Multimodal fusion of liquid biopsy and CT enhances differential diagnosis of early-stage lung adenocarcinoma.

This research explores the potential of multimodal fusion for the differential diagnosis of early-stage lung adenocarcinoma (LUAD) (tumor sizes < 2 cm). It combines liquid biopsy biomarkers, specifically extracellular vesicle long RNA (evlRNA) and the computed tomography (CT) attributes. The fusion model achieves an impressive area under receiver operating characteristic curve (AUC) of 91.9% for the four-classification of adenocarcinoma, along with a benign-malignant AUC of 94.8% (sensitivity: 89.1%, specificity: 94.3%). These outcomes outperform the diagnostic capabilities of the single-modal models and human experts. A comprehensive SHapley Additive exPlanations (SHAP) is provided to offer deep insights into model predictions. Our findings reveal the complementary interplay between evlRNA and image-based characteristics, underscoring the significance of integrating diverse modalities in diagnosing early-stage LUAD.

Safety and effects of a home-based Tai Chi exercise rehabilitation program in patients with chronic heart failure: study protocol for a randomized controlled trial.

Introduction: Chronic heart failure (CHF), as the final stage of the progression of many cardiovascular disorders, is one of the main causes of hospitalization and death in the elderly and has a substantial impact on patients' quality of life (QOL). Exercise-based cardiac rehabilitation (CR) has been shown to considerably enhance QOL and prognosis. Given the barriers to center-based CR faced by most developing countries in the form of expensive instruments, the development of home-based CR is necessary. Tai Chi, as an instrument-free exercise, has been shown to be successful in treating elderly CHF individuals. Fu Yang, as one of the academic concept of Traditional Chinese Medicine (TCM), believes that the fundamental pathogenesis of CHF is the gradual decline of Yang, and emphasizes the restoration of Yang physiological function in the treatment process. Therefore, we develope a home-based Tai Chi exercise rehabilitation program called Fu Yang Tai Chi (FYTC) for elderly CHF patients by combining the Fu Yang Theory of TCM with the CR theory. The objective of this study is to evaluate the effectiveness, acceptability, and safety of the program. Methods and analysis: We suggest conducting a parallel randomized controlled clinical trial with open label. Eighty CHF elderly participants will be randomly assigned in a 1:1 ratio to the FYTC rehabilitation program group or the moderate-intensity aerobic walking control group. Eligible participants will engage in either three sessions weekly of FYTC or walking exercise for 12 weeks. The primary outcome is the relative change in 6 min walk distance (6MWD). The secondary outcomes are the plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), QOL, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDd), self-rating anxiety scale (SAS) and depression scale (SDS), exercise skills, and noninvasive hemodynamic monitoring. Throughout the trial, adverse events will be recorded for safety evaluation. Researchers who are blinded to the treatment allocation will analyze the data. Ethics and dissemination: This research was authorized by the Guang'anmen Hospital Ethics Committee of the Chinese Academy of Medical Sciences (2022-141-KY). Our findings will be shared online and in academic conferences as well as in peer-reviewed journals. Trial registration number: ChiCTR2200063511.

PEG2000-PLA-based nanoscale polymeric micelles reduce paclitaxel-related toxicity in beagle dogs.

Nanoplatform-based drug delivery plays an important role in clinical practice. Polymeric micellar (Pm) nanocarriers have been demonstrated to reduce the toxicity of paclitaxel in rats and non-small cell lung cancer (NSCLC) patients. However, the underlying toxicological profile needs to be further illustrated. Here, we used beagles as study subjects and sought to further observe the toxicological profile of polymeric micellar paclitaxel (Pm-Pac) via acute toxicity tests and short-term and long-term toxicity tests. The results from the acute toxicity test indicated that the lethal dose of Pm-Pac in beagles was 20-30 mg/kg, and the acute toxicity-targeted organs were the digestive system and immuno-haematopoietic system. The short-term toxicity test suggested that paclitaxel-induced toxicity (peripheral neuropathy toxicity, haemopoietic toxicity, heart system toxicity, and so on) in beagles can be reduced when paclitaxel is delivered via the Pm delivery system. The long-term toxicity test suggested that Pm-Pac can reduce haemopoietic toxicity in beagles. Collectively, this study provides novel insight into the toxicological profile of Pm-Pac in healthy beagles and provides a potential basis for promising clinical combination strategies in the future.

