American journal of cancer research最新文献

Colorectal cancer (CRC) is among the most prevalent malignancies worldwide, with approximately 40% of the patients carrying KRAS mutations. Among these, the KRAS G12C mutation accounts for approximately 4% of the cases. This mutation introduces a unique cysteine residue at codon 12, enabling covalent binding and rendering KRAS G12C a tractable therapeutic target. Recently, selective small-molecule inhibitors of KRAS G12C, including sotorasib and adagrasib, have shown encouraging activity in early clinical trials, indicating potential clinical benefits for this subset of patients. However, their translation into routine clinical practice has been challenged by intrinsic and acquired resistance, treatment-related toxicities, and the absence of reliable predictive biomarkers. The aim of this study is to construct a clear knowledge framework that could inform the design of future clinical trials and optimize clinical practice. Future studies should focus on developing more potent next-generation inhibitors, exploring and optimizing rational combination strategies with other targeted agents or immunotherapies, investigating innovative therapeutic methods, and systematically identifying and validating predictive biomarkers. Collectively, with these efforts, we aim to enhance the efficacy, overcome resistance, and advance precision therapy for patients with KRAS G12C-mutant CRC.

Gynecological tumors represent a significant health burden worldwide. Protein lactylation has emerged as a novel post-translational modification (PTMs) that directly links metabolic reprogramming to epigenetic and functional regulation. Lactylation occurs when lactate covalently modifies the lysine residues of proteins. Initially discovered on histones, lactylation was shown to influence gene transcription; however, accumulating evidence reveals its broader impact on nonhistone proteins, affecting diverse processes. Elevated lactate levels in the tumor microenvironment increase protein lactylation. Evidence suggests a dynamic interplay between tumor metabolism and cancer progression. In this review, we provide an overview of the fundamental aspects of protein lactylation, including the key enzymes that catalyze the addition and removal of lactyl groups. We further emphasize recent discoveries on how lactylation influences the development and progression of gynecological malignancies. Finally, we explore the potential of targeting protein lactylation as an emerging therapeutic strategy in the management of gynecological cancers.

The spine is a common site for metastases in lung cancer. Precise identification of factors associated with survival and reliable prediction of prognosis are essential for clinical decision-making in patients with spinal metastasis from lung cancer. A retrospective analysis was conducted on 148 lung cancer patients with spinal metastases between January 2018 and December 2020 to identify prognostic factors and develop a nomogram for predicting survival outcomes. Another 30 patients with spinal metastases due to lung cancer, treated between January 2021 and February 2022, served as an external validation cohort to assess the nomogram's predictive performance. Multivariate analysis identified Karnofsky Performance Status (KPS) score, carbohydrate antigen 125 (CA125), radiotherapy, chemotherapy, and targeted therapy as independent prognostic factors. The nomogram achieved a concordance index of 0.713. The AUCs for the nomogram in predicting 1-, 2-, and 3-year survival were 0.834, 0.750, and 0.733 in the training set; 0.803, 0.738, and 0.713 in the internal validation set; and 0.749, 0.738, and 0.729 in the external validation set. Calibration curves showed good agreement between predicted and observed outcomes. Compared with the modified Tokuhashi and Tomita scores, the nomogram demonstrated superior predictive accuracy and provided greater net clinical benefit in decision curve analysis, indicating good clinical utility. This model may aid individualized prognosis assessment and treatment planning in lung cancer patients with spinal metastases.

Metastasis, the leading cause of death in patients with solid tumors, involves the spread of cancer cells to distant organs. While genetic and environmental factors contribute, chronic stress is a crucial factor in metastatic progression by disrupting neuroendocrine, immune, metabolic, and microbial homeostasis. This review synthesizes evidence linking chronic stress to tumor metastasis through three pathways: (1) direct effects on tumor cell metabolism, (2) remodeling of the tumor microenvironment, and (3) dysregulation of the gut microbiota. Describe how activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system influence epithelial-mesenchymal transition, immune evasion, and angiogenesis via β-adrenergic and glucocorticoid receptor signaling. Explore how microbial metabolites and barrier dysfunction influence immune and neuroendocrine circuits, creating a pro-metastatic loop. Finally, we highlight therapeutic strategies, including psychological interventions and pharmacologic approaches, to alleviate chronic stress. This review proposes a mechanistic framework linking neuroendocrine signaling, metabolic reprogramming, and the microbiome-immune axis.

