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Interfacial debonding is one of the key failure modes in carbon fibre textile reinforced cementitious mortar (TRCM) under marine environment, therefore the long-term interfacial degradation of TRCM submerged in seawater is experimentally investigated in this study. The moisture-induced degradation has been targeted, particularly on the effects of hygroscopic expansion and interfacial ageing. In order to accelerate the ageing process, elevated temperature ageing treatment were adopted in this study. It is found that accelerated ageing can reduce the pull-out performance by nearly half when it is immersed under 60 °C, whilst the reduction can be neglected at 20 °C., Paper 169

Rationale The female menstrual or estrous cycle and its associated fluctuations in circulating estradiol (E2), progesterone, and other gonadal hormones alter orexin or hypocretin peptide production and receptor activity. Depending on the estrous cycle phase, the transcription of prepro-orexin mRNA, post-translational modification of orexin peptide, and abundance of orexin receptors change in a brain region-specific manner. The most dramatic changes occur in the hypothalamus, which is considered the starting point of the hypothalamic-pituitary–gonadal axis as well as the hub of orexin-producing neurons. Thus, hypothalamus-regulated behaviors, including arousal, feeding, reward processing, and the stress response depend on coordinated efforts between E2, progesterone, and the orexin system. Given the rise of orexin therapeutics for various neuropsychiatric conditions including insomnia and affective disorders, it is important to delineate the behavioral outcomes of this drug class in both sexes, as well as within different time points of the female reproductive cycle. Objectives Summarize how the menstrual or estrous cycle affects orexin system functionality in animal models in order to predict how orexin pharmacotherapies exert varying degrees of behavioral effects across the dynamic hormonal milieu.

Nonlinear Hall effects have been previously investigated in non-centrosymmetric systems for electronic systems. However, they only exist in metallic systems and are not compatible with ferroelectrics since these latter are insulators, hence limiting their applications. On the other hand, ferroelectrics naturally break inversion symmetry and can induce a non-zero Berry curvature. Here, we show that a non-volatile electric-field control of heat current can be realized in ferroelectrics through the nonlinear phonon Hall effects. More precisely, based on Boltzmann equation under the relaxation-time approximation, we derive the equation for nonlinear phonon Hall effects, and further show that the behaviors of nonlinear phonon (Boson) Hall effects are very different from nonlinear Hall effects for electrons (Fermion). Our work provides a route for electric-field control of thermal Hall current in ferroelectrics., 16 pages, 2 figures

The endocannabinoid and orexin systems share many biological functions, including wakefulness, stress response, reward processing, and mood. While these systems work against one another with respect to arousal, chronic stress-induced downregulation of both systems often leads to anhedonia or the inability to experience pleasure from natural rewards. In the current study, a 24 h restraint stress test (24 h RST) reduced sucrose preference in adult male and female C57BL/6 mice. Prior to the stressor, subsets of mice were intraperitoneally administered cannabinoid and orexin receptor agonists, antagonists, and combinations of these drugs. Restraint mice that received the cannabinoid receptor type 1 (CB1R) antagonist SR141716A, orexin receptor type 2 (OX2R) agonist YNT-185, and the combination of SR141716A and YNT-185, exhibited less anhedonia compared to vehicle/control mice. Thus, the 24 h RST likely decreased orexin signaling, which was then restored by YNT-185. Receptor colocalization analysis throughout mesocorticolimbic brain regions revealed increased CB1R-OX1R colocalization from SR141716A and YNT-185 treatments. Although a previous study from our group showed additive cataleptic effects between CP55,940 and the dual orexin receptor antagonist (TCS-1102), the opposite combination of pharmacological agents proved additive for sucrose preference. Taken together, these results reveal more of the complex interactions between the endocannabinoid and orexin systems.

Junhui Ji,1,&ast; Xiafang Gu,2,&ast; Chengjiao Xiao1 1Anesthesiology Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Anesthesiology Department, The No.2 People’s Hospital of Suzhou Xiangcheng District, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengjiao XiaoAnesthesiology Department, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Gusu District, Suzhou, 215000, Jiangsu, People’s Republic of ChinaTel +86-13962100544Email xiaocj1646@126.comBackground: Whether intraoperative temperature management can help patients recover quickly in the postanesthesia care unit (PACU) still remains to be investigated. This study aimed to investigate the effect of intraoperative temperature management on the quality of postoperative recovery of patients who underwent pulmonary lobectomy in the PACU.Methods: Totally, 98 patients aged 45– 60 years with a body mass index of 20– 25 kg/m2 who underwent elective thoracoscopic lobectomy were enrolled. Patients were categorized into two groups using a random number table: the conventional group received routine intervention to maintain normothermia (Group C, n = 49) and the aggressive group received integrated interventions (Group A, n = 49). In Group C, normothermic fluid was infused intravenously, the heating blanket was turned on when the intraoperative temperature was < 35.0 °C, and the warming was stopped when the temperature reached 36.5 °C. In Group A, the fluid heated to 37 °C was infused intravenously, and the heating blanket was used intraoperatively. When the body temperature was > 37 °C, the heating blanket was turned off, and when the body temperature was < 36.5 °C, the heating blanket was turned on to continue heating.Results: Steward awakening scores at 1 min and 5 min after extubation and PaO2 levels at 15 min after extubation were higher in Group A than in Group C (P < 0.05); incidence of chills, nausea, and vomiting in the PACU was lower in Group A than in Group C (P < 0.05); and length of stay in the PACU was shorter in Group A than in Group C (P < 0.05).Conclusion: Aggressive intraoperative temperature management of patients undergoing thoracoscopic lobectomy can improve the quality of postoperative recovery in the PACU through a safe and smooth transition compared with routine insulation measures.Keywords: hypothermia, recovery room, thoracoscopy, thoracic surgery

Jianhong Ji,1,&ast; Li Wang,2,&ast; Haiyang Guan,2 Yaqiong Jiang,1 Sanlian Zhou,2 Junhua Sheng,3 Lihua Wang4 1Intensive Care Unit, The Second Affiliated Hospital of Nantong University, Nantong, People’s Republic of China; 2Department of Emergency, The Second Affiliated Hospital of Nantong University, Nantong, People’s Republic of China; 3Department of Medical, The Second Affiliated Hospital of Nantong University, Nantong, People’s Republic of China; 4Department of Nursing, The Second Affiliated Hospital of Nantong University, Nantong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lihua WangDepartment of Nursing, The Second Affiliated Hospital of Nantong University, Nantong, 226001, People’s Republic of ChinaTel +86 13815219995Email lihua_wangdr@outlook.comObjective: This study was designed to verify the effect of group random quality control on the first aid ability of ward doctors and nurses with regard to the resuscitation of patients with in-hospital cardiac arrest (IHCA).Methods: The first aid quality control team of our hospital was established in December 2018, when the number, qualifications, organizational structure, quality control methods, and responsibilities of the team and team members were determined. The baseline data and assessment results of examinees, the rates of return of spontaneous circulation (ROSC), and the discharge survival rate of IHCA patients in 2019 and 2020 were compared.Results: There were no significant differences in the baseline data of examinees at each stage (p > 0.05). As time went on, the results of the four practical examinations were significantly improved (pairwise comparison, p < 0.05). The number of problems in examinations was significantly higher for physicians than for nurses. After guidance in department relearning, the incidence of related problems was significantly reduced, but the mastery of the frequency and depth of extracorporeal cardiac compression were not always up to standard. The proportion of critically ill patients and the incidence of IHCA in the hospital in 2020 was higher than in 2019 (p < 0.05), and the ROSC rate was also significantly higher than it was in 2019 (p < 0.05), but the difference in the survival rate at discharge was not statistically significant (p > 0.05).Conclusion: Group random quality control meets the needs of IHCA emergencies, and it can improve the first aid skills and organizational coordination of doctors and nurses on the ward through continuous discovery and problem solving so that the ultimate goal of improving the success rate of resuscitation can be achieved.Keywords: in-hospital cardiac arrest, cardiopulmonary resuscitation, quality control, patient outcomes, survival, ability

Jianlei Ji,&ast; Qinghai Wang,&ast; Tao Huang, Ziyu Wang, Pingli He, Chen Guo, Weijia Xu, Yanwei Cao, Zhen Dong, Hongyang Wang Department of Kidney Transplantation, the Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhen Dong; Hongyang WangDepartment of Kidney Transplantation, the Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266000, People’s Republic of ChinaTel +8613455263336; +8618661803752Email dong266000@163.com; why19850804@163.comBackground: Trimethoprim/sulfamethoxazole (TMP-SMX) is considered the first-choice treatment for Pneumocystis jirovecii pneumonia (PJP) in recipients of solid organ transplantation. However, this treatment is associated with various severe adverse events that might not be tolerable for some renal transplant recipients, and the optimal dose remains elusive. The present study assessed the efficacy of low-dose TMP-SMX in recipients of a deceased donor kidney.Methods: A total of 37 adult deceased donor kidney recipients who suffered PJP between January 2015 and June 2020 were included. The survival rates of the patients and grafts, the rate of invasive ventilation, and adverse events, including gastrointestinal discomfort, hematologic side effects, hyperkalemia, and renal function impairments, were assessed.Results: The patient and graft survival rates were both 100%. Two patients (5.4%) required invasive ventilation. Eight patients (21.6%) reported gastrointestinal discomfort, but none required dose reduction or discontinued treatment. The frequencies of hematologic side effects, hyperkalemia and impaired kidney function were 5.4% (2/37), 2.7% (1/37), and 2.7% (1/37), respectively.Conclusion: Optimization of TMP-SMX dose may reduce the risk of adverse events without compromising efficacy for the treatment of PJP in deceased donor kidney recipients.Keywords: efficacy, low dose, trimethoprim/sulfamethoxazole, Pneumocystis jirovecii pneumonia, deceased donor kidney recipients

A new type of solar active carbon-doped Bi3O4Br catalyst was synthesized by combining hydrothermal and post-thermal treatment. The activity of the material under sunlight and visible light was 3.3 times and 2.7 times that of Bi3O4Br, respectively. The C-doping on Bi3O4Br nanosheets increased the built-in electric field strength, thus significantly promoted the migration of charge carriers and enhanced the photocatalytic activity. In addition, replacing Br with C with a smaller atomic radius can shorten the interlayer spacing, which is beneficial to carrier separation. Experiments showed that the doping of C shortened the semiconductor band gap by 9.8% and expanded the absorption range of visible light. Among the photogenerated reactive species, h+ played a major role in the degradation of 1-methylpyrene (a typical polycyclic aromatic hydrocarbons), followed by O2∙- and •OH. Based on intermediate analysis and DFT calculation, we proposed the degradation mechanism and pathways. Quantitative structure–activity relationship (QSAR) analysis showed that some toxic intermediates were produced during the photocatalysis process, but the overall environmental risk was greatly reduced. This work provides new perspective for understanding non-metallic doping in semiconductor photocatalysts to enhance the built-in electric field, and this technology can be extended to other semiconductor materials.

