Laminin subunit gamma 2 (LAMC2) is a molecule related to the extracellular matrix. It plays a vital role in many cancers. But its effect in bladder cancer (BCa) is still undefined. This study was aimed at exploring the biological function, downstream mechanism, and therapeutic potential of LAMC2 in BCa. We combined single-cell RNA sequencing data from 13 BCa samples and data from TCGA-BLCA, GSE13507, and IMvigor210 cohorts. Bioinformatics analyses were carried out, including epithelial cell subclustering, pathway enrichment, GSVA, HdWGCNA, and RNA sequencing. The expression of LAMC2 in BCa tissues was confirmed through immunohistochemistry and immunofluorescence. Then shRNA was used to knock down LAMC2 in 5637 and T24 cells to test its effects in vitro and in vivo. These results were also tested in a xenograft tumor model. Potential inhibitors of LAMC2 were screened by molecular docking and in vitro experiments. We found that LAMC2 was enriched in a malignant epithelial cell subgroup and was linked to higher tumor grade, advanced tumor stage, poor prognosis and inferior response to immunotherapy. LAMC2 regulated bladder cancer cell proliferation, migration, and invasion through the SerpinB3/STAT3/CD44 axis based on the results of in vitro and single-cell analysis. Diosmetin was found to suppress LAMC2-related signaling in bladder cancer cells, providing a new strategy for BCa treatment.

PD-1/L1 inhibitors improve the prognosis of patients with advanced bladder cancer, but the clinical remission rate remains below 25

ABSTRACT Brigatinib, an oral ALK inhibitor for metastatic NSCLC, lacks dosing guidance for special populations such as the Chinese. This study developed a physiologically based pharmacokinetic (PBPK) model using European data from patients with hepatic/renal impairment and drug–drug interaction (DDI) studies (itraconazole, rifampin). The model was then applied to predict (1) pharmacokinetics (PK) in the Chinese population; (2) PK in Chinese patients with hepatic/renal impairment; and (3) DDI in Chinese patients. Validated against clinical data, the model successfully predicted brigatinib PK alone and with CYP3A4 modulators. Food simulations showed a slight absorption delay without clinically meaningful exposure reduction. In hepatic/renal impairment, the model accurately predicted exposure changes across severity groups (fold error < 2). Extending the European‐validated model to Chinese populations, the findings demonstrate reliable predictions of brigatinib PK in Chinese individuals as well as in Chinese patients with hepatic or renal impairment.

The precise recognition of high-value proteins from complex biological matrices remains a critical challenge in separation science. In this work, a tailored interfacial modulation strategy was developed to construct high-performance lysozyme-imprinted polymers. The combination of interfacial microenvironment regulation and a dual-monomer approach enabled the formation of stable and specific recognition sites. The obtained polymers exhibited a competitive adsorption capacity (395.13 mg/g) and a high imprinting factor (8.78), with equilibrium reached within 30 min. They showed good selectivity toward lysozyme over competing proteins and stable performance over repeated adsorption-desorption cycles. The practical applicability was further confirmed by the one-step isolation of lysozyme from a real biological matrix. Overall, this work provides a stepwise strategy to modulate the interfacial microenvironment for efficient protein separation.

