Objective Gastric cancer (GC) has a complex pathogenesis driven by infection, genetic mutations, epigenetic reprogramming, and tumor microenvironment (TME) remodelling, all of which contribute to tumorigenesis, metastasis, and immune evasion. Retinoic acid receptor gamma (RARG) is implicated in many cancers, but its role in GC remains unclear. This study investigates the function of RARG in GC and explores its underlying regulatory mechanisms. Methods Transcription factor prediction and CUT&Tag sequencing were used to identify upstream regulators of PMEPA1. RARG expression in GC was assessed by western blotting and immunohistochemistry (IHC). The impact of RARG on GC via PMEPA1 was evaluated through functional assays. The mechanism of RARG in GC was further analysed using single-cell RNA sequencing (scRNA-seq) and validated in vitro and in vivo. Results We identify RARG as a transcriptional regulator of PMEPA1 and show that RARG abundance is elevated in GC epithelial cells and associated with poorer overall survival. RARG depletion suppressed GC cell proliferation, invasion, and migration, whereas PMEPA1 re-expression partially rescued these phenotypes. Additionally, RARG directly binds β-catenin to promote its nuclear accumulation, consistent with enhanced Wnt/β-catenin signalling. Conclusion RARG overexpression promotes GC progression by transcriptionally activating PMEPA1 via a genomic mechanism and, in parallel, directly binding β-catenin to enhance Wnt/β-catenin signalling.

BackgroundGastric cancer (GC) constitutes a substantial global public health challenge, and the lack of tractable molecular targets limits therapeutic progress. Mesoderm-Specific Transcript (MEST) has been implicated in tumor-related signaling, yet its functional role and druggability in GC remain undefined.MethodsThe analyses of GC tissue microarrays and cohorts were performed to evaluate MEST expression and its clinical significance. CRISPR/Cas9-mediated MEST knockout was used to characterize its oncogenic functions in GC cells and xenograft models. Integrated RNA sequencing and pathway analysis was utilized to elucidate signaling pathways under the regulation of MEST. A structure-guided virtual screen combined with SPR binding and phenotypic assays were employed to discover small molecules targeting MEST. The therapeutic effects and mechanism of the lead compound were evaluated using GC cell lines, patient-derived organoids, cell-derived xenograft (CDX), and patient-derived xenograft (PDX) models.MethodsMEST expression in GC tissues was elevated and linked to poor prognosis. Functionally, genetic ablation of MEST impaired GC cell proliferation, invasion, migration, and suppressed tumor growth in CDX models. Screening of approved-compound libraries identified cobicistat as a previously unrecognized high-affinity candidate MEST-inhibitory compound. Cobicistat suppressed tumor growth across a panel of preclinical GC models, including cell lines, organoids, CDX and PDX. Mechanistically, MEST may drive GC progression by activating the NF-κB pathway, whereas cobicistat may antagonize MEST binding and blocked NF-κB pathway.ConclusionMEST functions as a key oncoprotein driving GC progression via NF-κB activation. Cobicistat, a candidate MEST-inhibitory compound, exhibits favorable preclinical efficacy and safety, providing a promising candidate for targeted GC therapy.

BACKGROUND:Trastuzumab is the first-line therapy for human epidermal growth factor receptor-2 (HER2)-positive gastric cancer (GC). However, intrinsic and acquired resistance due to hyperactivation of intracellular signaling pathway such as MEK/ERK pathways limit its clinical benefits. Plant-derived bioactive compounds have emerged as promising candidates to overcome trastuzumab resistance due to their multi-target effects and favorable safety profiles. PURPOSE:To identify a small-molecule compound derived from Traditional Chinese Medicine (TCM) that could enhance trastuzumab sensitivity in HER2-positive GC by suppressing ERK hyperactivation. METHODS:An ERK kinase translocation reporter (ERK-KTR) was established for screening. Spontaneous gastric tumors derived from KrasG12D/+;Trp53R172H/+; Smad4flox/flox;Anxa10-CreERT2 (KPSA) mice were transplanted into C57BL/6 N mice for evaluating the therapeutic effect of kaempferitrin. We developed a F127-kaempferitrin (FKF) nano-delivery system, and generated patient-derived xenograft (PDX) models using HER2-positive GC tissues from a patient to evaluate efficiency of FKF. RESULTS:We identified kaempferitrin as a potentiator of trastuzumab efficacy in HER2-positive GC. Trastuzumab plus kaempferitrin inhibits the proliferation and invasion of SNU-216 cells and impedes tumor growth and lung metastasis in mouse with gastric tumors from KPSA mice. Kaempferitrin targeted COX2 to suppress ERK activation, thereby inhibiting gastric cancer progression and sensitizing trastuzumab therapy via interactions at Glu603, Thr198, and Gln440. Toxicological evaluations show that the combination of trastuzumab and kaempferitrin were well-tolerated, and FKF nanoparticle exhibited potent anti-tumor efficacy in HER2-positive GC PDX models. CONCLUSION:Our study shows that kaempferitrin as a promising sensitizer of trastuzumab, which enhances its therapeutic efficacy against HER-positive GC progression by suppressing COX2/ERK signaling.