Efficacy of ICI-based treatment in advanced NSCLC patients with PD-L1≥50% who developed EGFR-TKI resistance.

Introduction: Platinum-based chemotherapy is still the standard of care for Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients after developing EGFR-TKI resistance. However, no study focusing on the role of immuno checkpoint inhibitor (ICI) based treatments for EGFR mutated NSCLC patients who carried programmed death ligand 1 (PD-L1) tumor proportion score (TPS) greater than 50% progressed after EGFR-TKI therapy. In this study, we retrospectively investigated the outcomes of ICI-based treatments for EGFR mutated NSCLC patients carried PD-L1 TPS≥50% after developing EGFR-TKI resistance and to explore the population that may benefited from ICI-based treatment. Methods: We retrospectively collected data of advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation at Shanghai Chest Hospital between January 2018 and June 2021. Progression-free survival (PFS) and overall survival (OS) were utilized to evaluate the outcomes of this study. Results: A total of 146 patients were included. Up to June 20th, 2022, median follow-up was 36.7 months (IQR, 12.5-44.2 months). Among the population, 66 patients (45.2%) received chemotherapy, the remaning (54.8%) received ICI-based treatment, including 56 patients(70.0%) received ICI combined with chemotherapy (IC) and 24 patients (30.0%) received ICI monotherapy (IM). In IC group,31 patients received ICI combined with chemotherapy,19 patients received ICI combined with antiangiogenic therapy and remaing received ICI combined with chemotherapy and antiangiogenic therapy. Survival analysis shown that patients who received ICI-based treatment had better progress-free survival (PFS) and overall survival (OS) compared with those treated with other therapy (median PFS, 10.0 vs. 4.0 months, P<0.001; median OS, 39.5 vs. 24.2 months, P<0.001). What's more, patients who treated with IC treatment had a superior survival time than those received IM treatment (median PFS, 10.3 vs. 7.0 months, P<0.001; median OS, 41.6 vs. 32.4 months, P<0.001). Subgroup analysis found that the PFS and OS benefit of IC was evident in all subgroups. Conclusions: For advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation, ICI-based treatment could provide a more favorable survival than classical chemotherapy. What' s more, compared with ICI monotherapy, ICI combined with chemotherapy seems to be the preferred treatment.

A 5.3 pJ/Spike CMOS Neural Array Employing Time-Modulated Axon-Sharing and Background Mismatch Calibration Techniques.

Inspired by the human brain, spiking neuron networks are promising to realize energy-efficient and low-latency neuromorphic computing. However, even state-of-the-art silicon neurons are orders of magnitude worse than biological neurons in terms of area and power consumption due to the limitations. Moreover, limited routing in typical CMOS processes is another challenge for realizing the fully-parallel high-throughput synapse connections compared to biological synapses. This paper presents an SNN circuit that utilizes resource-sharing techniques to address the two challenges. Firstly, a comparator sharing neuron circuit with a background calibration technique is proposed to shrink the size of a single neuron without performance degradation. Secondly, a time-modulated axon-sharing synapse system is proposed to realize a fully-parallel connection with limited hardware overhead. To validate the proposed approaches, a CMOS neuron array is designed and fabricated under a 55-nm process. It consists of 48 LIF neurons with 3125 neurons/mm 2 area density, power consumption of 5.3 pJ/spike, and equivalent 2304 fully parallel synapses providing a unit throughput of 5500 events/s/neuron. It proves the proposed approaches are promising to realize a high-throughput high-efficiency SNN with CMOS technology.

Paclitaxel Has a Reduced Toxicity Profile in Healthy Rats After Polymeric Micellar Nanoparticle Delivery.