Si-Jia Zhao,1 Hong Jia,2 Xiu-Lian Xu,1 Wen-Bo Bu,3 Qian Zhang,3 Xi Chen,4 Juan Ji,2 Jian-Fang Sun1 1Department of Pathology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, People’s Republic of China; 2Department of Dermatology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, People’s Republic of China; 3Department of Dermatologic Surgery, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, People’s Republic of China; 4Department of Medicine 3, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen Nuremberg, Erlangen, Bavaria, GermanyCorrespondence: Jian-Fang SunInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, People’s Republic of ChinaTel +86 25 8547 8015Fax +86 25 8541 4477Email JianfangSunPUMC@outlook.comPurpose: Vitiligo is an acquired depigmentation skin disease, which affects an average of 1% of the world’s population. The purpose of this study is to identify the key genes and pathways responsible for vitiligo and find new therapeutic targets.Methods: The datasets GSE65127, GSE53146, and GSE75819 were downloaded from the Gene Expression Omnibus (GEO) database. R language was used to identify the differentially expressed genes (DEGs) between lesional skin of vitiligo and non-lesional skin. Next, the key pathways were obtained by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The protein–protein interaction (PPI) networks were conducted by STRING database and Cytoscape software. Subsequently, module analysis was performed by Cytoscape. Among these results, the Wnt/β-catenin pathway and melanogenesis pathway caught our attention. The expression level of β-catenin, microphthalmia-associated transcription factor (MITF) and tyrosinase (TYR) was detected by immunofluorescence in vitiligo lesions and healthy skin. Moreover, zebrafish was treated with XAV-939, an inhibitor of the Wnt/β-catenin pathway. After that, the area of melanin granules as a percentage of the head area was measured. The mRNA expression of β-catenin, lymphoid-enhancing factor 1(lef1), tyr and mitf were detected by q-PCR (quantitative polymerase chain reaction) in zebrafish (Danio rerio).Results: A total of 2442 DEGs were identified, including 1068 upregulated and 1374 downregulated DEGs. The key pathways were identified by GO and KEGG analyses, such as “NOD-like receptor signaling pathway”, “Wnt signaling pathway”, “Melanogenesis”, “mTOR signaling pathway”, “PI3K-Akt signaling pathway”, “Calcium signaling pathway” and “Rap1 signaling pathway”. The immunofluorescence results showed that the level of β-catenin, MITF and TYR was significantly downregulated in vitiligo lesional skin. In zebrafish, the mean percentage area of melanin granules and the expression of β-catenin, lef1, tyr and mitf were decreased after treated with XAV-939.Conclusion: The present study identified key genes and signaling pathways associated with the pathophysiology of vitiligo. Among them, the Wnt/β-catenin pathway played an essential role in pigmentation and could be a breakthrough point in vitiligo treatment.Keywords: vitiligo, zebrafish, melanogenesis, Wnt/β-catenin, calcium signaling, Rap1

Feifei Yang,1,2,&ast; Chunhong Liu,3,&ast; Jian Ji,3 Wenjun Cao,3 Baixing Ding,1,2 Xiaogang Xu1,2 1Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, People’s Republic of China; 3Department of Clinical Laboratory, Eye and ENT Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenjun CaoDepartment of Clinical Laboratory, Eye and ENT Hospital, Fudan University, Shanghai, People’s Republic of ChinaEmail wgkjyk@aliyun.comBaixing DingInstitute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaEmail dingbaixing@163.comPurpose: To investigate molecular characteristics, antimicrobial resistance, and biofilm formation ability of Pseudomonas aeruginosa strains isolated from patients with aural infections.Methods: Isolates (n = 199) were collected from ear discharges of patients with aural infections from January 2019 to December 2020. Antimicrobial susceptibility testing was performed according to the Clinical and Laboratory Standards Institute guidelines. All isolates were subjected to multilocus sequence typing (MLST) with amplification and sequencing of seven housekeeping genes. Biofilm formation and eradication were quantitatively assessed in microtiter plates. Genes associated with biofilm formation and the quinolone-resistance-determining region (QRDR) of genes gyrA and parC were investigated using polymerase chain reaction amplification and sequencing.Results: Of the 199 P. aeruginosa strains isolated, 109 (54.77%) were from females and 90 (45.23%) were from males. The isolates exhibited very low rates of resistance to most antibiotics tested, including piperacillin (1.51%), ceftazidime (0.50%), and imipenem (3.52%); however, the quinolones ciprofloxacin (80.40%) and levofloxacin (82.91%) were notable exceptions. The QRDR sequence results of the quinolone-resistant P. aeruginosa isolates showed Thr83Ile (n = 155) was the most common amino acid mutation in gyrA (n = 165), while Ser87Leu (n = 157) was widely detected in parC (n = 165). MLST analysis identified 34 sequence types (STs) with most isolates belonging to ST316 (73.87%). Almost all of the P. aeruginosa isolates (96.98%) produced biofilms and biofilm-forming genes algD (98.49%), pslD (96.98%), and pelF (96.48%) were highly prevalent.Conclusion: The P. aeruginosa strains isolated from aural discharges in this study exhibited very low rates of resistance to most antibiotics tested, except for the resistance rates to quinolones, which were relatively high. The isolates also exhibited a strong biofilm formation ability and low susceptibility to eradication, indicating that more effective drugs and treatment methods are needed to combat these infections.Keywords: Pseudomonas aeruginosa isolate, ear infection, antimicrobial resistance, ST316, biofilm

Qinghai Wang,1 Kai Zhao,2 Chen Guo,1 Hong Li,1 Tao Huang,1 Jianlei Ji,1 Xiaoxia Sun,1 Yanwei Cao,1 Zhen Dong,1 Hongyang Wang1 1Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China; 2Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of ChinaCorrespondence: Zhen Dong; Hongyang WangDepartment of Kidney Transplantation, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266000, People’s Republic of ChinaTel +8613455263336; +8618661803752Email dong266000@163.com; why19850804@163.comObjective: This study aimed to determine the prevalence of antibiotic resistance and virulence genes of Escherichia coli strains among patients with urinary tract infections (UTIs) after kidney transplantation from deceased donors.Methods: Between January 2014 and June 2018, 64 patients who received kidney transplants from deceased donors at our institution developed a UTI due to E. coli. Polymerase chain reaction was used to detect virulence genes in E. coli strains. The Kirby–Bauer method was used to evaluate the antibiotic susceptibility pattern of the isolates.Results: Among the study cohort, 46 (71.9%) UTIs were community-acquired (CA), and 18 (28.1%) were hospital-acquired (HA). The percentages of isolated E. coli strains that showed antibiotic resistance were as follows: 92.2% to ampicillin, 76.6% to cefalotin, 81.3% to carbenicillin, 29.7% to ciprofloxacin, 62.5% to cotrimoxazole, 35.9% to gentamicin, 34.4% to levofloxacin, 28.1% to norfloxacin, 68.8% to pefloxacin, 57.8% to trimethoprim/sulfamethoxazole, and 20.3% to amikacin. HA E. coli showed higher resistance to ciprofloxacin, cotrimoxazole, trimethoprim/sulfamethoxazole and amikacin, compared with CA E. coli (P< 0.05). The most prevalent virulence genes among the E. coli strains were fim (64.1%), followed by irp2 (56.3%), iroN (46.9%), pap GII (45.3%), sfa (31.3%), pap (25%), iuc (23.4%), pap GI (15.6%), pap GIII (14.1%), hly (9.4%), and cnf (4.7%). The irp2 and iroN genes were found more frequently in the HA E. coli than in the CA E. coli (P< 0.05).Conclusion: The E. coli strains, especially HA E. coli, isolated from UTI patients after kidney transplantation from deceased donors showed resistance to multiple antibiotics and harbored numerous virulence genes. These findings provide insight for genetic characterizations and epidemiological studies of E. coli strains causing UTIs in patients after kidney transplantation from deceased donors.Keywords: Escherichia coli, antimicrobial resistance, virulence genes, urinary tract infections, kidney transplantation

