LS‐106, a novel EGFR inhibitor targeting C797S,exhibits antitumor activities both in vitro and in vivo

With the wide clinical use of the third‐generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of EGFR‐mutated non–small cell lung cancer (NSCLC), acquired resistance caused by EGFR C797S tertiary mutation has become a concern. Therefore, fourth‐generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS‐106 as a novel EGFR inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo. In cell‐free assay, LS‐106 potently inhibited the kinase activities of EGFR^{19del/T790M/C797S} and EGFR^{L858R/T790M/C797S} with IC₅₀ values of 2.4 nmol/L and 3.1 nmol/L, respectively, which was more potent than osimertinib. Meanwhile, LS‐106 exhibited comparable kinase inhibitory effect to osimertinib on EGFR^L858R/T790M and wild‐type EGFR. Results from cellular experiments demonstrated that LS‐106 potently blocked the phosphorylation of EGFR C797S triple mutations in the constructed BaF3 cells that highly expressed EGFR^{19del/T790M/C797S} or EGFR^{L858R/T790M/C797S}, and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR^{19del/T790M/C797S} (named PC‐9‐OR cells) using the CRISPR/Cas9 system and found that LS‐106 markedly suppressed the activation of EGFR^{19del/T790M/C797S} and the proliferation of PC‐9‐OR cells. Moreover, cells harboring EGFR^{19del/T790M/C797S} underwent remarkable apoptosis upon LS‐106 treatment. In vivo experiments further demonstrated that oral administration of LS‐106 caused significant tumor regression in a PC‐9‐OR xenograft model, with a tumor growth inhibition rate (TGI) of 83.5% and 136.6% at doses of 30 and 60 mg/kg, respectively. Taken together, we identified LS‐106 as a novel fourth‐generation EGFR inhibitor against C797S mutation and confirmed its preclinical antitumor effects in C797S–triple‐mutant tumor models.     

Comparison between Piezoelectric and Piezoresistive Wearable Gait Monitoring Techniques

Insole plantar stress detection (PSD) techniques play an important role in gait monitoring. Among the various insole PSD methods, piezoelectric- and piezoresistive-based architectures are broadly used in medical scenes. Each year, a growing number of new research outcomes are reported. Hence, a deep understanding of these two kinds of insole PSD sensors and state-of-the-art work would strongly benefit the researchers in this highly interdisciplinary field. In this context, this review article is composed of the following aspects. First, the mechanisms of the two techniques and corresponding comparisons are explained and discussed. Second, advanced materials which could enhance the performance of current piezoelectric and piezoresistive insole prototypes are introduced. Third, suggestions for designing insole PSD prototypes/products for different diseases are offered. Last, the current challenge and potential future trends are provided.     

Pre-attack and pre-episode symptoms in cluster headache: a multicenter cross-sectional study of 327 Chinese patients

BackgroundThere have been a few studies regarding the pre-attack symptoms (PAS) and pre-episode symptoms (PES) of cluster headache (CH), but none have been conducted in the Chinese population. The purpose of this study was to identify the prevalence and features of PAS and PES in Chinese patients, as well as to investigate their relationships with pertinent factors.MethodsThe study included patients who visited a tertiary headache center and nine other headache clinics between January 2019 and September 2021. A questionnaire was used to collect general data and information about PAS and PES.ResultsAmong the 327 patients who met the CH criteria (International Classification of Headache Disorders, 3rd edition), 269 (82.3%) patients experienced at least one PAS. The most common PAS were head and facial discomfort (74.4%). Multivariable logistic regression analysis depicted that the number of triggers (OR = 1.798, p = 0.001), and smoking history (OR = 2.067, p = 0.026) were correlated with increased odds of PAS. In total, 68 (20.8%) patients had PES. The most common symptoms were head and facial discomfort (23, 33.8%). Multivariable logistic regression analysis showed that the number of triggers were associated with increased odds of PES (OR = 1.372, p = 0.005).ConclusionsPAS are quite common in CH patients, demonstrating that CH attacks are not comprised of a pain phase alone; investigations of PAS and PES could help researchers better understand the pathophysiology of CH.     

