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Background. Lung cancer remains the leading cause of cancer death worldwide, and the most subtype is lung adenocarcinoma (LUAD). Tumor-infiltrating immune cells (TIICs) greatly impact the prognosis of LUAD. Tumor necrosis factor–like weak inducer of apoptosis (TWEAK), signal via its receptor fibroblast growth factor-inducible 14 (Fn14), dysregulates immune cell recruitment within tumor environment, thus promoting the progression of autoimmune diseases and cancer. We aimed to explore its role in LUAD. Methods. The expression level of TWEAK was explored in Tumor Immune Estimation Resource 2.0 (TIMER2.0) and Oncomine databases. The Tumor Immune Dysfunction and Exclusion (TIDE) and Lung Cancer Explorer (LCE) databases were applied to evaluate the survival in correlation to TWEAK expression. TIICs were assessed with TIMER2.0 and TIDE datasets. The expression of TWEAK protein was detected in LUAD cell lines and also in tissue samples from LUAD patients via western blotting or combination with immunochemistry. Results. Our results showed that TWEAK was downregulated in LUAD tumors compared to normal tissues in TIMER2.0, Oncomine, cell lines, and clinical specimens. Poor survival was uncovered in lower TWEAK expression of LUAD patients in LCE ( meta − HR = 0.84 [95% CI, 0.76-0.92]) and TCGA ( Continuous Z = − 1.97 , p = 0.0486 ) and GSE13213@PRECOG ( Continuous Z = − 4.25 , p = 2.12 e − 5 ) in TIDE. Multiple tumor-infiltrating immune cells (TIICs) were found closely correlated with TWEAK expression in LUAD, especially hematopoietic stem cell ( Rho = 0.505 , p = 2.78 e − 33 ), common lymphoid progenitor ( Rho = − 0.504 , p = 3.79 e − 33 ), and myeloid-derived suppressor cells (MDSCs) ( Rho = − 0.615 , p = 1.36 e − 52 ). Conclusion. Lower level of TWEAK was linked with poor survival and aberrant recruitment and phenotype of TIICs in LUAD, which might motivate immune escape and weaken the effects of immunotherapy.

Introduction: Aspirin is used to prevent and treat cardiovascular diseases; however, some patients develop aspirin resistance. Aim: We aimed to explore the potential molecular mechanisms underlying aspirin resistance in people living in the Chinese plateau area. Methods: In total, 91 participants receiving aspirin treatment from the Qinghai plateau area were divided into the aspirin resistance and aspirin sensitivity groups. Genotyping was performed using the Sequence MASSarray. Differentially mutated genes between the two groups were analyzed using MAfTools. The annotation of differentially mutated genes was conducted based on the Metascape database. Results and Discussion: In total, 48 differential SNP and 22 differential InDel mutant genes between the aspirin resistance and aspirin sensitivity groups were screened using Fisher’s exact test (P < 0.05). After the χ2 test, a total of SNP mutant genes, including ZFPL1 and TLR3, and 19 InDel mutant genes were found to be differentially expressed between the two groups (P < 0.05). Functional analysis revealed that these differential SNP mutations were mainly enriched in aspirin resistance pathways, such as the Wnt signaling pathway. Furthermore, these genes were related to many diseases, including various aspirin indications. Conclusion: This study identified several genes and pathways that could be involved in arachidonic acid metabolic processes and aspirin resistance progression, which will provide a theoretical understanding of the molecular mechanism of aspirin resistance.

Non-invasive prediction for KIT/PDGFRA status in GIST is a challenging problem. This study aims to evaluate whether CT based sarcopenia could differentiate KIT/PDGFRA wild-type gastrointestinal stromal tumor (wt-GIST) from the mutant-type GIST (mu-GIST), and to evaluate genetic features of GIST. A total of 174 patients with GIST (wt-GIST = 52) were retrospectively identified between January 2011 to October 2019. A sarcopenia nomogram was constructed by multivariate logistic regression. The performance of the nomogram was evaluated by discrimination, calibration curve, and decision curve. Genomic data was obtained from our own specimens and also from the open databases cBioPortal. Data was analyzed by R version 3.6.1 and clusterProfiler (http://cbioportal.org/msk-impact). There were significantly higher incidence (75.0% vs. 48.4%) and more severe sarcopenia in patients with wt-GIST than in patients with mu-GIST. Multivariate logistic regression analysis showed that sarcopenia score (fitted based on age, gender and skeletal muscle index), and muscle fat index were independent predictors for higher risk of wt-GIST (P

Cardiotoxicity linked to doxorubicin (DOX) is primarily caused by inflammation, oxidative stress, and apoptosis. The role of tubeimoside I (TBM) in DOX-induced cardiotoxicity remains ambiguous, despite growing evidence that it could reduce inflammation, oxidative stress, and apoptosis in various diseases. This study was designed to investigate the role of TBM in DOX-induced cardiotoxicity and uncover the underlying mechanisms. H9c2 cell line and C57BL/6 mice were used to construct an in vitro and in vivo model of DOX-induced myocardial injury, respectively. We observed that DOX treatment provoked inflammation, oxidative stress, and cardiomyocyte apoptosis, which were significantly alleviated by TBM administration. Mechanistically, TBM attenuated DOX-induced downregulation of sirtuin 3 (SIRT3), and SIRT3 inhibition abrogated the beneficial effects of TBM both in vitro and in vivo. In conclusion, TBM eased inflammation, oxidative stress, and apoptosis in DOX-induced cardiotoxicity by increasing the expression of SIRT3, suggesting that it holds great promise for treating DOX-induced cardiac injury.