Chao Li,1 Zhenchun Shi,2 Jiacui Ji,2 Gengyun Niu,1 Zengxun Liu2 1Department of Psychiatry, Jining Medical University, Jining, 272067, People’s Republic of China; 2Department of Psychiatry, Shandong Mental Health Center, Jinan, 250014, People’s Republic of ChinaCorrespondence: Zengxun LiuDepartment of Psychiatry, Shandong Mental Health Center, No. 49 Wenhua Eastern Road, Jinan, 250014, People’s Republic of ChinaTel +86-13583135343Email zengxunliu@126.comPurpose: Agitation is prevalent among inpatients with schizophrenia. The aim of this study was to investigate whether biochemical parameters are associated with agitation in schizophrenia.Patients and Methods: Agitation was evaluated by the Positive and Negative Syndrome Scale-Excited Component questionnaire (PANSS-EC). Fasting serum levels of C-reactive protein (CRP), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), uric acid (UA), creatinine, glucose and lipids were measured.Results: The analysis included 154 inpatients with schizophrenia (71 with agitation, 83 without agitation) and 75 healthy control subjects. Patients with schizophrenia and agitation had higher serum levels of CRP, FT3, FT4 and UA as well as lower levels of serum TSH and creatinine than patients without agitation (all P < 0.05). Multivariate logistic regression analysis indicated that serum CRP (odds ratio [OR] = 1.470, P = 0.001), FT3 (OR = 13.026, P < 0.001), TSH (OR = 0.758, P = 0.033) and creatinine (OR = 0.965, P = 0.004) were significantly associated with agitation in schizophrenia. CRP, FT3, TSH and creatinine achieved an area under the ROC curve of 0.626, 0.728, 0.620 and 0.663 respectively in discriminating schizophrenia with or without agitation.Conclusion: Increased serum CRP and FT3 levels and decreased serum TSH and creatinine levels are independent risk factors for agitation in hospitalized patients with schizophrenia. Inflammation, thyroid hormones and renal function may be involved in the pathogenesis of agitation in schizophrenia.Keywords: schizophrenia, psychomotor agitation, C-reactive protein, triiodothyronine, thyroid-stimulating hormone, creatinine

Jinyu Zhu,1,2,&ast; Bufu Tang,1,3,&ast; Yang Gao,1,4 Suqin Xu,5 Jianfei Tu,1,4 Yajie Wang,4 Weibin Yang,1,4 Shiji Fang,4 Qiaoyou Weng,4 Zhongwei Zhao,1,4 Min Xu,1,4 Yang Yang,1,4 Minjiang Chen,1,4 Chenying Lu,1,4 Jiansong Ji1,4 1Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People’s Republic of China; 2Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China; 3Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China; 4Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People’s Republic of China; 5Clinical Laboratory, Fuyuan Hospital of Yiwu, Jinhua, 321000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiansong Ji; Chenying Lu Email jijiansong@zju.edu.cn; luchenying@zju.edu.cnIntroduction: Hepatocellular carcinoma (HCC) is a heterogeneous molecular disease with complex molecular pathogenesis that influences the efficacy of therapies. Exosomes play a crucial role in tumorigenesis and poor disease outcomes in HCC.Objective: The aim of this study was to identify the optimal gene set derived from exosomes in HCC with substantial predictive value to construct models for determining prognosis, recurrence risk and diagnosis and to identify candidates suitable for immunotherapy and chemotherapy, thereby providing new ideas for the individualized treatment of patients and for improving prognosis.Methods: Weighted correlation network analysis (WGCNA) and univariate and multivariate Cox PH regression analyses were applied to identify exosome-related signatures in the TCGA and exoRbase databases associated with clinical relevance, immunogenic features and tumor progression in HCC. Cell experiments were performed to further confirm the oncogenic effect of MYL6B and THOC2.Results: The models for prognosis and recurrence risk prediction were built based on two exosomal genes (MYL6B and THOC2) and were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC datasets, namely, the TCGA cohort (HR=2.5, P< 0.001), the ICGC cohort (HR=3.15, P< 0.001) and the GSE14520 cohort (HR=1.85, P=0.004). A higher recurrence probability was found in HCC patients with high recurrence risk than in HCC patients with low recurrence risk in the TCGA cohort (HR=2.44, P< 0.001) and the GSE14520 cohort (HR=1.54, P=0.025). High prognostic risk patients had higher expression of immune checkpoint genes, such as PD1, B7H3, B7H5, CTLA4 and TIM3 (P< 0.05). Diagnostic models based on the same two genes were able to accurately distinguish HCC patients from normal individuals and HCC from dysplastic nodules.Conclusion: Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.Keywords: exosome, hepatocellular carcinoma, HCC, immune checkpoint, prognosis

Early detection of chronic kidney disease is important to prevent progression of irreversible kidney damage, reducing the need for renal transplantation. Shear wave elastography is ideal as a quantitative imaging modality to detect chronic kidney disease because of its non-invasive nature, low cost and portability, making it highly accessible. However, the complexity of the kidney architecture and its tissue properties give rise to various confounding factors that affect the reliability of shear wave elastography in detecting chronic kidney disease, thus limiting its application to clinical trials. The objective of this review is to highlight the confounding factors presented by the complex properties of the kidney, in addition to outlining potential mitigation strategies, along with the prospect of increasing the versatility and reliability of shear wave elastography in detecting chronic kidney disease.

Feiyang Jin,1 Di Liu,1 Xiaoling Xu,1 Jiansong Ji,2 Yongzhong Du1 1Institute of Pharmaceutics, College of Pharmaceutics Sciences, Zhejiang University, Hangzhou, 310058, People’s Republic of China; 2Department of Radiology, Lishui Hospital of Zhejiang University, Lishui, 323000, People’s Republic of ChinaCorrespondence: Jiansong JiDepartment of Radiology, Lishui Hospital of Zhejiang University, Lishui, 323000, People’s Republic of ChinaTel +86-578-2285011Email lschrjjs@163.comYongzhong DuInstitute of Pharmaceutics, College of Pharmaceutics Sciences, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou, 310058, People’s Republic of ChinaTel +86-571-88981651Email duyongzhong@zju.edu.cnAbstract: Benefiting from the rapid development of nanotechnology, photodynamic therapy (PDT) is arising as a novel non-invasive clinical treatment for specific cancers, which exerts direct efficacy in destroying primary tumors by generating excessive cytotoxic reactive oxygen species (ROS). Notably, PDT-induced cell death is related to T cell-mediated antitumor immune responses through induction of immunogenic cell death (ICD). However, ICD elicited via PDT is not strong enough and is limited by immunosuppressive tumor microenvironment (ITM). Therefore, it is necessary to improve PDT efficacy through enhancing ICD with the combination of synergistic tumor therapies. Herein, the recent progress of nanomaterials-based PDT combined with chemotherapy, photothermal therapy, radiotherapy, and immunotherapy, employing ICD-boosted treatments is reviewed. An outlook about the future application in clinics of nanomaterials-based PDT strategies is also mentioned.Keywords: photodynamic therapy, immunogenic cell death, antitumor immunity, immunosuppressive tumor environment, nanomedicines

Chunhong Liu,1,2,* Baixing Ding,3,* Jian Ji,1 Zhujian Wang,1 Huiwen Chen,1 Wenjun Cao1,2 1Clinical Laboratory, Eye & ENT Hospital, Fudan University, Shanghai, People’s Republic of China; 2Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People’s Republic of China; 3Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenjun Cao Email wgkjyk@aliyun.comPurpose: To report antibiotic resistance rates and trends of common ocular isolates collected over a 15-year period.Methods: We collected 3533 isolates from July 1, 2005 to July 31, 2020. Antibiotic sensitivity was determined according to the guidelines of the Clinical and Laboratory Standards Institute. Chi-squared (χ2) test was used to analyze changes in antibiotic susceptibility over 15 years.Results: Among the 3533 isolates, the predominant pathogens were the staphylococcal species. Methicillin resistance was observed in 381 Staphylococcus aureus (S. aureus) isolates (46.4%) and 1888 coagulase-negative staphylococci (CoNS) isolates (61.1%), and methicillin-resistant (MR) isolates had a high probability of concurrent resistance to fluoroquinolones and aminoglycosides. The mean percentage of resistance in staphylococcal isolates did not reach statistical significance across patient age groups (P = 0.87). Methicillin resistance did not increase in the CoNS (P = 0.546) isolates, and resistance to methicillin slightly decreased among S. aureus (P = 0.04) isolates over 15 years. Additional exploratory analysis revealed a small decrease in resistance to tobramycin (P = 0.01) and chloramphenicol (P < 0.001) among the CoNS isolates. All staphylococcal isolates were susceptible to vancomycin.Conclusion: Staphylococci were the most common microorganisms responsible for causing ocular infections. Antibiotic resistance was high among staphylococci, with nearly half of these isolates were resistant to methicillin and these had a high probability of concurrent resistance among MR staphylococci to other antibiotics. Overall, ocular resistance did not significantly change during the 15-year study period. We conclude that continued surveillance of antibiotic resistance provides critical data to guide antibiotic selection.Keywords: methicillin, antibiotic resistance, ocular isolate, staphylococci

