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(1) Background: It has yet to be determined whether preoperative flexible bronchoscopy (FB) should be routinely performed in patients with peripheral lung cancer. The aim of this study was to construct a model to predict the probability of positive FB findings, which would help assess the necessity of preoperative FB. (2) Methods: A total of 380 consecutive patients with peripheral lung cancer who underwent preoperative FB were recruited for this study. A prediction model was developed through univariate and multivariate logistic regression, with predictors including gender, age, body mass index (BMI), smoking, history of chronic lung diseases, respiratory symptoms, lesion size, lesion type, lesion location in the bronchi, and lesion location in the lobe. The predictive performance of the model was evaluated by validation using 1000 iterations of bootstrap resampling. Model discrimination was assessed using the area under the receiver operating characteristics curve (AUC), and calibration was assessed using the Brier score and calibration plots. (3) Results: The model suggested that male patients with respiratory symptoms, decreased BMI, solid lesions, and lesions located in lower-order bronchi were more likely to have positive FB findings. The AUC and Brier score of the model for internal validation were 0.784 and 0.162, respectively. The calibration curve for the probability of positive FB findings showed convincing concordance between the predicted and actual results. (4) Conclusions: Our prediction model estimated the pretest probability of positive FB findings in patients with peripheral lung cancers. Males and patients with lower BMI, the presence of respiratory symptoms, larger lesions, solid lesions, and lesions located in lower-order bronchi were associated with increased positive FB findings. The use of our model can be of assistance when making clinical decisions about preoperative FB.

Alectinib has been approved as first-line treatment for anaplastic lymphoma kinase (ALK)-positive non-small cell lung carcinoma. Oncologists are also exploring the possibility of applying alectinib in the perioperative period. Here, we present a patient with locally advanced lung adenocarcinoma associated with EML4-ALK fusion mutation, who received neoadjuvant chemotherapy and alectinib treatment, and then underwent thoracoscopic left lower lung lobectomy. The patient initially received eight chemotherapy cycles and achieved partial remission. After eight cycles of chemotherapy, the lymph nodes in the hilar region again enlarged. The patient was then switched to 4 months of alectinib therapy, but no significant lesion changes were detected on imaging during this period. This raised the question of whether the patient developed alectinib resistance. The pathological findings of the postoperative lung lobe specimens indicated extensive necrosis in the tumor area with no residual tumor cells and massive chronic inflammatory cell infiltration around the tumor area, confirming inconsistency between the imaging findings and pathological results. Multi-point tumor specimen sampling was postoperatively performed. Tumor immune-related gene expression was detected in the sample with the help of the PanCancer IO360™ panel based on the nCounter platform. This is a rare case of a patient who was treated with neoadjuvant alectinib and had paradoxical radiographic findings and pathological responses. The possibility that intratumoral immune heterogeneity was responsible for this phenomenon has been discussed. Based on the findings, it is argued that the pathological response should be an important basis for assessing the effectiveness of neoadjuvant alectinib therapy.

The analysis of drop formation and the transition between separated and non-separated oil–water flows enables us to better regulate flow parameters and pipe inclination angle, which is of great significance for improving the efficiency of oil transportation. Previous studies mainly carried out qualitative analysis through experiments and studied the transition between separated flows, very few studies are conducted on the transition between separated flow and dual continuous flow or intermittent flow. In addition, the influence of pipe inclination angle was not considered in the study of drop formation, which results in inadequate force analysis of drop. This article presents the use of dimensionless numbers to predict the transition between separated flow and dual continuous flow or intermittent flow. The relation expression between dimensionless numbers is obtained by regression of experimental data. The critical values of flow parameters and pipe inclination angle can be calculated by the relation expression between dimensionless numbers and flow parameters. In addition, this article proposes a three-dimensional interfacial wave shear deformation mechanism by adding volume forces to the force analysis for the possible inclined pipe. The prediction equation is obtained and the critical value of flow parameters and pipe inclination angle for drop formation can be calculated, which are in good agreement with the experimental data.