Background: Nanocarrier platforms have been indicated to have great potential in clinical practice to treat non-small cell lung cancer (NSCLC). Our previous Phase III clinical study revealed that polymeric micellar paclitaxel (Pm-Pac) is safe and efficacious in advanced NSCLC patients. However, the histopathological-toxicological profile of Pm-Pac in mammals remains unclear. Methods: We examined the Pm-Pac-induced antitumour effect in both A549/H226 cells and A549/H226-derived xenograft tumour models.. And then, we evaluated the short-term and long-term toxicity induced by Pm-Pac in healthy Sprague‒Dawley (SD) rats. The changes in body weight, survival, peripheral neuropathy, haematology, and histopathology were studied in SD rats administered Pm-Pac at different dosages. Results: In the A549-derived xenograft tumour model, better therapeutic efficacy was observed in the Pm-Pac group than in the solvent-based paclitaxel (Sb-Pac) group when an equal dosage of paclitaxel was administered. Toxicity assessments in healthy SD rats indicated that Pm-Pac caused toxicity at an approximately 2- to 3-fold greater dose than Sb-Pac when examining animal body weight, survival, peripheral neuropathy, haematology, and histopathology. Interestingly, based on histopathological examinations, we found that Pm-Pac could significantly decrease the incidences of paclitaxel-induced brain and liver injury but could potentially increase the prevalence of paclitaxel-induced male genital system toxicity. Conclusion: This study introduces the toxicological profile of the engineered nanoparticle Pm-Pac and provides a novel perspective on the Pm-Pac-induced histopathological-toxicological profile in a rat model.

LncRNA MEG3: Potential stock for precision treatment of cardiovascular diseases.

The prevalence and mortality rates of cardiovascular diseases are increasing, and new treatment strategies are urgently needed. From the perspective of basic pathogenesis, the occurrence and development of cardiovascular diseases are related to inflammation, apoptosis, fibrosis and autophagy of cardiomyocytes, endothelial cells and other related cells. The involvement of maternally expressed gene 3 (MEG3) in human disease processes has been increasingly reported. P53 and PI3K/Akt are important pathways by which MEG3 participates in regulating cell apoptosis. MEG3 directly or competitively binds with miRNA to participate in apoptosis, inflammation, oxidative stress, endoplasmic reticulum stress, EMT and other processes. LncRNA MEG3 is mainly involved in malignant tumors, metabolic diseases, immune system diseases, cardiovascular and cerebrovascular diseases, etc., LncRNA MEG3 has a variety of pathological effects in cardiomyocytes, fibroblasts and endothelial cells and has great clinical application potential in the prevention and treatment of AS, MIRI, hypertension and HF. This paper will review the research progress of MEG3 in the aspects of mechanism of action, other systemic diseases and cardiovascular diseases, and point out its great potential in the prevention and treatment of cardiovascular diseases. lncRNAs also play a role in endothelial cells. In addition, lncRNA MEG3 has shown biomarker value, prognostic value and therapeutic response measurement in tumor diseases. We boldly speculate that MEG3 will play a role in the emerging discipline of tumor heart disease.

Different clinical characteristics and survival between surgically resected pure and combined small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is the most malignant and common form of neuroendocrine lung cancer with pure (P-SCLC) and combined subtypes (C-SCLC). However, little is known about the differences between these two groups and in this study we aimed to provide a more comprehensive insight into SCLC. METHODS: Data from 580 postoperative patients with pathologically confirmed SCLC in Shanghai Chest Hospital from January 2010 to December 2020 were collected retrospectively. The clinical characteristics and prognosis were analyzed. RESULTS: A total of 357 P-SCLC patients and 223 C-SCLC patients were included. The results indicated that P-SCLC appeared to have a higher proportion of being located in the middle lobe than C-SCLC. The incidences of P-SCLC in patients with visceral pleural invasion (VPI) and in stage II were higher than C-SCLC, while C-SCLC was more likely to be accompanied by higher incidences of epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) rearrangement, and higher levels of CEA, SCCA and CYFRA21-1 than P-SCLC. The most common were SCLC combined with large cell neuroendocrine components among 223 C-SCLCs. Survival analysis confirmed a more favorable disease-free survival (DFS) (p = 0.016) and overall survival (OS) (p = 0.024) in patients with P-SCLCs compared with C-SCLCs. Histological type, tumor location, pN stage, adjuvant chemotherapy, serum NSE and CA125 levels were independent risk factors for survival rate in SCLC. In addition, adjuvant chemotherapy was beneficial in improving stage I P-SCLC and C-SCLC DFS and OS rates, and similar results were not seen in adjuvant radiation therapy. CONCLUSIONS: Patients with C-SCLC have a poorer prognosis than P-SCLC patients. We determined that large cell neuroendocrine carcinoma was the most common additional component of C-SCLC, and patients with this component appeared to have a longer DFS and OS than other combined components.