Background: Sustainable Development Goal 3.2 has targeted elimination of preventable child mortality, reduction of neonatal death to less than 12 per 1000 livebirths, and reduction of death of children younger than 5 years to less than 25 per 1000 livebirths, for each country by 2030. To understand current rates, recent trends, and potential trajectories of child mortality for the next decade, we present the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 findings for all-cause mortality and cause-specific mortality in children younger than 5 years of age, with multiple scenarios for child mortality in 2030 that include the consideration of potential effects of COVID-19, and a novel framework for quantifying optimal child survival. Methods: We completed all-cause mortality and cause-specific mortality analyses from 204 countries and territories for detailed age groups separately, with aggregated mortality probabilities per 1000 livebirths computed for neonatal mortality rate (NMR) and under-5 mortality rate (U5MR). Scenarios for 2030 represent different potential trajectories, notably including potential effects of the COVID-19 pandemic and the potential impact of improvements preferentially targeting neonatal survival. Optimal child survival metrics were developed by age, sex, and cause of death across all GBD location-years. The first metric is a global optimum and is based on the lowest observed mortality, and the second is a survival potential frontier that is based on stochastic frontier analysis of observed mortality and Healthcare Access and Quality Index. Findings: Global U5MR decreased from 71·2 deaths per 1000 livebirths (95% uncertainty interval [UI] 68·3-74·0) in 2000 to 37·1 (33·2-41·7) in 2019 while global NMR correspondingly declined more slowly from 28·0 deaths per 1000 live births (26·8-29·5) in 2000 to 17·9 (16·3-19·8) in 2019. In 2019, 136 (67%) of 204 countries had a U5MR at or below the SDG 3.2 threshold and 133 (65%) had an NMR at or below the SDG 3.2 threshold, and the reference scenario suggests that by 2030, 154 (75%) of all countries could meet the U5MR targets, and 139 (68%) could meet the NMR targets. Deaths of children younger than 5 years totalled 9·65 million (95% UI 9·05-10·30) in 2000 and 5·05 million (4·27-6·02) in 2019, with the neonatal fraction of these deaths increasing from 39% (3·76 million [95% UI 3·53-4·02]) in 2000 to 48% (2·42 million; 2·06-2·86) in 2019. NMR and U5MR were generally higher in males than in females, although there was no statistically significant difference at the global level. Neonatal disorders remained the leading cause of death in children younger than 5 years in 2019, followed by lower respiratory infections, diarrhoeal diseases, congenital birth defects, and malaria. The global optimum analysis suggests NMR could be reduced to as low as 0·80 (95% UI 0·71-0·86) deaths per 1000 livebirths and U5MR to 1·44 (95% UI 1·27-1·58) deaths per 1000 livebirths, and in 2019, there were as many as 1·87 million (95% UI 1·35-2·58; 37% [95% UI 32-43]) of 5·05 million more deaths of children younger than 5 years than the survival potential frontier. Interpretation: Global child mortality declined by almost half between 2000 and 2019, but progress remains slower in neonates and 65 (32%) of 204 countries, mostly in sub-Saharan Africa and south Asia, are not on track to meet either SDG 3.2 target by 2030. Focused improvements in perinatal and newborn care, continued and expanded delivery of essential interventions such as vaccination and infection prevention, an enhanced focus on equity, continued focus on poverty reduction and education, and investment in strengthening health systems across the development spectrum have the potential to substantially improve U5MR. Given the widespread effects of COVID-19, considerable effort will be required to maintain and accelerate progress. This article was supported by the European Research Council, ERC 848325. Alberto Ortiz was supported by FIS/Fondos FEDER (PI18/01366, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009). Daniela Ribeiro acknowledges the financial support from the European Union [FEDER funds through COMPETE, POCI-01-0145-FEDER-029253). Joan B Soriano acknowledges support from the Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain Funding: Bill & Melinda Gates Foundation

To evaluate glycaemic profiles of COVID-19 patients without diabetes receiving dexamethasone and determine factors associated with hyperglycaemia.All subjects without pre-existing diabetes receiving dexamethasone 6 mg for COVID-19 in a non-critical care setting were identified. Glucose profiles were obtained from capillary blood glucose (BG). Univariate and multivariate analyses were performed to identify factors associated with dexamethasone-induced hyperglycaemia (BG ≥ 10 mmol/L).Of 254 subjects, 129 (50.8%) were male with age 51.1 ± 18.2 years and weight 89.7 ± 26.3 kg. Hyperglycaemia post-dexamethasone occurred in 121 (47.6%). Glucose excursions began within three hours (6.8 ± 1.4 mmol/L pre-dexamethasone vs 8.7 ± 2.4 mmol/L at ≤ 3 h, p 0.001) and peaked at 7-9 h (10.5 ± 2.3 mmol/L, p 0.001 vs pre-dexamethasone). BGs post-intravenous were higher than post-oral administration for the initial six hours. Hyperglycaemic subjects were older (57.8 ± 17.5 years vs 45.0 ± 16.6 years, p 0.001), had higher initial glucose (6.3 ± 1.0 vs 5.9 ± 0.9 mmol/L, p = 0.004), higher HbA1c (5.8 ± 0.3% [40 ± 3.5 mmol/mol] vs 5.5 ± 0.4% [37 ± 4.1 mmol/mol], p 0.001) higher C-reactive protein (CRP) (100 ± 68 vs 83 ± 58 mg/L, p = 0.026), and lower eGFR (79 ± 17 vs 84 ± 16 mL/min/1.73 mHalf of subjects without diabetes experienced hyperglycaemia post-dexamethasone for COVID-19, peak occurring after 7-9 h. Age, HbA1c and CRP were associated with hyperglycaemia.

Background: Dexamethasone improves COVID-outcomes. Detailed glycemic profile for patients receiving dexamethasone for COVID-is lacking. Methods: Our hospital recommends routine blood glucose monitoring for patients with COVID-receiving dexamethasone 6mg daily. Subjects without prior history of diabetes admitted in a non-critical care setting over a 1-month period were identified and evaluated. The primary outcome was hyperglycemia post-dexamethasone, defined as glucose ≥10mmol/L. Results: Of 277 subjects (52% male, age 52±18 yrs, weight 90±26 kg, 7% with newly diagnosed diabetes [HbA1c ≥6.5%]) , hyperglycemia post-dexamethasone occurred in 51%, with peak glucose 12.4±2.3 (mean 2.2 tests/day) . Glucose excursions peaked 7-9 hours post-dexamethasone (figure) . Hyperglycemic subjects were older (58±17 vs. 45±7 yrs, p Conclusions: Dexamethasone led to hyperglycemia in half of patients without prior diabetes admitted with COVID-19, with peak occurring 7-9 hours after dexamethasone. Older age, higher HbA1c and initial CRP predicted development of hyperglycemia. Disclosure Y.J.Rhou: None. A.Hor: None. M.Wang: None. Y.Wu: None. D.R.Chipps: None. N.Cheung: None.

Sexual dimorphisms are observed in cannabinoid pharmacology. It is widely reported that female animals are more sensitive to the cataleptic, hypothermic, antinociceptive, and anti-locomotive effects of cannabinoid receptor agonists such as CP55,940. Despite awareness of these sex differences, there is little consideration for the pharmacodynamic differences within females. The mouse estrus cycle spans 4-5 days and consists of four sex hormone-mediated phases: proestrus, estrus, metestrus, and diestrus. The endocannabinoid system interacts with female sex hormones including β-estradiol, which may influence receptor expression throughout the estrus cycle. In the current study, sexually mature female C57BL/6 mice in either proestrus or metestrus were administered either 1 mg/kg i.p. of the cannabinoid receptor agonist CP55,940 or vehicle. Mice then underwent the tetrad battery of behavioral assays measuring catalepsy, internal body temperature, thermal nociception, and locomotion. Compared with female mice in metestrus, those in proestrus were more sensitive to the anti-nociceptive effects of CP55,940. A similar trend was observed in CP55,940-induced catalepsy; however, this difference was not significant. As for cannabinoid receptor expression in brain regions underlying antinociception, the spine tissue of proestrus mice that received CP55,940 exhibited increased expression of cannabinoid receptor type 1 relative to treatment-matched mice in metestrus. These results affirm the importance of testing cannabinoid effects in the context of the female estrus cycle.

Meihong Sheng,1 Juan Ji,1 Chenying Zhang,1 Zirui Zhang,1 Shenchu Gong,1 Yihua Lu2 1Department of Radiology, Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong, Jiangsu, 226001, People’s Republic of China; 2Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, 226019, Jiangsu, People’s Republic of ChinaCorrespondence: Shenchu Gong Email gongshenchu@msn.comBackground: Full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) are used separately or in combination to identify small breast lesions. The dose of the examination depends on the density of the breast and the imaging (FFDM or DBT) performed. We have performed a retrospective review of FFDM and DBT in women with denser breasts in order to demonstrate how varying the combination of FFDM and DBT in CC and MLO views affects lesion detection and the average gland dose.Methods: Eighty-one patients with dense breast received both full-field digital mammography (FFDM) and DBT bilateral screening. The recorded data included the display rates for small lesions or other positive lesions, the type of breast gland, the average gland dose (AGD), and the compression thickness of different collection methods. ANOVA was used to compare the AGD among different collection combinations, and t-test was used to perform pairwise comparison between groups with the same gland type. The relationship between AGD and compression thickness was analyzed by Pearson linear correlation, and the lesion display rates were compared using Chi-square test.Results: We found that AGDs were significantly different among the 6 collection methods (F = 119.06, p< 0.01), but were not obviously different between groups with the same gland type (F = 0.848, p> 0.05). The types of dense glands were correlated with compression thickness, and the thickness was moderately to strongly correlated with AGD (r=0.596– 0.736). The combination of single-view DBT(CC-DBT) and FFDM showed significantly higher mass display rates than the two-view FFDM (p< 0.05), while the display rates for other positive lesions were similar (p> 0.05).Conclusion: Our study showed that in opportunistic screening of patients with small breast masses that can be easily detected by ultrasound, MLO-FFDM+CC-DBT or CC-FFDM+MLO-DBT combinations can better balance the individual average gland dose and detection accuracy. The study result cannot be applied to the detection of non-mass lesions as the numbers are too small.Keywords: breast, breast tomography, screening, digital mammography, average gland dose

Zining Liu,* Yinkui Wang,* Fei Shan, Xiangji Ying, Yan Zhang, Shuangxi Li, Yongning Jia, Ziyu Li, Jiafu Ji Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziyu LiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaEmail ziyu_li@hsc.pku.edu.cnBackground: The duration and the optimal time to adjuvant chemotherapy (TAC) in locally advanced gastric cancer (LAGC) have net not been sufficiently demonstrated. Sequential adjuvant chemotherapy (AC) after neoadjuvant chemotherapy plus gastrectomy is increasingly utilized, making the question more complicated.Patients and Methods: Data were collected from patients with LAGC who underwent 5-Fu-based doublet regimens as adjuvant treatment after gastrectomy in a single-center database. TAC and duration (cycles) were used to evaluate survival outcomes.Results: A total of 816 patients were included. Patients received over six cycles and TAC less than 42 days significantly correlated with better survival (log-rank Ptrend< 0.001). The analysis of TAC and number cycles were separately applied in perioperative chemotherapy (PEC) and postoperative chemotherapy (POC) group using Cox regression. The number of cycles revealed a statistical significance improving OS rate both in POC (HR=0.904, 95% CI=0.836– 0.977, P=0.011) and PEC (HR=0.887, 95% CI=0.798– 0.986, P=0.026), while only in POC did the TAC show an increasing trend of risk with borderline significance (OS: HR=1.008, 95% CI=0.999– 1.018, P=0.094; PFS: HR=1.009, 95% CI=1.000– 1.018, P=0.055). A spline model demonstrates the less improvement in survival after cycles of chemotherapy reaching six.Conclusion: Our findings suggest that TAC is more likely to downregulate the survival benefit in POC rather than PEC, while overall survival is susceptible to cumulative cycles of chemotherapy in both groups. Furthermore, six cycles of chemotherapy tended to reach the maximum survival benefits. Prospective confirmation is required.Keywords: gastric cancer, chemotherapy, time to initiation, duration, restricted cubic spline

