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Benzo(a)pyrene (BaP) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), as typical environmental carcinogens, are widely present in tobacco smoke and air pollution. Their combined exposure is an important cause of high incidence of laryngeal cancer. However, the molecular mechanism of their synergistic carcinogenesis remains unclear. To fill this gap, this study employed an integrated strategy combining network toxicology, multi-dimensional transcriptomics (bulk and single-cell), machine learning, molecular simulation, and cell function verification to systematically explore the mechanism by which BaP and NNK combined exposure induce laryngeal cancer. Through multi-dimensional data mining and machine learning algorithms, the core molecule FADS1 was identified. Functional enrichment analysis revealed that FADS1-related genes mainly participate in lipid metabolism reprogramming and tumor malignant phenotype regulation pathways. Molecular docking and 100 ns kinetic simulation confirmed that both BaP and NNK can stably bind to FADS1, with a stronger binding affinity for BaP (ΔG = -9.0 kilocalories/mole), and the binding mode is mainly based on van der Waals forces and hydrophobic interactions. Cell experiments demonstrated that combined exposure of BaP and NNK can significantly upregulate the expression of FADS1 in laryngeal cancer cells, enhance cell proliferation, migration, and invasion abilities, while silencing FADS1 can effectively reverse these malignant phenotypes. In summary, this study clarified the key role of FADS1 in mediating the synergistic promotion of laryngeal cancer by BaP/NNK, providing experimental support for understanding the carcinogenic mechanism of environmental compound pollutants, and also offering potential targets for risk assessment, early diagnosis, and precise prevention and control of air pollution and tobacco exposure-related laryngeal cancer.

Multi-parametric quantitative magnetic resonance imaging (mqMRI) holds significant clinical potential through multi-parametric tissue characterization, yet its adoption is hindered by prolonged scan time and sensitivity to non-ideal signal conditions, especially in high-resolution whole-brain protocols. To address these challenges, we propose a novel signal encoding method integrating phase-modulated three dimensional steady-state free precession with multiple overlapping-echo detachment (3D SSFP-MOLED). This method simultaneously encodes six physiological parameters (M0, T1, T2, T2*, B1+, ΔB0) into k-space by controlling overlapping echo detachment in signal acquisition. A physics-constrained synthetic data pipeline was developed to simulate MR signal evolutions with realistic field variations (ΔB0, B1+ inhomogeneities), enabling robust training of network for real-time parameter mapping. Whole-brain parametric maps (1×1×2 mm³ resolution) can be delivered within 3 minutes with only 2x parallel acquisition acceleration. Validation was performed on phantom, healthy volunteers, and clinical cases with tumors/hemorrhage. Experimental results show that our method can achieve rapid multi-parametric quantitation with high accuracy and reproducibility. By synergizing adaptive signal encoding, physics-informed synthetic training, and reproducible deep learning reconstruction, this work establishes a new paradigm for efficient and reliable mqMRI in clinical signal processing applications.

Triple-negative breast cancer (TNBC) represents a formidable oncological threat, distinguished by its elevated malignancy and limited therapeutic outlook for female patients. The efficacy of conventional therapeutic regimens including surgery and targeted small-molecule inhibitors is often compromised by severe adverse systemic effects and the acquisition of drug resistance. Guided by the concept of targeted drug conjugates (TDCs), we engineered GN-604 through the covalent integration of a Pt(II) pharmacophore into the molecular scaffold of GNS561, a known autophagy inhibitor. GN-604 selectively inhibits palmitoyl-protein thioesterase 1 (PPT1) both in vitro and in vivo, leading to lysosomal dysfunction and autophagy inhibition. Furthermore, GN-604 facilitates the targeted intracellular sequestration of Pt(II), thereby triggering robust DNA lesions and suppressing malignant cell expansion. In vivo evaluations utilizing a MDA-MB-231 xenograft model demonstrated that GN-604 achieved superior antitumor potency to GNS561, cisplatin, or their co-administration. In summary, GN-604 emerges from this study as an encouraging bifunctional therapeutic modality tailored for the management of aggressive TNBC.

Tumor-associated macrophages (TAMs) represent a dominant, plastic component of the tumor microenvironment (TME) that orchestrates immunosuppression, angiogenesis, and therapeutic resistance. Since static biopsies fail to capture the spatiotemporal heterogeneity and dynamic phenotypic evolution of TAMs (e.g., M1/M2 polarization), non-invasive imaging is critical. This review systematically critiques the evolution of Positron Emission Tomography (PET) strategies for TAM quantification, classifying innovations into metabolic, functional, and molecular approaches. Moving beyond the limitations of indirect methods-such as [18F]FDG and "Trojan horse" nanoparticles constrained by mononuclear phagocyte system (MPS) sequestration-we emphasize the paradigm shift toward high-affinity molecular probes. These target specific biomarkers (e.g., CD206, CD163, CSF1R) and recruitment pathways (e.g., CCR2). We particularly highlight the clinical potential of nanobody- and peptide-based tracers, which demonstrate superior tumor penetration and rapid clearance compared to full-sized antibodies. Concluding with an analysis of translational hurdles, such as interspecies marker discordance, we propose future directions that integrate theranostics, spatial transcriptomics, and AI-driven radiomics. Ultimately, molecular TAM-PET imaging is poised to evolve from an experimental tool into a precision oncology platform for patient stratification and monitoring of immunomodulatory therapies.

Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) are overexpressed in breast cancer and drive oncogenesis, rendering PI3K/mTOR inhibitors as promising therapeutic agents. However, tumor cells readily develop resistance to single-agent PI3K or mTOR inhibitors. In this study, 40 novel bis-aryl urea-linked triazine derivatives were designed and synthesized as dual PI3K/mTOR inhibitors using a scaffold hopping strategy. Their biological activities were evaluated. The results showed that J-33 was a dual inhibitor of PI3K and mTOR kinases, with IC50 values of 400.5 nM and 8.2 nM, respectively, and it inhibited other tested kinases by less than 50%. The antiproliferative IC50 value of J-33 against MCF-7 cells was 1.5 ± 0.2 μM. Hemolysis assays indicated that J-33 exhibited low hemolytic toxicity. Apoptosis and AO staining experiments demonstrated that J-33 induced apoptosis in MCF-7 cells in a concentration-dependent manner. Western blot analysis showed that J-33 significantly downregulated the phosphorylation level of the PI3K-AKT-mTOR pathway. Therefore, we conducted in vivo antitumor studies using a nude mouse model with MCF-7 cell xenografts. The results demonstrated that at the same dose of 75 mg/kg, J-33 exhibited a higher tumor inhibition rate (44.9%) compared to PKI-587 (43.6%). In summary, a highly potent and low-toxic dual PI3K/mTOR inhibitor was developed, which deserves further investigation.

Light chain amyloidosis (AL) and multiple myeloma (MM) are interrelated plasma cell disorders characterized by malignant proliferation, yet they demonstrate distinct pathophysiological mechanisms and clinical progression patterns. The clinical differentiation between these conditions presents significant challenges, frequently resulting in delayed diagnosis, particularly for AL amyloidosis, which adversely affects patient prognosis. Current diagnostic methodologies predominantly depend on invasive tissue biopsies and extended serological testing, underscoring the urgent requirement for rapid, non-invasive auxiliary diagnostic approaches. In this investigation, we developed an innovative analytical framework integrating serum Raman spectroscopy with an advanced one-dimensional convolutional neural network (1D-CNN) to achieve precise discrimination between AL and MM. Serum specimens were collected from clinically diagnosed patients and analyzed using a 785 nm excitation Raman system spanning the spectral range of 200-2000 cm-1. Following comprehensive preprocessing procedures, our specially designed 1D-CNN architecture attained exceptional classification performance, demonstrating area under the curve (AUC) values of 0.94 for AL and 0.96 for MM, with overall accuracy reaching 92.5%, accompanied by 91.4% sensitivity and 93.1% specificity. The proposed model exhibited statistically superior performance (p < 0.01) compared to conventional machine learning algorithms, including support vector machines (AUC = 0.78), and other deep learning architectures. Critical spectral analysis identified prominent Raman band variations at 500 cm-1, 1150 cm-1, and 1750 cm-1, providing molecular-level insights into the discriminatory characteristics. This spectroscopy-based deep learning platform represents a substantial advancement in clinical diagnostics, offering a rapid, non-invasive methodology with significant potential for early disease screening and enhanced decision-support in differential diagnosis of plasma cell dyscrasias.

The C797S mutation in epidermal growth factor receptor (EGFR) is a major mechanism of resistance to third-generation tyrosine kinase inhibitors (TKIs), such as Osimertinib, in non-small cell lung cancer (NSCLC), creating an urgent need for effective therapeutic strategies. To address this challenge, we designed the structure-guided optimization of a 2-aryl-4-aminoquinazoline scaffold, leading to the discovery of a potent fourth-generation EGFR inhibitor, compound 6g. The design focused on introducing flexible nitrogen-rich side chains to enable effective non-covalent interaction with the mutant Ser797 residue. Compound 6g exhibited superior activity against EGFRDel19/T790M/C797S with an enzymatic IC50 of 0.056 μM and potently inhibited the proliferation of resistant PC-9 cells (IC50 = 0.143 μM), outperforming the parent lead Angew-1 and Osimertinib by 6-fold and 16-fold, respectively. Further biological evaluation revealed that 6g effectively suppressed proliferation, migration, and induced apoptosis in Osimertinib-resistant cells, concomitant with the inhibition of EGFR and its downstream AKT/MAPK signaling pathways. Favorable pharmacokinetic properties were observed in rats, with an absolute oral bioavailability of 22.33% and a high safety margin (selectivity index >500 in normal human lung epithelial BEAS-2B cells). In a PC-9Del19/T790M/C797S xenograft model, 6g achieved significant dose-dependent tumor growth inhibition (TGI: 47.3% at 5 mg/kg; 64.2% at 10 mg/kg), markedly surpassing Osimertinib (TGI: 16.07% at 10 mg/kg), with no observed significant toxicity. These results establish 6g as a promising fourth-generation EGFR-TKI candidate with potent activity, favorable pharmacokinetics, and a high safety profile, offering a potential therapeutic strategy against Osimertinib resistance driven by the C797S mutation.