BACKGROUND:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with dismal outcomes, especially in relapsed/refractory settings. Chimeric antigen receptor natural killer (CAR-NK) cell therapy holds promise but is constrained by the immunosuppressive tumor microenvironment (TME), where adenosine-mediated suppression is a key barrier. OBJECTIVE:To develop a novel CAR-NK construct cotargeting AML cells and the adenosine-rich TME to enhance antileukemia efficacy. METHODS:Ex vivo expanded primary NK cells were used to compare the effects of CD39 versus CD73 blockade on NK cell function via messenger RNA-electroporated antibodies. A CD33-CD73 dual-function CAR-NK construct (integrating CD33-specific lysis and anti-CD73scFv secretion for TME disruption) was designed and transduced into NK cells via retrovirus. Engineered NK cells were characterized for transduction efficiency, expansion, purity, viability, and CAR stability. In vitro cytotoxicity against AML cell lines and primary blasts was assessed, and in vivo efficacy was evaluated in a MOLM-13 xenograft mouse model. RESULTS:CD73 blockade more potently enhanced NK cell activity than CD39 blockade. Retroviral transduction achieved >50% efficiency, and expansion with K562-4-1BBL-mbIL-21/-15 feeder cells yielded NK cells with ≥6,000 fold expansion, >93% purity, >98% viability, and stable CAR expression. At an effector-to-target ratio of 0.5:1, CD33-CD73 CAR-NK cells mediated ~80% specific lysis, with superior cytotoxicity vs conventional CD33 CAR-NK cells. In xenografts, CD33-CD73 CAR-NK cells achieved robust tumor clearance, extended median survival by 24.5 days (59.5 vs 35 days) versus standard CD33 CAR-NK cells, and five out of six mice achieved long-term survival (>50 days). CONCLUSION:The CD33-CD73 dual-targeting CAR-NK platform synergistically targets AML cells and the adenosine-rich TME, exhibiting superior anti-leukemia efficacy. This strategy advances AML immunotherapy and provides a translational blueprint for TME-targeted therapies in other cancers.

Rocbrutinib is a fourth-generation Bruton's tyrosine kinase (BTK) inhibitor that covalently binds wild-type BTK and non-covalently engages the C481S mutant. Its pharmacokinetic (PK) characteristics in healthy Chinese subjects remain unclear. This study aimed to support maximum recommended starting dose (MRSD) selection and predict exposure of rocbrutinib in healthy Chinese subjects via an integrated model-informed strategy. We determined key extrapolation parameters and preclinical PK in CD-1 mice and beagle dogs. Three approaches were employed to determine the MRSD: The no observed adverse effect level (NOAEL) dose method based on body surface area, the NOAEL exposure method based on a physiologically based pharmacokinetic (PBPK) model, and the minimum effective dose method based on a PBPK model. The PBPK model was developed and validated using preclinical and clinical PK data. Predicted MRSD values by the NOAEL dose method, the NOAEL exposure method, and the minimum effective dose method were 48.7, 9.8, and 10.5 mg, respectively. Considering the lowest predicted value and available tablet strength, a starting dose of 12.5 mg was selected. Predicted plasma concentration-time profiles were consistent with those observed in animals and humans. The fold error for Cmax and AUC fell within the 0.5-2.0 range. The model further predicted brain tissue exposure across species. Moreover, the predicted brain BTK occupancy at 12.5 mg was approximately 37% for wild-type BTK and 6% for C481S mutant BTK. The PBPK model serves as a valuable tool for dose selection, PK prediction, and CNS target engagement evaluation, supporting the clinical development of rocbrutinib.

The intratumoral mycobiome plays a crucial role in the tumor microenvironment, but its impact on renal cell carcinoma (RCC) remains unclear. We collected and quantitatively profiled the intratumoral mycobiome data from 1044 patients with RCC across four international cohorts, of which 466 patients received immunotherapy. Patients were stratified into mycobiota ecology-depauperate and mycobiota ecology-flourishing (MEF) groups based on fungal abundance. The MEF group had worse prognosis, higher fungal diversity, down-regulated lipid catabolism, and exhausted CD8+ T cells. We developed the intratumoral mycobiota signature and intratumoral mycobiota-related genes expression signature, which robustly predicted prognosis and immunotherapy outcomes in RCC and other cancers. Aspergillus tanneri was identified as a potential key fungal species influencing RCC prognosis. Our findings suggest that the intratumoral mycobiome suppresses lipid catabolism and induces T cell exhaustion in RCC.