Currently, the mechanisms of non-visual effects of road lighting environments on drivers are unclear. In this paper, Electroencephalography (EEG) and other measures were used to record physiological and psychological indicators during driving at different correlated color temperature(CCT) levels (3500k vs. 4500k vs. 5500k vs. 6500k), with the aim of preliminarily verifying the existence of non-visual effects of the lighting environment on drivers on urban motor vehicle roads. The results suggest that 3500k and 4500k help to improve the subjects' mood, while 5500k and 6500k are more likely to induce negative emotions in the subjects.

Background Color has considerable effects on physiological and psychological perception in human-machine interaction, but it is unclear how the coding methods of interface color affect users’ perception. The present study investigated the impacts of two dimensions of color coding, quantity and hue contrast, on visual perception from three aspects: brain activity, emotional experience, and visual comfort. Methods Based on the HSV color space, two sets of experiments were designed with three quantity levels of colors and four quantity levels of hues (8, 16, 36 X 1, 2, 4, Random) as well as five combinations of two hue contrasts (30º, 60º, 120º, 180º, 240º in the HSV hue wheel). Participants’ brain activities were monitored within 2000ms of viewing the color stimuli, and subjective evaluations of their emotional and visual experiences were collected. Significant differences were observed in the synchronization of delta (0-4 Hz) and theta (4–8 Hz) bands in the 0-500ms time window and gamma (30-100Hz) oscillation throughout the presentation by using event-related spectral perturbations (ERSPs). Results Expanded color elicited significantly higher arousal of emotion, along with stronger delta and theta band synchronization in the parietal and occipital lobes and enhanced gamma power in the posterior cortex, indicating increased visual processing workload and attention input. Grouping on identical hue significantly weakened the activation of delta and theta bands and did not enhance gamma oscillation as shape Gestalt as the number of groups rose, suggesting that color grouping capably lessens the perceptual load of visual processing. In addition, sharper hue contrasts significantly boosted delta and theta band activity and enhanced low gamma (30-50Hz) activation, and undermined visual experience compared with softer combinations, which might relate to the concentric antagonistic receptive fields of visual cells. Conclusion This paper gives the first elucidation of the effects of color coding on neural activity and subjective perceptions, contributing to the neuroergonomic study of interface color design. These findings bridge the gap between the neural activity of color vision and mental experience during color perception.

CRISPR/Cas9 has been adapted to disrupt endogenous genes in adoptive T-lymphocyte therapy to prevent graft-versus-host disease. However, genome editing also generates prevalent deleterious structural variations (SVs), including chromosomal translocations and large deletions, raising safety concerns about reinfused T cells. Here, we dynamically monitored the progression of SVs in a mouse model of T-cell receptor (TCR)-transgenic T-cell adoptive transfer, mimicking TCR T therapeutics. Remarkably, CRISPR/Cas9-induced SVs persist and undergo clonal expansion in vivo after three weeks or even two months, evidenced by high enrichment and low junctional diversity of identified SVs post infusion. Specifically, we detected 128 expanded translocations, with 20 615 as the highest number of amplicons. The identified SVs are stochastically selected among different individuals and show an inconspicuous locus preference. Similar to SVs, viral DNA integrations are routinely detected in edited T cells and also undergo clonal expansion. The persistent SVs and viral DNA integrations in the infused T cells may constantly threaten genome integrity, drawing immediate attention to the safety of CRISPR/Cas9-engineered T cells mediated immunotherapy.

Background Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF. Methods Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM. Results High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy. Conclusion DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

Abnormal CaMyocardial infarction (MI) was established by ligation of the left anterior descending coronary artery in rats. Two-week later, rats with post-infarction HF were randomly treated with saline (MI group) or CST (MI + CST group) for 4-week. Cellular CaIn atrial CMs, compared with the sham group, the sarcoplasmic reticulum (SR) CaChronic CST treatment reduces AF vulnerability in rats with MI-induced HF by improving Ca

