Outcomes in non-small cell lung cancer with uncommon epidermal growth factor receptor L858 substitutions under first-line epidermal growth factor receptor tyrosine kinase inhibitors: A large real-world cohort study.

Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFRL858R mutation caused by c.2573 T > G, have been identified in non-small cell lung cancer (NSCLC), yet their genomic features and survival benefits with EGFR tyrosine kinase inhibitor (TKI) treatment have not been fully explored. We retrospectively enrolled 489 NSCLC patients with baseline tumor tissue/plasma samples carrying uncommon EGFRL858R (N = 124), EGFRL858Q/M (N = 17), or classical EGFRL858R mutations (N = 348). The comparison of molecular features was performed using treatment-naïve tumor tissues. Survival benefits and resistance mechanisms of first-line EGFR TKI treatment were studied in an advanced disease subcohort. NSCLCs harboring uncommon EGFRL858R had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFRL858R. Concomitant EGFRL861Q mutations were enriched in NSCLCs with EGFRL858Q/M (p < 0.01), with cooccurrence in those carrying EGFRL858M. Patients with uncommon EGFRL858R experienced improved progression-free survival (PFS) compared to those with classical EGFRL858R (median: 13.0 vs. 10.0 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.41-0.80). The association remained significant when adjusting for sex, age, histological subtype, TKI category, and anti-vascular therapy (HR: 0.55, 95% CI: 0.39-0.77). Furthermore, EGFRL858Q/M patients showed enhanced first-line PFS (vs. classical EGFRL858R, HR: 0.26, 95% CI: 0.10-0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFRL858R and classical EGFRL858R had similar resistance profiles to EGFR TKIs. In conclusion, NSCLCs carrying atypical EGFR L858 aberrations, which had fewer TP53 mutations and higher chromosome stability, exhibited improved PFS under first-line EGFR TKIs than those with the classical EGFRL858R.

Tumor Customized 2D Supramolecular Nanodiscs for Ultralong Tumor Retention and Precise Photothermal Therapy of Highly Heterogeneous Cancers.

Target therapy for highly heterogeneous cancers represents a major clinical challenge due to the lack of recurrent therapeutic targets identified in these tumors. Herein, the authors report a tumor-customized targeting photothermal therapy (PTT) strategy for highly heterogeneous cancers, by which 2D supramolecular self-assembled nanodiscs are modified with tumor-specific binding peptides identified by phage display techniques. Taking osteosarcoma (OS) as a model heterogeneous cancer, an OS targeting peptide (OTP) is first selected after biopanning and is demonstrated to successfully bind to this heterogeneous cancer cells/tissues. Successful conjugation of OTP to heptamethine cyanine (Cy7)-based 2D nanodiscs Cy7-TCF (2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran,TCF) enables the 2D nanodiscs to specifically target the heterogeneous tumor. Notably, a single dose injection of this targeted nanodisc (T-ND) not only effectively induces enhanced photothermal tumor ablation under near-infrared light, but also exhibits sevenfold increase of tumor retention time (more than 24 days) compared to generic nanomedicine. Thus, the authors' findings suggest that the combination of phage display-based affinity peptides selection and 2D supramolecular nanodiscs leads to the development of a platform technology for highly heterogeneous cancers precise therapy, offering specific tumor targeting, ultralong tumor retention, and precise PTT.

MicroRNA-133a alleviates airway remodeling in asthtama through PI3K/AKT/mTOR signaling pathway by targeting IGF1R.

Asthma is characterized by chronic inflammation, and long-term chronic inflammation leads to airway remodeling. But the potential regulatory mechanism of airway remodeling is not clearly understood, and there is still no effective way to prevent airway remodeling. Present studies have confirmed the role of microRNAs (miRNAs) in the development of disease, which is known as suppressing translation or degradation of messenger RNA (mRNA) at the posttranscriptional stage. In this study, we described the role of miRNA-133a in asthma and demonstrated it in regulating airway remodeling of asthma through the phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway by targeting IGF-1 receptor (IGF1R). IGF1R helps in mediating the intracellular signaling cascades. Asthmatic mice models were established by sensitization and Ovalbumin challenge. Adenovirus transfer vector carrying miR-133a or miR-133a sponge sequence was used to build the overexpression or downexpression of miR-133a modeling. Real-time polymerase chain reaction and Western blot were used to determine the alterations in the expression of miR-133a and mRNAs and their corresponding proteins. Results showed that miR-133a was downregulated in asthma. Upregulation of miR-133a expression in airway smooth muscle cells in vivo and in vitro could inhibit the activation of PI3K/AKT/mTOR pathway, and reduce the expression of α-smooth muscle actin (α-SMA), indicating that airway remodeling was inhibited. Functional studies based on luciferase reporter revealed miR-133a as a direct target of IGF1R mRNA. In conclusion, these data suggested that miR-133a regulated the expression of α-SMA through PI3K/AKT/mTOR signaling by targeting IGF1R. miR-133a plays a key role in airway remodeling of asthma and may serve as a potential therapeutic target for managing asthmatic airway remodeling.