Yuanyuan Wang,1 Jingjing Chen,1 Wei Chen,2 Ling Liu,2 Mei Dong,2 Juan Ji,2 Die Hu,3 Nianzhi Zhang2 1Graduate School, Anhui University of Chinese Medicine, Anhui, Hefei 230012, People’s Republic of China; 2Department of Respiratory Medicine, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui, Hefei, 230031, People’s Republic of China; 3Department of Scientific Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui, Hefei 230031, People’s Republic of ChinaCorrespondence: Nianzhi Zhang Tel +86 551-62850057Email dczhangnz@126.comBackground: Chronic obstructive pulmonary disease (COPD) is the third cause of disease-related death and brings a heavy burden to human health. Long non-coding RNA (lncRNA) was revealed to participate in COPD pathogenesis. This study aims to establish the effects and regulatory mechanism of lncRNA long intergenic non-coding 00987 (LINC00987) in lipopolysaccharide (LPS)-induced apoptosis, oxidative stress, inflammation and autophagy in BEAS-2B cells.Methods: The expression levels of LINC00987 and let-7b-5p were detected by real-time quantitativepolymerase chain reaction (RT-qPCR). The expression of apoptosis-associated proteins, oxidative stress (ROS)-related proteins, autophagy-related proteins and sirtuin1 (SIRT1) protein was determined by Western blot. Cell viability was illustrated by cell counting kit-8 (CCK-8) assay. Cell apoptosis was investigated by caspase3 activity and apoptosis analysis assays. ROS, inflammation and autophagy were demonstrated by detecting reactive ROS level and superoxide dismutase (SOD) activity, enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. The binding sites between let-7b-5p and LINC00987 or SIRT1 were predicted by lncBase or miRWalk online database, and identified by dual-luciferase reporter assay.Results: LINC00987 expression was strikingly downregulated and let-7b-5p expression was obviously upregulated in COPD tissues and LPS-induced BEAS-2B cells compared with control groups. LINC00987 overexpression promoted BEAS-2B cells against LPS-mediated viability, apoptosis, oxidative stress, inflammation and autophagy, whereas these effects were attenuated by let-7b-5p mimic or SIRT1 knockdown. Furthermore, LINC00987 sponged let-7b-5p and let-7b-5p bound to SIRT1.Conclusion: LINC00987 ameliorated COPD through modulating LPS-induced cell apoptosis, oxidative stress, inflammation and autophagy via sponging let-7b-5p to associate with SIRT1. This finding will provide a theoretical basis for the research of LncRNA-mediated treatment in COPD.Keywords: COPD, LINC00987, let-7b-5p, SIRT1, LPS

Qiang Yu,1,2 Liwei Wu,2 Jie Ji,2 Jiao Feng,2 Weiqi Dai,1– 3 Jingjing Li,1,2 Jianye Wu,1 Chuanyong Guo1,2 1Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai 200060, People’s Republic of China; 2Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China; 3Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200336, People’s Republic of ChinaCorrespondence: Jianye Wu; Chuanyong GuoDepartment of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai 200060, People’s Republic of ChinaEmail wjymail@163.com; guochuanyong@hotmail.comAbstract: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. HCC incidence rate is sixth and mortality is fourth worldwide. However, HCC pathogenesis and molecular mechanisms remain unclear. The incidence of HCC is associated with genetic, environmental, and metabolic factors. The role of gut microbiota in the pathogenesis of HCC has attracted researchers’ attention because of anatomical and functional interactions between liver and intestine. Studies have demonstrated the involvement of gut microbiota in the development of HCC and chronic liver diseases, such as alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and liver cirrhosis. Peroxisome proliferator-activated receptors (PPARs) are a group of receptors with diverse biological functions. Natural and synthetic PPAR agonists show potential for treatment of NAFLD, liver fibrosis, and HCC. Recent studies have demonstrated that PPARs take part in gut microbiota inhabitation and adaptation. This manuscript reviews the role of gut microbiota in the development of HCC and precancerous diseases, the role of PPARs in modulation of gut microbiota and HCC, and potential of gut microbiota for HCC diagnosis and treatment.Keywords: gut microbiota, hepatocellular carcinoma, PPARs, carcinogenesis

Thermochemical ablation (TCA) is a thermal ablation therapy that utilises heat released from acid-base neutralisation reaction to destroy tumours. This procedure is a promising low-cost solution to existing thermal ablation treatments such as radiofrequency ablation (RFA) and microwave ablation (MWA). Studies have demonstrated that TCA can produce thermal damage that is on par with RFA and MWA when employed properly. Nevertheless, TCA remains a concept that is tested only in a few animal trials due to the risks involved as the result of uncontrolled infusion and incomplete acid-base reaction. In this study, a computational framework that simulates the thermochemical process of TCA is developed. The proposed framework consists of three physics, namely chemical flow, neutralisation reaction and heat transfer. An important parameter in the TCA framework is the neutralisation reaction rate constant, which has values in the order of 10

We report an extended measurement of the neutron cross section on argon in the energy range of 95-720 MeV. The measurement was obtained with a 4.3-hour exposure of the Mini-CAPTAIN detector to the WNR/LANSCE beam at LANL. Compared to an earlier analysis of the same data, this extended analysis includes a reassessment of systematic uncertainties, in particular related to unused wires in the upstream part of the detector. Using this information we doubled the fiducial volume in the experiment and increased the statistics by a factor of 2.4. We also shifted the analysis from energy bins to time-of-flight bins. This change reduced the overall considered energy range, but improved the understanding of the energy spectrum of incoming neutrons in each bin. Overall, the new measurements are extracted from a fit to the attenuation of the neutron flux in five time-of-flight regions: 140 ns - 180 ns, 120 ns - 140 ns, 112 ns - 120 ns, 104 ns - 112 ns, 96 ns - 104 ns. The final cross sections are given for the flux-averaged energy in each time-of-flight bin: $\sigma(146~\rm{MeV})=0.60^{+0.14}_{-0.14}\pm0.08$(syst) b, $\sigma(236~\rm{MeV})=0.72^{+0.10}_{-0.10}\pm0.04$(syst) b, $\sigma(319~\rm{MeV})=0.80^{+0.13}_{-0.12}\pm0.040$(syst) b, $\sigma(404~\rm{MeV})=0.74^{+0.14}_{-0.09}\pm0.04$(syst) b, $\sigma(543~\rm{MeV})=0.74^{+0.09}_{-0.09}\pm0.04$(syst) b., Comment: 15 pages, 7 tables, 11 figures. Prepared for submission to PRD

PubMed: 31209238, The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells. © 2019, The Author(s)., National Institute for Health Research, NIHR Wellcome Trust, WT: 102696, 206194 Magyar Tudományos Akadémia, MTA Bayer 668858 PrECISE AstraZeneca, We thank the Genomics of Drug Sensitivity in Cancer and COSMIC teams at the Wellcome Trust Sanger Institute for help with the preparation of the molecular data, Denes Turei for help with Omnipath, and Katjusa Koler for help with matching drug names across combination screens. We thank AstraZeneca for funding and provision of data to the DREAM Consortium to run the challenge, and funding from the European Union Horizon 2020 research (under grant agreement No 668858 PrECISE to J.S.R.), the Joint Research Center for Computational Biomedicine (which is partially funded by Bayer AG) to J.S.R., National Institute for Health Research (NIHR) Sheffield Biomedical Research Center, Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences. M.G lab is supported by Wellcome Trust (102696 and 206194)., Competing interests: K.C.B., Z.G., G.Y.D., E.K.Y.T., S.F., and J.R.D. are AstraZeneca employees. K.C.B., Z.G., E.K.Y.T., S.F., and J.R.D. are AstraZeneca shareholders. Y.G. receives personal compensation from Eli Lilly and Company, is a shareholder of Cleerly, Inc., and Ann Arbor Algorithms, Inc. M.G. receives research funding from AstraZeneca and has performed consultancy for Sanofi. The remaining authors declare no competing interests.

Liyun Zheng,1,2,* Shiji Fang,1,2,* Junguo Hui,3 Vinothkumar Rajamanickam,2 Minjiang Chen,2 Qiaoyou Weng,2 Xulu Wu,2 Zhongwei Zhao,1 Jiansong Ji1– 3 1Interventional Diagnosis and Treatment Center, Lishui Hospital of Zhejiang University, Lishui, Zhejiang 323000, People’s Republic of China; 2Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital of Zhejiang University, Lishui, Zhejiang 323000, People’s Republic of China; 3Department of Radiology, Lishui Hospital of Zhejiang University, Lishui, Zhejiang 323000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiansong JiLishui Hospital of Zhejiang University, Lishui, Zhejiang 323000, People’s Republic of ChinaTel +86-13648782878Fax +86-578-2133457Email lschrjjs@163.comBackground: Osteosarcoma (OS) is the most common primary malignancy arise from bone and is one of the causes of cancer-related deaths. Triptonide (TN), a diterpenoid epoxide presented in Tripterygium wilfordii, is shown to possess a broad spectrum of biological properties.Methods: In this study, we investigate the growth inhibitory effect of TN against human OS cells and its underlying molecular mechanism of action.Results: Findings of our in vitro study revealed that TN exhibited a dose-dependent cytotoxic effect in MG63 and U-2OS cells. ROS-mediated cytotoxic effect was achieved in OS cells treated with TN which was reversed upon NAC treatment. Significantly, increased expression of PERK, p-EIF2, GRP78, ATF4 and CHOP in TN-treated OS cells unfolds the molecular mechanism of TN targets ER stress-mediated apoptosis. Modulation of ERK MAPK pathway was also observed as evidenced by the increased phosphorylation of ERK (p-ERK) and p-p38 in TN-treated OS cells.Conclusion: Altogether, the outcome of the study for the first time revealed that TN exhibited its potential chemotherapeutic effects through ROS-mediated ER stress-induced apoptosis via p38 and ERK MAPK signaling pathways.Keywords: osteosarcoma, triptonide, ER stress, apoptosis, MAPK signaling