BACKGROUND:Aberrant activation of Wnt/β-catenin signaling is a major driver of Gastric cancer (GC) progression. However, the upstream mechanisms that sustain receptor-ligand engagement within this pathway remain insufficiently characterized. METHODS:Comprehensive analyses of GC cohorts and tissue microarrays were performed to evaluate Josephin Domain Containing 1 (JOSD1) expression and its clinical significance. The impact of JOSD1 on cell proliferation, migration, invasion, apoptosis, and epithelial mesenchymal transition (EMT) was examined in vitro employing CCK-8, colony formation, Transwell, flow cytometry, Western blotting, and immunofluorescence assays. Subcutaneous xenograft models were used to assess the effects of JOSD1 on tumor growth in vivo. Mechanistic studies, including co-immunoprecipitation, ubiquitination, and rescue experiments, were employed to elucidate the molecular relationship between JOSD1, Heparan sulfate 6-O-endosulfatase 1 (SULF1), and the Wnt7B/FZD1/β-catenin signaling axis. RESULTS:JOSD1 expression was markedly elevated in GC tissues (log₂ FC > 1, FDR < 0.05) and correlated with advanced stage (P < 0.05) and poor patient prognosis (HR > 1, log-rank P < 0.05). Functionally, JOSD1 promoted GC cell proliferation, invasion, and EMT, while inhibiting apoptosis (P < 0.05). Mechanistically, JOSD1 functioned as a critical deubiquitinase that stabilized SULF1. Stabilized SULF1 directly bound the Wnt co-receptor Frizzled class receptor 1 (FZD1) and facilitated Wnt7B-FZD1 complex formation (P < 0.05), thereby activating canonical Wnt/β-catenin signaling and inducing β-catenin nuclear accumulation (P < 0.05). Ubiquitination and rescue assays confirmed that JOSD1-driven oncogenic effects were strictly dependent on SULF1 stabilization (P < 0.05). In vivo modulation of the JOSD1-SULF1 axis significantly altered tumor growth, apoptotic activity, EMT marker expression, and Wnt pathway activation (P < 0.05). CONCLUSION:JOSD1 functions as a critical deubiquitinase that stabilizes SULF1 to activate Wnt/β-catenin signaling, thereby driving GC progression. Targeting the JOSD1-SULF1-Wnt7B/FZD1/β-catenin axis may provide a promising therapeutic strategy for patients with GC.

BACKGROUND Colonic perforation secondary to a metallic clip following peroral endoscopic myotomy is exceptionally rare, particularly in patients with achalasia and concomitant chronic constipation. CASE SUMMARY We presented a case of a 48-year-old woman with acute abdominal symptoms in which intraoperative exploration revealed a detached metal clip adjacent to the colonic perforation site. A sigmoid colectomy with colostomy was subsequently performed. No discomfort was reported during the 5-month follow-up period. CONCLUSION This case highlights vigilance for acute abdominal pain after peroral endoscopic myotomy in chronically constipated patients with possible clip migration.