Augmentation of endogenous double-stranded RNA (dsRNA) has become a promising strategy for activating anti-tumor immunity through induction of type I interferon (IFN) in the treatment of ovarian carcinoma. However, the underlying regulatory mechanisms of dsRNA in ovarian carcinoma remain elusive. From The Cancer Genome Atlas (TCGA), we downloaded RNA expression profiles and clinical data of patients with ovarian carcinoma. Using the consensus clustering method, patients can be classified by their expression level of core interferon-stimulated genes (ISGs): IFN signatures high and IFN signatures low. The IFN signatures high group had a good prognosis. Gene set enrichment analysis (GSEA) showed that differentially expressed genes (DEGs) were primarily associated with anti-foreign immune responses. Based on results from protein-protein interaction (PPI) networks and survival analysis, ISG20 was identified as a key gene involved in host anti-tumor immune response. Further, elevated ISG20 expression in ovarian cancer cells led to increased IFN-β production. The elevated interferon improved the immunogenicity of tumor cells and generated chemokines that attract immune cells to infiltrate the area. Upon overexpression of ISG20, endogenous dsRNA accumulated in the cell and stimulated IFN-β production through the Retinoic acid-inducible gene I (RIG-I)-mediated dsRNA sense pathway. The accumulation of dsRNA was associated with the ribonuclease activity of ISG20. This study suggests that targeting ISG20 is a potential immune therapeutic approach to treat ovarian cancer.

Abstract Background We have looked at antimony (Sb) as a new neurotoxin which causes neuronal apoptosis in animal studies. At the population level, however, there is no direct evidence for a relationship between Sb exposure and cognitive performance. Method The study comprehensively assessed the correlation between urinary antimony levels and cognitive test scores in 631 creatinine-corrected older persons using data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. Results Using logistic regression, the study looked at the prevalence of cognitive impairment at different levels of urine antimony concentrations and found that, after controlling for covariates, higher doses of urinary antimony were positively associated with cognitive function compared to controls, odds ratio (ORs) with 95% confidence interval (CI) were 0.409 (0.185–0.906) and 0.402 (0.186–0.871) respectively. Restricted cubic spline curves showed a non-linear and dose-specific correlation between urinary antimony and cognitive performance, with lower doses associated with better cognitive performance, while higher doses may be associated with cognitive impairment. Conclusions Our data provide evidence for a correlation between Sb and cognitive function at the population level, although the specific mechanisms need to be investigated further.

Abstract Monoclonal antibodies are at the vanguard of the most promising cancer treatments. Whereas traditional therapeutic antibodies have been limited to extracellular antigens, T cell receptor mimic (TCRm) antibodies can target intracellular antigens presented by cell surface major histocompatibility complex (MHC) proteins. TCRm antibodies can therefore target a repertoire of otherwise undruggable cancer antigens. However, the consequences of off-target peptide/MHC recognition with engineered T cell therapies are severe, and thus there are significant safety concerns with TCRm antibodies. Here we explored the specificity and safety profile of a new TCRm-based T cell therapy for hepatocellular carcinoma (HCC), a solid tumor for which no effective treatment exists. We targeted an alpha-fetoprotein peptide presented by HLA-A*02 with a highly specific TCRm, which crystallographic structural analysis showed binds directly over the HLA protein and interfaces with the full length of the peptide. We fused the TCRm to the γ and δ subunits of a TCR, producing a signaling AbTCR construct. This was combined with an scFv/CD28 co-stimulatory molecule targeting glypican-3 for increased efficacy towards tumor cells. This AbTCR + co-stimulatory T cell therapy showed potent activity against AFP-positive cancer cell lines in vitro and an in an in vivo model and undetectable activity against AFP-negative cells. In an in-human safety assessment, no significant adverse events or cytokine release syndrome were observed and evidence of efficacy was seen. Remarkably, one patient with metastatic HCC achieved a complete remission after nine months and ultimately qualified for a liver transplant.

