Jianya Zhou

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with distinct inflammatory profiles that may be associated with key pathological features, including emphysema and airway wall remodeling. This study aimed to identify COPD subgroups based on circulating pro- and anti-inflammatory cytokine activity and airflow limitation and to examine their clinical, physiological, and quantitative CT characteristics. Methods: Demographic characteristics, symptom scores, pulmonary function parameters, and quantitative CT indices were collected from patients with stable COPD. Serum levels of pro- and anti-inflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA). Cluster analysis was performed using a Gaussian mixture model (GMM). Results: A total of 319 stable COPD patients were included. Four distinct clusters were identified. Cluster 1 (Severe-low inflammation) was characterized by the lowest circulating inflammatory cytokine levels, the greatest symptom burden, the most severe airflow limitation, an increased exacerbation frequency, and the most extensive emphysema. Cluster 2 (Mild-low inflammation) exhibited low levels of pro- and anti-inflammatory cytokines, mild symptoms, relatively preserved lung function, and a low frequency of annual exacerbations. Cluster 3 (Moderate-elevated inflammation) had moderately elevated levels of pro- and anti-inflammatory cytokines, with intermediate mMRC and CAT scores, pulmonary function impairment and exacerbation frequency. Cluster 4 (Extremely high inflammation) was characterized by markedly elevated levels of pro- and anti-inflammatory cytokines, intermediate symptom burden, relatively preserved pulmonary function, pronounced airway wall thickening and a high frequency of moderate-to-severe exacerbations. Further cytokine ratio analysis revealed an IL-6-related shift in Clusters 3 and 4 and an IL-17-related shift predominantly in Cluster 3. Conclusion: Integrating cytokine profiles with airflow limitation identified four exploratory COPD phenotypes, highlighting a potential dissociation between systemic inflammation and disease severity. External and longitudinal validation is needed to confirm their reproducibility and clinical relevance.

Background/Objectives: Lung cancer is increasingly recognized in young adults, but data specific to patients younger than 30 years remain scarce. We aimed to characterise the clinicopathological features, molecular profiles, and survival outcomes of lung cancer in adults younger than 30 years. Methods: A retrospective cohort study was conducted at the Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Patients aged 18 to 30 years with pathologically confirmed primary lung cancer, admitted between August 2011 and October 2021, were identified from the pathology and oncology databases of the study centre; eligibility and exclusion criteria and the resulting analytic cohort are summarized below (a screened/excluded patient count could not be reconstructed retrospectively; see Limitations). Demographics, histology, stage (eighth-edition TNM), driver mutations, and treatment were extracted, and the extent of missing data for each variable was assessed. Molecular testing was not performed prospectively for this study; rather, we report driver-mutation results that had already been generated as part of routine clinical care for patients in whom testing was clinically indicated and archived tissue was available. Overall survival (OS) was estimated using the Kaplan–Meier method and compared using the log-rank test; hazard ratios (HRs) were derived from univariate Cox regression and are reported as exploratory/descriptive given the non-randomized comparison (see Discussion). Results: Among 139 patients meeting eligibility criteria, the cohort was predominantly female (65.5%) and most individuals were never-smokers (92.8%), with adenocarcinoma predominating (93.5%). Stage I (61.2%) and stage IV (30.2%) were most common. Of 34 patients (24.5%) with available molecular testing results, 23 (67.6%) carried a driver mutation, of whom 19 (82.6%) had stage IV disease. Among mutation-positive patients—drawn from a selectively tested subcohort enriched for advanced-stage disease—ALK rearrangement was most frequent (13; 56.5%). In the stage IV subgroup, patients who received first-line tyrosine kinase inhibitors (TKIs) had a longer observed OS than those who did not (median, 88 vs. 24 months); this exploratory, non-randomized comparison is reported descriptively rather than as an adjusted treatment-effect estimate (see Limitations). Conclusions: In this single-centre retrospective cohort, adults aged <30 years with lung cancer were predominantly female never-smokers with adenocarcinoma. Among the selectively tested advanced-stage subgroup, ALK fusions were common. These data justify further multicentre study and broader contemporary molecular characterisation.

Molecular residual disease (MRD), detected through circulating tumor DNA, has emerged as a promising biomarker for surveillance in patients with early-stage non-small cell lung cancer (NSCLC) following curative-intent resection. Here we report the MRD analysis from the phase 3 EVIDENCE trial, which includes patients with stage II–IIIA resected EGFR-mutated NSCLC who have received either adjuvant icotinib or chemotherapy. A total of 1,352 plasma samples from 175 patients are analyzed using the MinerVa Prime assay, a personalized tumor-informed MRD platform. At the landmark timepoint, MinerVa Prime detects MRD positivity in 35.8% (38/106) of patients with stage III disease and 14.7% (10/68) of patients with stage II disease, with a longitudinal positivity rate of 47.4%. MRD-positive status is significantly correlated with inferior disease-free survival (DFS), both at landmark (hazard ratio [HR]: 4.44, P < 0.001) and during longitudinal monitoring (HR: 7.82, P < 0.001). Icotinib confers DFS benefits over chemotherapy in both MRD subgroups, enhancing MRD clearance in MRD-positive patients while reducing molecular recurrence in landmark MRD-negative patients. Longitudinal MRD shows a 91.3% negative predictive value, with a median lead time of 169 days prior to clinical recurrence. Among serial monitoring timepoints, MRD status at 24 weeks post-randomization demonstrates the highest prognostic value.