Abstract The KRASG12D mutation is a key oncogenic factor in pancreatic cancer, present in over 40% of cases, making it the most prevalent and the most poorly prognostic mutation. However, KRASG12D has been considered "undruggable," and thus remains a challenging target for therapeutic intervention. The novel KRASG12D inhibitor, RMC-9805 (Zoldonrasib), has shown promising efficacy and safety in clinical trials, offering hope to address the therapeutic void in KRASG12D-driven cancers. In this study, we utilized single-cell RNA sequencing to reveal that Zoldonrasib suppresses the SPP1/CD44 intercellular communication between tumor cells and macrophages, while promoting the antigen-presenting function of tumor-associated macrophages. Mechanistically, we observed that Zoldonrasib treatment induces mitochondrial damage and mtDNA release in tumor cells, leading to the activation of the cGAS/STING signaling pathway. Subsequently, STING-mediated phosphorylation of STAT1 inhibits the transcriptional activity of the key SPP1 transcription factor, STAT3, thereby downregulating SPP1 expression in tumor cells. Zoldonrasib enhances macrophage MHC-I antigen presentation by suppressing SPP1/CD44 signaling. In both immune-competent KPC mice and immune-reconstituted PDX models, the use of a clinical-stage STING1 agonist further promoted macrophage antigen presentation and enhanced the therapeutic efficacy of Zoldonrasib, while also sensitizing pancreatic cancer to immune checkpoint inhibitors. This study uncovers the regulatory role of KRASG12D inhibition via Zoldonrasib in anti-tumor immunity and proposes a promising combinatorial therapeutic approach for clinical trials. Citation Format: Xiaoe He, Xiangyan Jiang, Wengui Shi, Long Qin, Tao Wang, Zuoyi Jiao. KRASG12D inhibition enhances macrophage-mediated anti-tumor immunity via STING activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2566.

[This corrects the article DOI: 10.34133/research.0838.].

Background: Globally, gastric cancer is a significant health burden. Neoadjuvant chemoimmunotherapy (NACI) has emerged as a promising strategy for locally advanced gastric cancer, but responses vary substantially among patients. Predicting major pathological response (MPR) is crucial for treatment personalization. Objective: To develop and validate a web-based nomogram that integrates readily available clinical and serological markers to predict MPR in gastric cancer patients receiving NACI. Methods: This retrospective study analyzed 325 gastric cancer patients who underwent NACI and radical resection. A nomogram was constructed using R software and validated with metrics including receiver operating characteristic curve (ROC), area under curve (AUC), calibration curves, and decision curve analysis (DCA), compared to the use of a single biomarker. Results: The MPR was 53.5%. Multivariate analysis identified lower stomach location (odds ratio (OR) = 2.90; 95% confidence interval (CI): 1.35- 6.22; P = 0.006), histological differentiation grade (OR = 3.43; 95% CI: 1.77- 6.63; P < 0.001), systemic inflammatory response index (SIRI) (OR = 2.02; 95% CI: 1.02- 3.97; P = 0.043) and lactate dehydrogenase (LDH) (OR = 1.02; 95% CI: 1.01- 1.03; P < 0.001) as independent predictors of MPR. The nomogram demonstrated robust discriminative ability, with AUC values of 0.807 (95% CI: 0.751- 0.863) and 0.799 (95% CI: 0.711- 0.888) in the training and testing sets, respectively. Furthermore, DCA further confirmed its significant clinical utility. Conclusion: We developed and internally validated a nomogram that accurately predicts MPR after NACI. Implemented as a user-friendly web-based calculator, this model enables real-time, individualized estimation of MPR probability and may assist clinicians in tailoring treatment strategies for patients with gastric cancer. Further external and prospective validation is warranted.