Bone cancer pain (BCP) is a frequent and debilitating complication in patients with malignant tumors, arising from a multifactorial interplay of bone destruction, neural injury, and inflammatory responses. Microglia can polarize into either an M1 phenotype, which aggravates nociception, or an M2 phenotype, which facilitates pain resolution. Activation of the TLR4/NF-κB signaling cascade is known to drive M1 polarization, thereby amplifying inflammation and neuronal damage. This study aimed to investigate whether macrophage-derived exosomes could mitigate BCP by modulating the TLR4/NF-κB pathway, suppressing M1 polarization, and enhancing M2 microglial polarization. In vitro, RAW264.7 macrophages were polarized to the M2 phenotype via IL-4 stimulation, and exosomes were subsequently isolated and applied to LPS-challenged BV2 microglial cultures. Polarization profiles were analyzed using flow cytometry, immunofluorescence, qRT-PCR, and Western blotting. In vivo, a rat BCP model was established, and exosome treatments were administered. Behavioral assays were performed to assess pain responses, followed by evaluation of microglial polarization and TLR4/NF-κB pathway activity in spinal cord tissue. Results demonstrated that IL-4 treatment effectively induced M2 polarization in RAW264.7 cells, and the isolated exosomes displayed characteristic morphology and marker expression. BV2 microglia internalized these vesicles, leading to pronounced inhibition of LPS-induced M1 polarization, promotion of M2 polarization, suppression of pro-inflammatory cytokine release, and downregulation of TLR4/NF-κB activation. In vivo, exosome administration elevated the mechanical pain threshold and attenuated pain-related behaviors, while spinal cord analyses revealed reduced expression of M1 markers, increased M2 markers, and marked suppression of TLR4/NF-κB signaling. Collectively, these findings indicate that macrophage-derived exosomes alleviate BCP through coordinated regulation of TLR4/NF-κB signaling and microglial polarization, suggesting their potential as a novel therapeutic option for managing bone cancer pain.

In non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) is one of the most prevalent driver gene, whose expression and recurrent mutations are closely related to the prognosis of patients. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are ones of the most used among the first line treatment of NSCLC, but their efficacy is significantly reduced due to the inevitable development of acquired EGFR-TKI resistance. Consequently, searching for innovative drugs to overcome this challenge is urgent. Immune checkpoint inhibitors such as antibodies against the programmed cell death protein-1 (PD-1) or its ligand (PD-L1), have exhibited remarkable potential in NSCLC therapy. While the response rates of PD-1/PD-L1 blockade in EGFR-mutated NSCLC patients remain controversial. To gain deeper insights, we first analyzed the different therapeutic effect of PD-1/PD-L1 blockade between EGFR wild-type and mutated NSCLC patients. Meanwhile, the factors and the mechanisms that affect therapeutic effect of PD-1/PD-L1 blockade were summarized, including PD-1/PD-L1 expression levels, the tumor microenvironment (TME), and the adoption of combination therapy strategies. Furthermore, we comprehensively evaluated the combinatorial therapeutic effect with established synergistic potential within these factors. Moreover, we further explored the potential of PD-1/PD-L1 as a predictive biomarker for EGFR mutations by conducting a systematic and multidimensional analysis, aiming to refine therapeutic decision-making and facilitate personalized treatment strategies for EGFR-mutated NSCLC. Additionally, we also discussed the novel strategies that could alleviate the EGFR-TKIs resistance in NSCLC base on PD-1/PD-L1 immune inhibitors, shedding light on challenges facing future research.

IDH1 and ATRX mutations frequently co-occur in several glioma subtypes, including secondary glioblastomas (GBMs), suggesting that these alterations may function cooperatively during tumor development. However, the molecular basis of their interaction remains poorly defined. In present study, we demonstrate that the IDH1-R132H mutation acts synergistically with ATRX loss to upregulate pro-proliferative genes while suppressing interferon (IFN) signaling. This coordinated effect supports the notion that the two mutations jointly promote tumor growth and attenuate anti-tumor immune responses. Notably, we also found that the combined IDH1/ATRX mutations increase GBM cell sensitivity to various forms of cell death, particularly ferroptosis. Mechanistically, the dual IDH1/ATRX alteration upregulates pro-ferroptotic genes (HMOX1 and ACSL4) while downregulating anti-ferroptotic genes (SLC7A11 and GPX4), thereby sensitizing GBM cells to ferroptosis induction. Together, our findings provide new biological insights into IDH1/ATRX-driven GBM pathogenesis and highlight ferroptosis as a potential therapeutic vulnerability in this aggressive tumor subtype.

Objective: To evaluate the diagnostic value of combined detection of serum carcinoembryonic antigen (CEA), thyroglobulin (Tg), calcitonin (CT), and thyroid-stimulating hormone (TSH) using a chemiluminescence assay in thyroid carcinoma (TC).