Melatonin inhibits EMT and PD‐L1 expression through the ERK1/2/FOSL1 pathway and regulates anti‐tumor immunity in HNSCC

Melatonin is an endogenous hormone with various biological functions and possesses anti‐tumor properties in multiple malignancies. Immune evasion is one of the most important hallmarks of head and neck squamous cell carcinoma (HNSCC) and is closely related to tumor progression. However, as an immune modulator under physiological conditions, the roles of melatonin in tumor immunity in HNSCC remains unclear. In this study, we found that the endogenous melatonin levels in patients with HNSCC were lower than those in patients with benign tumors in head and neck. Importantly, lower melatonin levels were related to lymph node metastasis among patients with HNSCC. Moreover, melatonin significantly suppressed programmed death‐ligand 1 (PD‐L1) expression and inhibited epithelial–mesenchymal transition (EMT) of HNSCC through the ERK1/2/FOSL1 pathway in vitro and in vivo. In SCC7/C3H syngeneic mouse models, anti‐programmed death‐1 (PD‐1) antibody combined with melatonin significantly inhibited tumor growth and modulated anti‐tumor immunity by increasing CD8⁺ T cell infiltration and decreasing the regulatory T cell (Treg) proportion in the tumor microenvironment. Taken together, melatonin inhibited EMT and downregulated PD‐L1 expression in HNSCC through the ERK1/2/FOSL1 pathway and exerted synergistic effects with anti‐PD‐1 antibody in vivo, which could provide promising strategies for HNSCC treatment.     

Network pharmacology explores the mechanisms of Eucommia ulmoides cortex against postmenopausal osteoporosis

Postmenopausal osteoporosis (PMOP) has become one of most frequent chronic disease worldwide with aging population. Eucommia ulmoides cortex (EU), a traditional Chinese medicine, has long since been used to treat PMOP. The aim of this study is to explore pharmacological mechanisms of EU against PMOP through using network pharmacology approach.The active ingredients of EU were obtained from Traditional Chinese Medicine System Pharmacology database, and target fishing was performed on these ingredients in UniProt database for identification of their relative targets. Then, we screened the targets of PMOP using GeneCards database and DisGeNET database. The overlapping genes between PMOP and EU were obtained to performed protein–protein interaction, Gene Ontology analysis, Kyoto encyclopedia of genes, and genomes analysis.Twenty-eight active ingredients were identified in EU, and corresponded to 207 targets. Also, 292 targets were closely associated with PMOP, and 50 of them matched with the targets of EU were considered as therapeutically relevant. Gene ontology enrichment analysis suggested that EU exerted anti-PMOP effects via modulating multiple biological processes including cell proliferation, angiogenesis, and inflammatory response. Kyoto encyclopedia of genes and genomes enrichment analysis revealed several pathways, such as PI3K-AKT pathway, mitogen-activated protein kinase pathway, hypoxia-inducible factors-1 pathway, tumor necrosis factor pathway, and interleukin-17 pathway that might be involved in regulating the above biological processes.Through the method of network pharmacology, we systematically investigated the mechanisms of EU against PMOP. The multi-targets and multi-pathways identified here could provide new insights for further determination of more exact mechanisms of EU.     

Evaluation of efficacy and safety of esmolol in treating patients with septic shock: A protocol for systematic review and meta-analysis

Background:In septic shock cases, tachycardia and a hyperdynamic hemodynamic profile are characteristics of the condition. It has been reported that using beta antagonist esmolol constitutes a form of treatment to reduce heart rate to improve diastolic filling time and elevate cardiac output, which reduces vasopressor support. Still, there are controversial results. Therefore, in this study, the primary objective is to perform a meta-analysis by systematically evaluating the efficiency and security of using esmolol to treat septic shocks.Methods:A systematic literature search for relevant randomized controlled trials that report evaluations on the efficiency and safety of using esmolol to treat septic shock patients from their inception to February 2022 will be conducted in three databases containing publications in Chinese language (WanFang, Chinese BioMedical Literature Database, and China National Knowledge Infrastructure) and four databases containing English language publications (Cochrane Library, PubMed, Web of Science, and EMBASE). The screening of the relevant studies will be performed by a pair of authors independently, and the screening involves examining the title, abstract and full-text stages, data extraction, and bias risk assessment. The results are summarized through the fixed-effects and random-effects models, the respective models will be utilized for data pooling according to the heterogeneity of studies that will be included. Moreover, publication bias is assessed if more than ten studies are considered.Results:The results are a high-quality synthesis of the most recent evidence for esmolol usage in septic shock treatment.Conclusion:Up-to-date evidence will be provided through the results of this systematic review related to assessing the efficacy and safeness of esmolol usage in treating septic shock.Ethics and dissemination:Ethical permissions are not required as prepublished data are used.OSF registration number:DOI 10.17605/OSF.IO/SKEZ7     

Efficacy and safety of transcatheter arterial chemoembolization-lenvatinib sequential therapy for patients with unresectable hepatocellular carcinoma: a single-arm clinical study