DNA oxidative damage of lens epithelium cells (LECs) has been proved to be significantly related to age-related cataract (ARC). DCLRE1A, as a member of the DNA interstrand cross-links pathway, can repair damaged DNA. However, DCLRE1A has not been addressed in maintaining mitochondrial healthy. Our findings demonstrated that DCLRE1A alleviated mtDNA oxidative damage and mitochondrial dysfunction. Besides, the E3 ubiquitin ligase SYVN1 interacts with DCLRE1A and promotes its ubiquitination and degradation. Furthermore, SYVN1 knockdown exacerbated H2O2-induced lens opacity in both ex-vitro rat lenses and ARC mouse. Together, these results underscore the pivotal role of DCLRE1A ubiquitination in modulating mitochondrial homeostasis, offering novel insights into ARC pathogenesis. The E3 ubiquitin ligase SYVN1, related to DNA damage repair, offers a promising avenue for treating cataracts with antioxidative.

ABSTRACT Background Emerging evidence implicates mechanotransduction pathways in modulating bladder carcinoma (BLCA) pathogenesis. However, the crosstalk between Piezo1 and integrin β1 (ITGB1) in extracellular matrix (ECM) stiffness‐driven tumorigenesis remains a critical knowledge gap. This study systematically investigates the functional synergy of Piezo1/ITGB1 in orchestrating ECM biomechanical remodeling to fuel BLCA progression. Methods Utilizing an integrative framework combining clinical histopathology, in vivo tumor models, multiomics profiling, molecular biology experiments, matrix stiffness quantification, calcium flux analysis, and YAP signaling interrogation, we dissected the mechanochemical interplay between Piezo1/ITGB1 activation and ECM dynamics. Results Clinical and animal data revealed that Piezo1/ITGB1 coactivation was strongly correlated with ECM stiffness‐induced BLCA proliferation and poor clinical prognosis. The coordinated expression of Piezo1/ITGB1 enhanced ECM interaction, organization, adhesion, and collagen binding. Crucially, Piezo1/ITGB1 overexpression promoted cancer development by suppressing apoptosis and enhancing proliferation. Mechanistically, ECM stiffness triggered Piezo1/ITGB1‐dependent Ca2+ influx, which facilitated YAP nuclear translocation and subsequent upregulation of downstream targets CTGF, α‐SMA, and COL1A1, thereby reinforcing collagen deposition and matrix stiffening. Conclusion Our work uncovers a feedforward mechano‐oncogenic axis wherein Piezo1/ITGB1 cooperativity converts ECM cues into sustained protumorigenic signaling through Ca2+/YAP‐mediated transcriptional reprogramming. This paradigm redefines ECM stiffness not merely as a pathological consequence but as an active driver of BLCA progression, proposing precision targeting of the Piezo1/ITGB1 triad as a mechanotherapy strategy.

The progression of bladder cancer (BC) from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) significantly increases disease severity. Although the tumor microenvironment (TME) plays a pivotal role in this process, the heterogeneity of tumor cells and TME components remains underexplored. We characterized the transcriptomes of single cells from 11 BC samples, including 4 NMIBC, 4 MIBC, and 3 adjacent normal tissues. Bulk RNA-seq data were used to validate the clinical features of characteristic cells, and protein levels of these cells were further confirmed through immunohistochemistry (IHC) and multiplex immunofluorescence. Bladder cancer progression was associated with distinct transcriptomic features in the TME. Tumor cells in MIBC displayed enhanced glycolytic activity and downregulation of chemokines and MHC-II molecules, reducing immune cell recruitment and facilitating immune evasion. This highlights glycolysis as a potential therapeutic target for disrupting tumor progression. We identified a T cell exhaustion pathway from naive CD8 + T cells (CD8 + TCF7) to terminally exhausted CD8 + STMN1 cells, with progressively declining immune surveillance. Targeting intermediate exhaustion states may restore T cell function and improve anti-tumor immunity. Macrophages polarized toward a pro-tumorigenic phenotype, while VEGFA + mast cells promoted angiogenesis in early-stage BC, suggesting their role as potential targets for therapeutic intervention in NMIBC. Furthermore, conventional dendritic cells (DCs) transformed into LAMP3 + DCs, contributing to an immunosuppressive microenvironment and enabling immune evasion. This study reveals dynamic changes in the TME during BC progression, including enhanced glycolysis, T cell exhaustion, and immune cell remodeling, which contribute to immune evasion and tumor progression. These findings identify critical pathways and cell populations as potential therapeutic targets, offering new strategies to improve treatment outcomes in BC patients.

