Lung adenocarcinoma(LUAD) is the primary reason for cancer-related deaths globally. GINS1 has a significant regulatory function in DNA replication. It is overexpressed in various malignant tumors, but the specific molecular mechanisms of GINS1 in LUAD pathogenesis are not fully elucidated. This is the first report that GINS1 enhances LUAD by activating Wnt/β-catenin signaling pathway, and may serve as a potential target for therapy.

Bioinformatic analysis including analysis of difference, survival analysis and pathway enrichment, immunohistochemistry(IHC), western blotting(WB), and quantitative real time polymerase chain reaction(qRT-PCR) were used to detect GINS1 expression in LUAD cell lines and tissues. A range of in vivo and in vitro experiments, such as cck-8, EdU, cloning experiment, wound healing experiment and transwell experiment, confirmed that GINS1 facilitated the proliferation and migration of LUAD. Additionally, the potential mechanism of GINS1 was hypothesized through WB and transcriptome sequencing. The rescue experiment was used to verify our conclusion.

In this study, we discovered that GINS1 is significantly overexpressed in LUAD cell lines and tissues. Analysis of Kaplan - Meier survival data indicated that high levels of GINS1 expression are often linked to unfavorable survival outcomes. Additionally, a series of experiments showed that silencing GINS1 led to less proliferation and migration of LUAD cell lines, while its overexpression enhanced tumor progression. Furthermore, subcutaneous tumor experiments in nude mice supported the role of GINS1 in promoting tumor development in vivo. Lastly, transcriptome sequencing revealed that tumor progression is related to cell cycle (G1 to S phase transition associated with cyclinD) and β-catenin signaling pathway, which we subsequently validated using WB. A series of rescue experiment further confirmed that GINS1 facilitates the advancement of LUAD via the β-catenin signaling pathway.

Our findings suggest that GINS1 plays a critical role in the progression of LUAD by modulating key molecular pathways, particularly the β-catenin signaling pathway., and it might serve as a potential new target of β-catenin signaling pathway for treatment of LUAD.

Protein kinase C (PKC) isozymes play critical roles in diverse cellular processes and are implicated in numerous diseases, including cancer, diabetes, and autoimmune disorders. Despite extensive research efforts spanning four decades, only one PKC inhibitor has received clinical approval, highlighting the challenges in developing selective and efficacious PKC-targeting therapeutics. Here we review recent advances in the development of small-molecule PKC inhibitors, focusing on structural design strategies, pharmacological activities, and structure-activity relationships. We analyze emerging approaches including fragment-based drug design, allosteric targeting, and natural product derivatization that have yielded promising new scaffold classes. Special attention is given to innovations in achieving isozyme selectivity, particularly for PKCα and PKCβ, which have proven crucial for therapeutic applications. We discuss how integration of computational methods, structural biology insights, and rational design principles has advanced our understanding of PKC inhibition mechanisms. This comprehensive analysis reveals key challenges in PKC drug development, including the need for enhanced selectivity and reduced off-target effects, while highlighting promising directions for future therapeutic development. Our findings provide a framework for designing next-generation PKC inhibitors with improved clinical potential.

Reactive oxygen species (ROS) play a dual role in the chemotherapy of cancer with cisplatin, providing both anti-tumor effects and contributing to drug resistance at various stages of treatment which seriously affects treatment effectiveness. The detailed mechanism of ROS is urgently necessary to be explored. To address this issue in the non-small-cell lung cancer (NSCLC) with cisplatin-resistance, a reliable assay was developed by synthesizing and characterizing an interesting near-infrared (NIR) ONOO- probe BPB with high specificity, quick response (<30 s) and excellent limitation of detection (59 nM), which was further convinced through living cell imaging techniques providing different fluorescence variation between cell and cuvette. All the results revealed that ONOO- might be a practical biomarker to comprehend the detail molecular mechanism in cisplatin-resistant A549 cells. The elevated levels of ONOO- in cisplatin-resistant A549 cells, accompanied by a significant reduction in fluorescence following the knockout of miR-125a-5p in these cells and strong fluorescence without knockout of miR-125a-5p ignoring the presence of cisplatin. Comparing with cisplatin-resistant cells, the control would provide a rational background and then showed distinct fluorescence from BPB with ONOO- toward cisplatin. This assay offers a promising tool for exploring the molecular mechanisms associated with miR-125a-5p and its potential linkage to therapeutic efficacy involving ONOO- signaling. By utilizing this innovative assay, researchers can gain valuable insights into the treatment strategies and underlying mechanisms of cisplatin-resistant cancers, which should be beneficial to the therapy of cancers.

Lung cancer stands as the leading cause of cancer-related death worldwide, impacting both men and women in the United States and beyond. Radiation therapy (RT) serves as a key treatment modality for various lung malignancies. Our study aims to systematically assess the prognosis and influence of RT on metabolic reprogramming in patients diagnosed with nonsmall-cell lung cancer (NSCLC) through longitudinal metabolic profiling. A cohort of 54 NSCLC patients underwent thoracic radiotherapy, with 96% receiving a total radiation dose ranging from 40 to 70 Gy, averaging 56.3 Gy. Blood biospecimens were collected before RT, during RT, and at the first follow-up after RT, with a total of 126 serum samples randomized for liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis using a high-performance LC (HPLC)-Q-Exactive mass spectrometry system. Our results indicated that the serum metabolite coumarin derivatives prior to radiotherapy exhibited the strongest unfavorable outcome with overall survival in these NSCLC cases. The metabolites in the blood samples can reflect the responses during RT. Notably, over half of the metabolites (12/23) were found to be fatty acids in the longitudinal analysis. This pilot study indicated that metabolic profiling of biofluids from NSCLC patients undergoing RT has the potential to assess the patient outcomes during and after treatment.

