Renal cell carcinoma (RCC) is a common urological tumor, with clear cell renal cell carcinoma (ccRCC) being the most prevalent subtype. Metabolic reprogramming plays a critical role in ccRCC progression, making it a promising target for therapeutic intervention, though effective treatments remain unavailable. Our previous studies have shown that mitochondrial ribosomal protein L12 (MRPL12) contributes to various metabolic diseases, including diabetic kidney disease and HCC, by regulating mitochondrial biosynthesis. In this study, we demonstrated that MRPL12 is acetylated at lysine 163 (K163) in ccRCC cells, a key modification that influences its regulatory effect on mitochondrial metabolism. Mechanistically, we clarified that acetylation at the K163 site enhances mitochondrial biosynthesis by promoting MRPL12's binding to POLRMT, which subsequently increases mitochondrial metabolism and suppresses cellular glycolysis. Additionally, we found that MRPL12 K163 acetylation levels were significantly downregulated in ccRCC and that restoring this acetylation inhibited ccRCC progression in both in vitro and in vivo models. Furthermore, we demonstrated that the acetyltransferase TIP60 and the deacetylase SIRT5 bind to MRPL12 and regulate its acetylation. These findings highlight K163 acetylation as a critical site for MRPL12-mediated regulation of mitochondrial metabolism and reveal that this modification inhibits renal cancer development by promoting mitochondrial biosynthesis, reducing glycolysis, and driving metabolic reprogramming. This study suggests a potential therapeutic strategy for targeting MRPL12 acetylation in ccRCC.

Lineage switching (LS) is the conversion of cancer cell lineage during the course of a disease. LS in leukemia cell lineage facilitates cancer cells escaping targeting strategy like CD19 targeted immunotherapy. However, the genetic and biological mechanisms underlying immune evasion by LS leukemia cells are not well understood. Here, we conduct a multi-omics analysis of patient samples and find that lineage-switched acute myeloid leukemia (LS AML) cells with KMT2A rearrangement (KMT2A-r) possess monocytic myeloid derived suppressor cell (M-MDSC)-like characteristics. Single-cell mass cytometry analysis reveals an increase in the M-MDSC like LS AML as compared to those of lineage-consistent KMT2A-r AML, and single-cell transcriptomics identify distinct expression patterns of immunoregulatory genes within this population. Furthermore, in vitro assays confirm the immunosuppressive capacity of LS AML cells against T cells, which is analogous to that of MDSCs. These data provide insight into the immunological aspects of the complex pathogenesis of LS AML, as well as development of future treatments.

Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the first rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP), is a pivotal regulator of HBP flux. Despite its established significance, the molecular underpinnings of GFAT1's role in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we found that GFAT1 was upregulated in HCC, and high GFAT1 level was correlated with poor patient prognosis. Our in vitro and in vivo studies demonstrated that GFAT1 facilitated hepatoma cell proliferation and invasion by enhancing HBP and O-GlcNAcylation through its enzymatic activity. Global profiling of O-GlcNAcylation identified vascular endothelial zinc finger protein 1 (VEZF1) as a key substrate heavily O-GlcNAcylated in GFAT1-overexpressing hepatoma cells. Notably, O-GlcNAcylation at specific serine residues (Ser123 and Ser124) within VEZF1 attenuated its proteasomal degradation, thereby enhancing its protein stability and promoting tensin 1 (TNS1) transcription in HCC. In addition, we designed a bioactive VEZF1-derived peptide to competitively inhibit GFAT1-mediated O-GlcNAcylation of VEZF1. This intervention effectively reduced TNS1 expression and suppressed the progression of HCC in a mouse model. Collectively, our findings underscore the therapeutic potential of targeting the GFAT1-VEZF1-TNS1 signaling axis in HCC.

Osteosarcoma (OS) is the most frequent primary bone sarcomas with high recurrence and poor prognosis. Emerging evidence indicates that membraneless organelles stress granules (SGs), whose assemblies are driven by scaffold protein G3BP1, are extensively involved in tumor, especially in OS. However, how SGs behave and communicate with organelles, particularly nucleoli and mitochondria, during drug challenges remain unknown. This study revealed that chemotherapeutic drugs activated the cysteine protease asparagine endopeptidase (AEP) to specifically cleave the SG core protein G3BP1 at N258/N309 in OS and malignant glioma. tG3BP1-Ns modulated SG dynamics by competitively binding to full-length G3BP1. Strikingly, tG3BP1-Cs, containing a conserved RNA recognition motif CCUBSCUS, sequestered mRNAs of ribosomal proteins and oxidative phosphorylation genes in the nucleoli and mitochondria to repress translation and oxidative stress. Moreover, the inhibition of AEP promoted the tumor-suppressing effect of chemotherapeutic drugs, whereas AEP-cleaved G3BP1 rescue reversed the effect in both OS and glioma models. Cancerous tissues exhibited high levels of AEP and G3BP1 truncations, which were strongly associated with poor prognosis. Accordingly, this study proposed a new paradigm and potential therapeutic targets to address chemotherapy sensitivity conferred by AEP-cleaved G3BP1-mediated SGs/nucleoli/mitochondria coordination.