Shiwei Liu,1 Exian Mou,1 Shiyan Zeng,1 Lu Wang,2 Hao Dong,3 Juan Ji,3 Hong Yang,3 Junjie Li,1 Hao Wang,1 Hui Li,1 Jia Xu1 1Department of Breast Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Operating Room, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, People’s Republic of China; 3Department of Pathology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, People’s Republic of ChinaCorrespondence: Hui Li; Jia XuDepartment of Breast Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, No. 55, Section 4, South Renmin Road, Chengdu, Sichuan Province, People’s Republic of ChinaTel/Fax +86-02885420456Email zlyy_lh@163.com; scszlyyxujia@sohu.comPurpose: The aim of the present study was to investigate the effect of trastuzumab on the pathological complete response (pCR) rate and event-free survival (EFS) in neoadjuvant-treated HER2-positive breast cancer with a low infiltrating level of tumor-infiltrating lymphocytes (TILs).Patients and Methods: The infiltrating level of TILs was evaluated in hematoxylin and eosin-stained slides from diagnostic needle biopsies, and a low infiltrating level of TILs was defined as TILs < 10%. Data of 179 HER2-positive patients with a low infiltrating level of TILs were retrospectively reviewed and compared according to whether trastuzumab was administered or not. The associations of clinicopathological characteristics with pCR or EFS were assessed in univariate and multivariate analyses. EFS was estimated by the Kaplan–Meier method and compared by the log rank test.Results: Of 179 patients, the overall pCR rate was 20.1%, and 74 patients (41.3%) received trastuzumab. Patients treated with trastuzumab showed a pCR rate of 20.3% compared with 20.0% for those without trastuzumab (P = 0.965). Trastuzumab administration was not associated with pCR in univariate (P = 0.965) and multivariate (P = 0.994) analyses. Negative status of hormone receptor (HR) (P < 0.001) and histological grade 3 (P = 0.007) were independent predictors for pCR in multivariate analyses. Trastuzumab usage had no significant impact on EFS in univariate (P = 0.916) and multivariate (P = 0.431) analyses, and pCR was the only independent predictor for favorable EFS (P = 0.012) in multivariate analyses.Conclusion: In neoadjuvant-treated HER2-positive breast cancer with a low infiltrating level of TILs, additional trastuzumab had no significant influence on the pCR rate and EFS. HR-negative status and histological grade 3 were independently associated with higher pCR rates, and pCR was the only independent predictor for improved survival. Our findings may help identify patients who are resistant to trastuzumab, thereby guiding the de-escalating choice of anti-HER2 therapy.Keywords: HER2, trastuzumab, tumor-infiltrating lymphocytes, pathological complete response, event-free survival

Ziyu Li, 1,* Qiyan Xiao, 1,* Yinkui Wang, 1,* Wei Wang, 2,* Shuangxi Li, 1 Fei Shan, 1 Zhiwei Zhou, 2 Jiafu Ji 1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiafu JiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Beijing 100142, People’s Republic of ChinaTel +86-10-88196598Fax +86-10-8819-6698Email jijiafu@hsc.pku.edu.cnZhiwei ZhouState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of ChinaTel +86-20-87343123Fax +86-20-87343910Email zhouzhw@sysucc.org.cnPurpose: Neoadjuvant chemotherapy is now widely used in gastric cancer patients. However, the current 8th ypTNM staging system is developed based on patients with less extensive lymph node dissection and the predictive value is relatively limited. In this study, we aim to develop and validate a nomogram that predicts overall survival in gastric cancer patients received neoadjuvant chemotherapy.Patients and Methods: From January, 2007 to December, 2014, 471 patients receiving neoadjuvant chemotherapy at our center were enrolled in the study. Based on the Cox proportional hazard model, a nomogram was developed from them and then an external validation was conducted on a cohort of 239 patients from another cancer center.Results: The overall survival (OS) rates of 1 year and 3 years were 90.0% and 64.1%, respectively. Body mass index category, tumor location, T stage and N stage were independent prognostic factors for the survival outcome. The C-index of the model was 0.74 in the development cohort and 0.69 in the validation cohort. Our nomogram also showed good calibration in both cohorts.Conclusion: We developed and validated a nomogram to predict the 1- and 3-year OS of patients who received neoadjuvant chemotherapy and radical gastrectomy with D2 lymph node dissection. This nomogram predicts survival more accurately than the AJCC TNM staging system, which is the current golden standard.Keywords: stomach neoplasms, perioperative chemotherapy, survival, nomograms

Tong Liu, 1–3,* Sainan Li, 2,* Liwei Wu, 2 Qiang Yu, 2, 4 Jingjing Li, 1 Jiao Feng, 2 Jie Zhang, 2, 4 Jiaojiao Chen, 2, 4 Yuting Zhou, 2, 4 Jie Ji, 2 Kan Chen, 2 Yuqing Mao, 5 Fan Wang, 6 Weiqi Dai, 7 Xiaoming Fan, 8 Jianye Wu, 1 Chuanyong Guo 1, 2 1Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai 200060, People’s Republic of China; 2Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China; 3Department of Gastroenterology, Shandong Provincial Hospital of Shandong University, Ji’nan 250000, People’s Republic of China; 4Department of Gastroenterology, Shanghai Tenth People’s Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai 200072, People’s Republic of China; 5Department of Gerontology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 6Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 7Department of Gastroenterology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, People’s Republic of China; 8Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai 201508, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianye WuDepartment of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai 200060, People’s Republic of ChinaEmail wjymail@163.comChuanyong GuoDepartment of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of ChinaEmail guochuanyong@hotmail.comObjective: Shikonin is a natural product with many activities, including anti-cancer effects. Pyruvate kinase type M2 (PKM2) plays a crucial role in the growth of tumor cells. However, the effect of shikonin on PKM2 in hepatocellular carcinoma (HCC) is unclear.Methods: Cell viability, apoptosis level, glucose uptake, and lactate production were detected in HCC cells. Lentivirus-overexpressed and –shRNA of PKM2 were used to verify the key target of shikonin. A xenograft mouse model was used to detect the efficacy of shikonin and its combination with sorafenib in vivo.Results: Shikonin inhibited proliferation and glycolysis and induced apoptosis in HCC cells. Either PKM2-overexpressed or PKM2-shRNA alleviated or enhanced this effect. The results of CCK-8 showed that shikonin significantly inhibited cell viability of HCC cells. The levels of glucose uptake and lactate production were dramatically decreased by shikonin-treated. Results of flow cytometry and Western blot showed that the levels of apoptosis of HCC cells were significantly increased in a dose-dependent manner after shikonin treatment. In addition, shikonin enhanced the anti-cancer effect of sorafenib in vitro and in vivo. Our results showed that SK combined with sorafenib markedly inhibits tumor growth in HCC-transplanted nude mice compared to SK or sorafenib alone.Conclusion: By inhibiting PKM2, shikonin inhibited proliferation and glycolysis and induced cell apoptosis in HCC cells. The effect of shikonin on tumor cell proliferation, apoptosis and glycolsis will make it promising drug for HCC patients.Keywords: shikonin, PKM2, glycolysis, apoptosis, proliferation, hepatocellular carcinoma

Yuzhu Hu, 1–3 Yihong He, 1–3 Jianrui Ji, 1 Songping Zheng, 1–3 Yongzhong Cheng 1–3 1Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, People’s Republic of China; 2Department of Medical Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People’s Republic of China; 3Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People’s Republic of ChinaCorrespondence: Songping Zheng; Yongzhong ChengDepartment of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People’s Republic of ChinaTel +86 28 8516 4063Email 13618088051@163.com; chengyz@scu.edu.cnIntroduction: Curcumin (Cur) is a natural extract of Asian spice Curcumin longa, showing multi-targeting capability and low toxicity in anti-tumor activities. The low bioavailability restricts its application as a therapeutic agent. Folate (FA) receptors are highly expressed in many malignant tumors while low expressed in normal tissue. Herein, we developed a self-assembled FA modified MPEG-PCL micelle to incorporate Cur (FA/Nano-Cur) and applied it for colorectal cancer therapy.Methods: We prepared FA/Nano-Cur micelles and identified their characteristics. The drug release behavior, pharmacokinetics and in vitro anti-tumor activities of FA/Nano-Cur were studied. Furthermore, the in vivo anti-tumor ability assessment and anti-tumor mechanisms investigation were carried out in murine colorectal cancer model.Results: FA/Nano-Cur micelles had an average particle size of 30.47 nm. Elongated T 1/2 and larger AUC were found in FA/Nano-Cur group than that in the Free Cur group. MTT assay and apoptotic study indicated the growth inhibitory effect and pro-apoptotic effect of FA/Nano-Cur were the most significant among all treatments. Moreover, the in vivo study demonstrated that FA/Nano-Cur micelles exhibited a much stronger effect to suppress tumor growth, promote tumor apoptosis and attenuate tumor angiogenesis than Free Cur and Nano-Cur micelles.Conclusion: The present study demonstrated FA/Nano-Cur micelles might be a promising therapeutic agent in colorectal cancer treatment with distinctive advantages of improved bioavailability, sustained drug release, tumor-targeted delivery and low toxicity.Keywords: curcumin, colorectal cancer, folate, nanoformulation, apoptosis, angiogenesis

The no-touch bipolar radiofrequency ablation (RFA) for cancer treatment is advantageous primarily because of its capability to prevent tumour track seeding (TTS). In this technique, the RF probes are placed at a distance (no-touch gap) away from the tumour boundary. Ideally, the RF probes should be placed sufficiently far from the tumour in order to avoid TTS. However, having a gap that is too large can lead to ineffective ablation. This paper investigates how the selection of the no-touch gap can affect the tissue electrical and thermal responses during the no-touch bipolar RFA treatment. Simulations were carried out on a two compartment model using the finite element method. Results obtained indicated that a gap that is too large may lead to incomplete ablation and failure to achieve significant ablation margin. However, keeping the gap to be too small may not be clinically practical. It was suggested that the incomplete ablation and the insufficient ablation margin observed in some of the cases may require the placement of additional probes around the tumour. The present study stresses on the importance of identifying the optimal no-touch gap that can avoid TTS without compromising the treatment outcome.