Tractable, patient-relevant models are needed to investigate cancer progression and heterogeneity. Here, we report an alternative in vitro model of lung squamous cell carcinoma (LUSC) using primary human bronchial epithelial cells (hBECs) from three healthy donors. The co-operation of ubiquitous alterations (TP53 and CDKN2A loss) and components of commonly deregulated pathways including squamous differentiation (SOX2), PI3K signalling (PTEN) and the oxidative stress response (KEAP1) is investigated by generating hBECs harbouring cumulative alterations. Our analyses confirms that SOX2-overexpression initiates early preinvasive LUSC stages, and co-operation with the oxidative stress response and PI3K pathways to drive more aggressive phenotypes, with expansion of cells expressing LUSC biomarkers and invasive properties. This cooperation is consistent with the classical LUSC subtype. Importantly, we connect pathway dysregulation with gene expression changes associated with cell-intrinsic processes and immunomodulation. Our approach constitutes a powerful system to model LUSC and unravel genotype-phenotype causations of clinical relevance.

Cigarette smoke (CS) creates a "cancer field" in the lung that promotes malignant transformation. The molecular changes within this field are not fully characterized. We examined the significance of microRNA-1 (miR-1) downregulation as one of these changes. We found that tumor miR-1 levels in three non-small cell lung cancer cohorts show inverse correlations with the smoking burden. Lung MiR-1 levels follow a spatial gradient, have prognostic significance, and correlate inversely with the molecular markers of injury. In CS-exposed lungs, miR-1 is specifically downregulated in the endothelium. Exposure to CS induces angiogenesis by selectively degrading mature miR-1 via a vascular endothelial growth factor-driven pathway. Applying a multi-step molecular screen, we identified angiogenic genes regulated by miR-1 in the lungs of smokers. Knockdown of one of these genes, Notch homolog protein 3, simulates the anti-angiogenic effects of miR-1. These findings suggest that miR-1 can be used as an indicator of malignant transformation.

"Epidermal growth factor receptor (EGFR)" mutations are pivotal in the pathogenesis of "Non-Small Cell Lung Cancer (NSCLC)," which is associated with high morbidity and mortality rates. The advent of third and fourth-generation EGFR tyrosine kinase inhibitors (TKIs) has significantly advanced the therapeutic landscape for EGFR-mutant NSCLC, particularly in overcoming resistance mutations such as T790M and C797S. This review delves into the current clinical status, efficacy, safety profiles, and regulatory approvals of third-generation EGFR TKIs, including Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Rezivertinib, Befotertinib, Sunvozertinib. Furthermore, it explores emerging fourth-generation EGFR TKIs designed to address resistance mechanisms beyond those targeted by their predecessors. Notable fourth-generation candidates such as TQB3804, BPI-361175, BDTX-1535, WJ13404, QLH11811, H002, HS-10375, BBT-207, JIN-A02, and HS-10504 are highlighted for their potential to overcome the C797S mutation. The review emphasizes the importance of these advanced inhibitors in enhancing "progression-free survival and overall survival rates". By evaluating the therapeutic potential and limitations of these EGFR TKIs, this review aims to guide future research in the management of EGFR-mutant NSCLC. This acts as guiding beacon for the strategic design and development of third and fourth generation EGFR-TK inhibitors to overcome the drug resistance hurdles in the development of EGFR-TK inhibitors.

Brain metastases frequently occur in patients with non-small cell lung cancer (NSCLC) and are associated with poor prognosis and shortened overall survival, despite the advances in both imaging and therapeutic fields. Data are scarce regarding the utility of brain magnetic resonance imaging (MRI) screening in NSCLC patients. We aimed to characterize the impact of brain MRI screening on stage IV NSCLC patients and their survival.

A retrospective analysis was performed in 609 newly-diagnosed patients with stage IV NSCLC treated at our center during 2019-2020. Patients with neurological symptoms at presentation were excluded (n = 230). The remaining 379 patients comprised the study group and were divided into two groups - those who underwent brain MRI screening within 12 weeks of diagnosis (n = 170), and those who did not (n = 209). The clinical data retrieved from patients' medical files included demographics, performance status (PS), brain metastases during follow-up, tumor molecular profiling, and oncology treatment.

Median survival among patients who underwent brain MRI screening was 24 months from diagnosis, versus 18 months for those who did not (p = 0.003). Among patients with good PS (ECOG 0-2), median OS was longer among patients who underwent screening MRI (25 months), versus those who did not (21 months) (p = 0.025). Among patients with low PS (ECOG 3-4), the between-group difference for OS did not reach statistical significance.

Our study supports the use of brain MRI screening among good PS patients diagnosed with stage IV NSCLC lung cancer. Brain MRI screening correlated with better survival among patients with good functional status in this patient population.

Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer, causing a considerable number of deaths globally. Mitochondrial dysfunction was found to promote malignant progression. However, the underlying mechanism remains unclear. Acyl-CoA synthetase short chain family member 3 (ACSS3) is mainly located in mitochondria, which abnormal regulation is usually accompanied by the occurrence and development of tumors. In this study, we found that the expression level of ACSS3 was correlated with poor prognosis in patients with NSCLC. Moreover, we demonstrated that ACSS3 knockdown led to mitochondrial contraction, increased reactive oxygen species levels, decreased mitochondrial membrane potential, and subsequently inhibited tumor growth of NSCLC cells in vitro and in vivo, whereas its overexpression promoted these processes. Mechanistically, ACSS3 knockdown promoted ferroptosis through transcriptional control of SLC7A11 and GPX4. Further investigations indicated that ACSS3 loss inhibited the SLC7A11/GPX4 axis by enhancing p53 stability. Taken together, our data confirmed that ACSS3 promotes NSCLC tumorigenesis through inhibiting the p53-mediated ferroptosis. Hence, ACSS3 emerges as a promising therapeutic target for NSCLC treatment.

Osimertinib is a third-generation EGFR-TKI and preferred first-line (1L) treatment for EGFR positive (EGFR+) metastatic non-small cell lung cancer (mNSCLC). This study compared real-world clinical outcomes of 1L osimertinib versus 1st or 2nd generation EGFR-TKIs (1/2G-TKIs) in patients with EGFR+ mNSCLC.

Nine academic cancer centers in the US participated in the retrospective cohort study. Patients aged ≥18 years with EGFR+ mNSCLC and treated with 1L EGFR-TKI were included. Clinical outcomes included real-world progression-free survival (rwPFS), duration of treatment (DOT), time to next treatment (TTNT), central nervous system incidence-free survival (CNS-IFS), and overall survival (OS). Multivariable regression models were used to control for differences in patient characteristics (p < 0.1) between the osimertinib and 1/2G-TKI cohorts.