A Delta-radiomics model for preoperative evaluation of Neoadjuvant chemotherapy response in high-grade osteosarcoma.

BACKGROUND: The difficulty of assessment of neoadjuvant chemotherapeutic response preoperatively may hinder personalized-medicine strategies that depend on the results from pathological examination. METHODS: A total of 191 patients with high-grade osteosarcoma (HOS) were enrolled retrospectively from November 2013 to November 2017 and received neoadjuvant chemotherapy (NCT). A cutoff time of November 2016 was used to divide the training set and validation set. All patients underwent diagnostic CTs before and after chemotherapy. By quantifying the tumor regions on the CT images before and after NCT, 540 delta-radiomic features were calculated. The interclass correlation coefficients for segmentations of inter/intra-observers and feature pair-wise correlation coefficients (Pearson) were used for robust feature selection. A delta-radiomics signature was constructed using the lasso algorithm based on the training set. Radiomics signatures built from single-phase CT were constructed for comparison purpose. A radiomics nomogram was then developed from the multivariate logistic regression model by combining independent clinical factors and the delta-radiomics signature. The prediction performance was assessed using area under the ROC curve (AUC), calibration curves and decision curve analysis (DCA). RESULTS: The delta-radiomics signature showed higher AUC than single-CT based radiomics signatures in both training and validation cohorts. The delta-radiomics signature, consisting of 8 selected features, showed significant differences between the pathologic good response (pGR) (necrosis fraction ≥90%) group and the non-pGR (necrosis fraction < 90%) group (P < 0.0001, in both training and validation sets). The delta-radiomics nomogram, which consisted of the delta-radiomics signature and new pulmonary metastasis during chemotherapy showed good calibration and great discrimination capacity with AUC 0.871 (95% CI, 0.804 to 0.923) in the training cohort, and 0.843 (95% CI, 0.718 to 0.927) in the validation cohort. The DCA confirmed the clinical utility of the radiomics model. CONCLUSION: The delta-radiomics nomogram incorporating the radiomics signature and clinical factors in this study could be used for individualized pathologic response evaluation after chemotherapy preoperatively and help tailor appropriate chemotherapy and further treatment plans.

Lipoxin A4 reduces hyperoxia-induced lung injury in neonatal rats through PINK1 signaling pathway.

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants and is mainly caused by hyperoxia exposure and mechanical ventilation. Alveolar simplification, pulmonary vascular abnormalities and pulmonary inflammation are the main pathological changes in hyperoxic lung injury animals. Lipoxin A4 (LXA4) is an important endogenous lipid that can mediate the regression of inflammation and plays a role in acute lung injury and asthma. The purpose of this study was to evaluate the effects of LXA4 on inflammation and lung function in neonatal rats with hyperoxic lung injury and to explore the mechanism of the PINK1 pathway. After 85% oxygen exposure in newborn rats for 7 days, the BPD model was established. We found that LXA4 could significantly reduce cell and protein infiltration and oxidative stress in rat lungs, improve pulmonary function and alveolar simplification, and promote weight gain. LXA4 inhibited the expression of TNF-α, MCP-1 and IL-1ß in serum and BALF from hyperoxic rats. Moreover, we found that LXA4 could reduce the expression of the PINK1 gene and down-regulate the expression of PINK1, Parkin, BNIP3L/Nix and the autophagic protein LC3B.These protective effects of LXA4 could be partially reversed by addition of BOC-2.Thus, we concluded that LXA4 can alleviate the airway inflammatory response, reduce the severity of lung injury and improve lung function in a hyperoxic rat model of BPD partly through the PINK1 signaling pathway.