Single-agent maintenance poly(ADP-ribose) polymerase (PARP) inhibition may represent an effective strategy in patients with advanced/metastatic endometrial cancer responding to platinum-based chemotherapy, including for molecular subtypes with suboptimal options. To explore this approach, we initiated the randomized phase IIb UTOLA trial (NCT03745950). Female patients without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer were randomized 2:1 to twice-daily maintenance oral olaparib 300 mg or placebo until progression or intolerance, stratified by p53 status, mismatch repair status, and response to initial chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints were PFS in subgroups, time to second progression or death, time to first and second subsequent therapy, objective response rate, overall survival, patient-reported outcomes, and safety. In the intention-to-treat population (n = 145), there was no PFS difference between olaparib and placebo (median 5.6 vs. 4.0 months, respectively; hazard ratio 0.94, 95% confidence interval 0.65-1.35; p = 0.74). However, intriguing numerical PFS effects were observed in exploratory analyses of pre-specified subgroups (p53-abnormal, complete response to initial chemotherapy, chromosomal instability). There was no overall survival difference between treatments. Grade 3/4 adverse events occurred in 36% versus 10% of olaparib- versus placebo-treated patients and were consistent with the olaparib safety profile in other cancers. Maintenance olaparib did not improve PFS, but promising numerical effects in subsets of patients warrant prospective evaluation.

Gastric cancer (GC) is a common and aggressive malignancy worldwide. Increasing evidence has shown that epigenetic changes are closely related to the development of cancer and tumor-associated macrophages. Here, we report that PRMT1 is a key immunosuppressive factor in GC. PRMT1 is upregulated in GC and promotes tumor progression. PRMT1 knockdown in GC leads to the activation of the cGAS/STING pathway through the enhancement of dsDNA aggregation, which subsequently increases IFN-β secretion. Notably, after PRMT1 knockdown, M1-like tumor-associated macrophage (TAM) infiltration increased, whereas M2-like TAM infiltration decreased in vivo and in vitro. After the targeted inhibition of STING by siRNA or H151, the improvement in the progression of GC caused by PRMT1 knockdown decreased, and the changes in macrophage polarization were reversed. Furthermore, we found that PRMT1 knockdown in GC affects the STAT pathway in TAMs, inducing changes in their polarization and promoting GC apoptosis by enhancing IFN-β secretion through the cGAS/STING pathway. In summary, our findings revealed that PRMT1 knockdown inhibits the cGAS/STING pathway in GC, which produces type I IFNs to promote the polarization of M1-like macrophages in the tumor microenvironment.

Head and neck squamous cell carcinoma (HNSCC) has a high rate of metastasis and recurrence, and poses a considerable threat to patient survival. Autophagy, an intracellular degradation pathway, plays a crucial role in tumor progression; however, the underlying mechanisms of action remain unclear. This study aimed to explore the role of the ACSS2-TFEB axis in the regulation of autophagy and its impact on HNSCC cell proliferation, migration, invasion, and lysosomal function. HNSCC tumor tissues and cell lines were analyzed for ACSS2 protein expression. The effects of the ACSS2 knockdown on cell proliferation, migration, invasion, and autophagic flux were also assessed. The interaction between ACSS2 and transcription factor EB (TFEB) and its influence on lysosomal function were also examined. In this study, we found that ACSS2 protein expression was significantly upregulated and correlated with metastasis and poor prognosis. ACSS2 knockdown inhibited the proliferation, migration, and invasion of HNSCC cells, and disrupted autophagy flux, primarily by impairing lysosomal function. Additionally, ACSS2 was found to sustain autophagic flux through TFEB activation, a key regulator of the autophagy-lysosome pathway. TFEB activation promotes lysosomal function and autophagic flux, thereby facilitating tumor cell growth and metastasis. This study elucidated the molecular mechanism by which ACSS2 enhances HNSCC cell proliferation and invasion via TFEB activation. The ACSS2-TFEB axis is a potential therapeutic target for HNSCC and provides a foundation for the development of targeted therapies.