Background:Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, highlighting the urgent need for effective and accessible therapies. Drug repurposing offers a cost-effective strategy to identify novel candidates from approved drugs. Terfenadine, a classical antihistamine with an established safety profile, has demonstrated antitumor activity in various malignancies; however, its efficacy and mechanism in GC have not been systematically explored. This study investigates the therapeutic potential of terfenadine in GC and elucidates its underlying molecular mechanisms. Methods:Cytotoxicity was assessed in AGS, HGC27, and MKN45 GC cell lines. Effects on proliferation, colony formation, migration, apoptosis, cell cycle distribution, and mitochondrial membrane potential were examined. Mechanisms were explored through bioinformatics analysis, molecular docking, and Western blotting. Synergy with 5-fluorouracil (5-Fu) was evaluated using checkerboard assays and analyzed by SynergyFinder. In vivo efficacy was validated in a patient-derived xenograft (PDX) model. Results:Terfenadine exhibited potent cytotoxicity against GC cells, with IC50 values of 5.14 μM (AGS), 3.95 μM (HGC27), and 5.01 μM (MKN45) at 48 h, demonstrating superior potency compared to 5-Fu in AGS and HGC27 cells. It significantly suppressed colony formation and migration, induced G0/G1 phase arrest via downregulation of CDK4/6 and phosphorylated Rb, and promoted mitochondrial apoptosis as evidenced by nuclear condensation and loss of mitochondrial membrane potential. Molecular docking predicted strong binding affinity to AKT (score: 9.09). Western blot analysis revealed that terfenadine treatment reduced the expression of PI3K, total and phosphorylated AKT, and mTOR, indicating modulation of the PI3K/AKT/mTOR pathway. Combination with 5-Fu produced synergistic cytotoxicity (synergy scores >10 b y Loewe and HSA models). In the PDX model, terfenadine (10 mg/kg) significantly suppressed tumor growth, reducing final tumor weight by 41.2% (p < 0.001). Conclusion:This study demonstrates that terfenadine exerts multifaceted antitumor effects in GC through modulation of the PI3K/AKT/mTOR pathway, exhibits synergistic activity with 5-Fu, and shows in vivo efficacy in a clinically relevant PDX model. These findings support the repurposing of terfenadine as a promising therapeutic agent for GC.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited therapeutic options, largely due to its metabolic adaptability and immunosuppressive tumor microenvironment. Cuproptosis has emerged as a promising therapeutic strategy, however, its efficacy in solid tumors is constrained by intracellular redox buffering and insufficient bioavailable copper. Here, we developed a redox-responsive copper-based nanoplatform (ICMNs) by integrating icaritin (ICA) into a copper metal-organic framework to synergistically induce cuproptosis and immunotherapy. After cell internalization, ICMNs underwent glutathione (GSH)-triggered disassembly, co-releasing Cu2+ and ICA. Mechanistically, ICMNs elevated intracellular reactive oxygen species levels by similar to 145-fold while depleted GSH by 56%, thereby amplifying oxidative stress and mitochondrial dysfunction. Furthermore, ICMNs triggered prominent immunogenic cell death, evidenced by a 5.4-fold increase in calreticulin exposure, enhanced HMGB1 release, and ATP secretion, which promoted dendritic cell maturation and CD8(+) T-cell activation. In patient-derived organoids, ICMNs reduced organoid viability by over 85%. In PDAC KPC subcutaneous transplant tumor mouse models, ICMNs achieved an 85.6% tumor inhibition rate and significantly prolonged median survival (41.5 vs. 15 days) without obvious systemic toxicity. Collectively, our findings demonstrate that redox potentiates copper-induced tumor cell death and antitumor immunity, offering a promising nanotherapeutic strategy for PDAC treatment.

Gastric cancer is one of the most common and deadly malignancies worldwide, ranking among the highest in both incidence and mortality. Despite notable advances in diagnostic technologies and therapeutic approaches, the five-year survival rate for patients with advanced disease remains below 30%, primarily due to pronounced molecular heterogeneity, drug resistance, and the lack of effective targeted strategies. Epigenetic studies have revealed that aberrant DNA methylation, histone modifications, and non-coding RNA regulation play pivotal roles in gastric tumorigenesis and progression. These alterations can reprogram transcription, reshape the tumor microenvironment, and promote therapeutic resistance, thereby accelerating malignant evolution without requiring genetic mutations. Recent advances have not only broadened our understanding of the molecular pathogenesis of gastric cancer but also provided breakthrough targets for clinical intervention, exemplified by the application of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors. This review summarizes advances in gastric cancer epigenetics, with a focus on their translational value in early non-invasive diagnosis, the development of epigenetic-targeted drugs and combination therapies, and prognostic assessment to guide personalized management. In addition, we highlight the integration of multi-omics approaches and emerging clinical trials to outline future directions and challenges. Overall, elucidating the mechanisms of epigenetic regulation and promoting their clinical translation hold promise for improving early detection and therapeutic response, providing new theoretical and practical foundations for precision medicine in gastric cancer.