Supplementary methods and clinical trial protocol

Glioblastoma (GBM), the most lethal of all brain cancers, resists therapy by rewiring metabolism and relying on GTP signaling to promote DNA repair and radiation therapy (RT) resistance. How GBM modulates GTP levels for this signaling in response to RT-induced DNA damage, and the therapeutic tractability of this metabolic activity in the context of standard-of-care chemoradiation therapy, remain unaddressed. Here, we identify acute changes in glioma metabolism within hours of RT, including an acute post-RT rewiring of guanylate synthesis driven by nuclear translocation of the rate-limiting de novo guanylate synthesis enzyme IMPDH1. This subcellular IMPDH1 re-localization and nuclear GTP accumulation are dependent on the DNA damage signal kinase DNA-PK. Targeting intracranial GTP synthesis with the FDA-approved inhibitor mycophenolate mofetil (MMF) slows repair of DNA damage and extends survival of orthotopic murine models treated with combined RT and temozolomide. Extending our findings to humans, we performed a phase 0 clinical trial revealing that oral MMF administration leads to active intracranial drug concentrations, with target engagement indicated by reversal of IMPDH upstream and downstream metabolites in recurrent GBM tumors. Together, these findings implicate IMPDH as a potential metabolic target in GBM whose pharmacological inhibition is feasible and could complement standard-of-care chemoradiation therapy.

The intricate relationship between tumor-associated macrophages (TAMs) and cancer cells is pivotal for carcinogenesis, with TAMs being integral to the tumor microenvironment (TME). This study explores the novel mechanisms by which TAMs regulate the progression of triple-negative breast cancer (TNBC) within the TME. Using a co-culture system and methodologies such as cytokine arrays, proteomics, and CRISPR-Cas9, we investigated the crosstalk between TAMs and TNBC cells. We found that high levels of CD163+ TAMs in TNBC tissues correlate with poor prognosis. TNBC cell-conditioned medium induces macrophage polarization towards the M2 phenotype, enhancing TNBC cell migration, invasion, and stemness through the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT). eNAMPT binding to CCR5 on TNBC cells activates STAT3, leading to the downregulation of the tumor suppressor DIRAS2 and an increase in CCL2, which promotes a macrophage recruitment loop. Intervention at the eNAMPT/CCR5 or CCL2 level disrupts this loop, mitigating TAM-induced effects. Our findings uncover a cytokine communication mechanism between immune and cancer cells, suggesting potential targets for TNBC detection and treatment.

Table S1. Clinicopathological characteristics of 20 patients in our study. Table S2. Representativeness of study participants. Table S3. Adverse events associated with toripalimab. Table S4. SNVs and InDels of therapy-naïve neoplastic tissues detected by whole exome sequencing. Table S5. SNVs and InDels of basal urine samples detected by whole exome sequencing. Table S6. SNVs and InDels detected by personalized MRD panel sequencing. Table S7. SNVs and InDels detected by the fixed actionable/hotspot panel sequencing. Table S8. Mutational measurements of each urine/plasma sample in our study.