Xiaoshuai Zhang,1 Fang Tang,2 Jiadong Ji,1 Wenting Han,3 Peng Lu3 1School of Statistics, Shandong University of Finance and Economics, Jinan, People’s Republic of China; 2Center for Data Science in Health and Medicine, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, People’s Republic of China; 3Department of Preventive Medicine, School of Public Health and Management, Binzhou Medical University, Yantai, People’s Republic of ChinaCorrespondence: Xiaoshuai ZhangSchool of Statistics, Shandong University of Finance and Economics, Jinan 250014, People’s Republic of ChinaTel +86 13589896463Email zhxiaoshuai@gmail.comObjective: Dyslipidemia has been recognized as a major risk factor of several diseases, and early prevention and management of dyslipidemia is effective in the primary prevention of cardiovascular events. The present study aims to develop risk models for predicting dyslipidemia using Random Survival Forest (RSF), which take the complex relationship between the variables into account.Methods: We used data from 6328 participants aged between 19 and 90 years free of dyslipidemia at baseline with a maximum follow-up of 5 years. RSF was applied to develop gender-specific risk model for predicting dyslipidemia using variables from anthropometric and laboratory test in the cohort. Cox regressionwas also adopted in comparison with the RSF model, and Harrell’s concordance statistic with 10-fold cross-validation was used to validate the models.Results: The incidence density of dyslipidemia was 101/1000 in total and subgroup incidence densities were 121/1000 for men and 69/1000 for women. Twenty-four predictors were identified in the prediction model of males and 23 in females. The C-statistics of the prediction models for males and females were 0.731 and 0.801, respectively. The RSF model shows better discriminative performance than CPH model (0.719 for males and 0.787 for females). Moreover, some predictors were observed to have a nonlinear effect on dyslipidemia.Conclusion: The RSF model is a promising method in identifying high-risk individuals for the prevention of dyslipidemia and related diseases.Keywords: random survival forest, Cox proportional hazard model, dyslipidemia, risk prediction

Xihui Ying,1 Jianfei Tu,1 Wenxian Wang,2 Xingliang Li,3 Chunwei Xu,4 Jiansong Ji1 1Department of Radiology, Lishui Central Hospital/Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Lishui, Zhejiang 323000, People’s Republic of China; 2Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People’s Republic of China; 3Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, Jiaxing, Zhejiang 314000, People’s Republic of China; 4Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, People’s Republic of ChinaCorrespondence: Jiansong JiDepartment of Radiology, Lishui Central Hospital/Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Lishui, Zhejiang 323000, People’s Republic of ChinaEmail lschrjjs@163.comAbstract: Fibroblast growth factor receptor (FGFR) family includes four highly conserved receptor tyrosine kinases. Particularly, FGFR2 has been identified as a potential target for tyrosine kinase inhibitor (TKI) treatment. Except for immunohistochemistry and fluorescence in situ hybridization, next-generation sequencing (NGS) technology represents a novel tool for FGFR2 detection that covers a wide range of fusion genes. In the present work, we present a case of cholangiocarcinoma who had FGFR2-BICC1 rearrangement detected by NGS. A 76-year-old female diagnosed with cholangiocarcinoma underwent four cycles of chemotherapy. The NGS assay showed that the tumor had a FGFR2-BICC1 rearrangement. The patient had a favorable tumor response to sorafenib. Herein, we report the first case with cholangiocarcinoma harboring FGFR2-BICC1 who is sensitive to sorafenib therapy.Keywords: cholangiocarcinoma, NGS, FGFR2 rearrangement

The endocannabinoid and orexin neuromodulatory systems serve key roles in many of the same biological functions such as sleep, appetite, pain processing, and emotional behaviors related to reward. The type 1 cannabinoid receptor (CB1R) and both subtypes of the orexin receptor, orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R) are not only expressed in the same brain regions modulating these functions, but physically interact as heterodimers in recombinant and neuronal cell cultures. In the current study, male and female C57BL/6 mice were co-treated with the cannabinoid receptor agonist CP55,940 and either the OX2R antagonist TCS-OX2-29 or the dual orexin receptor antagonist (DORA) TCS-1102. Mice were then evaluated for catalepsy, body temperature, thermal anti-nociception, and locomotion, after which their brains were collected for receptor colocalization analysis. Combined treatment with the DORA TCS-1102 and CP55,940 potentiated catalepsy more than CP55,940 alone, but this effect was not observed for changes in body temperature, nociception, locomotion, or via selective OX2R antagonism. Co-treatment with CP55,940 and TCS-1102 also led to increased CB1R-OX1R colocalization in the ventral striatum. This was not seen following co-treatment with TCS-OX2-29, nor in CB1R-OX2R colocalization. The magnitude of effects following co-treatment with CP55,940 and either the DORA or OX2R-selective antagonist was greater in males than females. These data show that CB1R-OX1R colocalization in the ventral striatum underlies cataleptic additivity between CP55,940 and the DORA TCS-1102. Moreover, cannabinoid-orexin receptor interactions are sex-specific with regards to brain region and functionality. Physical or molecular interactions between these two systems may provide valuable insight into drug-drug interactions between cannabinoid and orexin drugs for the treatment of insomnia, pain, and other disorders.

Thermochemical ablation (TCA) is a thermal ablation technique involving the injection of acid and base, either sequentially or simultaneously, into the target tissue. TCA remains at the conceptual stage with existing studies unable to provide recommendations on the optimum injection rate, and reagent concentration and volume. Limitations in current experimental methodology have prevented proper elucidation of the thermochemical processes inside the tissue during TCA. Nevertheless, the computational TCA framework developed recently by Mak et al. [Mak et al., Computers in Biology and Medicine, 2022, 145:105494] has opened new avenues in the development of TCA. Specifically, a recommended safe dosage is imperative in driving TCA research beyond the conceptual stage.The aforesaid computational TCA framework for sequential injection was applied and adapted to simulate TCA with simultaneous injection of acid and base at equimolar and equivolume. The developed framework, which describes the flow of acid and base, their neutralisation, the rise in tissue temperature and the formation of thermal damage, was solved numerically using the finite element method. The framework will be used to investigate the effects of injection rate, reagent concentration, volume and type (weak/strong acid-base combination) on temperature rise and thermal coagulation formation.A higher injection rate resulted in higher temperature rise and larger thermal coagulation. Reagent concentration of 7500 mol/mA guideline for a safe and effective implementation of TCA with simultaneous injection of acid and base was recommended based on the numerical results of the computational model developed. The guideline correlates the coagulation volume with the reagent volume and injection rate, and may be used by clinicians in determining the safe dosage of reagents and optimum injection rate to achieve a desired thermal coagulation volume during TCA.

Amorphous materials inherit short- and medium-range order from the corresponding crystal and thus preserve some of its properties while still exhibiting novel properties1,2. Due to its important applications in technology, amorphous carbon with sp2 or mixed sp2-sp3 hybridization has been explored and prepared3,4, but synthesis of bulk amorphous carbon with sp3 concentration close to 100% remains a challenge. Such materials inherit the short-/medium-range order of diamond and should also inherit its superior properties5. Here, we successfully synthesized millimetre-sized samples-with volumes 103-104 times as large as produced in earlier studies-of transparent, nearly pure sp3 amorphous carbon by heating fullerenes at pressures close to the cage collapse boundary. The material synthesized consists of many randomly oriented clusters with diamond-like short-/medium-range order and possesses the highest hardness (101.9 ± 2.3 GPa), elastic modulus (1,182 ± 40 GPa) and thermal conductivity (26.0 ± 1.3 W m-1 K-1) observed in any known amorphous material. It also exhibits optical bandgaps tunable from 1.85 eV to 2.79 eV. These discoveries contribute to our knowledge about advanced amorphous materials and the synthesis of bulk amorphous materials by high-pressure and high-temperature techniques and may enable new applications for amorphous solids.

The disk dynamo plays an important role in studying the geodynamo and much research works have been devoted to the understanding of dynamo dynamics. This paper further investigates an extended disk dynamo system having three coupled conducting disks and incorporates the interaction-induced time delay in the dynamic governing equations. By carrying out a comparative analysis, the dynamic behaviors of the coupled three-disk dynamo system with and without time delay are studied to explore novel and complex nonlinear dynamic phenomena in the coupled delayed dynamo system. It is found that the double Hopf bifurcations can be induced in the time-delayed dynamo system. Three different topological structures of the unfolding are obtained under different time delays. Accordingly, it is shown that the novel dynamic behaviors, including quasi-periodic torus, three-dimensional torus and the coexistence of multiple attractors, can appear in the time-delayed dynamo system. Furthermore, by performing the continuation analysis on the periodic orbit generated from the Hopf bifurcation of equilibrium, some new coexistence patterns, e.g., the coexistence of periodic orbits and chaos, the coexistence of quasi-periodic orbits and chaos, are observed in the dynamo system with time delay. Based on the obtained results, it is believed that the inclusion of time delay in the modelling of the three-disk dynamo system is necessary and meaningful for developing an in-depth understanding of dynamo dynamics. Finally, the results of theoretical analyses are verified by the numerical simulations.