The study included 181 osimertinib patients and 171 1/2G-TKI patients. Osimertinib had a longer rwPFS compared to 1/2G-TKIs (median PFS, 95 % confidence interval [CI]: 16.2 months (13.2-19.7) vs. 10.8 months (9.5-12.7); hazard Ratio [HR], 95 % CI: 0.60 (0.44-0.82). DOT and TTNT were significantly longer in patients treated with osimertinib versus 1/2G-TKI (HR, 95 % CI: 0.51 (0.38-0.68) for DOT; 0.54 (0.39-0.74) for TTNT). The respective HR point estimate for CNF-IFS and OS of 0.62 and 0.83 preferred osimertinib. However, small patient counts and number of events posed challenges in drawing conclusion regarding the significance of the delayed CNS-IFS or OS.

Patients treated with osimertinib had a prolonged time to progression and longer time maintain the treatment compared to 1/2G-TKI. This real-world evidence is aligned with clinical trial results.

Immune checkpoint inhibitor (ICI) has displayed considerable advantages in consolidation therapy of locally advanced non-small cell lung cancer (LA-NSCLC) after concurrent chemoradiotherapy (cCRT). However, many patients are considered unsuitable for cCRT owing to concerns with tolerability. In this study, we aimed to assess the efficacy and toxicity of induction immunochemotherapy followed by radiotherapy for unresectable LA-NSCLC who are not capable of receiving cCRT.

From January 2019 and December 2022, LA-NSCLC patients treated with induction immunochemotherapy followed by radiotherapy as initial treatment at our institution were retrospectively reviewed. The short-term efficacy, overall survival (OS), progression free survival (PFS) and tolerability of induction immunochemotherapy followed by radiotherapy were evaluated in these patients.

Overall, 24 patients were enrolled (median age 64 years, 33.3% with ECOG performance status score 2, and 62.5% with stage IIIB-IIIC). Median follow-up from the start of induction immunochemotherapy was 30.5 months. Median number of induction immunochemotherapy was 4 cycles. A median radiotherapy dose of 60 Gy was delivered. After radiotherapy, 16 patients (66.6%) received consolidation immunotherapy. The overall response rate in these patients was 87.5%. The 1-year, 2-year and 3-year OS were 91.7%, 74.8% and 57.0%, respectively. The 1-year, 2-year and 3-year PFS were 87.0%, 54.1% and 37.1%, respectively. The incidence of grade ≥ 2 and grade ≥ 3 pneumonitis were 37.5% and 16.7%, respectively. Radiation pneumonitis of any grade occurred in 8 patients (33.3%), and the incidence of grade ≥ 2 and grade ≥ 3 radiation pneumonitis were 16.7% and 12.5%, respectively.

Induction immunochemotherapy followed by radiotherapy and consolidated immunotherapy had encouraging efficacy with acceptable toxicity for LA-NSCLC not capable of receiving cCRT.

The management of Lung cancer, especially non-small cell lung cancer has undergone a paradigm shift recently with the advent of new treatment approaches including focused radiotherapy as well as evolution of a newer class of immunotherapy agents. Treatment efficacy and survival rates have improved and it is now even more important that patients are selected for appropriate interventions on the basis of a comprehensive assessment including a range of imaging as well as in-vitro tests such as immunohistochemistry. A new class of tracers targeting programmed cell death such as PD1 and PDL1 (broadly classed as Immuno PET) are being increasingly used in the molecular characterisation of patients deemed resistant to standard treatment approaches and being considered for additional interventions such as immunotherapy. In this review, we review the latest evidence in the field and propose a summary of clinical usefulness and provide a review of the research trends in this exciting and evolving field.

Adults with interstitial lung disease (ILD) have a higher risk of developing lung cancer compared to the general population. We aimed to identify ILD-specific risk factors that can be used to improve lung cancer detection in this high-risk population.

Adults ≥21 years who received at least two chest CT scans at an academic medical center between 2005 and 2020 and were found to have ILD were studied retrospectively. Lung cancer diagnoses were adjudicated based on pathology reports from lung biopsies. Logistic regression was used to evaluate associations of clinical variables with comorbid lung cancer.

Among 1,366 adults with ILD, the mean age was 67.2 ± 12.4 years and 639 (46.8 %) were men. In total, 227 adults (16.6 %) had a lung nodule on CT imaging, of whom 55 (24.3 %) were diagnosed with lung cancer. Radiographic usual interstitial pneumonia (UIP) (OR 3.00, 95 % CI 1.43-6.33) was independently associated with increased odds of lung cancer. Risk factors including age, sex, smoking status, pack-years, use of immunosuppression, and radiographic fibrosis pattern collectively demonstrated high discriminative accuracy in predicting comorbid lung cancer, even among adults who would not have qualified for lung cancer screening based on current guidelines (AUC 0.80, 95 % CI 0.72-0.88).

In a large study of adults with ILD, radiographic UIP was independently associated with comorbid lung cancer even after adjusting for established risk factors. Our results suggest radiographic UIP is an independent lung cancer risk factor and support the development of targeted lung cancer screening guidelines in adults with UIP.

Non-small-cell lung cancer (NSCLC) is one of the most malignant tumors and the leading cause of death from cancer worldwide and is increasing at a massive rate every year. Most NSCLC patients are diagnosed at advanced stages, which is associated with a poor prognosis and a very low 5-year survival rate. Therefore, the purpose of this study is to investigate molecular markers for early diagnosis, prognosis and therapy of NSCLC through the integration of bioinformatics and statistical methods. A total of 93 overlapping differentially expressed genes (oDEGs) were identified between NSCLC and normal samples through Linear Models for Microarray (LIMMA) and Significance Analysis of Microarrays (SAM) methods. Six top-degree oDEGs (CCNA2, CDC6, AURKA, CCNB1, MKI67, and PRC1) were identified as key genes (KGs) through the protein-protein interaction (PPI) network. The predictive accuracy analysis of the identified KGs revealed an accuracy of 96.92 %, with a sensitivity of 91.73 % and a specificity of 98.15 %. KGs associated with 3 molecular functions (MFs), 5 cellular components (CCs), 3 biological processes (BPs), and 4 pathways were identified through FunRich software. Analysis of expression levels using the UALCAN database revealed that KGs are significantly associated with potential early diagnostic biomarkers. Survival analysis using the GEPIA database demonstrated that the KGs possessed strong prognostic power for NSCLC. Finally, seven repurposed candidate drugs ENTRECTINIB, SORAFENIB, CHEMBL1765740, TOZASERTIB, NERVIANO, AZD-1152-HQPA, and SELICICLIB were proposed through molecular docking analysis. In conclusion, the findings of this study have the potential to significantly impact the early diagnosis, prognosis, and treatment of NSCLC.

