoms. The effect of different preoperative antibiotic regimens based on urine cultures and postoperative antibiotic treatment based on stone cultures were assessed.Results: Positive stone cultures (SC+) were significantly more common than positive urine cultures (UC+) (31.9% vs 20.9%, p < 0.05). Escherichia coli (E. coli) was the most common uropathogen in both urine (54.3%) and stones (43.9%). The difference was statistically significant (p < 0.05). Moreover, UC+SC-, UC-SC+, UC+SC+, and preoperative serum creatinine were independent risk factors of postoperative SIRS. The incidence of SIRS in the UC+SC+ patients with different bacteria in stones and urine (51.6%) was higher than that in other culture groups. The antibiotic resistance of E. coli inside the stone was increased when prolonged preoperative antibiotics were administered to UC+ patients.Conclusion: The bacterial spectrum and positive outcome of culture in urine and stones were significantly different. The incidence of postoperative SIRS was highest in patients with UC+SC+ but with different bacteria strains. Prolonged pre-surgical antibiotic treatment apparently induced higher drug resistance for bacteria inside the stone.Keywords: kidney stones, bacterial spectrum, antibiotic resistance, stone culture, urine culture

Hua Zheng,1 Changqing Li,1 Lirong Zhang,2 Tailin Wang,3 Zengliang Cai,4 Mingxing Lei5,6 1College of Physical Education and Health Science, Chongqing Normal University, Chongqing, 401331, People’s Republic of China; 2Department of Physical Education, Xiamen University of Technology, Xiamen, Fujian, 361024, People’s Republic of China; 3School of Physical Education, North University of China, Taiyuan, Shanxi, 030051, People’s Republic of China; 4Department of Physical Education, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 5Chinese PLA General School, Beijing, 100853, People’s Republic of China; 6Chinese PLA General Hospital, Beijing, 100853, People’s Republic of ChinaCorrespondence: Mingxing Lei, Department of Orthopedic Surgery, Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100039, People’s Republic of China, Tel +8618811772189, Email leimingxing@301hospital.com.cn Zengliang Cai, Department of Physical Education, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, People’s Republic of China, Email caizengliang@shutcm.edu.cnBackground: University students are a vulnerable population prone to mental health challenges. This study aimed to investigate depression and its associated factors among university students in terms of demographics, eating habits, and exercises.Methods: A total of 2891 university students from three universities participated in this study between January 2024 and February 2024. An online survey questionnaire was distributed using a snow-ball strategy. The survey collected demographic, lifestyle, and psychological data, including depression and anxiety scores using the PHQ-9 and GAD-7 screening tools. Subgroup analysis was conducted according to sport frequency and sport type using Chi-square test for qualitative data and t-test for quantitative data. Multiple linear regression analysis was performed to identify risk factors for depression.Results: A total of 44.2% and 39.5% of the participants reported symptoms of depression and anxiety, respectively. Significant differences were observed in various characteristics across different sport frequency groups, with participants with higher sport frequency tending to have less depression (P< 0.001) and anxiety (P< 0.001) symptoms. As the frequency of weekly exercise increased, anxiety and depression scores gradually decreased. The mean PHQ-9 and GAD-7 scores were highest in the group with no sports and lowest in the group with a sport frequency of 3– 4 times per week (P< 0.001). Additionally, once exercise frequency reached 5 times per week or more, anxiety and depression scores no longer decreased. Subgroup analysis based on sport type revealed that participants engaging in specific sports, such as basketball, tennis, dance, and running, had lower depression (P< 0.001) and anxiety (P< 0.001) scores compared to the overall average. Based on multiple linear regression analysis, married status (P=0.036), enjoying barbecue food (P< 0.001), prolonged sedentary time (P=0.001), experiencing stress events (P< 0.001), and electronic device usage time (P< 0.001) were positively associated with depression scores, while loving eating vegetables (P=0.007), a relatively longer sport time (P=0.005), a higher exercise frequency (P=0.064), and no chronic disease (P< 0.001) were negatively associated with depression scores.Conclusion: This study highlights the importance of a healthy lifestyle, including regular exercise, limited exposure to electronic screens, and a balanced diet, in preventing and mitigating depression among university students. This study also suggests that exercising 3– 4 times a week is associated with the lowest levels of anxiety and depression. Activities such as basketball, tennis, dance, and running are effective in alleviating these mental health issues through regular exercise.Keywords: depression, eating habits, sports, university students, cross-sectional study

Lirong Zhang,1 Shaocong Zhao,1 Zhongbing Yang,2 Hua Zheng,3 Mingxing Lei4,5 1Department of Physical Education, Xiamen University of Technology, Xiamen, Fujian, 361024, People’s Republic of China; 2School of Physical Education, Guizhou Normal University, Guizhou, 550025, People’s Republic of China; 3College of Physical Education and Health Sciences, Chongqing Normal University, Chongqing, 401331, People’s Republic of China; 4National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100039, People’s Republic of China; 5Department of Orthopedic Surgery, Chinese PLA General Hospital, Beijing, 100039, People’s Republic of ChinaCorrespondence: Hua Zheng, College of Physical Education and Health Sciences, Chongqing Normal University, No. 37, Middle Road, University Town, Shapingba District, Chongqing, 401331, People’s Republic of China, Tel +86+15923028254, Email 20130296@cqnu.edu.cn Mingxing Lei, Department of Orthopedic Surgery, Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China, Tel +86+18811772189, Email leimingxing@301hospital.com.cnBackground: Sleep problems are prevalent among university students, yet there is a lack of effective models to assess the risk of sleep disturbance. Artificial intelligence (AI) provides an opportunity to develop a platform for evaluating the risk. This study aims to develop and validate an AI platform to stratify the risk of experiencing sleep disturbance for university students.Methods: A total of 2243 university students were included, with 1882 students from five universities comprising the model derivation group and 361 students from two additional universities forming the external validation group. Six machine learning techniques, including extreme gradient boosting machine (eXGBM), decision tree (DT), k-nearest neighbor (KNN), random forest (RF), neural network (NN), and support vector machine (SVM), were employed to train models using the same set of features. The models’ prediction performance was assessed based on discrimination and calibration, and feature importance was determined using Shapley Additive exPlanations (SHAP) analysis.Results: The prevalence of sleep disturbance was 44.69% in the model derivation group and 49.58% in the external validation group. Among the developed models, eXGBM exhibited superior performance, surpassing other models in metrics such as area under the curve (0.779, 95% CI: 0.728– 0.830), accuracy (0.710), precision (0.737), F1 score (0.692), Brier score (0.193), and log loss (0.569). Calibration and decision curve analyses demonstrated favorable calibration ability and clinical net benefits, respectively. SHAP analysis identified five key features: stress score, severity of depression, vegetable consumption, age, and sedentary time. The AI platform was made available online at https://sleepdisturbancestudents-xakgzwectsw85cagdgkax9.streamlit.app/, enabling users to calculate individualized risk of sleep disturbance.Conclusion: Sleep disturbance is prevalent among university students. This study presents an AI model capable of identifying students at high risk for sleep disturbance. The AI platform offers a valuable resource to guide interventions and improve sleep outcomes for university students.Keywords: university students, sleep disturbance, machine learning, artificial intelligence, feature importance