Efficacy and safety of first-line anlotinib-based combinations for advanced non-small cell lung cancer: a three-armed prospective study.

Background: The evidence of combined therapies of multi-target agents in first-line treatment of advanced non-small cell lung cancer (NSCLC) was limited. This study aimed to evaluate the safety and efficacy of anlotinib combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), chemotherapy, or immune checkpoint inhibitor (ICI) in advanced NSCLC. Methods: This open-label, three-arm, prospective study (NCT03628521) enrolled untreated locally advanced/metastatic NSCLC patients. Patients with EGFR mutation NSCLC received anlotinib and erlotinib (cohort A). Patients without EGFR/ALK/ROS1 mutation received anlotinib combined with carboplatin plus pemetrexed/gemcitabine (cohort B), or sintilimab (cohort C). The primary outcomes were safety and objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), and overall survival (OS). Treatments were performed for at least 2 cycles and efficacy was evaluated every 2 cycles using RECIST version 1.1. Safety was assessed throughout the study. Results: A total of 30, 30, and 22 patients were enrolled in cohorts A, B, and C, respectively. There were 3 patients did not complete the treatment in cohort A. In cohorts A and B, ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 77.3% and 60.0% of patients, respectively. The most common TRAEs were rash (10.0%) and decreased platelet count (30.0%) in cohorts A and B, respectively. The ORRs were 92.9% and 60.0% in cohorts A and B, respectively, and DCRs were 96.4% and 96.7%, respectively. The ORR and incidence of ≥ grade 3 TRAEs of cohort C were, which 72.7% and 54.5%, which had been published previously. Median PFSs [95% confidence interval (CI)] were 21.6 (15.6 to 24.9), 13.0 [10.5 to not estimated (NE)], and 15.6 (12.9 to NE) months in cohorts A, B, and C, respectively. Median OS was 28.1 (95% CI: 21.82 to NE) months in cohort B. The 24-month OS rates in cohorts A and C were 87.1% and 83.9%, respectively. Conclusions: Anlotinib-based combinations with EGFR-TKI, chemotherapy, and ICI are well-tolerated and encouraging as first-line therapies for advanced NSCLC, which could be verified in future studies. Anlotinib-based combination might provide multiple choices for first-line treatment in patients with advanced NSCLC.

Screening anlotinib responders via blood-based proteomics in non-small cell lung cancer.

Anlotinib has been demonstrated to be effective in advanced non-small cell lung cancer (NSCLC) patients. The response stratification of anlotinib remains unclear. In this study, plasma samples from 28 anlotinib-treated NSCLC patients (discovery cohort: 14 responders and 14 non-responders) were subjected to proteomic analysis, and plasma samples from 35 anlotinib-treated NSCLC patients (validation cohort) were subjected to validation analysis. Liquid chromatography-tandem mass spectrometry analysis was performed on samples with different time points, namely baseline (BL), best response (BR), and progression disease (PD). Bioinformatics analysis was performed to screen for the underlying differential proteins. Enzyme-linked immunosorbent assay was performed to detect plasma ARHGDIB, FN1, CDH1, and KNG1 levels respectively. The Kaplan-Meier survival analysis was used for biomarker-based responsive stratification. Our results indicated that differential proteins between responders and non-responders showed that proteomic technology potentially contributes to biomarker screening in plasma samples at BL. Furthermore, our results suggested that the detection of plasma ARHGDIB, FN1, CDH1, and KNG1 levels have potential predictive value for anlotinib response both in the discovery cohort and validation cohort. Collectively, this study offers novel insights into the value of plasma biomarker screening via proteomic examination and suggests that plasma ARHGDIB, FN1, CDH1, and KNG1 levels could be used as biomarkers for anlotinib stratification in NSCLC patients.