Non-small cell lung cancer (NSCLC) remains one of the most prevalent and deadly malignancies. Despite advancements in molecular therapies and diagnostic methods, the 5-year survival rate for lung adenocarcinoma patients remains unacceptably low, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, a distinct form of regulated cell death, has emerged as a promising target in cancer treatment. This study investigates the role of TMEM164, a membrane protein, in promoting ferroptosis and modulating anti-tumor immunity in NSCLC, aiming to elucidate its therapeutic potential.

Using publicly available datasets, we performed bioinformatics analyses to identify TMEM164-regulated genes involved in ferroptosis. In addition, in vitro and in vivo assays were conducted to assess the impact of TMEM164 on cellular functions in NSCLC.

Functional assays demonstrated that TMEM164 overexpression significantly inhibited invasion, migration, and cell proliferation in both in vitro and in vivo models. TMEM164 was also found to induce ferroptosis in NSCLC cells by promoting autophagy. Specifically, we identified a mechanism whereby TMEM164 mediates ATG5-dependent autophagosome formation, leading to the degradation of ferritin, GPX4, and lipid droplets. This degradation facilitated iron accumulation and lipid peroxidation, which triggered iron-dependent cell death. Notably, co-administration of TMEM164 upregulation and anti-PD-1 antibodies exhibited synergistic anti-tumor effects in a mouse model.

These findings suggest that targeting TMEM164 to enhance ferroptosis and stimulate anti-tumor immunity may inhibit NSCLC progression. Consequently, TMEM164 holds promise as a new therapeutic target for NSCLC treatment.

To evaluate the association between sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and the risk of neoplasm in patients with Type 2 diabetes (T2D).

Literature retrieval was conducted using databases from inception to June 2024. Randomized controlled trials (RCTs) comparing SGLT-2i with placebo or other treatments in patients with T2D, and with reports of neoplasm events were included. Results were computed as the risk ratio (RR) with 95% confidence intervals (CI).

A total of 53 RCTs with 126,232 participants were included. No significant differences were found for the risk of overall neoplasm (RR = 1.08, 95% CI: 0.99 to 1.19, I2 = 23%) in patients with SGLT-2i treatment compared with non-users. However, decreased risk of pulmonary neoplasm (RR = 0.83, 95% CI: 0.69 to 0.99, I2 = 0.0%) was observed in SGLT-2i users compared to non-users, while increased risk of prostate neoplasm in SGLT-2i users was found (RR = 1.21, 95% CI: 1.00 to 1.47, I2 = 0.0%).

Compared with non-users, the use of SGLT-2i was not associated with the risk of overall neoplasm. However, pulmonary neoplasms were less frequent in SGLT-2i users, while an increased risk of prostate neoplasm was observed in SGLT-2i users compared to non-users.

www.crd.york.ac.uk/prospero identifier is CRD42021273681.

To date, no direct comparisons have been performed to compare the effectiveness of all epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) against EGFR mutation-positive non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy and safety of EGFR-TKIs in patients with EGFR mutation-positive NSCLC.

We conducted a network meta-analysis of randomized controlled trials comparing osimertinib, lazertinib, aumolertinib, befotertinib, furmonertinib, dacomitinib, afatinib, erlotinib, gefitinib, icotinib, and chemotherapy. Pooled estimations of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity (grade ≥ 3 adverse events) were performed within the Bayesian framework.

Twenty-three trials involving 11 treatments were included. All EGFR-TKIs improved PFS relative to chemotherapy, except for icotinib (hazard ratio [HR] = 0.61, 95% confidence interval [CI]: 0.26-1.44). All EGFR-TKIs demonstrated significant ORR benefits over chemotherapy. Osimertinib seemed to prolong PFS compared with icotinib (HR = 0.29, 95% CI: 0.1-0.86), gefitinib (HR = 0.39, 95% CI: 0.21-0.74), and erlotinib (HR = 0.53, 95% CI: 0.29-1.0). In addition, osimertinib showed favorable superiority in improving OS compared with chemotherapy (HR = 0.6, 95% CI: 0.43-0.82), gefitinib (HR = 0.61, 95% CI: 0.45-0.83), erlotinib (HR = 0.65, 95% CI: 0.48-0.89), and afatinib (HR = 0.65, 95% CI: 0.44-0.94). Among these regimens, afatinib showed the highest ORR (cumulative probability: 96.96%). Icotinib was associated with minimal toxicity among the EGFR-TKIs, followed by furmonertinib and osimertinib. Moreover, the toxicity spectra differed among the EGFR-TKIs. Subgroup analyses of patients with two common types of EGFR mutations indicated that furmonertinib possessed the greatest PFS benefit in patients with exon 19 deletion, and lazertinib showed the greatest PFS benefit in patients with Leu858Arg mutation. We also identified differences between EGFR-TKIs in prolonging PFS in patients with brain metastasis.

Osimertinib is the first choice of treatment with considerable efficacy and safety for EGFR mutation-positive NSCLC. The treatments associated with the best PFS in patients with exon 19 deletions and Leu858Arg mutations were furmonertinib and lazertinib, respectively.