Yixue Hu,1 Dongna Wang,2 Tianyu Zhang,2 Meng Lei,3 Yingnan Luo,2 Zhimeng Chen,3 Yuting Li,2 Dandan Duan,2 Liefeng Zhang,1 Yongqiang Zhu1,2 1College of Life Science, Nanjing Normal University, Nanjing, People’s Republic of China; 2School of Food and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, People’s Republic of China; 3College of Science, Nanjing Forestry University, Nanjing, People’s Republic of ChinaCorrespondence: Liefeng Zhang; Yongqiang Zhu, College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Qixia District, Nanjing, 210023, People’s Republic of China, Tel/Fax +86-25-85898184; +86-25-85891591, Email lfzhang@njnu.edu.cn; zhyqscu@hotmail.comIntroduction: Tumor hypoxia and invasion present significant challenges for the efficacy of photodynamic therapy (PDT) in triple-negative breast cancer (TNBC). This study developed a mitochondrial targeting strategy that combined PDT and gene therapy to promote each other and address the challenges.Methods: The positively charged amphiphilic material triphenylphosphine-tocopherol polyethylene glycol succinate (TPP-TPGS, TPS) and the photosensitizer chloride e6 (Ce6) formed TPS@Ce6 nanoparticles (NPs) by hydrophobic interaction. They electrostatically condensed microRNA-34a (miR-34a) to form stable TPS@Ce6/miRNA NPs.Results: Firstly, Ce6 disrupted the lysosomal membrane, followed by successful delivery of miR-34a by TPS@Ce6/miRNA NPs. Meanwhile, miR-34a reduced ROS depletion and further enhanced the effectiveness of PDT. Consequently, the mutual promotion between PDT and gene therapy led to enhanced anti-tumor effects. Furthermore, the TPS@Ce6/miRNA NPs promoted apoptosis by down-regulating Caspase-3 and inhibited tumor cell migration and invasion by down-regulating N-Cadherin. In addition, in vitro and in vivo experiments demonstrated that the TPS@Ce6/miRNA NPs achieved excellent anti-tumor effects. These findings highlighted the enhanced anticancer effects and reduced migration of tumor cells through the synergistic effects of PDT and gene therapy.Conclusion: Taken together, the targeted co-delivery of Ce6 and miR-34a will facilitate the application of photodynamic and genic nanomedicine in the treatment of aggressive tumors, particularly TNBC. Keywords: photodynamic therapy, gene therapy, hypoxia, invasion, mitochondrial target, triple-negative breast cancer

Ming Zhou,1,2,&ast; Peng Liu,1,2,&ast; Xiaoqin Yin,1 Caiting Deng,3,4 Yi Xiao,1 Meng Lei,1 Shuo Hu,1 Feifei An,3 Min Zhao1,5,6 1Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Key Laboratory of Biological, Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3School of Public Health, Health Science Center, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 4Institute of Medical Engineering, Department of Biophysics, School of Basic Medical Science, Health Science Center, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 5Department of Nuclear Medicine, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 6National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Zhao; Feifei An, Email mzhao1981@csu.edu.cn; anfeifei@xjtu.edu.cnBackground: Sentinel lymph node (SLN) mapping-guided biopsy is crucial for cancer staging and treatment. Optical/nuclide dual-modality imaging agents for mapping SLN are ideal for preoperative planning and intraoperative biopsy, which are enabled by penetration-depth unlimited nuclide imaging and dynamic real-time optical imaging, respectively. However, commonly reported dual-modality imaging agents are composed of novel but safety-unproven materials, making their quick clinical translation challenging. Herein, we report a novel nanoparticle composed of facile hospital-available drugs and isotope for single-photon emission computed tomography (SPECT)/near-infrared (NIR) fluorescence imaging to detect SLNs.Methods: Indocyanine green-human serum albumin (ICG-HSA) nanoparticles (NPs) were synthesized by ICG-induced HSA self-assembly and further 99mTc-labeling via a one-step, facile hospital-available method. After injecting 99mTc-ICG-HSA into the rats’ forepaw pads, the rats’ draining axillary lymph nodes were visualized by preoperative mapping with SPECT/CT and intraoperative biopsy with NIR fluorescence. The axillary lymph nodes of rats were identified by pathology and fluorescent staining after execution. Additionally, its toxicity testing and comparison with 99mTc-sulfur colloid imaging were also explored.Results: The study reported a self-assembled 99mTc-ICG-HSA with a high radiochemical yield (85.6 ± 3.8%). Compared with conventional 99mTc-sulfur colloid, 99mTc-ICG-HSA NPs showed faster SLN identification, higher renal clearance, and lower hepatic retention. Furthermore, NIRF imaging allowed for the accurate visualization of the SLN and guided SLN biopsy intraoperatively. Notably, the 99mTc-ICG-HSA NPs were composed of hospital-available drugs and isotope, which are safe for acute toxicity evaluation by a certified institute.Conclusion: The proposed 99mTc-ICG-HSA NPs are safe and capable of noninvasive SLN identification and biopsy guidance with multi-modal imaging strategies and could be a promising tool for clinically assisted SLN biopsy. Keywords: image-guided surgery, indocyanine green, albumin, fluorescence imaging, near-infrared, single-photon emission computed tomography

Abstract Cultural transmission is the domain-general social skill that allows agents to acquire and use information from each other in real-time with high fidelity and recall. It can be thought of as the process that perpetuates fit variants in cultural evolution. In humans, cultural evolution has led to the accumulation and refinement of skills, tools and knowledge across generations. We provide a method for generating cultural transmission in artificially intelligent agents, in the form of few-shot imitation. Our agents succeed at real-time imitation of a human in novel contexts without using any pre-collected human data. We identify a surprisingly simple set of ingredients sufficient for generating cultural transmission and develop an evaluation methodology for rigorously assessing it. This paves the way for cultural evolution to play an algorithmic role in the development of artificial general intelligence.

Abstract Background The emergency of new COVID-19 variants over the past three years posed a serious challenge to the public health. Cities in China implemented mass daily RT-PCR tests by pooling strategies. However, a random delay exists between an infection and its first positive RT-PCR test. It is valuable for disease control to know the delay pattern and daily infection incidences reconstructed from RT-PCR test observations. Methods We formulated the convolution model between daily incidences and positive RT-PCR test counts as a linear inverse problem with positivity restrictions. Consequently, the Richard-Lucy deconvolution algorithm was used to reconstruct COVID-19 incidences from daily PCR tests. A real-time deconvolution was further developed based on the same mathematical principle. The method was applied to an Omicron epidemic data set of a bar outbreak in Beijing and another in Wuxi in June 2022. We estimated the delay function by maximizing likelihood via an E-M algorithm. Results The delay function of the bar-outbreak in 2022 differs from that reported in 2020. Its mode was shortened to 4 days by one day. A 95% confidence interval of the mean delay is [4.43,5.55] as evaluated by bootstrap. In addition, the deconvolved infection incidences successfully detected two associated infection events after the bar was closed. The application of the real-time deconvolution to the Wuxi data identified all explosive incidence increases. The results revealed the progression of the two COVID-19 outbreaks and provided new insights for prevention and control strategies, especially for the role of mass daily RT-PCR testing. Conclusions The proposed deconvolution method is generally applicable to other infectious diseases if the delay model can be assumed to be approximately valid. To ensure a fair reconstruction of daily infection incidences, the delay function should be estimated in a similar context in terms of virus variant and test protocol. Both the delay estimate from the E-M algorithm and the incidences resulted from deconvolution are valuable for epidemic prevention and control. The real-time feedback is particularly useful during the epidemic’s acute phase because it can help the local disease control authorities modify the control measures more promptly and precisely.

