Clinical and Genetic Characteristics of Early-Onset Lung Adenocarcinoma in a Large Chinese Cohort.

BACKGROUND: The characteristics of early-onset lung adenocarcinoma (EOLA) have not been extensively studied. Our research aimed to comprehensively assess the clinical and genetic features of EOLA. METHODS: We conducted a retrospective analysis of surgically resected lung adenocarcinoma patients, categorizing them into the EOLA group (aged <40 years) and the late-onset lung adenocarcinoma (LOLA) group (aged >60 years). A comparative investigation of clinical, germline, and genomic features was conducted. Propensity score matching was used to balance baseline characteristics for gene mutation analysis. RESULTS: We enrolled 487 EOLA and 2507 LOLA patients. EOLA patients exhibited a higher female-to-male ratio (2.55 vs 1.19) and a higher proportion of family history of lung cancer in the ground-grass opacity subgroup (12.7% vs 8.9%). The EOLA group exhibited higher rates of earlier stage in the ground-grass opacity subgroup and solid subgroup. Preinvasive adenocarcinoma was the dominant histologic subtype in the EOLA group within the ground-glass opacity subgroup (73.8% vs 25.6%). After propensity score matching, we analyzed 241 stage 0/I patients with available genetic test results. Significant disparities in gene mutation rates emerged between the EOLA and LOLA patients, including Erb-B2 receptor tyrosine kinase 2 (ERBB2; 38.0% vs 2.8%), epidermal growth factor receptor (EGFR; 36.0% vs 64.5%), MET (0.0% vs 7.1%), neurofibromin 1 (NF1; 0.0% vs. 5.7%), and anaplastic lymphoma kinase (ALK) fusion (10.0% vs 1.4%). CONCLUSIONS: EOLA patients exhibited distinct clinical and genetic characteristics compared with LOLA patients.

Bidirectional Mendelian Randomization of Causal Relationship between Inflammatory Cytokines and Different Pathological Types of Lung Cancer.

Prior research has proposed a potential association between lung cancer and inflammatory cytokines, yet the specific causal relationship remains unclear, especially across various lung cancer pathologies. This study utilized bidirectional Mendelian randomization (MR) to explore these causal connections, unveiling novel insights. Our research revealed distinctive inflammatory cytokine profiles for each subtype of lung cancer and identified potential biomarkers that could refine diagnostic and therapeutic approaches. We applied two-sample Mendelian randomization, leveraging genetic variance data from three extensive genome-wide association studies (GWAS) focusing on different lung cancer types (lung adenocarcinoma: 1590 cases and 314,193 controls of healthy individuals of European descent; lung squamous cell carcinoma: 1510 cases and 314,193 controls of European ancestry; small cell lung cancer: 717 cases and 314,193 controls of European ancestry). A separate GWAS summary on inflammatory cytokines from 8,293 healthy participants was also included. The inverse variance weighting method was utilized to examine causal relationships, with robustness confirmed through multiple sensitivity analyses, including MR-Egger, weighted median, and MR-PRESSO. Our analysis revealed that elevated levels of IL_1RA were associated with an increased risk of lung adenocarcinoma (OR: 1.29, 95% CI: 1.02-1.64, p = 0.031), while higher MCP_1_MCAF levels correlated with a decreased risk of lung squamous cell carcinoma (OR: 0.77, 95% CI: 0.61-0.98, p = 0.031). Furthermore, IL_10, IL_13, and TRAIL levels were positively associated with lung squamous cell carcinoma risk (IL_10: OR: 1.27, 95% CI: 1.06-1.53, p = 0.012; IL_13: OR: 1.15, 95% CI: 1.06-1.53, p = 0.036; TRAIL: OR: 1.15, 95% CI: 1.06-1.53, p = 0.043). No association was found between inflammatory cytokine levels and small cell lung cancer development, whereas SDF_1A and B-NGF were linked to an increased risk of this cancer type (SDF_1A: OR: 1.13, 95% CI: 1.05-1.21, p = 0.001; B-NGF: OR: 1.13, 95% CI: 1.01-1.27, p = 0.029). No significant relationship was observed between the 41 circulating inflammatory cytokines and lung adenocarcinoma or squamous cell carcinoma development. Our findings indicate distinct associations between specific inflammatory cytokines and different types of lung cancer. Elevated IL_1RA levels are a risk marker for lung adenocarcinoma, whereas higher MCP_1_MCAF levels appear protective against lung squamous cell carcinoma. Conversely, elevated levels of IL_10, IL_13, and TRAIL are linked with an increased risk of lung squamous cell carcinoma. The relationships of SDF_1A and B-NGF with small-cell lung cancer highlight the complexity of inflammatory markers in cancer development. This study provides a nuanced understanding of the role of inflammatory cytokines in lung cancer, underscoring their potential in refining diagnosis and treatment strategies.

Quiescent Adult Neural Stem Cells: Developmental Origin and Regulatory Mechanisms.

The existence of neural stem cells (NSCs) in the adult mammalian nervous system, although small in number and restricted to the sub-ventricular zone of the lateral ventricles, the dentate gyrus of the hippocampus, and the olfactory epithelium, is a gift of evolution for the adaptive brain function which requires persistent plastic changes of these regions. It is known that most adult NSCs are latent, showing long cell cycles. In the past decade, the concept of quiescent NSCs (qNSCs) has been widely accepted by researchers in the field, and great progress has been made in the biology of qNSCs. Although the spontaneous neuronal regeneration derived from adult NSCs is not significant, understanding how the behaviors of qNSCs are regulated sheds light on stimulating endogenous NSC-based neuronal regeneration. In this review, we mainly focus on the recent progress of the developmental origin and regulatory mechanisms that maintain qNSCs under normal conditions, and that mobilize qNSCs under pathological conditions, hoping to give some insights for future study.