Jinchun Wu,1 Haiyan Zhou,2 Xiaoping Yi,3 Qiongzhi He,4 Tianxiang Lei,5 Fengbo Tan,5 Heli Liu,5 Bin Li1 1Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China; 2Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China; 3Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China; 4Geneplus-Beijing Institute, Beijing, People’s Republic of China; 5Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of ChinaCorrespondence: Heli Liu; Bin Li Email heliliu@csu.edu.cn; bincsuxy@csu.edu.cnPurpose: NF1-deficient GISTs account for about 1% of gastrointestinal stromal tumors (GISTs) and are usually considered as a subtype of KIT/PDGFRA wild-type GISTs that have no detectable KIT and PDGFRA mutations. Some KIT/PDGFRA wild-type GISTs actually have cryptic KIT mutations (mKIT). So we investigate whether concurrent mKIT existed in NF1-associated GISTs.Patients and Methods: Three independent cohorts were retrospectively analyzed. KIT/PDGFRA wild-type GISTs in Xiangya Hospital between May 2017 and Oct 2019 were investigated by next-generation sequencing (NGS) approach targeted 1021 cancer-related genes regions. GISTs cases in Gene+ dataset from May 2017 to May 2020 were collected from the platform of this company. The genotypes of GISTs in MSKCC cohort were downloaded from cBioPortal.Results: A total of 290 cases including 23 KIT/PDGFRA wild-type GISTs in Xiangya Hospital, 136 GISTs in Gene+ database, and 131 GISTs in MSKCC were enrolled. Twenty-six cases have NF1 mutations (mNF1), and 48% (12/26) of NF1-mutated GISTs have concurrent mKIT. Compared with MSKCC (2/10, 20%), a higher ratio of mKIT in NF1-associated GISTs was detected in Xiangya Hospital (3/5, 60%) and Gene+ (7/11, 64%) (p< 0.05). No mutation hotspot existed in mNF1. Most of mKIT centered within exon 11 (7/12, 58%) and others including exon 17 (3/12, 25%), exon 9(1/12, 8%), exon 13 (1/12, 8%) and exon 21 (1/12, 8%). No differences in age, gender, and location were detected between NF1-related GISTs with mKIT and those without mKIT. Three GIST cases of type I neurofibromatosis, skin neurofibromas and micro-GISTs (≤ 1 cm) were devoid of mKIT, but all the mini-GISTs (1∼ 2 cm) and clinic GIST lesions (> 2 cm) in two cases harbored mKIT.Conclusion: mKIT was not unusual in NF1-associated GISTs, especially in Chinese populations. The gain-of-function mKIT possibly facilitated the progression of NF1-deficient lesions to clinic GISTs, however, the underlying mechanism warrants further studies.Keywords: gastrointestinal stromal tumor, NF1, KIT, deep sequencing

Background Clear cell renal cell carcinoma is susceptible to ferroptosis, and immunotherapy is recently recommended as a priority for the initial treatment of metastatic clear cell renal carcinoma. Increased ferroptosis and immune activation can synergistically reinforce each other in killing cancer cells. NCOA4 depletion can eliminate iron accumulation and thus weaken ferroptosis. Here, we aim to identify and validate the association between NCOA4 expression, clinicopathologic characteristics, and overall survival in ccRCC by using The Cancer Genome Atlas and Gene Expression Omnibus databases. We further analyze the interacted proteins of NCOA4 and infiltrated immune cells via TIMER and GEPIA databases. Methods NCOA4 expression in clear cell renal carcinoma (ccRCC) tissues and normal adjacent tissues in The Cancer Genome Atlas (TCGA) data were primarily screened, and further validated in another independent cohort from the gene expression omnibus (GEO) database and human protein atlas. The relationships of NCOA4 expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which NCOA4 interacted were also built using the online STRING website. Meanwhile, we use TIMER and GEPIA databases to investigate the relationships between NCOA4 expression and infiltrated immune cells and their corresponding gene marker sets. Results Contrast to normal tissue, NCOA4 expression was lower in ccRCC tumor tissue(p p Conclusion Deficient NCOA4 expression was related to disease progression and poor prognosis, as well as impaired infiltration of immune cells in ccRCC.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new type of oral hypoglycaemic agent with good cardiovascular protective effects. There are several lines of clinical evidence suggest that SGLT2i can significantly reduce the risks of heart failure, cardiovascular death, and delay the progression of chronic kidney disease. In addition, recent basic and clinical studies have also reported that SGLT2i also has good anti-arrhythmic effects. However, the exact mechanism is poorly understood. The aim of this review is to summarize recent clinical findings, studies of laboratory animals, and related study about this aspect of the antiarrhythmic effects of SGLT2i, to further explore its underlying mechanisms, safety, and prospects for clinical applications of it.

Multiple or Large displays play an important role in collaboration scenarios, because they can provide more display space. However, they are challenging concerning effective manipulating and managing the display contents, particularly when the displays are beyond the users' reachable region and operational limit region. In this work, we explore a particular interactive input combination for multiple or large displays, the Speech + Posture interactive input mode. We integrate postures to point to target display areas and phonetic keywords to designate display contents. This method makes interactive input commands concise and explicit, and it can support interaction with multiple or large interactive displays effectively.