Abstract Background Chronic obstructive pulmonary disease (COPD) is a prevalent, progressive respiratory disease, and acute exacerbations of COPD (AECOPD) can accelerate the deterioration of the disease. Increasing evidence suggests that airway bacterial dysbiosis is associated with AECOPD. However, the exact relationship between changes in the sputum microbiome during AECOPD and clinical indices remains unclear. Methods In this study, a total of 76 sputum samples were collected from patients with AECOPD (n = 28), stable COPD (n = 23), recovery (n = 15) and healthy controls (HCs; n = 10). The sputum microbiome profile was analysed by sequencing the V3‑V4 amplicon of the 16S rRNA (ribosomal RNA) gene. Results The bacterial diversity (Shannon and Simpson’s index) was found to be significantly decreased in the AECOPD and recovery groups when compared to that in the stable COPD and HC groups. The most dominant phylum identified in the sputum samples of AECOPD patients was Proteobacteria, accounting for 30% of the microbiome. Compared to the stable COPD groups, the relative abundances of Firmicutes and Bacteroidetes were decreased, whereas those of Proteobacteria and Actinobacteria were increased in AECOPD patients. Furthermore, discriminative bacteria, such as Haemophilus, were identified as being specific taxa in AECOPD patients. Functional analysis showed that genes involved in membrane transport and signal transduction metabolism were enriched in the AECOPD group. Importantly, the proportions of Veillonella were positively correlated with lung function, and Staphylococcus was positively correlated with inflammatory indices. Conclusion Our study revealed variations in the sputum microbiome of AECOPD (based on composition and function) in a Chinese cohort and highlighted its correlation to clinical indices. These results indicated that microbial dysbiosis may contribute to disease progression and provide microbial biomarkers for the diagnosis of AECOPD.

Abstract Background Largely due to incidental detection, asymptomatic pancreatic cystic lesions (PCLs) have become prevalent in recent years. Among them, intraductal papillary mucinous neoplasm (IPMN) infrequently advances to pancreatic ductal adenocarcinoma (PDAC). Conservative surveillance versus surgical intervention is a difficult clinical decision for both caregivers and PCL patients. Because RNF43 loss‐of‐function mutations and KRAS gain‐of‐function mutations concur in a subset of IPMN and PDAC, their biological significance and therapeutic potential should be elucidated. Methods Pancreatic Rnf43 knockout and Kras activated mice (Rnf43−/−; KrasG12D) were generated to evaluate their clinical significance in pancreatic pre‐neoplastic initiation and malignant transformation. Results Loss of Rnf43 potentiated the occurrence and severity of IPMN and PDAC in oncogenic Kras mice. The Wnt/β‐catenin signaling pathway was activated in pancreatic KrasG12D and Rnf43 knockout mice and the PORCN inhibitor LGK974 blocked pancreatic IPMN initiation and progression to PDAC accordingly. Conclusions Rnf43 is a tumor suppressor in the prevention of pancreatic malignant transformation. This genetically reconstituted autochthonous pancreatic Rnf43−/−; KrasG12D preclinical cancer model recapitulates the pathological process from pancreatic cyst to cancer in humans and can be treated with inhibitors of Wnt/β‐catenin signaling. Since the presence of RNF43 and KRAS mutations in IPMNs predicts future development of advanced neoplasia from PCLs, patients with these genetic anomalies warrant surveillance, surgery, and/or targeted therapeutics such as Wnt/β‐catenin inhibitors.

