Discovery of a novel ROS-based signature for predicting prognosis and immunosuppressive tumor microenvironment in lung adenocarcinoma.

The role of reactive oxygen species (ROS) is critical in the emergence and progression of lung adenocarcinoma (LUAD), affecting cell survival, proliferation, angiogenesis, and metastasis. Further investigations are needed to elucidate these effects' precise pathways and devise therapeutic approaches targeting ROS. Moreover, the expression pattern and clinical significance of the ROS-related genes in LUAD remain elusive. Through comprehensive analysis incorporating 1494 LUAD cases from The Cancer Genome Atlas, six Gene Expression Omnibus series, and a Chinese LUAD cohort, we identified a ROS-related signature with substantial predictive value in various LUAD patient cohorts. The ROS-related signature has demonstrated a significant negative relationship with antitumor immunity and dendritic cell maturation and activation. Moreover, The ROS-related signature showed predictive value on immunotherapy outcomes across multiple types of solid tumors, including LUAD. These findings reinforce the ROS-related signature as a predictive tool for LUAD and provide new insights into its link with antitumor immunity and immunotherapy efficacy. These results have implications for refining clinical assessments and tailoring immunotherapeutic strategies for patients with LUAD.

Evaluation of first-line and salvage therapies for unresectable malignant mesothelioma: A systematic review and network meta-analysis.

BACKGROUND: Randomized controlled trials (RCTs) of systemic therapies for unresectable malignant mesothelioma have reported conflicting results. It is crucial and urgent to find optimal treatment options for this malignancy, which currently has a poor prognosis. METHODS: Databases PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences were searched until February 29, 2024. The main outcomes of interest were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). RESULTS: We analyzed 16 RCTs with a total of 5018 patients. Among first-line therapies, nivolumab and ipilimumab significantly increased OS and resulted in fewer grade ≥3 TRAEs. Bevacizumab plus chemotherapy significantly increased PFS. Among salvage therapies, ramucirumab and chemotherapy was associated with the best OS and PFS, but resulted in more grade ≥3 TRAEs. Subgroup analysis by histologic types suggested that in first-line settings, bevacizumab and chemotherapy increase OS the most for epithelioid type, while the nivolumab plus ipilimumab treatment increases OS the most for non-epithelioid type. In salvage therapies, ramucirumab and chemotherapy increase OS for both epithelioid and non-epithelioid types. CONCLUSION: Nivolumab plus ipilimumab was associated with the best OS among first-line treatments. Ramucirumab and chemotherapy was associated with the best clinical outcomes in salvage settings. Treatment for malignant mesothelioma should be tailored based on different clinicopathological characteristics.

Endogenous H2S-activated Ag nanoparticles embedded in programmed DNA-cubes for specific visualization of colorectal cancer cells.

To avoid the unexpected aggregation and reduce the cytotoxicity of nanomaterials as optical probes in cell imaging applications, we propose a programmed DNA-cube as a carrier for silver nanoparticles (Ag NPs) to construct a specific hydrogen sulfide (H2S) responsive platform (Ag NP@DNA-cube) for diagnosing colorectal cancer (CRC) in this study. The DNA-cube maintains good dispersion of Ag NPs while providing excellent biocompatibility. Based on the characteristic overexpression of endogenous H2S in CRC cells, the Ag NPs are etched by H2S within target cells into silver sulfide quantum dots, thereby selectively illuminating the target cells. The Ag NP@DNA-cube exhibits a specific fluorescence response to CRC cells and achieves satisfactory imaging.

Screening for depression and anxiety in lung cancer patients: A real-world study using GAD-7 and HADS.

BACKGROUND: The psychological well-being of lung cancer patients is critical in-patient care but frequently overlooked. METHODS: This study, employing a cross-sectional, questionnaire-based design, aimed to elucidate the prevalence of depressive and anxiety symptoms among lung cancer patients and identify associated risk factors. Participants' demographic, medical history, disease stage, and pathology were systematically collected. Psychological assessment was conducted using the general anxiety disorder-7 (GAD-7), patient health questionnaire-9 (PHQ-9), and hospital anxiety and depression scale (HADS). Statistical analyses were performed using SPSS software (version 25.0). RESULTS: Out of 294 distributed questionnaires, 247 lung cancer patients were included in the final analysis, with an average completion time of 9.08 min. Notably, 32.4% exhibited depressive symptoms, while 30% displayed signs of anxiety. A significant correlation was found between both depressive and anxiety symptoms and a history of tobacco and alcohol consumption. Specifically, increased nicotine dependence and greater cumulative tobacco use were linked to higher rates of depressive symptoms, whereas cumulative alcohol consumption was associated with increased risks of anxiety symptoms. CONCLUSION: The study affirms the feasibility of GAD-7, PHQ-9, and HADS as screening tools for depressive and anxiety symptoms in lung cancer patients. It further highlights tobacco and alcohol consumption as significant risk factors for poor psychological health in this population.