Cancer-associated fibroblasts (CAFs) are part of the tumor microenvironment (TME) that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identified a paracrine mechanism in which CAF-secreted asporin (ASPN) activated ErbB signaling and subsequent migration of adjacent prostate cancer cells. Our data support that ASPN bound directly to the ligand binding domain of human epidermal growth factor 3 (HER3) and induced HER2/HER3 heterodimerization and activation of the PI3K, MAPK, and calcium pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Clinically, ASPN was detected in the stroma of HER2/HER3-expressing human metastatic prostate cancer, supporting the clinical relevance of these findings and highlighting a potential therapeutic vulnerability. Antibody-drug conjugate (ADC) therapies designed to target HER2 (trastuzumab-deruxtecan) or HER3 (patritumab-deruxtecan) significantly diminished prostate cancer cell growth in vitro and tumor size in vivo, despite Aspn in the TME. Collectively, these findings indicate ASPN functions as a HER3 ligand to induce cellular migration, and inhibition with anti-HER2 or anti-HER3 ADC therapies highlights potential clinical utility for patients with metastatic castration-resistant prostate cancer that expresses HER2 or HER3.

The current research involves the preparation of novel thiazole derivatives, which was carried out via one-pot three-component reaction utilizing conventional and microwave irradiation (MW) methods. The MW method reduced the reaction time and allowed the reactions to be carried out with higher yields. 1H NMR, 13C NMR, EI-MS and FT-IR techniques were employed for the characterization of synthesized compounds. All compounds exhibited anti-cancer activity ranging from 0.190 to 0.273 µg/mL against SaOS-2 cell line and the best activity was shown by compound 4i which exhibited IC50 value = 0.190 ± 0.045 µg/mL. It is evident that the concentration of these compounds is a critical factor in determining their biological efficacy. This dose-dependent relationship highlights the importance of optimizing compound concentrations to achieve maximal therapeutic benefits while minimizing potential side effects. Moreover, these findings demonstrated the potential of thiazole derivatives as promising candidates for anti-cancer drug development and warrant further investigation into their mechanisms of action and therapeutic applications. Molecular modelling was utilized to predict potential interactions of the synthesized compounds that exhibited inhibitory effects. The analyses revealed that compound 4i exhibited strong inhibitory effects against EGFR (docking score: -6.434, MM-GBSA energy: -53.40 kcal/mol) in in silico studies.

The therapeutic efficacy of oncolytic vaccinia virus (JX-594) has been demonstrated in metastatic clear cell renal cell carcinoma (ccRCC); however, only selected patients respond, and there are no predictive biomarkers for therapeutic response. We aimed to identify predictive biomarkers for JX-594 treatment and elucidate the underlying mechanisms.

SLFN11, a member of the evolutionarily conserved SLFN gene family, is an interferon-stimulated early response gene. This review comprehensively explores its multifaceted roles. Structurally, its three distinct domains endow it with diverse functions. Epigenetic modifications, post-translational alterations, and multiple signaling pathways intricately regulate SLFN11 expression and activity. In terms of functions, it plays crucial roles in the DNA damage response during replication stress, distinct from traditional pathways. It also serves as a protector in the antiviral response and a valuable biomarker for predicting the efficacy of DNA-damaging agents and patient prognosis in various cancers. Beyond these, SLFN11 has non-canonical functions, including immune regulation, modulation of oncological behaviors, involvement in apoptosis, protection against proteotoxic stress, and association with Fanconi anemia. Looking ahead, SLFN11 holds great promise as a biomarker for personalized medicine, but challenges like developing accurate detection methods remain. In immunotherapy, understanding its dynamic changes is essential for optimizing treatment. Strategies to overcome SLFN11-low expression, such as epigenetic modulation, also need further investigation, which may open new avenues for disease treatment.

Neoadjuvant therapy (NAT) is a promising strategy to improve long-term outcomes in hepatocellular carcinoma (HCC), particularly for patients with borderline resectable. Targeted therapy, transarterial chemoembolization (TACE), immunotherapy, and radiotherapy are all effective NAT strategies for HCC; however, the optimal NAT regimen for HCC remains undefined.

Cell free DNA (cfDNA) is detectable at low concentrations in the plasma of healthy subjects and at high concentrations in disorders characterized by a high rate of necrotic events, such as tumors and vasculitis, leading to the release of necrotic DNA into the surrounding tissue and the bloodstream. Although cfDNA may act as a danger signal by binding to DNA sensors, triggering inflammation and immune responses, elevated cfDNA concentrations instead may exert immunoregulatory activities. Here, we show that exogenously administered cfDNA mediates immunoregulatory functions in vivo, in particular, it protects lupus-prone mice from disease progression and favors tumor growth in tumor-challenged mice. Our data suggest that cfDNA mediates immune regulatory activities by directly interacting with MHC class II molecules on antigen-presenting cells and through recruitment of regulatory T cells. This study unveils unprecedented biologic functions of cfDNA with significant pathogenic relevance and remarkable implications for the treatment of cancer patients.