Background & Aims: Hepatic fibrosis is characterized by hepatic stellate cell (HSC) activation and transdifferentiation-mediated extracellular matrix (ECM) deposition, which both contribute to cirrhosis. However, no antifibrotic regimen is available in the clinic. microRNA-23b/27b/24-1 cluster inhibition of transforming growth factor-β (TGF-β) signaling during hepatic development prompted us to explore whether this cluster inhibits HSC activation and hepatic fibrosis. Methods: Experimental fibrosis was studied in carbon tetrachloride (CCl4)-treated C57BL/6 mice. After administration of miR-23b/27b/24-1 lentivirus or vehicle, animals were euthanized for liver histology. In primary rat HSC and HSC-T6, the anti-fibrotic effect of miR-23b/27b/24-1 cluster was furtherly investigated by RNA-sequencing, luciferase reporter assay, western blotting and bioinformatic means. Results: In this study, we showed that increasing the miR-23b/27b/24-1 level through intravenous delivery of miR-23b/27b/24-1 lentivirus ameliorated mouse hepatic fibrosis. Mechanistically, the miR-23b/27b/24-1 cluster directly targeted messenger RNAs, which reduced the protein expression of 5 secretory profibrotic genes (TGF-β2, Gremlin1, LOX, Itgα2, and Itgα5) in HSCs. Suppression of the TGF-β signaling pathway by down-regulation of TGF-β2, Itgα2, and Itgα5, and activation of the bone morphogenetic protein signaling pathway by inhibition of Gremlin1, decreased extracellular matrix secretion of HSCs. Furthermore, down-regulation of LOX expression softened the ECM. Moreover, a reduction in tissue inhibitors of metalloproteinase 1 expression owing to weakened TGF-β signaling increased ECM degradation. Conclusions: Hepatic overexpression of the miR-23b/27b/24-1 cluster blocked hepatic fibrosis and may be a novel therapeutic regimen for patients with hepatic fibrosis.

Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance, preventing autoimmune responses, and minimizing tissue damage by regulating the duration and intensity of the immune response. Furthermore, immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor response. Based on substantial physiological analyses as well as preclinical and clinical studies, checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of cancers. In the last few years, extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines (TCMs). The main advantage of TCMs and natural medicine is that they usually contain multiple active components, which can act on multiple targets at the same time, resulting in additive or synergistic effects. The strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great interest. For example, Astragalus membranaceus polysaccharides can induce anti-PD-1 antibody responses in animals, and these antibodies can overcome the exhaustion of immune cells under tumor immune evasion. Furthermore, many other TCM molecules could also be novel and effective drug candidates for the treatment of cancers. Therefore, it is essential to assess the application of immune checkpoints in the development of new drugs and TCMs. In this review, we focus on research progress in the field of immune checkpoints based on three topics: (1) immune checkpoint targets and pathways, (2) development of novel immune checkpoint-based drugs, and (3) application of immune checkpoints in the development of TCMs.

BackgroundEpidemiological evidence on Urine metals and cognitive impairment in older individuals is sparse and limited. The goal of this study was to analyze if there was a link between urinary metal levels and cognitive performance in U.S. people aged 60 and up.MethodsThe National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2014 were utilized in this cross-sectional analysis. Memory function was quantified using the following methods: Established Consortium for Word Learning in Alzheimer's Disease (CERAD-WL) (immediate learning and recall and delayed recall), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). An inductively coupled plasma mass spectrometry (ICP-MS) was used to estimate urine metal concentrations. The connection of Urine metals level with cognitive function was investigated employing binary logistic regression and restricted cubic spline models.ResultsA total of 840 participants aged 60 years and over were enrolled in this study. After controlling for confounders, the association between cadmium, barium, cobalt, cesium, manganese, and thallium and poor cognitive performance showed significance in multiple logistic regression compared to the lowest quartile of metals. In the DSST test, the weighted multivariate adjusted ORs (95% CI) for cadmium in the highest quartile, barium and cesium in the third quartile were 2.444 (1.310–4.560), 0.412 (0.180–0.942) and 0.440 (0.198–0.979), respectively. There were L-shaped associations between urine cesium, barium, or manganese and low cognitive performance in DSST. Urine lead, molybdenum and uranium did not show any significant relationships with cognitive impairment, respectively, compared to the respective lowest quartile concentrations.ConclusionThe levels of barium (Ba), cobalt (Co), cesium (Cs), manganese (Mn), and thallium (Tl) in urine were found to be negatively related to the prevalence of impaired cognitive performance in our cross-sectional investigation. Higher cadmium (Cd) levels were associated with cognitive impairment.