Qiliang Liu,&ast; Yan Hu,&ast; Mei Lei, Chunlin Mei, Chengqing Yang Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan, Hubei, 430030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengqing Yang, Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan, Hubei, 430030, People’s Republic of China, Email 147391593@qq.comIntroduction: Tracheobronchopathia osteochondroplastica (TO) is a relatively rare benign tracheobronchial disease, which is often misdiagnosed or missed. To date, there is no specific treatment for TO. The aim of this study was to investigate the clinical manifestations, imaging features, bronchoscopy results, pathological findings, and diagnostic points of TO.Patients and methods: A total of 33 patients diagnosed with TO were enrolled. Clinical data were collected using retrospective methods in the period from January 2021 and November 2022. Descriptive analysis was used.Results: Patients included 17 (51.5%) male and 16 (48.5%) female, with a median age of 54 years. The main clinical manifestations included cough in 15 cases, fever in 6 cases, chest tightness in 4 cases, haemoptysis in 3 cases, and chest pain in 4 cases. The time from the onset of symptoms to diagnosis was 1 week to 96 months. Some patients were diagnosed with other lung diseases, including 16 patients with tuberculosis, 2 patients with lung cancer, 3 patients with nontuberculous mycobacteriosis, 3 patients with tuberculous pleurisy, 2 patients with bronchiectasis, and 1 patient with pneumonia. Chest computed tomography (CT) scan demonstrated calcified nodules in 10 (30.3%) patients. In bronchoscopy, entire tracheal involvement was found in 21 (63.6%) patients, 12 (36.4%) patients were found to have involvement of only part of the trachea. The patients were divided into three groups according to the bronchoscopic presentation, the largest proportion was stage II (19/33), followed by stage I (8/33) and stage III (6/33). Histopathological findings showed squamous metaplasia, cartilaginous, and bony tissues.Conclusion: TO is a slowly progressing disease with non-specific clinical symptoms and a low positive rate of imaging diagnosis, making it susceptible to misdiagnosis and missed diagnosis. The disease needs to be diagnosed by combining imaging features, fiberoptic bronchoscopy, and pathological findings.Keywords: benign tracheobronchial disease, tuberculosis, misdiagnosis, bronchoscopy

Abstract Background Closing gaps in draft genomes leads to more complete and continuous genome assemblies. The ubiquitous genomic repeats are challenges to the existing gap-closing methods, based on either the k-mer representation by the de Bruijn graph or the overlap-layout-consensus paradigm. Besides, chimeric reads will cause erroneous k-mers in the former and false overlaps of reads in the latter. Results We propose a novel local assembly approach to gap closing, called RegCloser. It represents read coordinates and their overlaps respectively by parameters and observations in a linear regression model. The optimal overlap is searched only in the restricted range consistent with insert sizes. Under this linear regression framework, the local DNA assembly becomes a robust parameter estimation problem. We solved the problem by a customized robust regression procedure that resists the influence of false overlaps by optimizing a convex global Huber loss function. The global optimum is obtained by iteratively solving the sparse system of linear equations. On both simulated and real datasets, RegCloser outperformed other popular methods in accurately resolving the copy number of tandem repeats, and achieved superior completeness and contiguity. Applying RegCloser to a plateau zokor draft genome that had been improved by long reads further increased contig N50 to 3-fold long. We also tested the robust regression approach on layout generation of long reads. Conclusions RegCloser is a competitive gap-closing tool. The software is available at https://github.com/csh3/RegCloser . The robust regression approach has a prospect to be incorporated into the layout module of long read assemblers.

Yi-Jin Wu,1– 3,&ast; Sa-Sa Zhang,1,&ast; Qin Yin,1 Ming Lei,2 Qi-Hai Wang,4 Wen-Gang Chen,1 Ting-Ting Luo,1 Peng Zhou,5 Cong-Lan Ji4,6 1Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 2Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Vascular Diseases Research Center of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 4School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, Anhui, 241000, People’s Republic of China; 5School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230000, People’s Republic of China; 6Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peng Zhou; Cong-Lan Ji, Email zhoupeng@ahtcm.edu.cn; 37709103@qq.comBackground: α-Mangostin (MG) showed the potentials in alleviating experimental arthritis, inhibiting inflammatory polarization of macrophages/monocytes, and regulating peroxisome proliferators-activated receptor γ (PPAR-γ) and silent information regulator 1 (SIRT1) signals. The aim of this study was to analyze the correlations among the above-mentioned properties.Methods: Antigen-induced arthritis (AIA) was established in mouse, which was treated with MG in combination with SIRT1/PPAR-γ inhibitors to clarify the role of the two signals in the anti-arthritic actions. Pathological changes were systematically investigated. Phenotypes of cells were investigated by flow cytometry. Expression and co-localization of SIRT1 and PPAR-γ proteins in joint tissues were observed by the immunofluorescence method. Finally, clinical implications from the synchronous up-regulation of SIRT1 and PPAR-γ were validated by experiments in vitro.Results: SIRT1 and PPAR-γ inhibitors (nicotinamide and T0070097) reduced the therapeutic effects of MG on AIA mice, and abrogated MG-induced up-regulation of SIRT1/PPAR-γ and inhibition of M1 polarization in macrophages/monocytes. MG has a good binding affinity to PPAR-γ, and MG promoted the co-expression of SIRT1 and PPAR-γ in joints. Synchronously activating SIRT1 and PPAR-γ was revealed to be necessary by MG to repress inflammatory responses in THP-1 monocytes.Conclusion: MG binds PPAR-γ and excites this signaling to initiate ligand-dependent anti-inflammatory activity. Due to certain unspecified signal transduction crosstalk mechanism, it then promoted SIRT1 expression and further limited inflammatory polarization of macrophages/monocytes in AIA mice.Graphical Abstract: Keywords: rheumatoid arthritis, mangosteen, metabolism, inflammation, immune

Nana Luo,1,2 Qiuyue Wang,2 Min Lei,2 Tianhao Li,1 Pingsheng Hao1 1Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of ChinaCorrespondence: Tianhao Li; Pingsheng Hao, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, People’s Republic of China, Tel +86-13880986337 ; +86-13881965024, Fax +86-28-87732407, Email litianhao_doctor@163.com; hpswl@126.comAbstract: Chronic prurigo (CPG) is a chronic inflammatory disease characterized by intense pruritus, and therapy is often challenging due to its unclear pathogenesis. Here, we report four patients with refractory CPG from different backgrounds who experienced failure of conventional therapy and were controlled with dupilumab, accompanied by a significant decrease in pruritus numerical rating scale, dermatology life quality index, and investigator global assessment, without adverse effects. Furthermore, dupilumab improved the condition of asthma in CPG patients along with an increase in asthma control test scores.Keywords: dupilumab, chronic prurigo, therapy, asthma

Xu Yang,1 Amin Liu,1 Lin Yang,1 Tiantian Wen,2 Jia Wang,3 Jingmiao Shi,3 Hui Zhou,2 Zhimeng Chen,1 Meng Lei,1 Yongqiang Zhu2 1College of Science, Nanjing Forestry University, Nanjing, People’s Republic of China; 2College of Life Science, Nanjing Normal University, Nanjing, People’s Republic of China; 3Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, Nanjing, People’s Republic of ChinaCorrespondence: Meng Lei; Yongqiang Zhu, Tel +86 25 85427621 ; +86 25 85891591, Email hk-lm@163.com; zhyqscu@hotmail.comIntroduction: FHND6091, a novel N-capped dipeptidyl boronic acid proteasome inhibitor with promising pharmacological properties, entirely converted into active form FHND6081 under physiological conditions. The proteasome, a key component of the ubiquitin-proteasome pathway (UPP), has emerged as a validated target of multiple myeloma (MM) therapeutics. FHND6091 is a selective oral proteasome inhibitor that binds irreversibly to the β 5 submit of the 20S proteasome and exerts anti-cancer roles.Methods: In this study, we investigated the metabolic stability, metabolite production, metabolic pathways and plasma protein binding (PPB) of FHND6081 along with its absorption, tissue distribution, excretion (ADME) and pharmacokinetics (PK) in animals.Results: Ultra-high performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) identified a total of nine new metabolites after co-incubation with FHND6091 in hepatocytes from different species. A hypothetical CYP450-metabolic pathway including dehydrogenation, N-dealkylation plus mono-oxygenation and other was proposed. In addition, FHND6081 was highly bound to plasma proteins (> 99%); nevertheless, it preferred to partition to red blood cells (B/P ratio: 4.91). The results of microsomal metabolic stability corroborated that FHND6081 was a moderate-clearance compound. In Caco-2 cell experiments, the compound displayed modest permeability suggesting that it may show limited bioavailability via oral routes. Furthermore, FHND6081 was extensively distributed in rats and the highest exposure was achieved in the stomach followed by the small intestine and adrenal gland. Pharmacokinetic studies were done by using Sprague-Dawley (SD) rats, oral absorption was fast and plasma exposure was dose-dependent and oral bioavailability were low. At the same dose, FHND6081 exposure was severalfold higher in whole blood than in plasma, which was consistent with blood cell partitioning. Moreover, only a small fraction of the parent compound was excreted via feces and urine and oxidative metabolites were detected in feces and plasma.Conclusion: The overall preclinical pharmacokinetic profile supported the selection and development of FHND6091 as a clinical candidate.Keywords: FHND6091, active form FHND6081, proteasome inhibitor, preclinical pharmacokinetics, tissue distribution, drug-availability