The present paper investigates weighted bipartite containment motion of networked Lagrangian systems with instantaneous cooperative–competitive interactions. A control scheme is proposed by introducing an auxiliary oscillatory system to each agent, where every Lagrangian system can obtain different levels of positive and negative information from its neighbors only at some impulsive time moments. Based on the generalized Barbalat’s lemma and Lyapunov stability theory, some conditions for the networked structure, the coupling strengthen, and the impulsive time interval are developed to guarantee that the followers can converge to the weighted intervals, which are determined by every leader’s weighted state and its symmetric weighted state. Finally, seven two-link manipulators are used to illustrate the performance of the proposed schemes.

Lin Wang,1,2 Xianzi Wen,1 Fengming Luan,1 Tao Fu,2 Chao Gao,2 Hong Du,1 Ting Guo,1 Jing Han,1 Longtao Huangfu,1 Xiaojing Cheng,1 Jiafu Ji1,21Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 2Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of ChinaCorrespondence: Xiaojing ChengKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaTel +86 108 819 6760Email chengli@bjmu.edu.cnJiafu JiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaTel +86 108 819 6048Email jijiafu@hsc.pku.edu.cnPurpose: Eukaryotic translation initiation factor (EIF) plays a vital role in protein synthesis. EIF3B is a core subunit of the EIF3 family, and is overexpressed in many tumors. EIF3B is associated with an unfavorable prognosis, as well as the genesis and development of tumors. However, the potential role of EIF3B in gastric cancer (GC) remains unknown. In the current study, we explored the clinical significance and the possible mechanism of EIF3B in the progression of GC.Methods: EIF3B expression was analyzed in 78 GC tissue samples through quantitative PCR and in 94 GC tissue samples through immunohistochemistry (IHC) staining. The correlation between EIF3B and clinicopathological features was analyzed in GC tissues. The role of EIF3B in GC progression was investigated through in vitro and in vivo assays.Results: EIF3B expression was upregulated in GC tissues (73.4%, IHC). High expression of EIF3B was significantly correlated with the depth of tumor invasion, lymph node metastasis and TNM stage (P=0.000, 0.000 and 0.000, respectively). Multivariate analysis indicated that GC patients with high EIF3B expression suffered a poorer 5-year survival. EIF3B promoted GC cell proliferation and was strongly associated with proliferating cell nuclear antigen (PCNA) expression in GC samples (P=0.009). It also enhanced tumor cell migration and invasion, which were affected through epithelial-mesenchymal transition (EMT) and the Stat3 signaling pathway. Knockdown of EIF3B in GC cells suppressed the growth of xenograft tumors and lung metastatic colonization in vivo. Furthermore, gene set enrichment analysis (GSEA) and Western blot results demonstrated that EIF3B activated the PI3K/AKT/mTOR signaling pathway.Conclusion: Our results suggest that EIF3B plays an oncogenic role in GC progression and serves as an independent prognostic factor for GC patients.Keywords: EIF3B, gastric cancer, prognosis, PI3K/AKT/mTOR pathway

Chen Huang,1,2 Qingyi Shi,1 Beiwen Zheng,1 Jinru Ji,1 Chaoqun Ying,1 Xiao Yu,1 Hui Wang,2 Yonghong Xiao11State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Respiratory Medicine, Lihuili Hospital, Ningbo Medical Center, Ningbo, People’s Republic of ChinaObjectives: Monte Carlo simulation (MCS) was used to evaluate optimal dosage for cefepime (FEP), moxalactam (MOX), and cefperazone/sulbactam (CFZ/SBT) against extended-spectrum β-lactamase (ESBL) producers isolated from the Blood Bacterial Resistant Investigation Collaborative System.Methods: Minimum inhibitory concentration (MIC) was tested by agar dilution, and ESBL producers were identified by modified Clinical and Laboratory Standards Institute tests. Pharmacokinetic parameters were derived from data on healthy individuals, and probability of target attainment (PTA) and cumulative fraction of response (CFR) %fT >MIC values were estimated by MCS.Results: A total of 2032 Escherichia coli (875 ESBL-producing) and Klebsiella pneumoniae (157 ESBL-producing) strains, and 371 other Enterobacteriaceae strains, were isolated from patients with bloodstream infections (BSIs). MIC90 values for FEP, MOX, and CFZ/SBT against ESBL-producing E. coli and K. pneumoniae were 64/64 mg/L, 2/32 mg/L, and 64/128 mg/L, respectively. Conventional MOX and CFZ/SBT doses failed to reach 90% PTA against isolates with MICs ≥8 mg/L and ≥4 mg/L, respectively. Against ESBL producers, neither FEP nor CFZ/SBT achieved ≥90% CFR, while CFRs for MOX (1g iv q6h, 2g iv q12h, and 2g iv q8h) exceeded 90% against ESBL-producing E. coli. Simulated CFRs for FEP and MOX were similar (>90%) against non-ESBL-producing Enterobacteriaceae, and higher than CFRs for CFZ/SBT.Conclusion: ESBL producers from BSIs were highly susceptible to MOX, and PTA values were generally higher for MOX than FEP or CFZ/SBT for conventional dosing regimens. This large MCS analysis shows that MOX but not FEP or CFZ/SBT can be used empirically to treat BSIs caused by ESBL-producing E. coli strains.Keywords: Monte Carlo simulation, Enterobacteriaceae, extended-spectrum β-lactamase, moxalactam, cefperazone/sulbactam, cefepime &nbsp

Jiali Ji,1 Xiaolan Dai,2 Sai-Ching Jim Yeung,3 Xuexin He11Department of Medical Oncology, The 2nd Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, School of Medicine, Shantou University, Shantou, Guangdong, People’s Republic of China; 3Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USAAbstract: Long non-coding RNAs (lncRNAs) have shown potential as a biomarker in the diagnosis and prognosis in multiple cancers. LncRNAs are dysregulated in various cancers, playing either oncogenic or tumor suppressive roles. Emerging evidences have proved that the growth arrest-specific 5 (GAS5) lncRNA can function as a tumor suppressor in several cancers. LncRNA GAS5 is downregulated in many types of cancer, regulating cellular processes such as cell proliferation, apoptosis and invasion. The low level of GAS5 expression often elevates capacity of proliferation and predicts poorer prognosis in some cancers. This review aims to summarize the recent published literature on the biogenesis, regulation mechanism and function of GAS5 in different types of cancers and explore its potential for cancer diagnosis, prognosis and treatment.Keywords: lncRNA, GAS5, tumor suppressor, tumor

Benquan Liu,1 Jiemei Ji,1 Qing Feng,1 Xi Luo,1 Xiurong Yan,1 Yuxia Ni,2 Yajun He,1 Zhongxuan Mao,1 Jingchen Liu1 1Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 2Department of Anesthesiology, Langdong Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China Background: Local anesthetics in spinal anesthesia have neurotoxic effects, resulting in severe neurological complications. Intrathecal monosialoganglioside (GM1) administration has a therapeutic effect on bupivacaine-induced neurotoxicity. The aim of this study was to determine the underlying mechanisms of bupivacaine-induced neurotoxicity and the potential neuroprotective role of GM1.Materials and methods: A rat spinal cord neurotoxicity model was established by injecting bupivacaine (5%, 0.12 µL/g) intrathecally. The protective effect of GM1 (30 mg/kg) was evaluated by pretreating the animals with it prior to the bupivacaine regimen. The neurological and locomotor functions were assessed using standard tests. The histomorphological changes, neuron degeneration and apoptosis, and endoplasmic reticulum stress (ERS) relevant markers were analyzed using immunofluorescence, quantitative real-time PCR, and Western blotting.Results: Bupivacaine resulted in significant neurotoxicity in the form of aberrant neurolocomoter functions and spinal cord histomorphology and neuronal apoptosis. Furthermore, the ERS specific markers were significantly upregulated during bupivacaine-induced neurotoxicity. These neurotoxic effects were ameliorated by GM1.Conclusion: Pretreatment with GM1 protects against bupivacaine-induced neurotoxicity via the inhibition of the GRP78/PERK/eIF2α/ATF4-mediated ERS. Keywords: bupivacaine, GM1 ganglioside, ERS, neurotoxicity &nbsp

Nannan Gao,1 Chunhou Li,2 Jiadong Ji,3 Yanli Yang,1 Shaoting Wang,1 Xinlun Tian,1 Kai-Feng Xu1 1Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; 2Office of Medical Insurance, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China; 3School of Statistics, Shandong University of Finance and Economics, Jinan, China Purpose: Evidence between air pollution and COPD admissions is inconsistent and limited in China. In this study, we aimed to explore the effects of air pollutants on COPD admissions in Beijing, China.Patients and methods: Daily COPD hospital admission visits derived from tertiary and secondary hospitals in Beijing were retrieved from January 2013 to February 2017. Air pollutant levels and meteorological data over the same periods were also achieved. Generalized additive model was applied to estimate the percentage changes with 95% CIs in daily admissions corresponding to 10 µg/m3 increases in pollutants levels [1 mg/m3 in carbon monoxide (CO)], stratified by age, gender, and season.Results: Seventy-three thousand seventy-six COPD hospital admission visits were included with mean daily visits of 48 (21). Cumulative lag effect with per 10 µg/m3 increase in air pollutant levels was largest for nitrogen dioxide (NO2) with 3.03% (95% CI: 1.82%–4.26%) at lag 06, for sulfur dioxide (SO2) with 2.07% (95% CI: 1.00%–3.15%) at lag 01, for particulate matter ≤10 µm in aerodynamic diameter (PM10) with 0.92% (95% CI: 0.55%–1.30%) at lag 07, and for particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5) with 0.82% (95% CI: 0.38%–1.26%) at lag 06, respectively. Percentage increase for each 1 mg/m3 increase in CO was 5.99% (95% CI: 2.74%–9.34%) at lag 06. Further, stronger effects on COPD admissions were found in warm seasons than in cold seasons.Conclusion: Short-term exposures to PM2.5, PM10, NO2, SO2, and CO had adverse effects on COPD hospitalizations in Beijing with different magnitudes and lag days. Keywords: adverse effects, air pollution, COPD, time series analysis, hospital visits