Defect detection of track fasteners is a prerequisite for safe and reliable railroad operation. The traditional manual visual inspection method has been unable to meet the growing demand for railroad network inspection in China. To achieve the need for accurate, fast, and intelligent detection of rail fasteners, this paper proposes a rail fastener defect detection model based on improved YOLOv5s. Firstly, the convolutional block attention module (CBAM) is added to the Neck network of the YOLOv5s model to enhance the extraction of essential features by the model and suppress the information of minor features. Secondly, a weighted bidirectional feature pyramid network (BiFPN) is introduced to realize the multi-scale feature fusion of the model. Finally, the K-means++ algorithm is used to re-cluster the dataset to obtain the anchor box suitable for the fastener dataset and improve the positioning ability of the model. The experimental results show that the improved model achieves an average mean precision (mAP) of 97.4%, a detection speed of 27.3 FPS, and a model memory occupancy of 15.5 M. Compared with the existing target detection model, the improved model has the advantages of high detection accuracy, fast detection speed, and small model memory occupation, which can provide technical support for edge deployment of rail fastener defect detection.

Abstract Background The echinoderm microtubule-associated protein-like-4 anaplastic lymphoma kinase (EML4-ALK) fusion gene was identified in a subset of non-small cell lung cancer (NSCLC) patients. They responded positively to ALK inhibitors. This study aimed to characterize the mechanisms triggered by EML4-ALK to induce NSCLC transformation. Methods HEK293 and NIH3T3 cells were transfected with EML4-ALK variant 3 or pcDNA3.1-NC. H2228 cells were transfected with siRNA-EML4-ALK or siRNA-NC. Cell viability and proliferation were measured by the CCK-8 and EdU methods, respectively. Flow cytometry revealed apoptosis. Gene expression profiles were generated from a signaling pathway screen in EML4-ALK-regulated lung cancer cells and verified by qPCR and Western blotting. The co-immunoprecipitation and immunohistochemistry/ immunofluorescence determined the interaction and colocalization of JAK2-STAT pathway components with EML4-ALK. Results Microarray identified several genes involved in the JAK2-STAT pathway. JAK2 and STAT6 were constitutively phosphorylated in H2228 cells. EML4-ALK silencing downregulated phosphorylation of STAT6. Expression of EML4-ALK in HEK293 and NIH3T3 cells activated JAK2, STAT1, STAT3, STAT5, and STAT6. In EML4-ALK-transfected HEK293 cells and EML4-ALK-positive H2228 cells, activated STAT6 and JAK2 colocalized with ALK. STAT3 and STAT6 were phosphorylated and translocated to the nucleus of H2228 cells following IL4 or IL6 treatment. Apoptosis increased, while cell proliferation and DNA replication decreased in H2228 cells following EML4-ALK knockdown. In contrast, HEK293 cell viability increased following EML4-ALK overexpression, while H2228 cell viability significantly decreased after treatment with ALK or JAK-STAT pathway inhibitors. Conclusions Our data suggest that the aberrant expression of EML4-ALK leads to JAK2-STAT signaling pathway activation, which is essential for the development of non-small cell lung cancer.

Abstract Intestinal epithelium serves as the first barrier against the infections and injuries that mediate colonic inflammation. Colorectal cancer is often accompanied with chronic inflammation. Differed from its well-known oncogenic role in many malignancies, we present here that Golgi membrane protein 1 (GOLM1, also referred to as GP73) suppresses colorectal tumorigenesis via maintenance of intestinal epithelial barrier. GOLM1 deficiency in mice conferred susceptibility to mucosal inflammation and colitis-induced epithelial damage, which consequently promoted colon cancer. Mechanistically, depletion of GOLM1 in intestinal epithelial cells (IECs) led to aberrant Notch activation that interfered with IEC differentiation, maturation, and lineage commitment in mice. Pharmacological inhibition of Notch pathway alleviated epithelial lesions and restrained pro-tumorigenic inflammation in GOLM1-deficient mice. Therefore, GOLM1 maintains IEC homeostasis and protects against colitis and colon tumorigenesis by modulating the equilibrium of Notch signaling pathway.