BackgroundRepeated transcatheter arterial chemoembolization (TACE) could cause ischemia of the tumor tissue and increases production of angiogenic factors in patients with hepatocellular carcinoma (HCC). Lenvatinib can inhibit the expression of angiogenic factors induced by ischemia after TACE and reduce angiogenesis and tumor recurrence. TACE-lenvatinib sequential therapy may improve clinical outcomes. There have been few investigations of TACE-lenvatinib sequential therapy for the treatment of unresectable HCC. We aimed to evaluate the efficacy and safety of TACE-lenvatinib sequential therapy for unresectable HCC.MethodsFrom May 2018 to May 2021, 53 consecutive patients who underwent TACE-lenvatinib sequential therapy were retrospectively reviewed. Of these, 30 patients who met the inclusion criteria were selected. Lenvatinib treatment started within 1 or 2 weeks after TACE at a dose of 8 or 12 mg once daily. Treatment response was assessed using dynamic magnetic resonance imaging (MRI) according to the modified response evaluation criteria in solid tumor (mRECIST). Blood tests were also performed at every response evaluation. Patients with complete response (CR) or partial response (PR) and stable disease (SD) received continuous lenvatinib therapy, and patients with progressive disease (PD) received repeated TACE. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were calculated. Statistical analysis was performed using the Kaplan-Meier method.ResultsThe median age was 58.5±9.1 years, and 16.7% (5/30) of patients were female. A total of 12 patients were categorized as Barcelona Clinic Liver Cancer (BCLC) Stage B and 18 were BCLC Stage C. The mean follow-up time was 15.7 months. The ORR was 76.7% (23/30), and the DCR was 96.7% (29/30). The median PFS was 6.1 months, and the median OS was 20.7 months. The most common lenvatinib-related AE was rash, and the most common TACE-related AE was elevated aspartate aminotransferase (AST). No treatment-related mortality was observed.ConclusionsFrom our findings, TACE-lenvatinib sequential therapy may prolong OS and PFS in patients with unresectable HCC, and the side effects are acceptable. The efficacy and safety of the sequential therapy should be confirmed in multiple center randomized controlled trials (RCTs) with a large sample and sufficient follow-up period.     

Efficacy analysis of Cheng’s GIRAFFE reconstruction after proximal gastrectomy for adenocarcinoma of esophagogastric junction

ObjectiveReconstruction of the digestive tract for adenocarcinoma of esophagogastric junction (AEG) is in dispute. This study evaluated Cheng’s gastric tube interposition esophagogastrostomy with reconstruction of His angle and fundus (Cheng’s GIRAFFE anastomosis) in laparoscopic/open proximal gastrectomy for Siewert type II AEG, which was performed at Zhejiang Cancer Hospital and the First Affiliated Hospital of Zhejiang Chinese Medical University. Here, we discuss the preliminary results of gastric emptying and anti-reflux.MethodsFrom a retrospective database, 74 patients with advanced Siewert type II AEG underwent curative proximal gastrectomy with GIRAFFE anastomosis, and their gastric emptying and anti-reflux outcomes were evaluated by the Reflux Disease Questionnaire (RDQ) score, nuclide gastric emptying, 24-h impedance-pH monitoring and gastroscopy.ResultsSeventy-four patients successfully completed proximal partial gastrectomy with Cheng’s GIRAFFE esophagogastric anastomosis. RDQ score six months after the operation was 2.2±2.5. Results of nuclide gastric emptying examinations showed that the gastric half-emptying time was 67.0±21.5 min, the 1-h residual rate was (52.2±7.7)%, the 2-h residual rate was (36.4±5.1)%, and the 3-h residual rate was (28.8±3.6)%; 24-h impedance-pH monitoring revealed that the mean DeMeester score was 5.8±2.9. Reflux esophagitis was observed by gastroscopy in 7 patients six months after surgery.ConclusionsCheng’s GIRAFFE anastomosis is safe and feasible for Siewert type II AEG.     

基于人工智能的骨龄辅助评价系统对四川地区完全性生长激素缺乏症患儿骨龄研究

目的 探讨采用基于“人工智能(AI)的骨龄辅助评价系统(上海初云医疗科技有限公司与四川大学华西第二医院合作开发)”(以下简称为AI系统)对完全性生长激素缺乏症(CGHD)患儿诊断及骨龄评价准确性。方法 选择2014年7月至2019年11月,于四川大学华西第二医院确诊的66例来自四川地区CGHD患儿为研究对象,纳入研究组。选择同期于病例收集医院儿童保健科进行骨龄测定的67例来自四川地区身高达标儿童作为对照,纳入对照组。对每例受试儿进行左手腕关节正位X射线摄片骨龄测定,由2位医师采用《TW₂骨龄评分法中国未成年人南方标准》(以下简称为TW₂CHN)》与《TW₃骨龄评分法标准》(以下简称为TW₃),盲法评价受试儿TW₂CHN-桡、尺、掌指骨(RUS)与TW₂CHN-腕骨(carpal)、TW₂CHN-20、TW₃-RUS及TW₃-carpal骨龄(以下简称为5种传统骨龄),以及以同性别、年龄身高达...