Cellular senescence and hypoxia-inducible factor (HIF) signaling are crucial in pulmonary aging and age-related lung diseases such as chronic obstructive pulmonary disease idiopathic pulmonary fibrosis and lung cancer. HIF plays a pivotal role in cellular adaptation to hypoxia, regulating processes like angiogenesis, metabolism, and inflammation. Meanwhile, cellular senescence leads to irreversible cell cycle arrest, triggering the senescence-associated secretory phenotype which contributes to chronic inflammation, tissue remodeling, and fibrosis. Dysregulation of these pathways accelerates lung aging and disease progression by promoting oxidative stress, mitochondrial dysfunction, and epigenetic alterations. Recent studies indicate that HIF and senescence interact at multiple levels, where HIF can both induce and suppress senescence, depending on cellular conditions. While transient HIF activation supports tissue repair and stress resistance, chronic dysregulation exacerbates pulmonary pathologies. Furthermore, emerging evidence suggests that targeting HIF and senescence pathways could offer new therapeutic strategies to mitigate age-related lung diseases. This review explores the intricate crosstalk between these mechanisms, shedding light on how their interplay influences pulmonary aging and disease progression. Additionally, we discuss potential interventions, including senolytic therapies and HIF modulators, that could enhance lung health and longevity.

Extracellular vesicles (EVs) are endogenous vesicles secreted by cells. Exosomes (30-150 nm), are a subset of EVs playing key roles in intercellular communication. Exosomes show promise as cancer chemotherapeutic drug delivery vehicles given their low immunogenicity and cell-specific cytosolic delivery of their contents. However, inefficient drug loading limits their therapeutic application. To address this, methods for the fusion of EVs with therapeutic drug-loaded synthetic liposomes have been developed. While more efficient than passive incubation of EVs with liposomes, these risk either damage to EV membrane proteins or contamination of the EV-liposome hybrids with residual depletant molecules, which can cause side effects or hinder content delivery. Here, we present a new, weakly perturbative method, which uses acidic conditions (pH 5) to enhance the fusion of EVs and synthetic, neutral liposomes (NLs) compared to passive incubation in pH 7.4 at 37 °C. An adapted Forster resonance energy transfer (FRET) based lipid mixing assay confirms that fusion is enhanced with this method, albeit less efficiently than with depletant-induced fusion. This significant finding implies that lipid-only synthetic liposomes can fuse with EVs, creating EV-liposome hybrids under relevant temperature and pH conditions, without nonlipidic components, such as fusogenic amphipathic peptides, added to the synthetic liposomes. Remarkably, differential interference contrast (DIC) and fluorescence microscopy show that this enhanced fusion corresponds with the clustering of mixtures of EVs and NLs, or EVs alone, in acidic but not neutral pH conditions. The findings support a hypothesis that content release from EVs in early to late endocytic environments may be a combination of protein-protein clustering interactions and a lipidic component. Further, this study provides a novel method for enhanced fusion of EVs and liposomes, which is expected to preserve EV membrane proteins and functionality toward the development of therapeutic hybrid drug delivery vehicles in nanomedicine applications.

One-year of immune checkpoint inhibitor (ICI) treatment after concurrent chemoradiation (CCRT) in unresectable stage III non-small cell lung cancer (NSCLC) is a standard of care. The precise predictive biomarkers are under investigations either immunological markers or clinical characteristics. Here, we explored immune repertoire of T cell receptor β-chain (TCRβ) during ICI treatment.

During August 2019 and September 2021, stage III NSCLC, post CCRT patients from Ramathibodi Hospital was enrolled. All patients were treated by durvalumab after CCRT. Blood samples were collected together with clinical data and tumor assessment every 3-4 months until disease progression or discontinuation of treatment due to adverse events. CDR3 region and TCRΒ polymorphisms was explored by RNA sequencing using Next-Generation Sequencing (NGS) TCR beta short-read assay. Bioinformatic analysis was performed to analyze clonal diversity, TCR convergence frequency and the Shannon diversity from each timepoint. Immune repertoire and clinical correlation were explored using Spearman's correlation and Pearson's correlation. RStudio software version 2021 build 372 was used for analyses. A significance level was at P < 0.05.

Forty-four blood samples from 12 patients were analyzed. Mean duration of durvalumab treatment was 284 days. After durvalumab treatment, increasing of TCR convergence frequency was found compared to baseline (R = 0.36). Interestingly, it was also significantly higher in non-progressive disease (non-PD) patients compared with progressive disease (PD) patients (P = 0.011). Furthermore, Shannon diversity was higher increasing in PD patients compared with non-PD patients. Taken together, our study found that increasing of TCR convergence with less T-cell diversity in non-PD patients probably demonstrated a T cell-specific clonal expansion response to durvalumab treatment in this population.

TCRβ repertoire is the potential biomarker for predicting durvalumab treatment response in post CCRT stage III NSCLC patients. However, a larger cohort with long-read assay should be explored.

The long-term outlook for patients grappling with lung cancer (LC) remains bleak, with lung adenocarcinoma (LUAD) emerging as the most predominant histological subtype. Our Mendelian randomization (MR) investigation spotlighted that heightened levels of the circulating protein serpin peptidase inhibitor family G1 (SERPING1) substantially mitigated LC risk. The fusion of multi-omics strategies unveiled that SERPING1 exhibited diminished expression in LUAD patients compared to healthy individuals both in tissues and serum, with LUAD individuals showcasing elevated SERPING1 expression demonstrating improved prognoses. Furthermore, SERPING1 expression exhibited a robust correlation with the efficacy of immunotherapy. Through meticulous in vivo and in vitro analyses, we unraveled that SERPING1 impeded the proliferation, migration, invasion and wound healing of LUAD cells via the tuberous sclerosis 2 (TSC2)/mammalian target of rapamycin (mTOR) pathway. Mechanistically, WNT inhibitor- Specificity Protein (SP5) was delineated as facilitator of SERPING1 transcription by binding to the SERPING1 gene promoter. Intriguingly, aside from the association between SERPING1 and systolic blood pressure, glycosylated hemoglobin (HbA1c), type I diabetes, no discernible link between SERPING1 overexpression and heightened risks of other cardiometabolic conditions and diseases was evident. In summary, SERPING1 emerges as a novel tumor suppressor gene and SP5/SERPING1/TSC2 is a promising therapeutic target in the context of LUAD.

Lung cancer, a significant global health challenge, notably the non-small-cell lung cancer (NSCLC) subtype, is a topic of utmost importance. The continuous advancements in NSCLC treatment, especially in the context of anaplastic lymphoma kinase (ALK)-positive NSCLC, are of great interest. A thorough review of alectinib's comparative efficacy and safety with other treatment modalities is a crucial step, and the role of clinicians and surgeons is integral in optimizing patient care. This review can also inform neoadjuvant therapies and enhance surgical education, facilitating more informed decision-making processes between surgeons and patients.