Stability improvement of 40Ca+ optical clock by using a transportable ultra-stable cavity.

The instability of the clock laser is one of the primary factors limiting the instability of the optical clocks. We present an ultra-stable clock laser based on a 30-cm-long transportable cavity with an instability of ∼3 × 10-16 at 1 s-100 s. The cavity is fixed by invar poles in three orthogonal directions to restrict the displacement, meeting the requirements of transportability and low vibration sensitivity. By applying the ultra-stable laser to a transportable 40Ca+ optical clock with a systematic uncertainty of 4.8 × 10-18 and using the real-time feedback algorithm to compensate the linear shift of the clock laser, the short-term stability of the transportable 40Ca+ optical clock has been greatly improved from 4.0×10-15/τ/s to 1.16×10-15/τ/s, measured at ∼100 s-1000 s of averaging time, enriching its applications in metrology, optical frequency comparison, and time keeping.

Comparative proteomic profiling of plasma exosomes in lung cancer cases of liver and brain metastasis.

BACKGROUND: Metastases within liver or the brain are the most common causes of mortality from lung cancer (LC). Predicting liver or brain metastases before having evidence from imaging of the tumors is challenging but important for early patient intervention. According to mounting evidence, exosomes circulating within blood may facilitate cancer spread by transporting certain proteins for target cells. METHODS: Using liquid chromatography-MS/MS, we investigated the plasma exosomes' proteomic profiles derived from 42 metastatic LC patients [16 solitary liver metastasis (LM), together with 26 solitary brain metastasis (BM)] and 25 local advanced (LA) lung cancer cases without metastasis, together with five healthy controls (HC), assessing the LM and BM pathogenesis and find potential novel organ-designated proteomic biomarkers. Using ELISA assay, we verified the expression levels of three plasma exosomal protein biomarkers in 110 LC patients, including 40 solitary LM, 32 solitary BM and 38 LA, and 25 HC. RESULTS: In total, 143 and 120 differentially expressed exosome-based proteins (DEEPs) were found to be dysregulated in LM and BM of lung cancer (LM-DEEPs, BM-DEEPs), compared for LA lung cancer samples, respectively. The bioinformatics analyses indicated the heterogeneity and homogeneity in LM-DEEPs and BM-DEEPs. They were primarily engaged within proteomic triggering cascade, ECM-receptor interaction, and the collagen-containing extracellular matrix. Regarding heterogeneity, LM-DEEPs primarily consisted of proteoglycans, lipoprotein, integrin, and heat shock protein, whereas the BM-DEEPs consisted of calcium-dependent/S100 proteins. Furthermore, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)-plasma-stemming exosome proteomics showed heterogeneity, which helped to explain some of the differences between SCLC and NSCLC's metastatic features. We also found that SELL and MUC5B could be used as diagnostic markers of BM, while APOH, CD81, and CCT5 could help diagnose LM in LC patients. Additionally, we demonstrated in a validation cohort that MUC5B and SELL could serve as biomarkers for diagnosing BM, and APOH could be a novel potential diagnostic biomarker of LM. CONCLUSION: We presented the comprehensive and comparative plasma-stemming exosomes' proteomic profiles from cases of LC who had isolated liver and brain metastases for the first time. We also suggested several possible biomarkers and pathogenic pathways that might be a great starting point for future research on LC metastasis.

Ablation of ERO1A induces lethal endoplasmic reticulum stress responses and immunogenic cell death to activate anti-tumor immunity.