Nana Luo,1,2 Qiuyue Wang,1 Min Lei,1 Zhiyong Li,1 Tianhao Li,2 Pingsheng Hao2 1School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of ChinaCorrespondence: Tianhao Li; Pingsheng Hao, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, Sichuan Province, People’s Republic of China, Tel +86-13880986337 ; +86-13881965024, Fax +86-28-87732407, Email litianhao_doctor@163.com; hpswl@126.comCase Report: We present the case of a 51-year-old male who experienced temporary desquamation and recurrent burning sensation in primary skin lesions after the injection of dupilumab. The scaling lasted for 1 week and subsided, while the burning became aggravated with each injection of dupilumab, which gradually subsides after 8 weeks, and there was no recurrence since then.Conclusion: Dupilumab is an emerging and efficacious biologics medication for AD. The burning sensation and scaling we report may be the adverse events of dupilumab. Rare adverse reactions to biologics deserve the attention of physicians.Keywords: dupilumab, atopic dermatitis, burning, scaling, adverse event

Qiuyue Wang,1,2 Nana Luo,1,2 Min Lei,1,2 Lingyuan Zhong,1,2 Chunxiao Li,2,* Pingsheng Hao2,* 1School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunxiao Li; Pingsheng Hao, Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610075, Sichuan, People’s Republic of China, Tel +86-18981937829 ; +86-13881965024, Fax +86-028-87732407, Email chunxiaolee@126.com; hpswl@126.comAbstract: Contact dermatitis and facial contact dermatitis caused by pesticides are not uncommon in China. However, clinically, due to the wide variety of pesticides, they mainly appear in the form of case reports. We reported a 70-year-old male patient developed facial irritant contact dermatitis (ICD) due to pyraclostrobin which was sprayed on his face. Initially, he felt facial burning and tingling, and localized erythematous-edematous and scaly rash appeared on his face as well as front hairline scalp. During the outpatient visit, the main symptoms were a facial burning sensation, itching, and tingling. The patient’s facial lesions improved after treatment. To better protect the skin of agricultural workers, preventive measures should be undertaken, such as personal protective equipment, gas masks, protective clothing and goggles, which are indispensable for manual pesticide spraying. Pyraclostrobin diluted according to the instructions is a potential source of ICD. Agricultural workers should undertake preventive measures during manual pesticide spraying. Safety education and publicity are particularly important. We need dermatologists to spread knowledge and agricultural workers to develop the right protective habits.Keywords: irritant contact dermatitis, pyraclostrobin, pesticide exposure, pesticides, farming, case report

Qiuyue Wang,1,2,&ast; Nana Luo,1,2,&ast; Min Lei,1,2 Xian Chen,3 Chunxiao Li,2 Pingsheng Hao2 1School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunxiao Li; Pingsheng Hao, Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610075, Sichuan, People’s Republic of China, Tel +86-18981937829 ; +86-13881965024, Fax +86-028-87732407, Email chunxiaolee@126.com; hpswl@126.comAbstract: Grover’s disease (GD), also known as Transient acantholytic dermatosis, has no typical clinical rash features. It usually occurs in elderly white men but very rarely in China. This is a disease of acantholysis and dyskeratosis, which is usually considered to be spontaneous remission. The skin lesions of the disease are diverse, and the main symptom is severe itching. We have reported a case of GD in a 14-year-old Chinese Tibetan male whose clinical manifestations were pruritic red papule, generalized red papules, papulo vesicles and blisters ranging from millet rice to soybean size. Skin lesions change rapidly and variously. In order to confirm the diagnosis, we have done skin biopsies, immunofluorescence, dermoscopy, microscopy and other examinations. Pathological skin biopsy showed acantholysis. Intraepidermal blisters and the presence of blisters on the basal cells as well as under the stratum corneum can be observed on the same pathological section. Type IV collagen immunohistochemistry showed blisters in the epidermis. The diagnosis of GD depended on the exclusion of other diseases. After we performed whole exon sequencing (WES) on DNA from the patient’s blood, pathogenic gene mutations were not found. Pustular psoriasis, Subcorneal pustular dermatosis, Herpesvirus infections, Dermatitis herpetiformis, Pemphigus vulgaris, Norwegian scabies, Darier’s disease, and Hailey-Hailey disease were all excluded. We successfully treated adolescent GD with minocycline combined with methotrexate. The patient was followed up for 19 months without recurrence.Keywords: Grover’s disease, Chinese, minocycline, methotrexate, adolescent, case report

Pancreatic islet failure is a key characteristic of type 2 diabetes besides insulin resistance. To get molecular insights into the pathology of islets in type 2 diabetes, we developed a computational approach to integrating expression profiles of Goto-Kakizaki and Wistar rat islets from a designed experiment with those of the human islets from an observational study. A principal gene-eigenvector in the expression profiles characterized by up-regulated angiogenesis and down-regulated oxidative phosphorylation was identified conserved across the two species. In the case of Goto-Kakizaki versus Wistar islets, such alteration in gene expression can be verified directly by the treatment-control tests over time, and corresponds to the alteration of α/β-cell distribution obtained by quantifying the islet micrographs. Furthermore, the correspondence between the dual sample- and gene-eigenvectors unveils more delicate structures. In the case of rats, the up- and down-trend of insulin mRNA levels before and after week 8 correspond respectively to the top two principal eigenvectors. In the case of human, the top two principal eigenvectors correspond respectively to the late and early stages of diabetes. According to the aggregated expression signature, a large portion of genes involved in the hypoxia-inducible factor signaling pathway, which activates transcription of angiogenesis, were significantly up-regulated. Furthermore, top-ranked anti-angiogenic genes THBS1 and PEDF indicate the existence of a counteractive mechanism that is in line with thickened and fragmented capillaries found in the deteriorated islets. Overall, the integrative analysis unravels the principal transcriptional alterations underlying the islet deterioration of morphology and insulin secretion along type 2 diabetes progression.