Background: Triple-Negative Breast Cancer (TNBC) accounts for 15–20% of all breast cancers and approximately 50% of breast cancer deaths. Chemotherapy remains the main-stay of systemic treatment due to the lack of effective therapy targets. Thus, more studies are urgently needed to identify new therapeutic targets in TNBC patients. Methods: GAPVD1 expression and prognosis value in breast cancer samples were explored in The Cancer Genome Atlas database (TCGA). GAPVD1 knockdown and overexpression TNBC cell lines were constructed. CCK-8 and colony formation assays were performed to detect cell viability. Flow cytometry analysis was performed to detect cell cycle variation. Western blotting was conducted to determine the levels of target genes. Finally, an enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were per-formed. Results: GAPVD1 is overexpressed in breast cancer tissues and predicts poor prognosis. In vitro experiments demonstrated that GAPVD1 is correlated with cell proliferation and the cell cycle of TNBC cells. Mechanistically, alteration in GAPVD1 expression was found to be associated with cell cycle-related proteins PCNA, Cyclin A, and the activity of the ERK/MAPK signaling pathway. Consistent with these findings, enrichment analysis of GAPVD1-involving partners and signaling pathways revealed that the cellular biosynthetic process, macromolecule biosynthetic process, and cell cycle signaling are related to GAPVD1. In vivo experiment demonstrated that GAPVD1 inhibition impedes tumor growth and expression of cell cycle-related proteins. Conclusion: Taken together, our results indicate that GAPVD1 may participate in TNBC cell growth by regulating the cell cycle and ERK/MAPK signaling pathway.

Accurate kidney function assessment supports healthcare and clinical decision‐making in practice and drug development. Measured glomerular filtration rate (mGFR) via iohexol clearance is the gold standard, but cost, supply issues, and logistical challenges limit its clinical use. Iopamidol, another iodinated contrast agent widely used in CT imaging, has not been studied in humans for mGFR assessment. This study aims to evaluate the pharmacokinetic interchangeability of iohexol and iopamidol for mGFR assessment and to develop a limited sampling strategy to facilitate clinical implementation. In a parallel‐group, single‐dose pharmacokinetic study, 24 healthy adult volunteers with varying kidney function, as defined by the 2021 CKD‐EPI eGFRcr equation (range: 35‐140 mL/min; median: 72 mL/min), received iohexol and iopamidol. Plasma concentrations were measured using liquid chromatography‐mass spectrometry, and population pharmacokinetic modeling estimated drug clearance. Clearance estimates for both agents showed strong agreement (R 2 = 0.82, p < .005), with Bland–Altman analysis indicating minimal bias (mean difference: 15.69 mL/min; LoA: −3.76 to 35.15). A limited sampling strategy using one (1‐h, R 2 = 0.91) or two (1 and 5 h, R 2 = 0.92) time points yielded accurate clearance estimates. These findings suggest that iopamidol may be a viable alternative to iohexol for mGFR determination. Broader access to accurate kidney function testing can enhance drug dosing, reduce misclassification, and improve care for patients with chronic kidney disease. Further research should validate these findings in larger, more diverse populations, including those with advanced kidney impairment.