Immunophenotyping of the tumor microenvironment (TME) is essential for enhancing immunotherapy efficacy. However, strategies for characterizing the TME exhibit significant heterogeneity. Here, we show that endoplasmic reticular oxidoreductase-1α (ERO1A) mediates an immune-suppressive TME and attenuates the response to PD-1 blockade. Ablation of ERO1A in tumor cells substantially incites anti-tumor T cell immunity and promotes the efficacy of aPD-1 in therapeutic models. Single-cell RNA-sequencing analyses confirm that ERO1A correlates with immunosuppression and dysfunction of CD8+ T cells along anti-PD-1 treatment. In human lung cancer, high ERO1A expression is associated with a higher risk of recurrence following neoadjuvant immunotherapy. Mechanistically, ERO1A ablation impairs the balance between IRE1α and PERK signaling activities and induces lethal unfolded protein responses in tumor cells undergoing endoplasmic reticulum stress, thereby enhancing anti-tumor immunity via immunogenic cell death. These findings reveal how tumor ERO1A induces immunosuppression, highlighting its potential as a therapeutic target for cancer immunotherapy.

Comprehensive Analyses and Immunophenotyping of LIM Domain Family Genes in Patients with Non-Small-Cell Lung Cancer.

The LIM domain family genes play a crucial role in various tumors, including non-small-cell lung cancer (NSCLC). Immunotherapy is one of the most significant treatments for NSCLC, and its effectiveness largely depends on the tumor microenvironment (TME). Currently, the potential roles of LIM domain family genes in the TME of NSCLC remain elusive. We comprehensively evaluated the expression and mutation patterns of 47 LIM domain family genes in 1089 NSCLC samples. Using unsupervised clustering analysis, we classified patients with NSCLC into two distinct gene clusters, i.e., the LIM-high group and the LIM-low group. We further investigated the prognosis, TME cell infiltration characteristics, and immunotherapy in the two groups. The LIM-high and LIM-low groups had different biological processes and prognoses. Moreover, there were significant differences in TME characteristics between the LIM-high and LIM-low groups. Specifically, enhanced survival, immune cell activation, and high tumor purity were demonstrated in patients of the LIM-low group, implying an immune-inflamed phenotype. Moreover, the LIM-low group had higher immune cell proportion scores than the LIM-high group and was more responsive to immunotherapy than the LIM-low group. Additionally, we screened out LIM and senescent cell antigen-like domain 1 (LIMS1) as a hub gene of the LIM domain family via five different algorithms of plug-in cytoHubba and the weighted gene co-expression network analysis. Subsequently, proliferation, migration, and invasion assays demonstrated that LIMS1 acts as a pro-tumor gene that promotes the invasion and progression of NSCLC cell lines. This is the first study to reveal a novel LIM domain family gene-related molecular pattern associated with the TME phenotype, which would increase our understanding of the heterogeneity and plasticity of the TME in NSCLC. LIMS1 may serve as a potential therapeutic target for NSCLC.

Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions.

With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations ("target-dependent resistance") and in the parallel and downstream pathways ("target-independent resistance"). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.

WITHDRAWN: Proteomic analysis of plasma-derived exosomes identifies biomarkers that distinguish brain and liver metastasis in lung cancer patients.

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Predictive Value of Max's Giant Associated Protein Mutation in Outcomes of Lung Adenocarcinoma Patients Treated With Immune Checkpoint Inhibitors.

Treatment with immune checkpoint inhibitors (ICIs) has considerably improved prognosis in multiple cancers. However, regardless of PD-L1 expression and TMB, better predictive biomarkers are required to identify ICI-responsive patients. We analyzed a pan-cancer cohort as the discovery cohort to identify the role of Max's giant associated protein (MGA) mutation in the outcome of ICI treatment in different types of cancers. A pooled lung adenocarcinoma (LUAD) cohort was considered as the validation cohort. Another two LUAD cohorts who received conventional treatment were included for prognostic analysis and mechanism exploration. In the discovery cohort, MGA mutation was a favorable survival biomarker for patients with LUAD than in those with other types of cancers. MGA mutation was positively correlated with the TMB score. The results of the validation cohort were consistent with those of the discovery cohort. Patients with MGA mutation in the TMB-low subgroup had longer survival. Two LUAD cohorts who received standard treatment showed that the MGA mutation was not a prognostic biomarker for standard treatment. Mechanically, we found that the co-mutant genes did not affect the prognostic role of MGA mutation. Gene-set enrichment analysis revealed that genes belonging to the immunodeficiency pathway were enriched in the MGA wild-type group in LUAD. Moreover, activated NK cells were more enriched in the MGA mutant LUAD group. In conclusion, our results demonstrated that MGA mutation was an independent predictive biomarker for ICI therapy. These results may provide a novel insight into identifying potential patients with LUAD for ICI therapy.