Xuedong Shi,1,&ast; Yunpeng Cui,1,&ast; Yuanxing Pan,1 Bing Wang,1 Mingxing Lei2,3 1Department of Orthopedic Surgery, Peking University First Hospital, Beijing, 100032, People’s Republic of China; 2Department of Orthopedic Surgery, Hainan Hospital of Chinese PLA General Hospital, Sanya, 572013, People’s Republic of China; 3Chinese PLA Medical School, Beijing, 100853, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuedong ShiDepartment of Orthopedic Surgery, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100032, People’s Republic of ChinaTel +86 10-83572211Email 172998774@qq.com; xuedongs@hotmail.comMingxing LeiDepartment of Orthopedic Surgery, Hainan Hospital of Chinese PLA General Hospital, Jianglin Road, Haitang District, Sanya, 572013, People’s Republic of ChinaTel +86-18811772189Email 825979020@qq.comPurpose: This study aimed to assess the risk variables for predicting intra-spinal canal cement leakage, especially among elderly patients with spine metastases after being treated with percutaneous vertebroplasty (PVP). Furthermore, we proposed and validated a nomogram to stratify risks of intra-spinal canal cement leakage.Methods: We retrospectively analyzed 163 elderly patients (age ≧65 years) with spine metastases who underwent PVP. Patients were randomly divided into a training cohort (n=100) and a validation cohort (n=63). The multivariate logistic regression analysis was used to screen potential risk variables in the training cohort. Significant risk variables were included in the nomogram, and the nomogram was developed according to the estimates of the each included variable. The predictive effectiveness of the nomogram was validated using discrimination and calibration performance.Results: The overall prevalence of intra-spinal canal cement leakage was 9.82% (16/163). In the training cohort, female patients (14.71%, 5/34) showed a higher rate of intra-spinal canal cement leakage as compared with male patients (4.55%, 3/66). The nomogram consisted of sex, cortical osteolytic destruction in posterior wall, and load-bearing lines of spine. The nomogram had acceptable discrimination, with the area under the receiver operating characteristic (AUROC) of 0.75 in the training cohort, 0.64 in the validation cohort, and 0.69 in the entire cohort, and also showed favorable calibration based on the goodness-of-fit test. According to the nomogram, three risk groups were developed: the low risk group had an actual probability of 7.03%, the medium risk group was 11.54%, and high risk group was 44.44%. The difference between the three groups was significant (P ˂ 0.01).Conclusion: Intra-spinal canal cement leakage after PVP is not scarce among elderly patients. We proposed and internally validated a nomogram that is capable of calculating the risk of intra-spinal canal cement leakage among elderly patients with spine metastases. Careful surgical plan should be conducted among patients with a high risk of developing intra-spinal canal cement leakage.Keywords: elderly patients, spine metastases, percutaneous vertebroplasty, cement leakage, nomogram

Yijin Yu,1 Lingyan Cui,1 Lu Qian,1 Min Lei,1 Qi Bao,1 Qingxin Zeng,2 Zhao Chen,2 Shaohua Xu,2 Junran Xie1 1Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Junran XieDepartment of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun Road East, Jianggan District, Hangzhou, Zhejiang, People’s Republic of ChinaTel +86 13858126216Email xiejunran@zju.edu.cnBackground: Chronic post-thoracotomy pain is still an obstacle for lung-cancer patients even after less invasive surgical procedures. It is unclear whether intercostal analgesia is as useful in the prevention of postoperative chronic pain as it is for acute pain for video-assisted thoracoscopic surgery (VATS). The purpose of this study was to evaluate the efficacy of perioperative intercostal analgesia for chronic pain via a multimodal analgesic regimen for VATS during 6 months of postoperative follow-up.Methods: We identified 837 cases of VATS from August 2016 to August 2018. Patients were treated by perioperative intercostal analgesia with 0.75% ropivacaine 50 mg through the intercostal catheter every 8 hours until chest tube extubation (INA group) or conventional analgesia with preoperative 0.75% ropivacaine 50 mg at incision once (CON group). Numerical rating scale (NRS) and neuropathic pain were evaluated in 6 months of post-surgery follow-up. Postoperative adverse effects were recorded.Results: In total, there were 419 patients in INA group and 418 patients in CON group. Scores of NRS with motion was lower in INA group at 3 postoperative days (P = 0.032). Occurrence of chronic pain was 28.4% in INA group and 32.8% in CON group at 6 postoperative months, 10.6% of patients experienced increasing pain from 3 to 6 months. Occurrence of considerable neuropathic pain (ID pain score ≥ 2) was 2.1% in INA group and 3.1% in CON group at 6 postoperative months. No differences were found between the two groups. Occurrence of numbness was lower in INA group (6.7% vs 10.5%, P = 0.031), and other pain symptoms did not differ between the groups. The incidence of dizziness, nausea, vomiting and atelectasis was not different between the two groups.Conclusion: In a multimodal analgesic regimen of VATS, perioperative intercostal analgesia with 0.75% ropivacaine infusion 50 mg three times in a day does not have an obvious effect on chronic post-thoracotomy pain.Keywords: chronic pain, neuropathic pain, intercostal analgesia, video-assisted thoracoscopic surgery

Abstract Background Normalization of RNA-seq data aims at identifying biological expression differentiation between samples by removing the effects of unwanted confounding factors. Explicitly or implicitly, the justification of normalization requires a set of housekeeping genes. However, the existence of housekeeping genes common for a very large collection of samples, especially under a wide range of conditions, is questionable. Results We propose to carry out pairwise normalization with respect to multiple references, selected from representative samples. Then the pairwise intermediates are integrated based on a linear model that adjusts the reference effects. Motivated by the notion of housekeeping genes and their statistical counterparts, we adopt the robust least trimmed squares regression in pairwise normalization. The proposed method (MUREN) is compared with other existing tools on some standard data sets. The goodness of normalization emphasizes on preserving possible asymmetric differentiation, whose biological significance is exemplified by a single cell data of cell cycle. MUREN is implemented as an R package. The code under license GPL-3 is available on the github platform: github.com/hippo-yf/MUREN and on the conda platform: anaconda.org/hippo-yf/r-muren. Conclusions MUREN performs the RNA-seq normalization using a two-step statistical regression induced from a general principle. We propose that the densities of pairwise differentiations are used to evaluate the goodness of normalization. MUREN adjusts the mode of differentiation toward zero while preserving the skewness due to biological asymmetric differentiation. Moreover, by robustly integrating pre-normalized counts with respect to multiple references, MUREN is immune to individual outlier samples.

Ming Lei,1 Guang-Yuan Yu,2 Yong-Gang Zhao,3 Ji-Ping Wang,1 Su-Yun Feng1 1Center of Hair Transplantation, Department of Burn and Plastic Surgery, The Fourth Medical Center of the General Hospital of PLA, Beijing, People’s Republic of China; 2Department of Dermatology, The Fourth Medical Center of the General Hospital of PLA, Beijing, People’s Republic of China; 3First Department of Surgery, Beijing Armed Police Corps Hospital, Beijing, People’s Republic of ChinaCorrespondence: Ji-Ping WangCenter of Hair Transplantation, Department of Burn and Plastic Surgery, The Fourth Medical Center of the General Hospital of PLA, No. 51 of Fucheng Road, Haidian District, Beijing, 100048, People’s Republic of ChinaTel +86 10-66867304Email wangjp693587@163.comObjective: This study aims to establish the concept of invalid extraction rates in follicular unit extraction and evaluate its clinical value.Methods: The present study involved 30 patients with alopecia. Three young surgeons (nominated A, B, and C) each performed follicular unit extraction on a randomly selected portion of the donor site of each patient for ten minutes. The outcomes were separately recorded and calculated, and converted to an invalid extraction rate for each surgeon using the formula, “invalid extraction rate = 1 − successfully extracted follicular units/actually extracted units × 100%.”Results: The follicular unit invalid extraction efficiency of each surgeon gradually declined. The average efficiency level of surgeon B was evaluated as excellent, while the levels of surgeons A and C were evaluated as good.Conclusion: With experience, surgeons can speed up the process of follicular unit extraction and gradually increase performance quality through both extraction speed and success rate.Keywords: follicular unit extraction, operating level, evaluation