Methods: A total of 320 inpatients with TC - including 261 with papillary TC, 37 with follicular TC, 19 with medullary TC, and 3 with undifferentiated TC - were enrolled as the TC group. Meanwhile, 120 healthy individuals undergoing routine examinations and 120 patients with benign thyroid diseases were included as the control group. Serum levels of CEA, Tg, CT, and TSH were compared between groups and among different pathological types of TC. ROC curves were constructed to assess the diagnostic performance of each biomarker alone and in combination.

Results: The combined detection of the four biomarkers yielded a sensitivity of 75.63%, accuracy of 75.54%, and negative predictive value of 69.88%, all higher than those of any single biomarker. ROC analysis showed that the AUC for the combined test of four markers and for the combination of CEA and Tg were 0.840 and 0.768, respectively, both exceeding those of individual tests. The four-marker combination demonstrated the highest diagnostic value.

Conclusion: Combined measurement of serum CEA, Tg, CT, and TSH significantly enhances the diagnostic efficacy for TC, reducing both misdiagnosis and missed diagnosis rates, and provides a reliable basis for early clinical detection and intervention.

Background: Accurate preoperative staging of endometrioma (EC) is essential for optimal treatment planning. This study aims to evaluate the diagnostic performance of intravenous contrast-enhanced ultrasound (IV-CEUS) as a potential modality for EC staging.

Methods: This retrospective study involved 71 patients with histologically confirmed EC who were admitted to Tianjin Central Hospital of Gynecology Obstetrics between January 2021 and August 2024. All patients had undergone both IV-CEUS and magnetic resonance imaging (MRI) within 14 days before surgery. IV-CEUS was performed using high-end Doppler ultrasound systems with SonoVue^® contrast, while MRI was conducted on a 1.5 T scanner employing T2 weighted, diffusion-weighted, and dynamic contrast-enhanced sequences. Deep myometrial invasion (DMI; ≥ 50%) and cervical stromal invasion (CSI) were assessed, with final histopathological findings serving as the reference standard. Diagnostic performance was evaluated using sensitivity, specificity, predictive values, accuracy, Kappa coefficients, and receiver operating characteristic (ROC) curves.

Results: For DMI diagnosis, IV-CEUS demonstrated a sensitivity of 74.2%, specificity of 92.5%, PPV of 88.5%, NPV of 82.2%, and accuracy of 84.5% (κ = 0.68). MRI showed a sensitivity of 90.3%, specificity of 85.0%, and accuracy of 87.3% (κ = 0.75). For CSI diagnosis, IV-CEUS had a sensitivity of 69.2%, specificity of 93.1%, an accuracy of 88.7% (κ = 0.62), while MRI had a sensitivity of 76.9%, specificity of 87.9%, and accuracy of 85.9% (κ = 0.60). The areas under the curves (AUCs) were 0.704 (95% CI: 0.584-0.824) for IV-CEUS and 0.718 (95% CI: 0.602-0.834) for MRI in diagnosing DMI; and those were 0.852 (95% CI: 0.743-0.961) for IV-CEUS and 0.838 (95% CI: 0.721-0.955) for MRI in diagnosing CSI.

Conclusion: IV-CEUS demonstrates comparable diagnostic performance to MRI in assessing DMI and CSI in EC patients. It may serve as a viable alternative when MRI is contraindicated or unavailable.

Lung cancer, one of the most prevalent and lethal malignancies in clinical practice, is characterized by high incidence and mortality, and poor prognosis. Cuproptosis, a recently identified form of cell death, has emerged as a focal point in tumor diagnosis and therapy. To elucidate the role of cuproptosis in lung cancer progression and identify potential therapeutic agents, we employed bioinformatics approaches to analyze public databases, aiming to uncover key copper-related genes and pathways associated with lung cancer. Using the GSE21933 dataset, we identified 2,892 differentially expressed genes (DEGs) in lung cancer, comprising 1,369 upregulated and 1,523 downregulated genes. By intersecting these DEGs with cuproptosis-related genes, we identified three hub genes (CDK1, FOXM1, and PRC1) using VM, random forest, and MCODE algorithms. Targeted drug prediction using the DsigDB module of the Enrichr website revealed LUCANTHONE as the top candidate. Western blot, RT-qPCR, and immunofluorescence analyses confirmed that CDK1, FOXM1, and PRC1 were highly expressed at both protein and mRNA levels in lung cancer tissues and cells. Treatment of A549 lung cancer cells with LUCANTHONE resulted in decreased expression of CDK1, FOXM1, and PRC1, reduced cell proliferation and invasiveness, and increased apoptosis. Our findings demonstrate that CDK1, FOXM1, and PRC1 are critical components of the cuproptosis pathway in lung cancer, and LUCANTHONE may serve as a promising therapeutic agent for inhibiting their expression and suppressing lung cancer progression.