Abstract Background With the ongoing development of targeted therapy and immunotherapy in recent years, the overall five‐year survival rate of NSCLC patients has not improved, and the search for novel diagnostic and prognostic markers for lung adenocarcinoma continues. Methods Lung adenocarcinoma (LUAD) gene expression data and relevant clinical information were obtained from the TCGA. Hub genes were identified with weighted gene co‐expression network analysis (WGCNA) and protein–protein interaction network (PPI). Survival analyses were also performed using GEPIA. The 536 LUAD patients were divided into two groups according to the SPRR1B expression level and analyzed by gene set enrichment analysis (GSEA) and verified by immunoblotting. The effects of SPRR1B on cell proliferation and cell metastasis and apoptosis were evaluated by 5‐ethynyl‐2′‐deoxyuridine (EdU) staining, colony formation assay, transwell migration and invasion assay, and flow cytometry, respectively. Results A total of 2269 DEGs were analyzed by WGCNA and five hub genes (CCK, FETUB, PCSK9, SPRR1B, and SPRR2D) were identified. Among them, SPRR1B was selected as one of the most significant prognostic genes in LUAD. SPRR1B was found to be highly expressed in lung adenocarcinoma cells compared with that in normal bronchial epithelial cells. In addition, silencing of SPRR1B could inhibit the cell proliferation, invasion, and migration of lung adenocarcinoma cells, but induced cell apoptosis and G2/M phase arrest in vitro. The result of GSEA and immunoblotting revealed that SPRR1B activated the MAPK signaling pathway involved in the proliferation and metastasis of lung cancer. Conclusions Our findings demonstrate that SPRR1B may function as a prognosis predictor in lung adenocarcinoma.

Abstract Background Lung cancer, mainly non‐small cell lung cancer (NSCLC), is one of the leading causes of death worldwide. Currently, chemotherapy is still the most significant treatment strategy for NSCLC. However, scant attention has been paid in previous studies to those patients who often experience various symptoms and discomfort during chemotherapy treatment cycles. Methods This study included 127 NSCLC patients who completed an EORTC QLQ‐C30 questionnaire and specifically designed symptom diary. Chi‐square test, factor analysis, Pearson correlation coefficient and hierarchical cluster analysis were used to perform multivariate analysis. Results We identified the top five most‐frequent symptoms within the chemotherapy cycle which included fatigue, insomnia, cough and sputum, appetite loss and hypodipsia. These symptoms were at a moderate level on chemotherapy treatment days 3–7, and were then reduced to a stable and lower level in the following two weeks. A statistically significant difference in adverse events (AEs) was found between 54 patients who received dexamethasone (treatment group) and the control group: fatigue (risk ratio [RR]: 1.48; 95% confidence interval [CI]: 1.120–1.961; p = 0.006), insomnia (RR: 1.34; 95% CI: 1.016–1.778; p = 0.038), cough and sputum (RR: 2.00; 95% CI: 1.484–2.695; p

Abstract Rosacea is a chronic inflammatory skin disorder whose pathogenesis is unclear. Here, several lines of evidence were provided to demonstrate that mTORC1 signaling is hyperactivated in the skin, especially in the epidermis, of both rosacea patients and a mouse model of rosacea‐like skin inflammation. Both mTORC1 deletion in epithelium and inhibition by its specific inhibitors can block the development of rosacea‐like skin inflammation in LL37‐induced rosacea‐like mouse model. Conversely, hyperactivation of mTORC1 signaling aggravated rosacea‐like features. Mechanistically, mTORC1 regulates cathelicidin through a positive feedback loop, in which cathelicidin LL37 activates mTORC1 signaling by binding to Toll‐like receptor 2 (TLR2) and thus in turn increases the expression of cathelicidin itself in keratinocytes. Moreover, excess cathelicidin LL37 induces both NF‐κB activation and disease‐characteristic cytokine and chemokine production possibly via mTORC1 signaling. Topical application of rapamycin improved clinical symptoms in rosacea patients, suggesting mTORC1 inhibition can serve as a novel therapeutic avenue for rosacea.