Xuedong Shi,1,* Yaosheng Liu,2,* Yunpeng Cui,1 Haifeng Qin,3 Shaoxing Yang,3 Mingxing Lei4 1Department of Orthopedic Surgery, Peking University First Hospital, Beijing, People’s Republic of China; 2Department of Orthopedic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of Pulmonary Neoplasms Internal Medicine, The Fifth Medical Center of the Chinese PLA General Hospital, Beijing, People’s Republic of China; 4Department of Orthopedic Surgery, Hainan Hospital of Chinese PLA General Hospital, Sanya, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yaosheng LiuDepartment of Orthopedic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, No. 8, Fengtaidongda Road, Beijing 100071, People’s Republic of ChinaTel/Fax +86-10-66947017Email 632763246@qq.comPurpose: The study aims to investigate and compare the efficacy and safety of intraoperative 125I implantation and postoperative irradiation after surgical decompression and stabilization in the treatment of patients with metastatic epidural spinal cord compression (MESCC).Methods: The study retrospectively enrolled 122 MESCC patients treated with surgical decompression and pedicle stabilization combined with 125I brachytherapy (the brachytherapy group) or postoperative radiotherapy (the irradiation group). Operation time, intraoperative blood loss, pain relief, postoperative ambulatory status, postoperative survival outcome, complications, and length of hospitalization were collected and compared between the two groups. Ten potential risk factors were analyzed for postoperative survival outcome.Results: No significant difference was found in baseline characteristics between the two groups (P> 0.05). Postoperative VAS score was significantly decreased, as compared with preoperative scores in both groups (P˂0.001). The VAS in the brachytherapy group was significantly lower than that in the irradiation group at postoperative 1 month, 3 months, and 6 months (P˂0.05). The postoperative ambulatory rates were 90.0% (54/60) in the brachytherapy group and 83.9% (52/62) in the irradiation group (P=0.32). The median overall survival time was similar between the two groups (7.43 months vs 7.27 months, P=0.37). Of all patients in the brachytherapy group, 25.0% (15/60) of patients suffered from complications, while 46.8% (29/62) of patients had complications in the irradiation group (P=0.0086). According to the multiple Cox regression, primary sites (P=0.038), ECOG performance status (P=0.014), and visceral metastases (P=0.0016) showed significance for postoperative survival outcome.Conclusion: Surgical decompression and spine stabilization combined with 125I brachytherapy is a relatively safe and useful method in MESCC patients.Keywords: metastatic epidural spinal cord compression, 125I brachytherapy, radiotherapy, surgical decompression and spine stabilization, prognosis

Wenjing Zheng,1 Mingxing Lei,2 Yaosheng Liu,1 Xin Lu,3 Dan Yu,4 Xin Zhang5 1Department of Orthopedic Surgery, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Orthopedic Surgery, The Hainan Hospital of Chinese PLA General Hospital, Sanya, People’s Republic of China; 3Department of General Surgery, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 4Department of Neurosurgery, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Nursing Department, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xin ZhangNursing Department, The Fifth Medical Center of Chinese PLA General Hospital, 100 the 4thWest Ring Middle Road, Fengtai District, Beijing 100071, People’s Republic of China+86-10-933045Email zhangxinliu@sina.comPurpose: We wish (1) to assess what variables are significantly associated with postoperative emotional distress in patients with the metastatic spinal disease after surgery and (2) to develop and validate an algorithm to stratify patients at risk of postoperative emotional distress.Patients and Methods: We retrospectively enrolled 171 patients with the metastatic spinal disease treated with surgery. Twelve potential variables were used to analyze postoperative emotional distress. Postoperative emotional well-being was measured using the Hospital Anxiety and Depression Scales (HADS). Significant variables were included in the algorithm and assigned scores based on odds ratios (ORs) from the multiple logistic regression analysis. The predictive performance of the risk algorithm was validated on the basis of discrimination and calibration.Results: Twenty-six (15.20%) patients had a HADS of 19 points or more. Of all the 12 variables, age (P=0.06), marital status (P=0.02), primary cancer types (P=0.004), and physical well-being (P=0.006) were included in the algorithm. This algorithm ranged from 0 to 24. Higher scores represented higher rates of postoperative emotional distress. Patients were stratified into three risk groups: patients in the group A had scores of 0 to 9 and the rate of postoperative emotional distress was only 1.14%, patient in the group B had scores of 10 to 15 and the rate of postoperative emotional distress was 21.31%, and patient in the group C had scores of 16 to 24 and the rate of postoperative emotional distress was up to 54.55%. The area under the receiver operating characteristic curve (AUROC) for the algorithm was 0.84, and the correct classification rate was 81.3%.Conclusion: Postoperative emotional distress is common in patients with the metastatic spinal disease after surgery. We propose and validate an algorithm that can be used as a potential screening tool to identify patients at high risk of postoperative emotional distress.Keywords: metastatic spinal disease, decompressive surgery, anxiety, depression, emotional distress, risk variables

Yunpeng Cui,1,* Yuanxing Pan,1,* Mingxing Lei,2 Chuan Mi,1 Bing Wang,1 Xuedong Shi1 1Department of Orthopedic Surgery, Peking University First Hospital, Beijing, People’s Republic of China; 2Department of Orthopedic Surgery, Hainan Hospital of Chinese PLA General Hospital, Sanya, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuedong ShiDepartment of Orthopedic Surgery, The Peking University First Hospital No. 8 Xishiku Street, Xicheng District Beijing 100032 People’s Republic of ChinaTel +86-010-83572211Email 172998774@qq.comPurpose: This study aims to develop an algorithm to predict cement injection volumes in patients with spine metastases treated with percutaneous vertebroplasty (PVP). Risk factors were also analyzed for intra-spinal canal cement leakages.Patients and Methods: A retrospective analysis of 584 vertebrae in 251 patients. Patients and vertebrae were divided into three groups based on grades of tumor invasion to the spinal cord. Patients with the complete posterior wall of vertebrae were classified into group A, patients without the complete posterior wall of vertebrae but with normal Dural sac were classified into group B, and patients with deformation of the Dural sac but without neurological symptom were classified into group C. We systematically reviewed demographic data, clinical parameters, radiology features, and cement leakages among the three groups. The multiple linear regressions were used to screen potential risk factors and develop the algorithm to predict injected cement volumes in vertebrae. Significant factors were included in the algorithm. Potential risk factors for intra-spinal canal cement leakage were analyzed using the multiple logistic regressions.Results: In the study, 17.1% (100/584) of vertebrae occurred cement leakages. Vertebrae in group C (28.6%, 8/28) had the highest cement leakage rate than patients in group A (14.4%, 61/424) and B (23.5%, 31/132) (P=0.014). Vertebrae in group C (14.3%, 4/28) were also more prone to intra-spinal canal leakages (P=0.003). The multiple logistic analysis showed that the Bilsky scale was significantly associated with intra-spinal canal cement leakages (P< 0.001). The multiple linear regression analysis showed that intercept (P< 0.001), treated vertebrae level (P< 0.001), cortical osteolytic destruction in posterior wall (P< 0.001), and Bilsky scale (P=0.014) were significant and those variables were included in the algorithm. The algorithm was Y=3.1627－0.8677×treated vertebrae level－0.6182×cortical osteolytic destruction in the posterior wall－0.2819×Bilsky scale.Conclusion: An algorithm is proposed and can be used to calculate cement injection volumes in spine metastases treated with PVP. This algorithm can facilitate surgical planning and guide cement injections. Bilsky scale is an independent risk factor for intra-spinal canal cement leakages. We do not recommend PVP treated in patients with a Bilsky scale of 2 and 3 mainly due to a high rate of intra-spinal canal cement leakages.Keywords: spinal metastases, percutaneous vertebroplasty, algorithm, intra-spinal canal leakages, risk factors

Abstract Background A key problem in systems biology is the determination of the regulatory mechanism corresponding to a phenotype. An empirical approach in this regard is to compare the expression profiles of cells under two conditions or tissues from two phenotypes and to unravel the underlying transcriptional regulation. We have proposed the method BASE to statistically infer the effective regulatory factors that are responsible for the gene expression differentiation with the help from the binding data between factors and genes. Usually the protein-DNA binding data are obtained by ChIP-seq experiments, which could be costly and are condition-specific. Results Here we report a definition of binding strength based on a probability model. Using this condition-free definition, the BASE method needs only the frequencies of cis-motifs in regulatory regions, thereby the inferences can be carried out in silico. The directional regulation can be inferred by considering down- and up-regulation separately. We showed the effectiveness of the approach by one case study. In the study of the effects of polyunsaturated fatty acids (PUFA), namely, docosahexaenoic (DHA) and eicosapentaenoic (EPA) diets on mouse small intestine cells, the inferences of regulations are consistent with those reported in the literature, including PPARα and NFκB, respectively corresponding to enhanced adipogenesis and reduced inflammation. Moreover, we discovered enhanced RORA regulation of circadian rhythm, and reduced ETS1 regulation of angiogenesis. Conclusions With the probabilistic definition of cis-trans binding affinity, the BASE method could obtain the significances of TF regulation changes corresponding to a gene expression differentiation profile between treatment and control samples. The landscape of the inferred cis-trans regulations is helpful for revealing the underlying molecular mechanisms. Particularly we reported a more comprehensive regulation induced by EPA&DHA diet.