This comprehensive systematic review results from rigorous screening. Following a rigorous screening process of the PubMed, PubMed Central, and Medline databases by quality assessment and application of inclusion/exclusion criteria filters, 9 relevant articles were identified that directly addressed the research question and provided a holistic understanding of it. The analysis included a total of 1403 patients from 9 different studies. Alectinib was given to 836 patients, while 567 patients received other chemotherapeutic drugs. The primary objective of this study was to evaluate and compare the efficacy of alectinib with other treatment modalities.

The analysis revealed that alectinib is promising for ALK-positive NSCLC cases, with significantly better efficacy and a positive impact on limiting central nervous system metastases. Alectinib's favorable safety profile, with medically manageable adverse events, provides reassurance about its safety compared with other treatment modalities.

Alectinib has emerged as a viable, significantly superior treatment option for patients with ALK-positive NSCLC. The superior efficacy and manageable safety profile are significant; it remains a novel therapy with much potential, such as neoadjuvant therapy, which will make significant strides in patient care of ALK-positive NSCLC. Therefore, it is crucial for healthcare professionals, including surgeons, to be well-versed in alectinib and its potential. This knowledge will empower them and instill confidence in their ability to provide the best care for their patients.

Increased stemness of cancer cells exacerbates radioresistance, thereby greatly limiting the efficacy of radiotherapy. In order to study the changes in cancer cell stemness during radiotherapy, we established a radioresistance model of human non-small cell lung cancer A549 cells and obtained A549 radioresistant cells (A549-RR). We sampled the cells at different time points during the modeling process and investigated the heterogeneity of each group of cells using single-cell sequencing. Cells in the early stages of fractionated irradiation were found to be significantly up-regulated in stemness, and a subpopulation of cells producing this response was screened and referred to as "radiation-induced stemness-responsive cancer cells". They were undergoing stemness response, energy metabolism reprogramming, and progressively differentiating into cells with more diverse and malignant phenotypes in order to attenuate the killing effect of radiation. Furthermore, we demonstrated that such responses might be driven by the activation of the EGFR-Hippo signaling pathway axis, which also plays a crucial role in the development of radioresistance. Our study reveals the dynamic evolution of cell subpopulation in cancer cells during fractionated radiotherapy; the early stage of irradiation can determine the destiny of the radiation-induced stemness-responsive cancer cells. The activation of stemness-like phenotypes during the development of radioresistance is not the result of dose accumulation but occurs during the early stage of radiotherapy with relatively low-dose irradiation. The degree of the radiation-induced stemness response of cancer cells mediated by the EGFR-Hippo signaling pathway might be a potential predictor of the efficacy of radiotherapy and the development of radioresistance.

This study reports a simple and rapid aptamer-based sensor platform designed for the sensitive and selective detection of human non-small cell lung cancer (NSCLC) cells. Under standard conditions, gold nanoparticles (AuNPs) remain dispersed and exhibit a characteristic peak at 520 nm. However, the addition of sodium chloride (NaCl) destabilizes the charge of the solution, leading to the aggregation of AuNPs. The AS1411 aptamer can adsorb onto the surface of AuNPs, effectively preventing their aggregation. In the presence of A549 cells, the AS1411 aptamer is induced to form stable G-tetrads, which allows for specific binding to the cells and results in the aggregation of AuNPs in the NaCl solution. This proposed aptasensor platform demonstrates high specificity for A549 cells when compared to other control human normal cells. The method exhibits a dynamic range of 101 to 106 cells per mL, with a detection limit of 7 cells per mL.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, necessitating the exploration of alternate therapeutic approaches. Tumor-reactive or activated-by-cytokine killers (TRACK) are PD-L1+, highly cytolytic NK cells derived from umbilical cord blood NK cells and engineered to express soluble IL-15 (sIL15), and these cells show promise in preclinical studies against NSCLC.

We assessed safety, persistence, homing, and cytotoxic activity in 6 patients with advanced, refractory, and progressing NSCLC who received a low dose of unmatched, allogeneic, off-the-shelf sIL15_TRACK NK cells. We evaluated NK cell presence and persistence with droplet digital PCR (ddPCR), flow cytometry, and immunofluorescence staining.

sIL15_TRACK NK cells had peak measurements at 1 hour and became undetectable 4 hours after each infusion. Cognate ligands to activating NK cell receptors were found in NSCLC. sIL15_TRACK NK cells were observed in a lung tumor biopsy 7 days after the final infusion, confirming their sustainment and tumor-homing ability. They retained cytolytic function following isolation from the lung tumor. Three of 6 patients achieved disease stabilization on repeat imaging, while the others progressed.

Unmatched, allogeneic, cryopreserved, off-the-shelf sIL15_TRACK NK cells express activating receptors, home to tumor sites that express their cognate ligands, and retain cytolytic activity after infusion, underscoring their potential as a therapeutic approach in solid tumors. At low doses, the therapy was safely administered and showed preliminary evidence of activity in 3 of 6 patients with advanced and progressive NSCLC. Additional dose escalation cohorts and coadministration with atezolizumab are planned.

gov NCT05334329.

Funding was provided by CytoImmune Therapeutics and grants from the National Cancer Institute (CA266457, CA033572, and CA210087).

Neuropilin 1 (NRP1) is upregulated in various types of malignant tumors, especially non-small-cell lung cancer (NSCLC). However, the precise mechanisms for membrane localization and regulation are not fully understood. Observations from super-resolution microscopy have revealed that NRP1 tends to form nanoscale clusters on the cell membrane, with these clusters varying significantly in size and density across different regions. Further research has shown that stimulation by hepatocyte growth factor (HGF) can reorganize the distribution of NRP1, reducing the number of small clusters while promoting the formation of larger ones. This suggests a propensity for internalization after activation. Additionally, dual-color dSTORM imaging has demonstrated a certain degree of colocalization between NRP1 and c-MET, indicating that c-MET plays an important role in stabilizing NRP1 clusters. This study provides new insights into the mechanism behind NRP1's clustered distribution on cell membranes and paves the way for developing more effective therapeutic strategies targeting NRP1 within tumors.