Although glycolysis is a metabolic hallmark of pancreatic ductal adenocarcinoma (PDAC), it remains unclear whether the excessive lactate produced regulates CAF lactylation to promote extracellular matrix (ECM) deposition. The multi-omics and spontaneous model findings indicate that lactate accumulation in the tumor microenvironment (TME) promotes histone H3 lysine 18 lactylation (H3K18la) and activation of cancer-associated fibroblasts (CAFs), leading to both ECM densification and impaired immunotherapy efficacy in PDAC. Mechanistically, ubiquitin-conjugating enzyme E2T (UBE2T) acts as an initiating factor that promotes p53 positive feedback degradation through modulation of ribosome biogenesis, thereby enhancing lactate metabolic crosstalk via glycolytic reprogramming. Genetic ablation or pharmacological inhibition of UBE2T using the selective inhibitor pentagalloylglucose (PGG) disrupts lactate metabolic crosstalk, suppresses stromal deposition, and promotes intratumoral CD8+ T cells infiltration. Furthermore, the combination of PGG and anti-PD-1 therapy exhibits synergistic effects and survival benefits in spontaneous PDAC mice and immune-reconstituted patient-derived xenografts. Collectively, these findings reveal that UBE2T drives p53 positive feedback degradation to enhance glycolysis of PDAC, leading to excessive lactate production, which promotes H3K18la in CAFs and subsequent ECM deposition. Targeting UBE2T represents a potential strategy to improve the efficacy of immunotherapy in PDAC.

Abstract Antiangiogenic immunotherapy represents a promising cancer treatment strategy. However, the efficacy of this combination approach is hindered by inadequate vascular normalization. While the fundamental role of canonical kinase-centric VEGFR–ERK signaling in angiogenesis is appreciated, the kinase–centric model overlooks non-kinase components of the pathway, such as adaptors, scaffolds, and other non-kinase interacting proteins, that could impact response to antiangiogenic therapy. Here, employing ERK kinase translocation reporter and CRISPRa screening, we revealed that the non-kinase SHC–SHCBP1 complex governed VEGFR2–ERK activity and was a dependency for aberrant tumor angiogenesis. Genetic knockout of Shcbp1 in mice sensitized tumors to VEGFR2 inhibition, preventing excessive angiogenesis, normalizing tumor vasculature, and reprogramming the immunosuppressive microenvironment to enhance immunotherapy efficacy. Mechanistically, ERK directly formed a complex with SHC and SHCBP1. Upon VEGF stimulation, active VEGFR2 recruited SHC to liberate the SHCBP1–ERK complex. SHCBP1 then triggered ERK hyperactivation by promoting ERK phosphorylation and NLS-importin-dependent nuclear shuttling, creating a feedforward loop to exacerbate pathological angiogenesis. Clinically, SHCBP1 overexpression negatively correlated with vascular normalization and antiangiogenic immunotherapy response in patients. High-throughput screening led to the development of MS1943, an inhibitor blocking SHCBP1–ERK nuclear transport. Combined with the VEGFR2 inhibitor rivoceranib and anti-PD1, MS1943 demonstrated antitumor activity against immunotherapy-resistant preclinical models, with favorable tolerance. These findings define a non-kinase-governed VEGFR2–ERK signaling pathway as a targetable dependency for tumor angiogenesis, offering the foundation for alternative antiangiogenic immunotherapy strategies.