Mingxing Lei,1,* Jun Yu,2,* Shiju Yan,1 Xiao An,1 Yaosheng Liu3 1Department of Orthopedic Surgery, Hainan Hospital of the PLA General Hospital, Sanya, People’s Republic of China; 2Department of Anesthesiology, The Fourth Medical Center of PLA General Hospital, Beijing, People’s Republic of China; 3Department of Orthopedic Surgery, The 307th Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work Purpose: The aim of this study was to investigate the clinical results of surgery for cervical spine metastasis and identify clinical risk factors affecting postoperative survival and neurological outcome.Patients and methods: A retrospective analysis of medical records was performed on 19 patients who had undergone decompressive surgery and spine stabilization due to metastatic spinal cord compression in the cervical spine. All patients had severe pain before surgery. Worst pain, average pain, and pain interference were evaluated using the visual analog scale (range, 0–10) for each patient at baseline and following surgery. Neurological recovery was assessed using the Japanese Orthopaedic Association Score (JOAS). In addition, associations between ten characteristics and postoperative survival and neurological outcomes were analyzed in the study.Results: The mean worst pain score in a 24-hour period was 8.6 before the operation. At 1 day, 1, 3, 6, and 12 months after the operation, the mean worst pain scores decreased to 5.6, 4.5, 3.8, 2.6, and 2.4 (all P

Yijin Yu,1 Nan Liu,2 Qingxin Zeng,3 Jing Duan,1 Qi Bao,1 Min Lei,1 Jinning Zhao,1 Junran Xie1 1Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Zhejiang, China; 2Department of Anesthesiology, Hangzhou Xiasha Hospital, Zhejiang, China; 3Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Zhejiang, China Purpose: Pregabalin is commonly used as an analgesic for neuropathic pain. But pregabalin as an adjunct to a multimodal analgesic regimen – although standard clinical protocol in some settings – has remained controversial. This meta-analysis was conducted to identify the efficacy of pregabalin for management of postoperative pain in thoracotomy.Materials and methods: Pubmed, Embase, Cochrane, Web of Science, Springer, and Clinical Trial Register database were searched for randomized controlled trials (RCTs) of pregabalin in preventing postoperative pain in thoracotomy. Review Manager 5.3 and STATA 12.0 were selected to conduct the meta-analysis. Trial sequential analysis was used to control random errors and calculate the required information size.Results: Nine RCTs with 684 patients were included in our meta-analysis. Outcomes favoring pregabalin included less pain on a 0–10 scale on 1 day [mean difference (MD): –0.87; 95% CI: –1.55 to –0.19; P=0.01], 3 days (MD: –1.55; 95% CI: –1.93 to –1.18; P

Abstract Type 2 diabetes (T2D) is a complex and polygenic disease yet in need of a complete picture of its development mechanisms. To better understand the mechanisms, we examined gene expression profiles of multi-tissues from outbred mice fed with a high-fat diet (HFD) or regular chow at weeks 1, 9, and 18. To analyze such complex data, we proposed a novel dual eigen-analysis, in which the sample- and gene-eigenvectors correspond respectively to the macro- and micro-biology information. The dual eigen-analysis identified the HFD eigenvectors as well as the endogenous eigenvectors for each tissue. The results imply that HFD influences the hepatic function or the pancreatic development as an exogenous factor, while in adipose HFD’s impact roughly coincides with the endogenous eigenvector driven by aging. The enrichment analysis of the eigenvectors revealed diverse HFD impact on the three tissues over time. The diversity includes: inflammation, degradation of branched chain amino acids (BCAA), and regulation of peroxisome proliferator activated receptor gamma (PPARγ). We reported that in the pancreas remarkable up-regulation of angiogenesis as downstream of the HIF signaling pathway precedes hyperinsulinemia. The dual eigen-analysis and discoveries provide new evaluations/guidance in T2D prevention and therapy, and will also promote new thinking in biology and medicine.

Abstract Background Phred quality scores are essential for downstream DNA analysis such as SNP detection and DNA assembly. Thus a valid model to define them is indispensable for any base-calling software. Recently, we developed the base-caller 3Dec for Illumina sequencing platforms, which reduces base-calling errors by 44-69% compared to the existing ones. However, the model to predict its quality scores has not been fully investigated yet. Results In this study, we used logistic regression models to evaluate quality scores from predictive features, which include different aspects of the sequencing signals as well as local DNA contents. Sparse models were further obtained by three methods: the backward deletion with either AIC or BIC and the L 1 regularization learning method. The L 1-regularized one was then compared with the Illumina scoring method. Conclusions The L 1-regularized logistic regression improves the empirical discrimination power by as large as 14 and 25% respectively for two kinds of preprocessed sequencing signals, compared to the Illumina scoring method. Namely, the L 1 method identifies more base calls of high fidelity. Computationally, the L 1 method can handle large dataset and is efficient enough for daily sequencing. Meanwhile, the logistic model resulted from BIC is more interpretable. The modeling suggested that the most prominent quenching pattern in the current chemistry of Illumina occurred at the dinucleotide “GT”. Besides, nucleotides were more likely to be miscalled as the previous bases if the preceding ones were not “G”. It suggested that the phasing effect of bases after “G” was somewhat different from those after other nucleotide types.

Mingxing Lei,1 Yaosheng Liu,1 Shaoxing Yang,2 Weigang Jiang,1 Yuncen Cao,1 Shubin Liu1 1Department of Orthopedic Surgery, 2Department of Pulmonary Neoplasms Internal Medicine, The Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China Abstract: Percutaneous cementoplasty has been shown to immediately restore the mechanical stability of affected bones, prevent further risk of bone fractures, and allow immediate weight bearing. It is emerging as one of the most promising procedures for patients with painful bone metastasis who are unsuitable for surgery or who show resistance to radiotherapy and/or analgesic therapies. This study aimed at describing the procedure, indications, and benefits of percutaneous cementoplasty for painful osteolytic distal femur metastases. We report the case of a painful metastatic lesion in the left distal femur secondary to non-small-cell lung cancer in a 58-year-old woman. The patient underwent percutaneous cementoplasty and experienced effective pain relief and recovery of knee function postoperatively. In addition, no perioperative complication was observed. Percutaneous cementoplasty for osteolytic distal femur metastases offers effective pain relief and restores impaired knee function. Although this method may be a safe option, larger samples of retrospective or prospective confirmation are warranted. Keywords: minimally invasive procedure, percutaneous cementoplasty, bone metastasis, distal femur

Zujian Lan, Xiaoyu Xu, Wenkai Xu, Jin Li, Zengrong Liang, Xuefei Zhang, Ming Lei, Chunshun Zhao School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China Abstract: To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a–i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke. Keywords: stroke, platelet aggregation, ischemia/reperfusion, middle cerebral artery occlusion, 3-alkyl-2,3-dihydro-1H-isoindol-1-ones