Efficacy and safety of microwave ablation and its synergistic potential in the treatment of early-stage non-small cell lung cancer.

Lung cancer remains the primary cause of cancer-related mortality globally. In the case of early-stage non-small cell lung cancer (NSCLC), surgical resection, such as lobectomy and sub-lobectomy, continues to be the established standard treatment. However, for patients with insufficient cardiopulmonary function and multiple comorbidities who are unable to undergo surgical resection, nonoperative local therapies, including radiotherapy and thermal ablation, are preferred. In recent years, microwave ablation (MWA) has gained popularity for treating early-stage NSCLC due to its high heating efficiency, good tissue conductance, and heat conduction capabilities. This review provides a comprehensive summary of the current efficacy and safety data regarding MWA for early-stage NSCLC and discusses the potential benefits of combining MWA with other therapies.

Evidence for developmental vascular-associated necroptosis and its contribution to venous-lymphatic endothelial differentiation.

During development, apoptosis removes redundant cells and ensures proper organ morphogenesis. Necrosis is long known as an adult-bound inflammatory and pathologic cell death. Whether there exists physiological necrosis during early development has been speculated but yet clearly demonstrated. Here, we report evidence of necroptosis, a type of programmed necrosis, specifically in perivascular cells of cerebral cortex and skin at the early stage of development. Phosphorylated Mixed Lineage Kinase Domain-Like protein (MLKL), a key molecule in executing necroptosis, co-expressed with blood endothelial marker CD31 and venous-lymphatic progenitor marker Sox18. Depletion of Mlkl did not affect the formation of blood vessel network but increased the differentiation of venous-lymphatic lineage cells in postnatal cerebral cortex and skin. Consistently, significant enhancement of cerebrospinal fluid diffusion and lymphatic drainage was found in brain and skin of Mlkl-deficient mice. Under hypobaric hypoxia induced cerebral edema and inflammation induced skin edema, Mlkl mutation significantly attenuated brain-blood-barrier damage and edema formation. Our data, for the first time, demonstrated the presence of physiological vascular-associated necroptosis and its potential involvement in the development of venous-lymphatic vessels.

Glycolysis mediates neuron specific histone acetylation in valproic acid-induced human excitatory neuron differentiation.

Pregnancy exposure of valproic acid (VPA) is widely adopted as a model of environmental factor induced autism spectrum disorder (ASD). Increase of excitatory/inhibitory synaptic transmission ratio has been proposed as the mechanism of VPA induced ASD. How this happened, particularly at the level of excitatory neuron differentiation in human neural progenitor cells (NPCs) remains largely unclear. Here, we report that VPA exposure remarkably inhibited human NPC proliferation and induced excitatory neuronal differentiation without affecting inhibitory neurons. Following VPA treatment, mitochondrial dysfunction was observed before neuronal differentiation, as showed by ultrastructural changes, respiratory complex activity, mitochondrial membrane potential and oxidation levels. Meanwhile, extracellular acidification assay revealed an elevation of glycolysis by VPA stimulation. Interestingly, inhibiting glycolysis by 2-deoxy-d-glucose-6-phosphate (2-DG) efficiently blocked the excitatory neuronal differentiation of human NPCs induced by VPA. Furthermore, 2-DG treatment significantly compromised the VPA-induced expression of H3ac and H3K9ac, and the VPA-induced binding of H3K9ac on the promoter of Ngn2 and Mash1, two key transcription factors of excitatory neuron fate determination. These data, for the first time, demonstrated that VPA biased excitatory neuron differentiation by glycolysis-mediated histone acetylation of neuron specific transcription factors.

Noncoding RNAs in drug-resistant pancreatic cancer: A review.

Pancreatic cancer is the fourth-leading cause of cancer-related deaths and is expected to be the second-leading cause of cancer-related deaths in Europe and the United States by 2030. The high fatality rate of pancreatic cancer is ascribed to untimely diagnosis, early metastasis and limited responses to both chemotherapy and radiotherapy. Although gemcitabine, 5-fluorouracil and some other drugs can profoundly improve patient prognosis, most pancreatic cancer patients eventually develop drug resistance, leading to poor clinical outcomes. The underlying mechanisms of pancreatic cancer drug resistance are complicated and inconclusive. Interestingly, accumulating evidence has demonstrated that different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play a crucial role in pancreatic cancer resistance to chemotherapy reagents. In this paper, we systematically summarize the molecular mechanism underlying the influence of ncRNAs on the generation and development of drug resistance in pancreatic cancer and discuss the potential role of ncRNAs as prognostic markers and new therapeutic targets for pancreatic cancer.

Synthesis, characterization and DNA-binding properties of Ln(III) complexes with 6-ethoxy chromone-3-carbaldehyde benzoyl hydrazone.

A novel 6-ethoxy chromone-3-carbaldehyde benzoyl hydrazone (L) and its Ln(III) complexes, [Ln = Sm (1), Eu (2), Gd (3), Tb (4)], have been synthesized and characterized. The fluorescence properties of the Eu(III) and Sm(III) complexes in solid state and Eu(III) complex in different solutions (DMF, DMSO, methanol and acetonitrile) were investigated. At the same time, the DNA-binding properties of the two complexes are investigated using UV-Vis absorption spectroscopy, fluorescence spectroscopy, viscosity measurement. All the experimental evidences indicate that the two complexes can bind to CT-DNA via an intercalation mechanism. Furthermore, antioxidant activity tests in vitro showed that the complexes have significant antioxidative activity against hydroxyl free radicals from the Fenton reaction.