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Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz–Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal‐specific Lkb1 is sufficient for the development of PJS‐like polyps in mice. However, the cellular origin and components of these Lkb1‐associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen‐inducible Lkb1flox/flox;Myh11‐Cre/ERT2 and Lkb1flox/flox;PDGFRα‐Cre/ERT2 mice, performed single‐cell RNA sequencing (scRNA‐seq) and imaging‐based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11‐Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA‐seq revealed aberrant stem cell‐like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11‐Cre/ERT2 mice. The Lkb1‐associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1–Cd44 or Spp1–Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1‐associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen‐inducible Lkb1flox/flox;PDGFRα‐Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2–3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1‐associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: In China, over 50% of lung cancer cases occur in nonsmokers. Thus, identifying high‐risk individuals for targeted lung cancer screening is crucial. Beyond age and smoking, determining other risk factors for lung cancer in the Asian population has become a focal point of research. Using 30,000 participants in the prospectively enrolled cohort at China's National Cancer Center (NCC) over the past 14 years, we categorized participants by risk, with an emphasis on nonsmoking females. Materials and Method s : Between November 2005 and December 2019, 31,431 individuals voluntarily underwent low‐dose computed tomography (LDCT) scans for lung cancer screening at the NCC. We recorded details like smoking history, exposure to hazards, and family history of malignant tumors. Using the 2019 NCCN criteria, participants were categorized into high‐, moderate‐, and low‐risk groups. Additionally, we separated non‐high‐risk groups into female never smokers (aged over 40) exposed to second‐hand smoke (SHS) and others. Any positive results from initial scans were monitored per the I‐ELCAP protocol (2006), and suspected malignancies were addressed through collaborative decisions between patients and physicians. We analyzed and compared the detection rates of positive results, confirmed lung cancers, and cancer stages across risk, age, and gender groups. Results: Out of 31,431 participants (55.9% male, 44.1% female), 3695 (11.8%) showed positive baseline LDCT scans with 197 (0.6%; 106 females, 91 males) confirmed as lung cancer cases pathologically. Malignancy rate by age was 0.1% among those aged under 40 years, 0.4% among those aged 40–49 years, 0.8% among those aged 50–59 years, and 1.2% among those aged 60 years and older. From the 25,763 participants (56.9% male, 43.1% female) who completed questionnaires, 1877 (7.3%) were categorized as high risk, 6500 (25.2%) as moderate risk, and 17,386 (67.5%) as low risk. Of the 23,886 in the non‐high‐risk category, 8041 (33.7%) were females over 40 years old exposed to SHS. The high‐risk group showed the highest lung cancer detection rate at 1.4%. However, females exposed to SHS had a notably higher detection rate than the rest of the non‐high‐risk group (1.1% vs. 0.5%; p < 0.0001). In this cohort, 84.8% of the detected lung cancers were at an early stage. Conclusions: In our study, using LDCT for lung cancer screening proved significant for high‐risk individuals. For non‐high‐risk populations, LDCT screening could be considered for nonsmoking women with exposure to SHS. [ABSTRACT FROM AUTHOR]

Lung cancer is a leading cause of cancer‐related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non‐small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR‐induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin‐18 and interleukin‐1 beta and the promotion of Gasdermin D cleavage in a Caspase‐1‐dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF‐κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR‐induced pyroptosis was suppressed by the inhibition of NF‐κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase‐1‐dependent pyroptosis through the NF‐κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment. [ABSTRACT FROM AUTHOR]

Force‐responsive molecules that produce fluorescent moieties under stress provide a means for stress‐sensing and material damage assessment. In this work, we report a mechanophore based on Diels‐Alder adduct TAD‐An of 4,4′‐(4,4′‐diphenylmethylene)‐bis‐(1,2,4‐triazoline‐3,5‐dione) and initiator‐substituted anthracene that can undergo retro‐Diels‐Alder (rDA) reaction by pulsed ultrasonication and compressive activation in bulk materials. The influence of having C−N versus C−C bonds at the sites of bond scission is elucidated by comparing the relative mechanical strength of TAD‐An to another Diels‐Alder adduct MAL‐An obtained from maleimide and anthracene. The susceptibility to undergo rDa reaction correlates well with bond energy, such that C−N bond containing TAD‐An degrades faster C−C bond containing MAL‐An because C−N bond is weaker than C−C bond. Specifically, the results from polymer degradation kinetics under pulsed ultrasonication shows that polymer containing TAD‐An has a rate constant of 1.59×10−5 min−1, while MAL‐An (C−C bond) has a rate constant of 1.40×10−5 min−1. Incorporation of TAD‐An in a crosslinked polymer network demonstrates the feasibility to utilize TAD‐An as an alternative force‐responsive probe to visualize mechanical damage where fluorescence can be "turned‐on" due to force‐accelerated retro‐Diels‐Alder reaction. [ABSTRACT FROM AUTHOR]

Insufficient immune cell infiltration into the tumor microenvironment (TME) greatly compromises the clinical application of immune‐checkpoint inhibitors (ICIs)‐based immunotherapy. Recent findings have shown that activation of the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway can enhance natural immunity and increase lymphocyte infiltration into the TME, which presents a promising strategy for cancer immunotherapy. In this study, we constructed hydroxyapatite nanoparticles co‐loaded with curcumin and L‐oxaliplatin (Cur/L‐OHP@HAP NPs). We analyzed the particle‐size distribution, zeta potential, spectral characteristics (Fourier‐transform infrared spectroscopy, X‐ray photoelectron spectroscopy, ultraviolet–visible spectroscopy), and drug‐release properties of the Cur/L‐OHP@HAP NPs. The cellular uptake of the Cur/L‐OHP@HAP NPs detected by flow cytometry and confocal laser‐scanning microscopy. We comprehensively evaluated the anti‐tumor properties and immune‐activating effects of the NPs, both in vitro and in vivo. Physicochemical characterizations demonstrated that the Cur/L‐OHP@HAP NPs were successfully synthesized and were capable of pH‐dependent drug release. Notably, the Cur/L‐OHP@HAP NPs efficiently entered cancer cells, after which the released L‐OHP induced nuclear DNA (nDNA) damage to some extent. HAP promoted the release of intracellular Ca2+ stores in cancer cells, and curcumin inhibited Ca2+ efflux, resulting in intracellular Ca2+ overload and the release of mitochondrial DNA (mtDNA). Damage to both nDNA and mtDNA greatly stimulated the cGAS‐STING pathway, thereby activating natural immunity, accompanied by immune cell recruitment to the TME. In summary, the Cur/L‐OHP@HAP NPs show good prospects for improving cancer immunotherapy. [ABSTRACT FROM AUTHOR]