Cohesin participates in loop formation by extruding DNA fibers from its ring-shaped structure. Cohesin dysfunction eliminates chromatin loops but only causes modest transcription perturbation, which cannot fully explain the frequently observed mutations of cohesin in various cancers. Here, we found that DNA replication initiates at more than one thousand extra dormant origins after acute depletion of RAD21, a core subunit of cohesin, resulting in earlier replicating timing at approximately 30% of the human genomic regions. In contrast, CTCF is dispensable for suppressing the early firing of dormant origins that are distributed away from the loop boundaries. Furthermore, greatly elevated levels of gross DNA breaks and genome-wide chromosomal translocations arise in RAD21-depleted cells, accompanied by dysregulated replication timing at dozens of hotspot genes. Thus, we conclude that cohesin coordinates DNA replication initiation to ensure proper replication timing and safeguards genome integrity.

To study effect of nanomedicine on lower extremity deep vein thrombosis (LEDVT) and its correlation with susceptibility genes (SGs), preliminary nanoparticle LSA was constructed using lauric acid and stearic acid, and CTAB-HAuCL4-TEOS (CHT) was obtained using cetyltrimethyl ammonium bromide (CTAB), chloroauric acid (HAuCL4), and tetraethoxysilane (TEOS) to prepare UK-LSA-CHT by combining with urokinase (UK). 20 rabbits were grouped into UK-LSA-CHT, LSA, UK, and D0 group. Human umbilical vein endothelial cells (HUVEC) were selected for cytotoxicity test. The plasma endothelin (ET-1), interleukin 6 (IL-6), and nuclear factor κβ (NF-κβ) of the rabbits were detected with double antibody sandwich method. Expression of platelet activating factor (PAF) was detected by immumohistochemical staining. Genotype distribution was detected with the second-generation sequencing technology (SGST). The results showed that expressions of ET-1, IL-6, and NF-κβ) in UK-LSA-CHT group were lower than those in the LSA group and the UK group after 12 hours (P < 0.05). Frequency of allele G and T, and GT and TT genotype ratio of SG NOS3 rs1799983 in UK -LSA-CHT group were less than those in LSA and UK group (P < 0.05). UK-LSA-CHT group had observably lower value in PAF positive expression than LSA and UK groups (P < 0.05). In short, UK-LSA-CHT had good biocompatibility and safety and good therapeutic effect on LEDVT. N0S3 rs1799983 alleles G and T may be the key risk factors for the occurrence and development of LEDVT.

Objective: The diagnostic performance of soluble suppression of tumorigenicity (sST2) in heart failure (HF) had been investigated in multiple studies, but the results were inconsistent. This meta-analysis evaluated the diagnostic value of sST2 in HF.Methods: Pubmed, Web of Science, Embase, and Cochrane Library databases were searched until March 2021. Cohort studies or case-control studies relevant to the diagnostic value of sST2 in HF were screened, and true positive (TP), false positive (FP), false negative (FN), and true negative (TN) data were extracted for calculating sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC). The quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS), the threshold effect was determined by calculating Spearman correlation coefficients and summary receiver operating characteristic (SROC) curve patterns, the heterogeneity was evaluated using the I2 statistic and the Galbraith radial plot, and sensitivity analysis was also performed. Deeks' test was used to assess publication bias.Results: A total of 11 studies from 10 articles were included in this meta-analysis. The Spearman correlation coefficient was 0.114, p = 0.739, and the SROC curve did not show a “shoulder-arm” shape, which suggests that there was no threshold effect, but study heterogeneity existed because of non-threshold effects. The combined sensitivity was 0.72 [95% confidence interval (CI): 0.65–0.78], specificity was 0.65 (95% CI: 0.45–0.81), PLR was 1.75 (95% CI: 1.33–2.31), NLR was 0.48 (95% CI: 0.37–0.63), DOR was 3.63 (95% CI: 2.29–5.74), and AUC was 0.75. The Deeks' test suggested no significant publication bias in the included studies (P = 0.94).Conclusion: sST has some diagnostic value in HF, but this should be further evaluated in additional studies with rigorous design and high homogeneity.

BackgroundEarly DNA replication occurs within actively transcribed chromatin compartments in mammalian cells, raising the immediate question of how early DNA replication coordinates with transcription to avoid collisions and DNA damage.ResultsWe develop a high-throughput nucleoside analog incorporation sequencing assay and identify thousands of early replication initiation zones in both mouse and human cells. The identified early replication initiation zones fall in open chromatin compartments and are mutually exclusive with transcription elongation. Of note, early replication initiation zones are mainly located in non-transcribed regions adjacent to transcribed regions. Mechanistically, we find that RNA polymerase II actively redistributes the chromatin-bound mini-chromosome maintenance complex (MCM), but not the origin recognition complex (ORC), to actively restrict early DNA replication initiation outside of transcribed regions. In support of this finding, we detect apparent MCM accumulation and DNA replication initiation in transcribed regions due to anchoring of nuclease-dead Cas9 at transcribed genes, which stalls RNA polymerase II. Finally, we find that the orchestration of early DNA replication initiation by transcription efficiently prevents gross DNA damage.ConclusionRNA polymerase II redistributes MCM complexes, but not the ORC, to prevent early DNA replication from initiating within transcribed regions. This RNA polymerase II-driven MCM redistribution spatially separates transcription and early DNA replication events and avoids the transcription-replication initiation collision, thereby providing a critical regulatory mechanism to preserve genome stability.

Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The fast-growing studies of ferroptosis in cancer have boosted a perspective for its usage in cancer therapeutics. Here, we review the current findings of ferroptosis regulation and especially focus on the function of ncRNAs in mediating the process of cell ferroptotic death and on how ferroptosis was in relation to other regulated cell deaths. Aberrant ferroptosis in diverse cancer types and tissues were summarized, and we elaborated recent data about the novel actors of some “conventional” drugs or natural compounds as ferroptosis inducers in cancer. Finally, we deliberate future orientation for ferroptosis in cancer cells and current unsettled issues, which may forward the speed of clinical use of ferroptosis induction in cancer treatment.

Human visual search performance in dynamic environment will be affected by the moving speed of background and object. Eye movement data can help us understand the reasons for this performance difference. This study investigated the changes of eye movement index of visual search under different task difficulty (high, low) and different moving speed (low, high). The results show that the moving speed of the object will affect the fixation numbers, fixation time, saccade amplitude and saccade speed. With the increase of speed, the number of fixation will increase significantly, and the fixation time, saccade amplitude and saccade speed will decrease significantly. Moreover, this index has nothing to do with the difficulty of the search task in this study. The research results can provide guidance for visual search design in dynamic environment.

Objective. To evaluate the efficacy of dual-antiplatelet treatment (DAPT) in patients with coronary heart disease (CHD) at high altitude by using thrombelastogram (TEG) and to analyze the related biochemical factors affecting drug reactivity. Methods. Totally 118 CHD patients who admitted to the Qinghai People’s Hospital from September 2019 to September 2020 were enrolled in the group. Those people have lived in Qinghai for a long time. Seven days after DAPT, venous blood was collected on an empty stomach in the early morning of the next day; blood routine, coagulation function, and biochemical items were tested. Thrombelastogram (TEG) was used to draw curves to calculate platelet, coagulation and fibrinolysis functions, and drug inhibition rate. Patients were divided into the aspirin resistance (AR) group, clopidogrel resistance (CR) group, dual-antiplatelet drug resistance (DAR) group, and drug-sensitive group according to different inhibition rates. The drug efficacy was analyzed, and the clinical data, biochemical indexes, and TEG parameters of each group were compared to identify the risk factors of drug resistance. Results. Those 118 CHD patients at high altitude were incorporated into the study, ranging from 38 to 84 years of age, including 81 males (68.64%) and 37 females (31.36%). The platelet function and coagulation-fibrinolysis function were detected by TEG, and MATHROMBI, MAADP, and MAAA were higher than the reference range. There were 82 cases (69.49%) of drug resistance, 36 cases (32.53%) of drug sensitivity, 17 cases (14.41%) of AR alone, and 16 cases (12.71%) of CR alone. There was no significant difference in age, gender, BMI, oxygen saturation, TG, GFR, and history of diabetes and hypertension between ACS and CCS groups ( P > 0.05 ). PLT and FIB in the ACS group were higher than those in the CCS group, and the difference was statistically significant ( P < 0.05 ). In addition, MATHROMBIN, MAFIBRIN, E, A, A30, and coagulation composite index were also higher than those in the CCS group, with a statistically significant difference ( P < 0.05 ). Univariate analysis and logistic regression analysis suggested that age, HbA1c, FBG, and diabetes were the main factors of drug resistance. Conclusion. Antiplatelet drugs aspirin and clopidogrel resistance are associated with increased age, elevated HbA1c and FBG, and diabetes. Therefore, it is necessary to take reasonable treatment measures based on the actual situation of patients.

Background: Lung adenocarcinoma (LUAD) is a common cancer. Immunotherapy is one of the major treatments but showing diverse efficacy in LUAD. Long non-coding RNAs (lncRNAs) are emerging as important players in immune regulation in cancer. Herein, we identified and validated a prognostic signature of immune-related lncRNAs in LUAD and explored its correlation with tumor-infiltrating immune cells (TIICs) by bioinformatics analysis.Methods: Immune-related lncRNAs were acquired using Pearson correlation analysis between lncRNAs from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and immune genes from the ImmPort website and Molecular Signatures Database. The risk signature was constructed in the TCGA group through univariable Cox, lasso and multivariable Cox regression analyses. The prognostic value of the established risk signature was validated in both TCGA and GEO datasets. The interacted TIICs and immune pathways with each single lncRNA and the risk signature were investigated respectively in ImmLnc database, Cibersortx database and gene set enrichment analysis (GSEA) analyses.Results: A seven immune-related lncRNAs prognostic signature was constructed and it stratified LUAD into high and low risk groups. High risk group showed poorer overall survival (OS) in comparison with low risk group via survival analysis.The seven-lncRNAs signature was closely correlated with various TIICs and immune pathways mostly involved in T cell activation, antigen processing and presentation, chemokines and cytokine receptors.Conclusions: The seven lncRNAs model was identified as a predictable signature for prognosis of LUAD patients probably due to its immunomodulation role. This study might provide a new target for enhancing the efficacy of immunotherapy in this mortal disease.