Mina Yan,1,2 Zhaoguo Zhang,2 Shengmiao Cui,3 Ming Lei,2 Ke Zeng,2 Yunhui Liao,2 Weijing Chu,2 Yihui Deng,1 Chunshun Zhao2 1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 2School of Pharmaceutical Sciences, Sun Yat-sen University, 3Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China Abstract: Layered double hydroxide (LDH) has attracted considerable attention as a drug carrier. However, because of its poor in vivo behavior, polyethylene glycolylated (PEGylated) phospholipid must be used as a coformer to produce self-assembled core–shell nanoparticles. In the present study, we prepared a PEGylated phospholipid-coated LDH (PLDH) (PEG-PLDH) delivery system. The PEG-PLDH nanoparticles had an average size of 133.2 nm. Their core–shell structure was confirmed by transmission electron microscopy and X-ray photoelectron spectroscopy. In vitro liposome-cell-association and cytotoxicity experiments demonstrated its ability to be internalized by cells. In vivo studies showed that PEGylated phospholipid membranes greatly reduced the blood clearance rate of LDH nanoparticles. PEG-PLDH nanoparticles demonstrated a good control of tumor growth and increased the survival rate of mice. These results suggest that PEG-PLDH nanoparticles can be a useful drug delivery system for cancer therapy. Keywords: lipid membrane, positive charge, delivery system, cancer therapy

Toll-like receptors (TLRs) recognise pathogen-associated molecular patterns (PAMPs) derived from pathogens and participate in activation of the immune responses. The TLR2 gene can recognise PAMPs specific to bacterial diseases such as pneumonia. In the present study, we sequenced the coding regions of the TLR2 gene in 18 rabbits from 5 breeds, including New Zealand White, Californian, Flemish Giant, Chinchilla and Fu Jian Yellow. In total, we discovered 11 single nucleotide polymorphisms (SNPs), including 4 non-synonymous SNPs located within the predicted TLR domains. Two non-synonymous SNPs (G205A and G265C) were located in the LRR (leucine-rich repeat) domains of the predicted protein, while another non-synonymous SNP (C943T) was situated in the regions involved in binding to ligands. In addition, one synonymous SNP (C1174T) was distributed in the nucleus regions of heterodimers formed. Then, we revealed five conservative regions in the LRR patterning by prediction and comparison of TLR2 protein domain architectures for multiple species. The SNPs in the TLR2 gene may increase the probability of adaptation to variability of PAMPs due to the rapid evolution of pathogens and the possibility of survival in rabbit populations. The SNPs reported here will be useful to investigate the association between the TLR2 gene and disease resistance in future studies.

Yan Xiao, Huafang Zhang, Zhaoguo Zhang, Mina Yan, Ming Lei, Ke Zeng, Chunshun Zhao School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, People's Republic of China Abstract: For the purposes of obtaining a hepatocyte-selective drug delivery system, a novel tetravalent galactosylated diethylenetriaminepentaacetic acid-distearoyl phosphatidylethanolamine (4Gal-DTPA-DSPE) was synthesized. The chemical structure of 4Gal-DTPA-DSPE was confirmed by proton nuclear magnetic resonance and mass spectrometry. The four galactose-modified liposomes (4Gal-liposomes) were prepared by thin-film hydration method, then doxorubicin (DOX) was encapsulated into liposomes using an ammonium sulfate gradient loading method. The liposomal formulations with 4Gal-DTPA-DSPE were characterized by laser confocal scanning microscopy and flow cytometry analysis, and the results demonstrated that the 4Gal-liposomes facilitated the intracellular uptake of DOX into HepG2 cells via asialoglycoprotein receptor-mediated endocytosis. Cytotoxicity assay showed that the cell proliferation inhibition effect of 4Gal-liposomes was higher than that of the conventional liposomes without the galactose. Additionally, pharmacokinetic experiments in rats revealed that the 4Gal-liposomes displayed slower clearance from the systemic circulation compared with conventional liposomes. The organ distributions in mice and the study on frozen sections of liver implied that the 4Gal-liposomes enhanced the intracellular uptake of DOX into hepatocytes and prolonged the circulation. Taken together, these results indicate that liposomes containing 4Gal-DTPA-DSPE have great potential as drug delivery carriers for hepatocyte-selective targeting. Keywords: targeted drug delivery, liposomes, pharmacokinetics, galactose, ASGP-R, doxorubicin

The effect of calorie restriction (CR) on life span extension, demonstrated in organisms ranging from yeast to mice, may involve the down-regulation of pathways, including Tor, Akt, and Ras. Here, we present data suggesting that yeast Tor1 and Sch9 (a homolog of the mammalian kinases Akt and S6K) is a central component of a network that controls a common set of genes implicated in a metabolic switch from the TCA cycle and respiration to glycolysis and glycerol biosynthesis. During chronological survival, mutants lacking SCH9 depleted extracellular ethanol and reduced stored lipids, but synthesized and released glycerol. Deletion of the glycerol biosynthesis genes GPD1, GPD2, or RHR2, among the most up-regulated in long-lived sch9Delta, tor1Delta, and ras2Delta mutants, was sufficient to reverse chronological life span extension in sch9Delta mutants, suggesting that glycerol production, in addition to the regulation of stress resistance systems, optimizes life span extension. Glycerol, unlike glucose or ethanol, did not adversely affect the life span extension induced by calorie restriction or starvation, suggesting that carbon source substitution may represent an alternative to calorie restriction as a strategy to delay aging.

MicroRNAs (miRNAs) play crucial roles in a variety of biological processes via regulating expression of their target genes at the mRNA level. A number of computational approaches regarding miRNAs have been proposed, but most of them focus on miRNA gene finding or target predictions. Little computational work has been done to investigate the effective regulation of miRNAs.We propose a method to infer the effective regulatory activities of miRNAs by integrating microarray expression data with miRNA target predictions. The method is based on the idea that regulatory activity changes of miRNAs could be reflected by the expression changes of their target transcripts measured by microarray. To validate this method, we apply it to the microarray data sets that measure gene expression changes in cell lines after transfection or inhibition of several specific miRNAs. The results indicate that our method can detect activity enhancement of the transfected miRNAs as well as activity reduction of the inhibited miRNAs with high sensitivity and specificity. Furthermore, we show that our inference is robust with respect to false positives of target prediction.A huge amount of gene expression data sets are available in the literature, but miRNA regulation underlying these data sets is largely unknown. The method is easy to be implemented and can be used to investigate the miRNA effective regulation underlying the expression change profiles obtained from microarray experiments.

Recent studies suggest that the regulation of longevity may be partially conserved in many eukaryotes ranging from yeast to mammals. The three yeast mutants sch9Delta, ras2Delta, tor1Delta show extended chronological life span up to three folds. Our aim is to dissect the mechanisms that lead to the yeast life span extension.We obtain gene expression profiles of sch9Delta, ras2Delta, tor1Delta as well as that for a wild type at day 2.5 in SDC medium using Affymetrix Yeast2.0 arrays. To accurately estimate the expression differentiation between the wild type and the long-lived mutants, we use sub-array normalization followed by a variant of the median-polishing summarization. The results are validated by the probe sets of S. pombe on the same chips. To translate the differentiation into changes of biological activities, we make statistical inference by integrating the expression profiles with biological gene subsets defined by Gene Ontology, KEGG pathways, and cellular localization of proteins. Other than subset-versus-other comparisons, we also make local comparisons between two directly-related gene subsets such as cytosolic and mitochondrial ribosomes. Our consensus is obtained by cross-examination of these inferences. The significant and systematic differentiation in the three long-lived strains includes: lower transcriptional activities; down-regulation of TCA cycle and oxidative phosphorylation versus up-regulation of the KEGG pathway Glycolysis/Gluconeogenesis; the overall reduction of mitochondrial activities. We also report some different expression patterns such as reduction of the activities relating to mitosis in ras2Delta.The modification of energy pathways and modification of compartment activities such as down-regulation of mitochondrial ribosome proteins versus up-regulation of cytosolic ribosome proteins are directly associated with the life span extension in yeast. The results provide a new and systematic S. cerevisiae version of the free radical theory from the perspective of functional genomics.