Figure S1. (A) Representative MRI images for radiographic evaluation of neoadjuvant toripalimab. (B) Representative hematoxylin and eosin staining for histopathological evaluation of neoadjuvant toripalimab. CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease. A modifier “p” refers to pathologic staging after cystectomy. Figure S2. (A) Stacked bar plot shows the percentage of patients with negative or positive PD-L1, low or high TMB, and negative or positive TLS. (B) Oncoprint chart for the mutational landscape of tDNA in patients with ypCR or non-ypCR. Samples were analyzed by whole exome sequencing, and the mutation frequencies of each gene are shown on the right. (C) The line plot illustrates tumor size changes measured by MRI imaging before and after neoadjuvant toripalimab. PD-L1 = programmed death ligand 1; TMB = tumor mutation burden; TLS = tertiary lymphoid structure; ypCR = pathological complete response; pre-tx = pre-treatment; post-tx = post-treatment; MRI = magnetic resonance imaging. Figure S3. (A) Oncoprint chart for the mutational landscape of tDNA and utDNA. Samples were analyzed by whole exome sequencing, and the mutation frequencies of each gene are shown on the right. (B) TMB correlation between tDNA and utDNA as assessed by whole exome sequencing. Red shading indicates 95% confidence interval. Spearman correlation coefficient (r) and P value are shown. tDNA = tumor DNA; utDNA = urinary tumor DNA; TMB = tumor mutation burden. Figure S4. (A) Box plot compares TFsm in utDNA versus ctDNA samples collected at baseline. (B) Venn plots show the number of shared and unique variants in matched utDNA and ctDNA samples. (C) Box plot compares TFcn in utDNA versus ctDNA samples at baseline. (D) Copy number gain (red) and loss (blue) of utDNA and ctDNA, as identified by GISTIC2.0. TFsm = tumor fraction estimate based on somatic mutations; utDNA = urinary tumor DNA; ctDNA = circulating tumor DNA; TFcn = tumor fraction estimate based on copy numbers. Figure S5. (A) The line plot illustrates TFsm changes in utDNA samples upon neoadjuvant toripalimab. (B) The line plot illustrates TFcn changes in utDNA samples before and after neoadjuvant toripalimab. (C) Stacked bar plot showed the percentage of patients with low or high pre-treatment TFsm, TFcn, and MRI measurements according to the optimal cutoff points defined by ROC analysis. (D) Stacked bar plot showed the percentage of patients with low or high post-treatment TFsm, TFcn, and MRI measurements according to the optimal cutoff points defined by ROC analysis. (E) Waterfall plot for the best change of target lesions in 20 patients. The post-treatment urinary MRD status of each patient are arranged along the x-axis. Bar color indicates the pathologic outcome of neoadjuvant toripalimab. TFsm = tumor fraction estimate based on somatic mutations; TFcn = tumor fraction estimate based on copy numbers; MRI = magnetic resonance imaging; utDNA = urinary tumor DNA; utDNA-pre = pre-treatment utDNA; utDNA-post =post-treatment utDNA; ypCR = pathological complete response; pre-tx = pre-treatment; post-tx = post-treatment; MRD = minimal residual disease. Figure S6. (A) Spider plot indicating dynamic changes of TFsm, TFcn, and MRI measurements for each patient during neoadjuvant toripalimab. (B) Box plot illustrates utDNA reduction (defined by TFsm + TFcn < 10%) in utDNA-pre versus utDNA-post samples. (C) IGV plot showing the FGFR3 S249C mutation in patient RZ12 detected by MRD panel sequencing or whole exome sequencing. (D) VAF changes of the FGFR3 S249C mutation in patient RZ12 with progressive disease. TFsm = tumor fraction estimate based on somatic mutations; TFcn = tumor fraction estimate based on copy numbers; MRI = magnetic resonance imaging; C1 = cycle 1; C2 = cycle 2; C3 = cycle 3; C4 = cycle 4; RC = radical cystectomy; ypCR = pathological complete response; MRD = minimal residual disease; WES = whole exome sequencing; tDNA = tumor DNA; utDNA = urinary tumor DNA; utDNA-pre = pretreatment utDNA; utDNA-post = post-treatment utDNA; C2D1 = cycle 2 day 1; VAF = variant allele frequency; PD = progressive disease.

Obesity significantly influences drug pharmacokinetics (PK), which challenges optimal dosing. This study examines the effects of diet-and-exercise-induced weight loss on key drug-metabolizing enzymes and gastric emptying in patients with obesity, who frequently require medications for comorbidities. Participants followed a structured weight management program promoting weight loss over 3-6 months and were not concomitantly on potential CYP inducers or inhibitors. Using a drug cocktail of acetaminophen, caffeine, omeprazole, and midazolam, we assessed UGT1A1, CYP1A2, CYP2C19, and CYP3A4 enzyme activities before and after weight loss, respectively, by measuring parent and metabolite concentrations. The time to maximum acetaminophen plasma concentrations reflected the gastric emptying time. PK profiles were compared across two phases: baseline (Phase 1) and post-weight loss (Phase 2). Twenty-four participants enrolled, 21 completed Phase 1 and 12 completed both phases. Statistically significant (N = 12, P < .05) gains in CYP2C19 and CYP3A4 activity were observed after weight loss of 7.6% to 26.2%, with a median [25th, 75th percentile] increase in activity of 90.5 [15.0, 194.3] % and 43.0 [7.5, 68.0] %, respectively. A 2- or 3-h single plasma sample-based ratio of the metabolite to parent concentration strongly correlated with the respective AUC ratio for the drug metabolism phenotype (N = 21). Our findings provide provisional data for evaluation of the effects of non-pharmacologically and non-surgically induced weight loss on gastric emptying and drug metabolism for future physiologically based PK models. Development of mechanistic models to optimize drug dosing in obesity are necessary since weight and body composition shifts are expected with emerging new treatments.