Pulmonary hypertension (PH) is defined as the mean pulmonary artery pressure (mPAP) ≥25 mmHg under the sea level in resting state. ROCK1 and ROCK2 can be combined to cause the damage of vascular endothelial function. To explore the differences of ROCK1 and ROCK2 in subjects with pulmonary hypertension or normal pulmonary artery pressure in plateau area, and to further understand the mechanism of Rho/rho-kinase pathway activation for promoting pulmonary hypertension, we collected 64 patients with pulmonary hypertension and 87 normal pulmonary artery healthy controls. All subjects were hospitalized in Cardiology or Respiration Department of Qinghai Provincial Peoples’ Hospital from December 2016 to June 2017. The pulmonary artery systolic pressure was measured by Doppler ultrasound, and serum ROCK1 and ROCK2 levels were tested by enzyme linked immunosorbent assay (ELISA). We found that the serum ROCK2 concentration in the pulmonary hypertension group was significantly higher than that in the control group, but serum ROCK1 level had no significant difference. ROCK2 plays a leading role in pulmonary hypertension in the plateau region, so selective ROCK2 inhibitors will be more effective in improving pulmonary hypertension.

A majority of existing studies have focused on the efficacy of inhaled long-acting bronchodilators (ILABs), such as long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs), and LABAs combined with LAMAs in treating chronic obstructive pulmonary disease (COPD). The current meta-analysis aimed to investigate the correlation of ILABs with specific cardiovascular adverse events (CAEs). Five electronic databases, including PubMed, Embase, Cochrane Library, Scopus, and Web of Science were systematically retrieved. Finally, 16 randomized controlled trials were enrolled into the current meta-analysis. Typically, the efficacy of 3 major classes of drugs (LABAs, LAMAs, and LABAs combined with LAMAs), and 7 specific drugs (including formoterol, glycopyrrolate, indacaterol, olodaterol, Salmeterol, tiotropium, and vilanterol) for 4 CAEs, including myocardial infarction, cardiac failure (CF), ischemic heart disease (IHD), and stroke in stable COPD patients, was examined. All the pooled results were analyzed through the odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). The direct meta-analysis results suggested that LABAs could increase the risk of CF in patients with stable COPD compared with placebo controls (OR 1.70, 95% CI, 1.00-2.90). In addition, network meta-analysis results indicated that LAMAs combined with LABAs would result in an increased risk of CF in patients with stable COPD (OR 2.31, 95% CI, 1.10-5.09). According to the ILABs specific drug analysis, formoterol may potentially have protective effects on IHD compared with placebo controls (OR 0.45, 95% CI, 0.18-1.00). In conclusion, among these 3 kinds of ILABs, including LAMAs, LABAs, and LABAs/LAMAs, for stable COPD patients, LAMAs and LABAs are associated with the least possibility to induce myocardial infarction and stroke, respectively. However, the application of LABAs will probably increase the risk of CF; they should be used with caution for stable COPD patients with CF. In addition, in specific-drug analysis, the use of formoterol can reduce the risk of treatment-related IHD. Nevertheless, more studies on different drug doses are needed in the future to further validate this conclusion.

Efficient and precise genome editing is essential for clinical applications and generating animal models, which requires engineered nucleases with high editing ability while low off-target activity. Here we present a high-throughput sequencing method, primer-extension-mediated sequencing (PEM-seq), to comprehensively assess both editing ability and specificity of engineered nucleases. We showed CRISPR/Cas9-generated breaks could lead to chromosomal translocations and large deletions by PEM-seq. We also found that Cas9 nickase possessed lower off-target activity while with some loss of target cleavage ability. However, high-fidelity Cas9 variants, including both eCas9 and the new FeCas9, could significantly reduce the Cas9 off-target activity with no obvious editing retardation. Moreover, we found AcrIIA4 inhibitor could greatly reduce the activities of Cas9, but off-target loci were not so effectively suppressed as the on-target sites. Therefore, PEM-seq fully evaluating engineered nucleases could help choose better genome editing strategy at given loci than other methods detecting only off-target activity.