Blood-based tumour mutation index act as prognostic predictor for immunotherapy and chemotherapy in non-small cell lung cancer patients.

BACKGROUND: Circulating tumour DNA (ctDNA)-based sequencing might provide a simple test for the stratified model of non-small cell lung cancer (NSCLC). Here, we aimed to assess the ctDNA sequencing-based tumour mutation index (TMI) model for screening responders (from non-responders) among NSCLC patients who received monotherapy with docetaxel or atezolizumab. METHODS: We performed a retrospective analysis of the POPLAR (NCT01903993) and OAK (NCT02008227) trials. We identified three biomarkers, blood tumour mutation burden (bTMB), sensitive blood tumour mutation burden (sbTMB) and unfavourable mutation score (UMS), of the ctDNA profiles. After integrating the advantages and disadvantages of the three independent biomarkers, we developed the TMI model and identified NSCLC patients who may benefit from monotherapy with docetaxel or atezolizumab in terms of overall survival (OS). RESULTS: The TMI model as a stratified biomarker for docetaxel responders provided a median OS duration of 5.55 months longer than non-responders in the OAK cohort, with a significantly decreased hazard ratio (HR). Moreover, atezolizumab responders had a 10.21-month OS advantage over atezolizumab non-responders in the OAK cohort via TMI stratification, and the HR was also decreased significantly. The TMI demonstrated effectiveness for stratifying responders in the POPLAR cohort. Importantly, we found that the TMI model could screen additional responders upon combining the cohorts from the POPLAR and OAK trials after adjustment. CONCLUSION: In the present study, we provide a novel TMI model for screening responders (from non-responders) among NSCLC patients who received the 2nd-line monotherapy with docetaxel or atezolizumab. We believe that the biomarker TMI will potentially be effective for the clinical treatment of NSCLC in the future.

Circular RNA EPB41 expression predicts unfavorable prognoses in NSCLC by regulating miR-486-3p/eIF5A axis-mediated stemness.

Dysregulation of circular RNAs (circRNAs) has recently been found to play an important role in the progression and development of cancers such as non-small cell lung cancer (NSCLC). Yet the functions of many circRNAs in NSCLC remain unclear. In this study, the circRNA expression profiles in NSCLC tumor tissues and adjacent non-tumorous tissues were detected by high-throughput sequencing. Bioinformatics analyses, the dual-luciferase reporter system, fluorescence in situ hybridization (FISH) and miRNA/mRNA high-throughput sequencing were used to identify circ-EPB41 and its downstream target. The subcutaneous tumor/caudal vein transfer mouse model was used for tumor growth and invasion analysis. The results show that the circ-EPB41 was upregulated in NSCLC tissues and cell lines. Increased circ-EPB41 expression in NSCLC was significantly correlated with malignant characteristics, and positive to post-surgical overall survival of NSCLC patients. Reduced circ-EPB41 expression in NSCLC decreased cell proliferation and invasion in both in vitro and in vivo experiments. The miRNA/mRNA high-throughput sequencing suggested that downregulation of circ-EPB41 promoted microRNA (miR)-486-3p and suppressed eukaryotic translation initiation factor 5A (eIF5A) expression. Luciferase reporter experiments confirmed that miR-486-3p/eIF5A were downstream targets of circ-EPB41. In addition, we also found that downregulation of circ-EPB41 suppressed self-renewal and decreased expression of stemness markers SOX2, OCT-4, Nanog and CD133 by sponging miR-486-3p to enhance eIF5A expression. Taken togeter, these data revealed the important role of circ-EPB41 in regulating NSCLC cell invasion and proliferation by modifying miR-486-3p/eIF5A axis-mediated stemness. We believe our study provides a novel perspective regarding the role of circRNAs in NSCLC progression.

Long-term semi-continuous acidogenic fermentation for food wastes treatment: Effect of high organic loading rates at low hydraulic retention times and uncontrolled pH conditions.