Constitutively active mutations of KRAS are prevalent in non-small cell lung cancer (NSCLC). However, the relationship between these mutations and resistance to platinum-based chemotherapy and the underlying mechanisms remain elusive. In this study, we demonstrate that KRAS mutants confer resistance to platinum in NSCLC. Mechanistically, KRAS mutants mediate platinum resistance in NSCLC cells by activating ERK/JNK signaling, which inhibits AlkB homolog 5 (ALKBH5) N6-methyladenosine (m6A) demethylase activity by regulating posttranslational modifications (PTMs) of ALKBH5. Consequently, the KRAS mutant leads to a global increase in m6A methylation of mRNAs, particularly damage-specific DNA-binding protein 2 (DDB2) and XPC, which are essential for nucleotide excision repair. This methylation stabilized the mRNA of these 2 genes, thus enhancing NSCLC cells' capability to repair platinum-induced DNA damage and avoid apoptosis, thereby contributing to drug resistance. Furthermore, blocking KRAS-mutant-induced m6A methylation, either by overexpressing a SUMOylation-deficient mutant of ALKBH5 or by inhibiting methyltransferase-like 3 (METTL3) pharmacologically, significantly sensitizes KRAS-mutant NSCLC cells to platinum drugs in vitro and in vivo. Collectively, our study uncovers a mechanism that mediates KRAS-mutant-induced chemoresistance in NSCLC cells by activating DNA repair through the modulation of the ERK/JNK/ALKBH5 PTM-induced m6A modification in DNA damage repair-related genes.

To explore the value of dual-layer spectral computed tomography (DLCT)-based radiomics for predicting epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC).

DLCT images and clinical information from 115 patients with NSCLC were collected retrospectively and randomly assigned to a training group (n = 81) and a validation group (n = 34). A radiomics model was constructed based on the DLCT radiomic features by least absolute shrinkage and selection operator (LASSO) dimensionality reduction. A clinical model based on clinical and CT features was established. A nomogram was built combining the radiomic scores (Radscores) and clinical factors. Receiver operating characteristic (ROC) analysis and decision curve analysis (DCA) were used for the efficacy and clinical value of the models assessment.

A total of six radiomic features and two clinical features were screened for modeling. The AUCs of the radiomic model, clinical model, and nomogram were 0.909, 0.797, and 0.922, respectively, in the training group and 0.874, 0.691, and 0.881, respectively, in the validation group. The AUCs of the nomogram and the radiomics model were significantly higher than that of the clinical model, but no significant difference was found between them. DCA revealed that nomogram had the greatest clinical benefit at most threshold intervals.

Nomogram integrating clinical factors and pretreatment DLCT radiomic features can help evaluate the EGFR mutation status of patients with NSCLC in a noninvasive way.

Guidelines recommend epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small cell lung cancer (NSCLC) and initiation of first-line EGFR tyrosine kinase inhibitors (EGFR-TKIs) for EGFR mutation-positive (EGFRm) NSCLC. We analyzed a nationwide electronic health record-derived de-identified database to describe EGFR testing practices, treatment choice, and outcomes in patients from the United States (US) with advanced NSCLC.

Adults diagnosed with stage IIIB-IV NSCLC January 2015-January 2020, who received first-line treatment from a network of ∼280 US cancer clinics were included. Demographics/characteristics, EGFR status, time from advanced diagnosis to EGFR test result, first-line treatment, time from treatment initiation to discontinuation/death (TTD), next treatment/death (TTNTD), and overall survival (OS) were extracted.

12,577/16,309 (77 %) eligible patients had an EGFR test recorded; 1,914/12,577 (15 %) patients had EGFRm NSCLC. Of 1,778 patients with confirmed EGFRm NSCLC before first-line treatment, 75 % received first-line EGFR-TKIs, 11 % chemotherapy, 9 % immunotherapy, and 4 % other treatment. Of 136 patients with an EGFRm result after initiating first-line treatment, 13 % received EGFR-TKIs, 50 % chemotherapy, 19 % immunotherapy, and 18 % other treatment in first-line. Among patients with EGFRm NSCLC, median time from advanced diagnosis to EGFR test result was shorter in patients who received first-line EGFR-TKIs versus first-line chemotherapy/immunotherapy/other treatment. Patients treated with first-line EGFR-TKIs had significantly improved TTD/TTNTD versus those who received first-line chemotherapy/immunotherapy/other treatment (p < 0.001). OS was significantly longer in patients receiving treatment ≥21 versus <21 days after index (p < 0.001).

Nearly one-quarter of patients with advanced NSCLC in a US health network were not tested for EGFR mutations. Of patients who received a EGFRm result after initiating first-line treatment, 13 % received first-line EGFR-TKIs. These real-world data support the need to improve EGFR testing implementation and time to result to optimize first-line treatment for advanced NSCLC.

With the continuous advancements in modern medicine, significant progress has been made in the treatment of lung cancer. Current standard treatments, such as surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, have notably improved patient survival. However, the adverse effects associated with these therapies limit their use and impact the overall treatment process. Traditional Chinese medicine (TCM) has shown holistic, multi-target, and multi-level therapeutic effects. Numerous studies have highlighted the importance of TCM's role in the comprehensive management of lung cancer, demonstrating its benefits in inhibiting tumor growth, reducing complications, mitigating side effects, and enhancing the efficacy of conventional treatments. Here, we review the main mechanisms of TCM in combating lung cancer, inducing cancer cell cycle arrest and apoptosis. These include inhibiting lung cancer cell growth and proliferation, inhibiting cancer cell invasion and metastasis, suppressing angiogenesis and epithelial-mesenchymal transition (EMT), and modulating antitumor inflammatory responses and immune evasion. This paper aims to summarize recent advancements in the application of TCM for lung cancer, emphasizing its unique advantages and distinctive features. In promoting the benefits of TCM, we seek to provide valuable insights for the integrated treatment of lung cancer.