e21594 Background: Skin cutaneous melanoma (SKCM) has a high incidence and mortality. Immune checkpoint inhibitors (ICIs) are promising but show heterogeneous efficacy in the SKCM treatment. T cell-promoted tumor ferroptosis is a vital anti-tumor mechanism of ICIs. Acyl-CoA synthetase long chain family member 4 (ACSL4) can sensitize ferroptosis by facilitating lipid peroxidation. So we proposed that ACSL4 is a positive predictor for ICIs efficacy and correlated with tumor-infiltrating immune cells (TIICs) in SKCM. Methods: The responses of SKCM patients to ICIs were evaluated from Tumor Immune Dysfunction and Exclusion (TIDE) using the gene expression data of The Cancer Genome Atlas (TCGA)-SKCM downloaded from UCSC Xena browser and datasets within TIDE. The correlation between ACLS4 expression and survival was obtained from the Online consensus Survival webserver for Skin Cutaneous Melanoma (OSskcm) and TIDE databases. The relationships between ACSL4 and TIICs were evaluated using the database of Tumor Immune Estimation Resource 2.0 (TIMER2.0). Results: ACSL4 expression was positively correlated with the predicted responder of ICIs in TCGA dataset (R = 0.12, p = 0.0093) and therapy outcomes of ICIs in Gide2019_PD1+CTLA4 (Progression-free survival(PFS), contimuous z = -2.39, p = 0.0169) and Lauss2017_ACT (PFS, contimuous z = -2.08, p = 0.0371; overall survival(OS), contimuous z = -2.96, p = 0.00309). Favorable OS was observed in the patients with high ACSL4 expression in the TCGA (HR = 0.6567, 95% CI = 0.5015̃0.8599, p = 0.0022) and GSE19234 (HR = 0.4135, 95% CI = 0.1748̃0.9784, p = 0.0445) from OSskcm and the GSE8401 (contimuous z = -2,24, p = 0.025) and GSE54467 (contimuous z = -2.26, p = 0.0239) from TIDE database. TIICs including CD8+ T cells, CD4+ T cells (memory, Th2), B cells, neutrophils, monocytes, M1 macrophages, and cancer-associated fibroblasts (CAFs) were positively associated with the expression level of ACSL4. Conclusions: High ACSL4 expression maybe indicates a good response to ICIs and long survival in SKCM. The increased T cells within the tumor microenvironment correlated with high ACSL4 expression possibly implied the synergism effects of ferroptosis and ICIs, deserving further investigation. Keywords: ACSL4, ICIs, TIICs, SKCM.

e14011 Background: Leptomeningeal metastasis (LM) is the deadliest complication of lung cancer. No standard therapy for the LM harbor non-sensitive epidermal growth factor receptor (EGFR)-mutant|(neither E19 del, E21 p.L858R nor E18 p. G719X mutation ). Previous studies showed cetuximab held the potential for treating the EGFR mutants who had failed 2 or more lines of standard cytotoxic chemotherapy and reversible EGFR TKIs. Methods: We screen the lung cancer patients with LM treated with Cetuximab-based regimen from July 1st, 2020 to Dec 31th 2020. The medical records were retrospectively reviewed and analyzed. Results: Three lung cancer patients with LM were included. All of them were heavily pretreated with various TKIs, chemotherapy, or/and with antiangiogenesis and PD-1 antibodies. When they were referred to our department, all these patients were in severe medical conditions. Case 1 has severe multiple cranial nerve impairment with cauda equina syndrome and massive malignant pleural effusion. Case 2 has intensively violent headaches with vomit and lumbosacral pain due to more than 500mm H2O of intracranial hypertension. Case 3 has acute pancreatitis due to oppressive obstruction of pancreatic duct by multiple metastatic tumors. The molecule test of tumor tissue or liquid from malignant pleural fluid have revealed E20 p.C797S in cis with p.T790M accompanied E19 del of EGFR gene in case 1, E21 p. R831H with E19 p.L747P of EGFR gene in case 2, and E20 p.S768_D770dup of EGFR gene in case 3, respectively. Their therapies were changed to cetuximab combined with TKI of afatinib or osimertinib, and local treatment including local radiation, intraventricular pemetrexed administration, or with intrathoracic drain. The disease control rate (DCR) was 100% of one partial remission (PR) and two stable disease (SD). The intracranial response was also observed in all the 3 patients showing CSF cytology turning negative or enhanced meningeal disappearance in MRI image with obviously relieved headache or/and improved cranial nerve palsy. The performance status of two patients was largely improved from Karnofsky Performance Status (KPS) scoring 20 to 90 and 50, respectively, and that of the other patient was stable with KPS scoring 50. The side effect is manageable skin rashes (grade II-III). Until this abstract was written, all the 3 patients were still alive. Conclusions: Cetuximab-based systemic therapy combined with local treatment demonstrated preliminary clinical activity in the rare EGFR-mutant lung cancer with LM who have already undergone heavily previous therapy, warranting further investigation.