Abstract As evidenced by the behavior of loss-of-function mutants of PTEN in the context of a gain-of-function mutation of AKT1, the PTEN-AKT1 signaling pathway plays a critical role in human cancers. In this study, we demonstrated that a deficiency in PTEN or activation of AKT1 potentiated the expression of platelet-derived growth factor receptor α (PDGFRα) based on studies on Pten−/− mouse embryonic fibroblasts, human cancer cell lines, the hepatic tissues of Pten conditional knockout mice, and human cancer tissues. Loss of PTEN enhanced PDGFRα expression via activation of the AKT1-CREB signaling cascade. CREB transactivated PDGFRα expression by direct binding of the promoter of the PDGFRα gene. Depletion of PDGFRα attenuated the tumorigenicity of Pten-null cells in nude mice. Moreover, the PI3K-AKT signaling pathway has been shown to positively correlate with PDGFRα expression in multiple cancers. Augmented PDGFRα was associated with poor survival of cancer patients. Lastly, combination treatment with the AKT inhibitor MK-2206 and the PDGFR inhibitor CP-673451 displayed synergistic anti-tumor effects. Therefore, activation of the AKT1-CREB-PDGFRα signaling pathway contributes to the tumor growth induced by PTEN deficiency and should be targeted for cancer treatment.

Abstract To evaluate the repeatability of Corvis ST corneal biomechanical, tonometry and pachymetry measurements, and agreement of pachymetry measures with the Pentacam HR and RTVue OCT. Three consecutive measurements of the right eye of 238 myopic subjects were acquired with the Corvis ST, Pentacam HR, and RTVue OCT. Repeatability of Corvis ST was evaluated by within-subject standard deviation [Sw] and repeatability limit [r]. The agreement of central corneal thickness (CCT) measurements were compared among the three instruments using the Bland–Altman limits of agreement. Comparisons were further stratified by CCT (Corneathin ≤ 500 µm; Corneanormal = 500–550 µm; Corneathick > 550 µm). Sw was below 1 mmHg in Corneathin, Corneanormal, and Corneathick groups for IOP and bIOP. Sw for SP-A1 were 4.880, 6.128, 7.719 mmHg/mm respectively. Sw for CBI were 0.228, 0.157, 0.076, and correspondingly Sw for TBI and SSI were 0.094 and 0.056, 0.079 and 0.053, 0.070 and 0.053. The Bland–Altman plots for CCT implied poor agreement with mean differences of 29.49 µm between Corvis and OCT, 9.33 µm between Pentacam and OCT, and 20.16 µm between Corvis and Pentacam. The Corvis ST showed good repeatability with the exception of CBI in the various CCT groups. The CCT measured by Corvis ST was not interchangeable with Pentacam HR and RTVue OCT.

Abstract Background Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells. Methods The RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting. Results EZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo. Conclusions These data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy.

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread from the early epicenter, Wuhan, to the rest of China, the virulence of SARS-CoV-2 might have evolved at different phases of the pandemic. We therefore compared the unique features among 62 coronavirus disease 2019 (COVID-19) inpatients who contracted SARS-CoV-2 in Wuhan (15 cases), exposed to the patients from Wuhan (26 cases), or acquired the disease without exposure to Wuhan patients (21 cases). Median incubation periods are 4.5 days (3–5) for Wuhan patients, 8 days (3–11) for those infected by Wuhan patients, and 12 days (7–13) for those without aforementioned experience. The disease onset dates are earliest for Wuhan patients and latest for those without exposure to Wuhan patients. Blood lymphocytes were lowest in Wuhan patients, lower in those affected by Wuhan patients, and modest reduced in remaining ones. Disease severity is worst for Wuhan patients, and modest for those without contact with Wuhan patients. Wuhan patients had longest (27 days, 18–28), those transmitted by Wuhan patients had intermediate (16 days, 8–23), and the rest of the patients had shortest (13 days, 8.5–22.5) hospital stay. Early viral exposure, older age, lymphocytopenia, and underlying conditions are risk factors which warrant aggressive intervention. Even though the virulence of SARS-CoV-2 appears decline over the course of serial transmissions, viral testing, contact tracing, social distancing, and face masking should be imposed on general public to contain viral dissemination from both symptomatic and asymptomatic patients with this highly contagious disease.