Restoring the tumor suppressive activity of the Hippo signaling pathway lost through dysregulation of the NUAK1/2 and MARK2/3 kinase axis and downstream transcriptional effectors YAP/TAZ has emerged as a new modality for the treatment of several human cancers. Small molecule inhibition of NUAK1/2 and MARK2/3 constitutes a rational approach to block YAP/TAZ nuclear translocation and prevent a pro-oncogenic gene expression program. Modest structural changes to lead compound OICR14489, discovered through computational studies using a NUAK2 homology model, afforded the potent and selective dual NUAK1/2 and MARK2/3 inhibitor OICR16422. Further optimization led to inhibitor OICR19451, which produced an increase in YAP phosphorylation and enhanced cytoplasmic YAP/TAZ localization. In vitro growth inhibition of several cancer cell lines, coupled with the robust in vivo pharmacokinetic properties of OICR19451 marked it as an advanced tool compound suitable for in vivo evaluation. Accordingly, in an orthotopic model of highly metastatic breast cancer, MDA-MB-231 tumor-bearing mice treated with OICR19451 showed reduced metastases, tumor encapsulation and an overall increase in survival indicative of favorable Hippo pathway modulation.

Fibroblast activation protein (FAP) over-expressed on cancer associated fibroblast represents an attractive pan-target for cancer theranostics. FAP inhibitors (FAPIs) have achieved remarkable success in cancer imaging, but its rapid blood clearance and short tumor retention limited application in radionuclide therapy. Strategies to prolong FAPI derivatives circulation, such as dimerization and albumin binding conjugates, often make limited improvement and increase background uptake. Porphyrins, are widely used as photosensitizers in photodynamic therapy, possess favorable pharmacokinetic properties including prolonged circulation and target to some tumors. Here, for the first time, we proposed integrating respective merits of porphyrin and FAPI to develop new radionuclide deliver system with ideal tumor targeting and retention for high-performance cancer endoradiotherapy. Two lutetium-177 (177Lu) radiolabeled FAPI derivatives, [177Lu]Lu-DOTA-P1-FAPI and [177Lu]Lu-DOTA-P2-FAPI were well developed and characterized, of which the anticancer effects were systematically evaluated. Both radiolabeled FAPI ligands showed excellent stability in vitro and higher specific binding ability toward FAP-positive cancer cells over widely-used 177Lu-DOTA-FAPI-04. Ex vivo biodistribution revealed much higher tumor retention ability of [177Lu]Lu-DOTA-P1-FAPI (111.26 ± 40.65 %ID/g) and [177Lu]Lu-DOTA-P2-FAPI (190.31 ± 91.16 %ID/g) compared to [177Lu]Lu-DOTA-FAPI-04 (3.69 ± 0.19 %ID/g) at 48 h. More importantly, [177Lu]Lu-DOTA-P1-FAPI and [177Lu]Lu-DOTA-P2-FAPI produced much stronger tumor growth inhibition and longer median survival in murine xenograft models than [177Lu]Lu-DOTA-FAPI-04 with equal dosage. The outcome of this work demonstrated that porphyrin modification allows a new development path and research perspective for FAPI radiopharmaceutical clinical translation.

Gastric and colorectal cancers are common and deadly across the globe. Preclinical findings propose that the pairing of MET inhibitors with anti-inflammatory drugs could synergistically impede tumor growth and reshape the tumor microenvironment. This study introduces AspMet, a novel dual-targeting inhibitor of c-Met and COX-2. In vitro experiments demonstrated that AspMet significantly inhibited the proliferation of MKN45 (IC50 = 1.05 ± 0.02 nM) and SW480 (IC50 = 1.32 ± 0.01 μM) cell lines. The experimental data indicate that AspMet effectively blocks several cancer-promoting signaling pathways, including c-Met、TRKB、COX-2 and HIF-1α, significantly inhibits epithelial-mesenchymal transition, thus decreasing tumor cell migration and invasion, and causes DNA damage, resulting in G0/G1 cell cycle arrest and the initiation of apoptosis. Furthermore, AspMet has strong anti-angiogenic properties. In animal models, AspMet significantly reduced the growth of subcutaneous tumors in both gastric and colorectal cancers，and it has an extremely high bioavailability. Therefore, the dual inhibition strategy targeting c-Met and COX-2 offers a promising novel approach for the treatment of cancers, particularly inflammatory cancers.