Concomitant anti-programmed cell death protein 1 (anti-PD-1) therapy and denosumab treatment can improve clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastasis. However, limited data are available among Chinese patients in real-world clinical practice, and the effect of this treatment combination on bone metastases has not been adequately studied. This single-centre, retrospective study analysed NSCLC patients with bone metastases who received first-line anti-PD1-therapy and concomitant denosumab treatment between March 2021 and June 2022. Clinical outcomes were described and bone lesion response was evaluated using a novel, exploratory quantitative method based on single photon emission computed tomography/computed tomography scans. Among 66 included patients, the median overall survival was 21.5 months (95% CI: 17.0-NR). The overall survival rate (95% CI) was 96.9% (92.9%-100.0%) at 6 months and 79.7% (70.4%-90.2%) at 12 months. The median progression-free survival was 7.7 months (95% CI: 6.2-12.8). The overall response rate was 36.4% (95% CI: 24.9%-49.1%), with 24 (36.4%) patients having partial response. An exploratory subgroup analysis showed that patients who received ≥ 6 doses of denosumab may have longer median overall survival compared to the < 6 doses subgroup (23.3 vs. 15.3 months, P = 0.023), though immortal time bias and confounding limit interpretation. Out of 33 bone lesions identified, 28 had decreased uptake values between consecutive bone scans (mean change in region-of-interest ratio: -32.7%±19.2%). This study described real-world clinical NSCLC patients with bone metastases receiving concomitant anti-PD-1 therapy and denosumab. The findings should be interpreted as exploratory and hypothesis-generating given the retrospective, single-arm design. The novel, quantitative assessment method may provide an exploratory approach to monitoring changes in bone lesions, and further validation in larger, prospective cohorts is required.

Objective: Osimertinib has demonstrated superior efficacy as a first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) in clinical trials. This study was aimed at providing real-world evidence of osimertinib treatment in Chinese populations. Methods: This prospective, multicenter, non-interventional study was conducted from July 27, 2020, to April 27, 2022. Treatment-naïve adults (≥18 years of age) with locally advanced or metastatic EGFR-mutated NSCLC scheduled to receive first-line osimertinib were included. Of 507 patients screened, 481 were eligible in the full analysis set. The primary endpoint was time to treatment discontinuation (TTD). Secondary endpoints included real-world progression-free survival (rwPFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Among 481 patients (median age 64.1 years; 62.2% women), the median follow-up was 31.3 months. The mTTD was 24.6 months (95% CI, 22.4–26.7), the median rwPFS was 19.4 months (95% CI, 16.2–20.4), and the mOS was 41.0 months [95% CI, 39.7 to not reached (NR)]. The mOS was 43.1 months (95% CI, 39.7 to NR) in FLAURA-eligible patients vs. 33.5 months (95% CI, 26.8 to NR) in FLAURA-ineligible patients. The mOS was 29.3 months (95% CI: 25.4 to NR) in patients with co-mutations vs. NR (95% CI: 32.9 to NR) in the cohort with EGFR-only mutations. Adverse events occurred in 71.7% of patients, and grade ≥3 events occurred in 11.4%. The safety profiles were similar between FLAURA-eligible and ineligible patients. Conclusions: First-line osimertinib demonstrated robust effectiveness and manageable safety in real-world Chinese patients with EGFR-mutated advanced NSCLC, including those ineligible for clinical trials. Patients with co-mutations showed diminished clinical benefit, thus suggesting a potential need for intensified treatment strategies in this population.

Post-translational modiffcations (PTMs) are pivotal in modulating protein function and cellular processes. However, experimental identiffcation of PTM sites remains costly and labor-intensive. Recent advances in artiffcial intelligence (AI) have empowered accurate and scalable in silico PTM site prediction from largescale proteomic data. In this review, we provide a comprehensive and up-to-date overview of AI-driven PTM site prediction across more than ten PTM classes, covering single-PTM site prediction, multiple-PTM site prediction, inter-site crosstalk prediction, and functional prediction of modiffcation sites. We systematically analyze and compare key AI frameworks, from conventional machine learning to deep learning, and summarize representative tools. We also identify key challenges and propose future directions for improvement. To foster application and ongoing progress, we provide practical guidelines for method selection and have established a dedicated website, which serves as a community benchmarking resource for the development of PTM site prediction tools. This website will be regularly updated with emerging prediction tools. By integrating comprehensive literature analysis with a dynamic online resource, we aim to provide a robust cornerstone for understanding current capabilities and guiding the future development of PTM site prediction tools, thereby promoting the integration of AI into practical biomedical research applications.

Research Advances in Obstructive Sleep Apnea and Lung Cancer Comorbidity

Aberrant DNA methylation has been implicated in tumorigenesis and the development of lung cancer. However, Nucleoside analog DNA methyltransferase inhibitors have demonstrated clinical utility in the treatment of myelodysplastic syndrome and acute myeloid leukemia; the drugs have not shown commensurate clinical efficacy in solid tumors. Mechanisms mediating the primary resistance to DNA hypomethylating agents in solid tumors are not fully understood. Here, we hypothesized that factors that limit incorporation of nucleoside analog DNA methyltransferase inhibitors in genomic DNA may underlie the tumor cell intrinsic primary resistance to decitabine (DAC) in lung cancer. We found that RRM1 expression levels were inversely correlated with DAC incorporation rates detected by LC–MS/MS. RNA interference-mediated depletion of RRM1, the catalytic subunit of ribonucleotide reductase (RNR), or pharmacological inhibition of RNR significantly potentiated inhibition of lung cancer cell clonogenic survival in vitro and xenograft growth in vivo by DAC treatment. Additionally, RRM1 inhibition enhances DAC-mediated tumor suppressor gene reactivation and STING pathway activation via DNA damage-induced IFI16 sensing. RNR inhibition led to increased incorporation of DAC into genomic DNA by reducing the availability of dCTP. These findings nominate the promising combination therapy of DAC and RNR inhibitors as being ripe for further clinical translation.