Metabolomics is a powerful tool that can be used to identify different stages in cancer development. In this study, the metabolomic profile of Lewis lung carcinoma (LLC) was characterized in C57BL/6 mice bearing LLC tumors. Magnetic resonance spectroscopy (nuclear magnetic resonance-NMR) was applied using a 400 MHz 1H NMR spectrometer. Two types of metabolites (polar and non-polar) were identified on LLC based on the analysis of methanol/water and chloroform extracts collected from lung cancer samples in mice. The investigated metabolomics show that the neoplastic processes of growing LLC on mice may affect carbohydrate; alanine and glutamate; leucine and isoleucine; lysine; creatine; and choline metabolism, whereas hypoxia states were identified due to elevated lactate in lung cancer tissues. The metabolomic profile of Lewis lung carcinoma could be considered to be a valuable biomarker in translational lung cancer research.

The liquid biopsy has gained significant attention in cancer diagnostics, with circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) being recognized as key biomarkers for tumor detection and monitoring. However, each biomarker possesses inherent limitations that restrict its standalone clinical utility, such as the rarity and heterogeneity of CTCs and the variable sensitivity and specificity of ctDNA assays. This highlights the necessity of integrating both biomarkers to maximize diagnostic and prognostic potential, offering a more comprehensive understanding of the tumor biology and therapeutic response. In this review, we summarize clinical studies that have explored the combined analysis of CTCs and ctDNA as biomarkers, providing insights into their synergistic value in diverse tumor types. Specifically, this paper examines the individual advantages and limitations of CTCs and ctDNA, details the findings of combined biomarker studies across various cancers, highlights the benefits of dual biomarker approaches over single-biomarker strategies, and discusses future prospects for advancing personalized oncology through liquid biopsies. By offering a comprehensive overview of clinical studies combining CTCs and ctDNA, this review serves as a guideline for researchers and clinicians aiming to enhance biomarker-based strategies in oncology and informs biosensor design for improved biomarker detection.

Drug resistance and off-target toxicity of cisplatin (CDDP) pose significant challenges in effectively treating non-small cell lung cancer (NSCLC). Recently, chemodynamic therapy (CDT), an emerging reactive oxygen species (ROS)-mediated tumor-specific therapeutic modality, has shown great potential in sensitizing multidrug resistance tumor cells. Herein, a glutathione (GSH)-responsive Pt(IV) prodrug-based oxidative stress nanoamplifier (CuBSO@PtC16) was developed for effective chemo/chemodynamic therapy to reverse CDDP resistance in NSCLC. CuBSO@PtC16, a lipid-coated nanoagent, was constructed by coordinating Cu2+ with l-buthioninesulfoximine (BSO) as the core framework, and Pt(IV) prodrug (PtC16) was concurrently loaded on the outer lipid bilayer. With appropriate particle size (∼35 nm) and good physiological stability, CuBSO@PtC16 efficiently accumulated at tumor tissue. Under high intracellular GSH levels, PtC16 was reduced to generate cytotoxic CDDP that induced cell-killing and boosted intracellular H2O2 levels, and the CuBSO core was disassembled to release Cu ions and BSO simultaneously. The released BSO could efficiently reduce the intracellular GSH content to weaken its detoxification effect on CDDP, leading to more Pt-DNA adduct formation and more severe DNA damage. Meanwhile, Cu ions catalyzed the intracellular elevated H2O2 into highly lethal •OH through Fenton-like reactions, and the reduction of GSH weakened the •OH elimination, which jointly amplified the intracellular oxidative stress levels, finally achieving enhanced chemo/chemodynamic therapeutic effect and reversing CDDP resistance in NSCLC. Therefore, this work offers an inspirational idea for effectively treating drug-resistant cancers. STATEMENT OF SIGNIFICANCE: Cisplatin (CDDP) faces challenges in treating non-small cell lung cancer (NSCLC) due to drug resistance and off-target toxicity. Herein, a GSH-responsive nanoreactor (CuBSO@PtC16) was developed for effective chemo/chemodynamic therapy to address CDDP resistance. CuBSO@PtC16 could efficiently traffic to tumor site and response to high GSH levels in tumor cells to release CDDP, Cu ions and buthioninesulfoximine (BSO) simultaneously. CDDP could induce DNA damage and boost intracellular H2O2 levels, which then served as the substrate of Cu to induce •OH generation through Fenton-like reactions. Meanwhile, the released BSO efficiently reduced the intracellular GSH content to weaken its detoxification effect on CDDP and the elimination of the •OH, leading to amplified intracellular oxidative stress and more severe damage to induce cell death.

Classification of adenocarcinoma (AC) and squamous cell carcinoma (SCC) poses significant challenges for cytopathologists, often necessitating clinical tests and biopsies that delay treatment initiation. To address this, we developed a machine learning-based approach utilizing resected lung-tissue microbiome of AC and SCC patients for subtype classification. Differentially enriched taxa were identified using LEfSe, revealing ten potential microbial markers. Linear discriminant analysis (LDA) was subsequently applied to enhance inter-class separability. Next, benchmarking was performed across six different supervised-classification algorithms viz. logistic-regression, naïve-bayes, random-forest, extreme-gradient-boost (XGBoost), k-nearest neighbor, and deep neural network. Noteworthy, XGBoost, with an accuracy of 76.25%, and AUROC (area-under-receiver-operating-characteristic) of 0.81 with 69% specificity and 76% sensitivity, outperform the other five classification algorithms using LDA-transformed features. Validation on an independent dataset confirmed its robustness with an AUROC of 0.71, with minimal false positives and negatives. This study is the first to classify AC and SCC subtypes using lung-tissue microbiome.

Animal models have become veritable tools in gaining insight into the pathogenesis and progression of several human diseases. These models could range in complexity from Caenorhabditis elegans to non-human primates. With the aid of these animal models, a lot of new knowledge has been gained about several diseases which otherwise would not have been possible. Most times, the utilization of these animal models is predicated on the level of homology they share with humans, which suggests that outcomes of studies using them could be extrapolated to humans. However, this has not always been the case. Drosophila melanogaster is becoming increasingly relevant as preferred model for understanding the biochemical basis of several human diseases. Apart from its relatively short lifespan, high fecundity and ease of rearing, the simplicity of its genome and lower redundancy of its genes when compared with vertebrate models, as well as availability of genetic tool kit for easy manipulation of its genome, have all contributed to its emergence as a valid animal model of human diseases. This review aimed at highlighting the contributions of selected animal models in biomedical research with a focus on the relevance of Drosophila melanogaster in understanding the biochemical basis of some diseases that have continued to plague mankind.