Expression Levels of Predominant Adipokines and Activations of STAT3, STAT6 in an Experimental Mice Model of Obese Asthma.

Obese asthma is a new asthma phenotype. The underlying mechanisms are not clearly understood. Leptin and adiponectin are two predominant adipokines produced by adipose tissue. Studies have demonstrated a role of leptin on regulating the Janus kinase/signal transducer and ativator of transcription protein (JAK/STAT) signaling pathway and STAT3, STAT6 were known to have essential role on inflammatory cytokines production. However, whether STAT3 and STAT6 are activated and related to leptin merit further investigation. The aim of this study was to investigate the expression levels of leptin/adiponectin ratio and the activations of STAT3 and STAT6 in the lungs of obese asthma mice. Experiments were carried out on male C57/B6J mice. The proteins in bronchoalveolar lavage fluid (BALF) were measured using ELISA. The expression levels of the transcriptional and translational factors in the lungs were examined using Quantitative Reverse Transcriptase Polymerase Chain reaction (qRT-PCR) and western blot. The expression levels of leptin in the BALF of normal weight group, asthma group, obese group and obese asthma group were 2.032±0.133, 5.375±0.123, 5.418±0.165 and 7.486±0.168, respectively. The expression of leptin in obese asthma group was the highest (p<0.05) ，while the expression of adiponectin the lowest (p<0.05). The expression level of P-STAT3 in the obese asthma group was 0.9244±0.014, and was significantly higher than three other groups (p<0.05). The expressions of P-STAT6 in three other groups were all significantly higher than normal weight group (p<0.05). Our data suggest that the function of leptin on the pulmonary inflammation of obese asthma may be partly through activating the STAT3 signaling pathway.

High-fat-diet induces airway hyperresponsiveness partly through activating CD38 signaling pathway.

CD38 is a plasma membrane bound multifunctional enzyme. It can be activated by inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-13, inducing calcium responses to agonist in airway smooth muscle cells (ASMC). Previous studies have found that high-fat-diet (HFD) induced obesity exhibited innate airway hyperresponsiveness (AHR). This study aimed to detect the effect of CD38 signaling pathway on the AHR of overweight/obese mice. The HFD-fed mice exhibited a significantly higher baseline airway resistance (Rn), and the increasing rates of Rn responded to increasing doses of methacholine compared with the LFD-fed mice. High-fat-diet increased CD38 expressions both in lung tissues and primary cultured ASMCs. Besides, preincubation with TNF-α led to a higher expression of CD38 protein and increased intracellular calcium in ASMC of the HFD-fed mice. Furthermore, CD38 gene knockdown through transfection of CD38 siRNA decreased the concentration of intracellular calcium. Additionally, the upregulations of CD38 protein and CD38 mRNA were also found in the lung tissues of HFD-fed mice challenged by ovalbumin (OVA). Collectively, our findings demonstrated a role of CD38 signaling pathway on the AHR of obesity and might be a potential therapeutic target for treating difficult-to-control obese asthma phenotype.

Pelvic reconstruction with different rod-screw systems following Enneking type I/I + IV resection: a clinical study.

The mechanical outcomes of patients with pelvic bone tumors involving zone I or zone I + IV who received resection and different reconstructions are not clear. Therefore, the purpose of this study was to compare the outcomes of different rod-screw systems in reconstruction for these patients, and evaluate the relative risk of mechanical failure for them. We reviewed 30 patients for a mean duration of 40.4 months of follow-up (range, 13.1-162.2 months), five patients had mechanical complications. The mechanical survival rate of two-rod and four-screw (TRFS) group was significantly higher than one-rod and two-screw (ORTS) group (p = 0.000). The implant survival rate was correlated with ages (p = 0.010), younger people are more likely to fail. Thus, TRFS fixation for pelvic reconstruction after Enneking type I/I + IV resection can provide better short to long-term mechanical stability compared with ORTS fixation, the strength of ORTS fixation is not enough. In addition, biological reconstruction such as autologous bone graft is recommended for the patients who are younger or suffered from benign tumor. As for the patients who are older, with malignant tumors, underwent adjuvant radiotherapy or chemotherapy, functional reconstruction with bone cement is a good choice.