The naval ship command cabin(NSCC) is an important part and the nerve centre of the whole ship. In order to achieve better evaluation and design improvements of the human-machine interface(HMI) of the naval shipborne command cabin in the design phase, we preliminarily expounded the ergonomic digital evaluation system of the NSCC based on extended JACK. The NSCC human-machine interface evaluation index system was constructed by using the improved Delphi method, and the quantitative and qualitative evaluation method was studied. The ergonomic digital evaluation system for the naval shipborne command cabin was developed by extending the JACK software, in which the mannequin module, human-machine interface design module, evaluation module and design standards module were integrated. Finally, the feasibility and applicability of the proposed ergonomic digital evaluation system were verified by an illustrated example.

e21017 Background: Lung adenocarcinoma (LUAD) occupies the most of non-small cell lung cancer (NSCLC) and shows promising response to PD-1 immunotherapy, but immune escape will cause treatment failure indicating poor prognosis. TWEAK (Tumor necrosis factor-related weak inducer of apoptosis, also known as TNFSF12) combining with its receptor FN14 (fibroblast growth factor–inducible 14) mediates crucial innate and adaptive immune pathways to promote the progression of multiple autoimmune diseases. So we assumed that TWEAK is a prognostic predictor and related with tumor-infiltrating immune cells (TIICs) in LUAD. Methods: TWEAK expression of LUAD was primarily investigated in The Cancer Immunome Atlas (TCIA) and then validated in Tumor Immune Estimation Resource (TIMER) databases. We assessed the effect of TWEAK on the survival via the Kaplan-Meier plotter, GEPIA2 (gene expression profiling interactive analysis) and PrognoScan databases. The relation between TWEAK and TIICs was explored in TIMER and TCIA, as well as the correlation of TWEAK and FN14 was analyzed in TIMER and GEPIA2. Results: Low TWEAK expression was significantly associated with poor relapse-free survival (RFS) (HR = 0.62, 95% CI = 0.4~0.97, logrank P = 0.035) and overall survival (OS) (HR = 0.61, 95% CI = 0.46~0.83, logrank P = 0.0012) in LUAD from Kaplan-Meier plotter. Similar impacts of TWEAK on the survival were validated in GEPIA2 and four independent cohorts from PrognoScan (jacob-00182-CANDF, GSE13213, jacob-00182-MSK and GSE31210). Moreover, reduced TWEAK expression was closely related with the paucity of TIICs which contributed to poor OS, including central memory CD8 T cells, plasmacytoid dendritic cells, activated CD8 T cells, monocytes, T follicular helper cells, immature B cells and eosinophils. In addition, TWEAK expression was positively related with the expression level of FN14 in both GEPIA2(R = 0.13, P= 0.0031) and TIMER (partial.cor = 0.212, P= 2.04e-06). Conclusions: Low TWEAK expression maybe indicate poor prognosis in LUAD, and correlated with the impaired infiltration of immune cells in the tumor region. The defective TWEAK/FN14 pathway possibly accounts for these observations, but the underlying mechanism needs to be further explored.

Multiple vertebrate embryonic structures such as organ primordia are composed of a volume of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show 3D mesenchymal cell intercalations, rather than cell divisions and biophysical tissue properties, are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor, we show that cortical force oscillations promote these intercalations. Genetic loss and gain of function approaches show thatWnt5afunctions as a spatial cue to coordinate cell polarity with cytoskeletal oscillation. YAP/TAZ and PIEZO1 serve as downstream effectors ofWnt5a-mediated actomyosin bias and cytosolic calcium transients, respectively, to ensure appropriate tissue form during growth. Our data support oriented 3D cell neighbour exchange as a conserved mechanism driving volumetric morphogenesis.

Background Endoscopic spine surgery has become increasingly popular. However, no study has researched the predictive factors for different outcomes. This study is the first to evaluate the outcome predictors of the transforaminal endoscopic spine system (TESSYS) technique for lumbar disk herniation (LDH). Methods We performed a prospective study of 80 patients meeting the inclusion criteria who underwent TESSYS for LDH. Clinical outcomes were assessed by the visual analog scale (VAS), the Oswestry Disability Index (ODI), and the modified MacNab criteria. Univariate and multivariate analyses were performed to evaluate the outcome predictors. Results There were 36 men and 44 women with a mean age of 48.76 ± 15.60 years (range: 24–78 years). The mean follow-up time was 25.15 ± 9.76 months (range: 12–48 months). The VAS and ODI scores at the last follow-up were significantly improved (p Conclusions TESSYS is an effective method to treat LDH. Older age, the existence of an HIZ, and a large disk herniation were the most important predictors for a worse outcome.

Multiple vertebrate embryonic structures such as organ primordia are composed of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show that 3D mesenchymal cell intercalations are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor that we knock-in to the mouse genome, we show that cortical force oscillations promote these intercalations. Genetic loss- and gain-of-function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity and cytoskeletal oscillation. These processes diminish tissue rigidity and help cells to overcome the energy barrier to intercalation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin polarity and cytosolic calcium transients that orient and drive mesenchymal cell intercalations. These findings advance our understanding of how developmental pathways regulate biophysical properties and forces to shape a solid organ primordium., Morphogenesis of tissue sheets is well studied, but mechanisms that shape bulk tissues are unclear. Here, the authors show that mesenchymal cells intercalate in 3D to shape the mouse branchial arch, with cortical forces driving intercalations in a Wnt5a-, Yap/Taz- and Piezo1-dependent manner.