There is a need for biomarkers to predict response and survival to immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC). Soluble PD-L1 (sPD-L1) has shown biomarker potential. The objective of this study was to evaluate sPD-L1 in patients with advanced NSCLC treated with first-line ICIs.

Background The prognostic implications of middle neck involvement, defined as cervical lymph node metastasis between the caudal border of the hyoid bone and the cricoid cartilage, remain unclear in nasopharyngeal carcinoma (NPC). Purpose To investigate the prognostic significance of middle neck involvement in patients with N1 or N2 NPC. Materials and Methods This retrospective analysis included patients with N1 or N2 NPC without distant metastasis treated between April 2009 and December 2017. Patients were categorized according to the presence or absence of middle neck involvement, as determined at MRI. Survival analysis was performed by incorporating TN category and middle neck involvement. Kaplan-Meier curves and the log-rank test were used to compare survival outcomes. Results This study included 9795 patients (mean age, 45 years ± 11 [SD]; 7135 male). Middle neck involvement was identified in 17.0% of patients (1668 of 9795), with prevalence rates of 11.4% (848 of 7429) in the N1 subgroup and 34.7% (820 of 2366) in the N2 subgroup. Multivariable analysis revealed that middle neck involvement was an independent prognostic factor for reduced metastasis-free survival (MFS), overall survival (OS), and disease-free survival (DFS) in both the N1 (all P < .001) and N2 subgroups (P = .001, .02, and .04, respectively). Patients with T1-T2 N1 NPC with middle neck involvement exhibited survival outcomes comparable to those in patients with T1-T2 N2 NPC (all P > .05). Conversely, patients with T3N1 disease without middle neck involvement had better 5-year MFS (91.7% vs 84.6%; P < .001), OS (90.6% vs 84.3%; P = .003), and DFS (83.6% vs 74.4%; P < .001) than those with middle neck involvement. Conclusion Middle neck involvement serves as a critical factor for risk stratification in N1 and N2 NPC. It helps identify patients at high risk within the T1-T2 N1 subgroup and those with T3N1 disease. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Jabehdar Maralani and Kang in this issue.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content.

Serum carcinoembryonic antigen (CEA) has potential prognostic and monitoring significance in lung adenocarcinoma (LUAD) patients undergoing different treatments, such as epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and chemotherapy. The changes in CEA expression during relapses, influenced by resistance mechanisms involving cytokines and epigenetic factors, may impact its utility in disease prognosis, monitoring, and management.

IntroductionThe OCRA Tabletop MRI System is a compact, low-field (0.24T) magnetic resonance platform originally developed as an educational device to teach MR physics using chemical test tube-sized samples. Given its capabilities, we explored its diagnostic potential by performing relaxometric analysis on freshly resected human tissue specimens.MethodsMatched pairs of histologically confirmed tumor and non-tumor samples were analyzed with the OCRA MRI system to determine T1 and T2 relaxation times via NMR spectroscopy. In parallel, mRNA expression levels of ZEB1, a key transcription factor involved in WNT signaling, stem cell maintenance and tumor-stroma interactions were quantified for each sample.ResultsThe measured T1 and T2 relaxation times showed distinct profiles between tumor and non-tumor tissues. These biophysical properties were correlated with ZEB1 mRNA expression, revealing preliminary associations between tissue relaxation behavior and molecular signatures relevant to tumor microenvironment dynamics.ConclusionAlthough this pilot study does not yet confirm clinical diagnostic utility, it offers initial biophysical insights into tumor-associated tissue alterations and provides a foundation for future validation studies in larger patient cohorts.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a safe and widely used technique for diagnosing mediastinal/hilar lesions. Recent studies showed that combining EBUS-TBNA with cryobiopsy (EBUS-transbronchial mediastinal cryobiopsy, EBUS-TMC) or forceps biopsy (EBUS-intranodal forceps biopsy, EBUS-IFB) enhances diagnostic accuracy by obtaining larger tissue samples. However, limited data is comparing the efficacy of EBUS-TMC and EBUS-IFB. This study aims to assess the effectiveness of these biopsy techniques in diagnosing mediastinal and hilar lesions.

In non-Hodgkin's lymphoma, diffuse large b-cell lymphoma (DLBCL) is one of the most prevalent and commonly diagnosed subtypes. There is a need to develop more effective drugs since the currently approved drugs still have limitations.