The expression of Family with sequence similarity 207 member A( FAM207A) is closely related to the development, growth, and progression of various cancers. However, extensive research into its biological functions remains unexplored. In this study, we conducted a comprehensive biological information analysis of the Lung adenocarcinoma (LUAD) dataset to elucidate the foundational mechanisms underlying FAM207A’s role in tumor development. The expression and clinical information of LUAD patients for FAM207A were extracted from the Cancer Genome Atlas (TCGA). Using Western blot, we assessed the expression levels of relevant proteins in LUAD cells and human lung epithelial cells. Subsequently, we employed Cox regression analysis to evaluate the prognostic significance of FAM207A in LUAD, along with gene set enrichment analysis (GSEA) to explore its potential biological functions and interactions with FAM207A’s immune microenvironment. Finally, in vitro experiments confirmed that FAM207A significantly influences the proliferation and migration of LUAD cells. The results indicate that FAM207A mRNA and protein expression levels in LUAD tissues and cell are significantly elevated. Additionally, FAM207A high expression is significantly associated with a shorter overall survival (OS) and more advanced pathological stages. Furthermore, FAM207A expression is significantly linked to the expression of immunogenic markers in the LUAD tumor microenvironment. Gene set and KEGG enrichment analyses revealed that FAM207A is primarily associated with genes involved in adhesion and immune signaling pathways. Additionally, in vitro experiments demonstrated that FAM207A can effectively promote the proliferation and migration of LUAD cells. Our findings revealed that FAM207A is overexpressed in LUAD and is linked to a poor prognosis. Our study demonstrates the potential of FAM207A as an immunotherapeutic and predictive biomarker in LUAD.

Advanced atherosclerotic lesions and vascular calcification substantially increase the risk of cardiovascular events. However, effective strategies for preventing or treating advanced atherosclerosis and calcification are currently lacking. This study investigated the efficacy of DT-109 (Gly-Gly-Leu) in attenuating atherosclerosis and calcification in nonhuman primates, exploring its broader therapeutic potential. In this study, twenty male cynomolgus monkeys were administered a cholesterol-rich diet ad libitum for 10 months. Then, the animals were treated either orally with DT-109 (150 mg/kg/day) or a vehicle (H2O) for 5 months while continuing on the same diet. Plasma lipid levels were measured monthly and at the end of the experiment, pathological examinations of the aortas and coronary arteries and RNA sequencing of the coronary arteries were performed. To explore possible molecular mechanisms, the effects of DT-109 on smooth muscle cells (SMCs) were examined in vitro. We found that DT-109 administration significantly suppressed atherosclerotic lesion formation in both the aorta and coronary arteries. Pathological examinations revealed that DT-109 treatment reduced lesional macrophage content and calcification. RNA sequencing analysis showed that DT-109 treatment significantly downregulated the pro-inflammatory factors NLRP3, AIM2, and CASP1, the oxidative stress factors NCF2 and NCF4, and the osteogenic factors RUNX2, COL1A1, MMP2, and MMP9, while simultaneously upregulating the expression of the SMCs contraction markers ACTA2, CNN1, and TAGLN. Furthermore, DT-109 inhibited SMC calcification and NLRP3 inflammasome activation in vitro. These results demonstrate that DT-109 effectively suppresses both atherosclerosis and calcification. These findings, in conjunction with insights from our previous studies, position DT-109 as a novel multifaceted therapeutic agent for cardiovascular diseases.