The present study investigated the effect of high organic loading rates at low hydraulic retention times without pH control on food wastes fermentation. The acidogenic fermentation was robust to the hydraulic retention time drawdown. Hydraulic retention time variation led to compositional changes of fermentation product. Lactic acid and ethanol were always the dominant end-products and achieved the highest proportion (90.9%) at the 1-day hydraulic retention time. CO2 was the dominant biogas with the absence of H2 and CH4. The concentration of total fermentation product decreased with the lower hydraulic retention time, but the highest fermentation products rate was obtained at the lowest hydraulic retention time. The dominant bacteria was Lactobacillus at the genus level. This work demonstrated the feasibility of operating an acidogenic fermentation reactor at a high organic loading rate, low hydraulic retention time, and uncontrolled pH for improved reactor capacity, construction and operation cost-saving, and easy operation.

Multi-Omics Signatures Identification for LUAD Prognosis Prediction Model Based on the Integrative Analysis of Immune and Hypoxia Signals.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer with heterogeneous outcomes and diverse therapeutic responses. However, the understanding of the potential mechanism behind LUAD initiation and progression remains limited. Increasing evidence shows the clinical significance of the interaction between immune and hypoxia in tumor microenvironment. To mine reliable prognostic signatures related to both immune and hypoxia and provide a more comprehensive landscape of the hypoxia-immune genome map, we investigated the hypoxia-immune-related alteration at the multi-omics level (gene expression, somatic mutation, and DNA methylation). Multiple strategies including lasso regression and multivariate Cox proportional hazards regression were used to screen the signatures with clinical significance and establish an incorporated prognosis prediction model with robust discriminative power on survival status on both the training and test datasets. Finally, combing all the samples, we constructed a robust model comprising 19 signatures for the prognosis prediction of LUAD patients. The results of our study provide a comprehensive landscape of hypoxia-immune related genetic alterations and provide a robust prognosis predictor for LUAD patients.

Regulatory mechanism of α-hederin upon cisplatin sensibility in NSCLC at safe dose by destroying GSS/GSH/GPX2 axis-mediated glutathione oxidation-reduction system.

Emerging studies showed that α-hederin induced autophagic cell death in different cancers via reactive oxygen species. Nevertheless, α-hederin role in non-small-cell lung cancer (NSCLC) remains unknown. So, the aim of this study was to explain whether ferroptosis is a therapeutic strategy to NSCLC, and to explore the effect of α-hederin on NSCLC ferroptosis. Current investigation found that α-hederin inhibited NSCLC cell proliferation, invasion, and migration in vitro and in vivo at toxic doses. The α-hederin treatment also increased NSCLC cell chemosensitivity to cisplatin and promoted ferroptosis and apoptosis at a safe dose. Proteomics, metabolomics, and high-throughput sequencing detection confirmed that α-hederin treatment downregulated glutathione peroxidase 2 (GPX2), and glutathione synthase (GSS) expression suppressed the synthesis of glutathione (GSH), which destroyed the GSH redox system. Eventually, it led to ferroptosis, apoptosis, and membrane permeabilization in NSCLC. Taken together, the study provided molecular data to confirm that α-hederin induced ferroptosis, apoptosis, and membrane permeabilization in NSCLC by destroying the GSS/GSH/GPX2 axis-mediated GSH oxidation-reduction system at a safe and low-toxicity dose.

Equivalent efficacy assessment of QL1101 and bevacizumab in nonsquamous non-small cell lung cancer patients: A two-year follow-up data update.