ERO1L Is a Novel and Potential Biomarker in Lung Adenocarcinoma and Shapes the Immune-Suppressive Tumor Microenvironment.

Background: The endoplasmic reticulum oxidoreductin-1-like (ERO1L) gene encodes an endoplasmic reticulum luminal localized glycoprotein known to associated with hypoxia, however, the role of ERO1L in shaping the tumor immune microenvironment (TIME) is yet to be elucidated in lung adenocarcinoma (LUAD). Methods: In this study, raw datasets (including RNA-seq, methylation, sgRNA-seq, phenotype, and survival data) were obtained from public databases. This data was analyzed and used to explore the biological landscape of ERO1L in immune infiltration. Expression data was used to characterize samples. Using gene signatures and cell quantification, stromal and immune infiltration was determined. These findings were used to predict sensitivity to immunotherapy. Results: This study found that ERO1L was significantly overexpressed in LUAD in comparison to normal tissue. This overexpression was found to be a result of hypomethylation of the ERO1L promoter. Overexpression of ERO1L resulted in an immune-suppressive TIME via the recruitment of immune-suppressive cells including regulatory T cells (Tregs), cancer associated fibroblasts, M2-type macrophages, and myeloid-derived suppressor cells. Using the Tumor Immune Dysfunction and Exclusion (TIDE) framework, it was identified that patients in the ERO1Lhigh group possessed a significantly lower response rate to immunotherapy in comparison to the ERO1Llow group. Mechanistic analysis revealed that overexpression of ERO1L was associated with the upregulation of JAK-STAT and NF-κB signaling pathways, thus affecting chemokine and cytokine patterns in the TIME. Conclusions: This study found that overexpression of ERO1L was associated with poor prognoses in patients with LUAD. Overexpression of ERO1L was indicative of a hypoxia-induced immune-suppressive TIME, which was shown to confer resistance to immunotherapy in patients with LUAD. Further studies are required to assess the potential role of ERO1L as a biomarker for immunotherapy efficacy in LUAD.

Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: A series of randomized controlled trials have investigated different first-line immunotherapy combinations, but the optimal combination strategy is yet to be established. METHODS: We performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences. We included published and gray sources of randomized clinical trials comparing immunotherapy combinations with other treatments as first-line treatments for patients with advanced NSCLC. This study was registered in the Prospective Register of Systematic Reviews (CRD42020210501) to ensure transparency. RESULTS: We analyzed a total of 16 studies involving 8278 patients and including 10 immunotherapy combinations. For patients without programmed death-ligand 1 (PD-L1) selection, pembrolizumab plus chemotherapy was found to be comparable with sintilimab plus chemotherapy in providing the best overall survival (OS) benefit (hazard ratio = 0.96, 95% confidence interval [CI]: 0.72-1.29). Furthermore, atezolizumab plus bevacizumab plus chemotherapy seemed to provide the best progression-free survival (hazard ratio = 0.45, 95% CI: 0.36-0.55) and the best objective response rate (OR = 0.23, 95% CI: 0.12-0.42). Subgroup analysis by PD-L1 suggested that nivolumab plus ipilimumab plus chemotherapy was associated with the best OS in patients with PD-L1 less than 1% and that pembrolizumab plus chemotherapy was associated with the best OS in patients with PD-L1 greater than or equal to 1%. Pembrolizumab and sintilimab were associated with relatively fewer grade greater than or equal to 3 adverse events when compared with other immunotherapies combined with chemotherapy. CONCLUSIONS: Our results suggest that antiprogrammed death-1 combinations are associated with potentially higher survival outcomes than anti-PD-L1 combinations with comparable safety profiles. Moreover, pem-chemo and nivo-ipi-chemo seem to be superior first-line immunotherapy combinations for patients with advanced NSCLC with positive and negative PD-L1 expression, respectively. Although atezo-beva-chemo treatment provided the best progression-free survival and objective response rate, the addition of chemotherapy to immunotherapy would increase the toxicity, especially when antiangiogenesis drugs are simultaneously added.