Objective: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies are an effective means of treating non-small cell lung cancer (NSCLC). Here, we aim to update the equivalent efficacy assessment between QL1101 and bevacizumab based on two-year follow-up data. Methods: In total, 535 eligible NSCLC patients were enrolled in this randomized controlled trial. Patients were randomly assigned 1:1 to the QL1101 group and the bevacizumab group. The full end time of this study was defined as 24 months after the last enrolled patient was randomized. The primary endpoint was the objective response rate (ORR); equivalence was confirmed if the two-sided 90% confidence interval (90% CI) of the relative risk was within the range of 0.75-1.33. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: The two-year updated data showed similar ORR (QL1101 vs. bevacizumab: 53.1% vs. 54.3%; relative risk=0.977; 90% CI: 0.838-1.144), PFS (235 d vs. 254 d, log-rank P=0.311), and OS (577 d vs. 641 d, log-rank P=0.099) results between the QL1101 group and the bevacizumab group. The mean shrinkage ratio of targeted lesions was also similar between the QL1101 group and the bevacizumab group (22.5% vs. 23.5%). For patients who received QL1101 maintenance therapy, similar results were shown between the QL1101 group (n=157) and the bevacizumab group (n=148) (PFS: 253 d vs. 272 d, log-rank P=0.387; OS: 673 d vs. 790 d, log-rank P=0.101; mean tumor shrinkage rate: 26.6% vs. 27.5%). Conclusions: This study reported that QL1101 had similar efficacy in treating nonsquamous NSCLC in terms of ORR, PFS and OS based on two-year updated data, providing a basis for the clinical application of QL1101.

The centromere-associated protein CENPU promotes cell proliferation, migration, and invasiveness in lung adenocarcinoma.

CENPU, encoding an important factor involved in kinetochore assembly during mitosis, is associated with shorter survival rates in lung adenocarcinoma (LUAD) patients. CENPU promotes growth rates and invasive behavior of LUAD cells; however, its mechanism of action in LUAD progression remains to be elucidated. CENPU mRNA and protein expression were elevated in LUAD tumors, and high CENPU gene expression was associated with inferior survival prognosis in LUAD patients. CENPU knockdown inhibited LUAD cell proliferation, clone formation, migration, invasion, and epithelial-mesenchymal transition (EMT) in addition to inducing cell cycle arrest and apoptosis in vitro and reduced LUAD xenograft tumor growth in vivo. Furthermore, we identified CENPU-regulated genes significantly enriched for proliferation and apoptosis pathways, and identified HSP Family Member C10 (DNAJC10) as putative effector of CENPU. CENPU knockdown produced DNAJC10 protein downregulation, and DNAJC10 overexpression partially rescued the phenotypic effects of CENPU knockdown in LUAD cells. Moreover, CENPU's coiled-coil domain was essential for CENPU's phenotypic effects in LUAD cells. In conclusion, the kinetochore component CENPU plays a critical role in LUAD cell proliferation and invasiveness. Targeting CENPU-DNAJC10 axis may inhibit LUAD tumor cell proliferation and metastasis.

The clinicopathological and molecular characteristics of resected EGFR-mutant lung adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations were frequently found with concomitant genetic alterations in lung adenocarcinoma (LUAD). This study aimed to investigate the profile of concomitant alterations of EGFR-mutant LUAD ≤3 cm in size and its prognostic effect on recurrence. METHODS: From January 2018 to December 2018, patients with resected LUAD ≤3 cm in size in Shanghai Chest Hospital were identified. All patients underwent capture-based targeted next-generation sequencing (NGS) with a panel of 68 lung cancer-related genes and were found with EGFR mutation. Clinicopathological and molecular characteristics and recurrence-free survival (RFS) were analyzed. RESULTS: A total of 637 patients were enrolled in this study. The top three frequent co-mutational genes were TP53 (179 of 637, 28.1%), PIK3CA (27 of 637, 4.2%), and ATM (22 of 637, 3.5%). The most common amplified genes were EGFR (37 of 637, 5.8%), followed by CDK4 (37 of 637, 5.8%) and MYC (12 of 637, 2.0%). Only TP53 mutation and EGFR amplification were adverse prognostic factors for RFS (all p < 0.001) in univariate analysis. Multivariable analysis further demonstrated that TP53 mutation and EGFR amplification were independent risk factors for RFS [(hazard ratio (HR) 2.07, 95% confidence interval (CI) 1.07-4.00, p = 0.030; HR 3.09, 95% CI 1.49-6.40, p = 0.002, respectively]. CONCLUSIONS: Concomitant TP53 mutation and EGFR amplification were poor prognostic factors for RFS in patients with EGFR-mutant resected LUAD. Our findings provide valuable understanding of the impact of concurrent alterations and implication for better implementation of precision therapy for patients.