BACKGROUND:Normothermic regional perfusion (NRP) is increasingly used in donation after circulatory death liver transplantation, yet the impact of the accompanying intestinal ischemia/reperfusion injury and gut microbiota dysbiosis on liver grafts remains unclear. METHODS:A rat model of donation after circulatory death followed by NRP was established. Intestinal microbiota composition was characterized by 16S rRNA gene sequencing, and the contribution of microbiota alterations to liver injury during NRP was assessed using antibiotic-treated rats and fecal microbiota transplantation. Untargeted metabolomics of intestinal contents was subsequently performed to identify candidate metabolites potentially involved in microbiota-associated liver injury. Lysophosphatidylcholine (LPC) was further investigated in vivo and in vitro by transcriptomic analysis and studies of lysosomal function and autophagic flux. RESULTS:NRP induced intestinal microbiota dysbiosis. Antibiotic treatment attenuated liver injury, whereas fecal microbiota transplantation from NRP donors aggravated liver injury. Untargeted metabolomics identified LPC as a markedly increased metabolite during NRP, with elevated levels in intestinal contents, portal venous plasma, and liver tissue. Transcriptomic analysis and complementary in vivo and in vitro experiments showed that increased LPC exposure exacerbated hepatocellular injury and was associated with lysosomal dysfunction and impaired autophagic flux. CONCLUSIONS:NRP induced gut microbiota dysbiosis and alterations in the intestinal metabolome. LPC was increased during NRP and aggravated liver injury, accompanied by lysosomal dysfunction and impaired autophagic flux, suggesting that modulation of the intestinal microenvironment and LPC-targeted intervention may offer potential strategies to mitigate liver injury during NRP.

Background The efficacy of chemo-immunotherapy in gastric cancer (GC) is limited by heterogeneous resistance and the lack of predictive biomarkers. However, the molecular mechanisms underlying concurrent intrinsic chemoresistance and extrinsic immunosuppression remain poorly understood.Methods We performed integrative analysis of single-cell RNA sequencing and bulk transcriptomic datasets from GC cohorts to identify key regulators of chemo-immunotherapy resistance. The functional role of activating transcription factor 4 (ATF4) was validated in GC cell lines, patient-derived organoids (PDOs), and patient-derived xenograft (PDX) models. Mechanistic investigations employed chromatin immunoprecipitation sequencing, RNA-seq, and multiplex immunofluorescence to elucidate the ATF4-HSPA9-DNA damage response (DDR) axis. Clinical relevance was assessed in GC patients treated with 5-fluorouracil (5-FU) monotherapy and those receiving combination 5-FU plus anti-PD-1 therapy.Results We identify integrated stress-response transcription factor ATF4 as a key regulator of dual resistance. Mechanistically, ATF4 transcriptionally upregulates HSPA9 to activate the DDR, which promotes both intrinsic chemoresistance and extrinsic immunosuppression. ATF4 overexpression reduces 5-FU sensitivity and induces CD8+ T cell exhaustion in PDOs and PDX models. Clinically, low ATF4 expression correlates with improved survival in GC patients receiving chemo-immunotherapy.Conclusions These findings establish the ATF4-HSPA9 axis as a dual-function therapeutic target and predictive biomarker in GC chemo-immunotherapy. This axis bridges DNA damage repair-mediated chemoresistance and T cell exhaustion, providing a strategy to overcome resistance to 5-FU and PD-1 blockade.

Inflammatory signaling, metabolic reprogramming, and stromal complexity have emerged as core hallmarks of pancreatic ductal adenocarcinoma (PDAC). Cross-talk between these programs could represent potential targets to concurrently perturb multiple tumor-promoting processes. By integrating multiomics data from clinical cohorts, patient-derived organoids, and autochthonous models, we uncovered tumor-intrinsic inflammatory cascades in PDAC as master regulators of mevalonate pathway hijacking, which drove both malignant progression and stromal coevolution. TNFSF13B+ tumor-associated macrophages activated STAT3 signaling in neoplastic epithelia, leading to the transcriptional upregulation of USP20. This deubiquitinase stabilized HMGCR to potentiate mevalonate flux, resulting in cholesterol and geranylgeranyl pyrophosphate overproduction. Stimulation of YAP/TAZ signaling induced by the USP20-mediated metabolic alterations promoted tumor cell proliferation and triggered the activation of cancer-associated fibroblasts. Genetic ablation or pharmacologic inhibition of USP20 using a selective inhibitor reversed tumor metabolic dysregulation, suppressing both tumor growth and stromal desmoplasia. Furthermore, the combination of USP20 inhibition and anti-PD-1/anti-CTLA4 immunotherapy resulted in enhanced antitumor efficacy. These findings reveal the STAT3-USP20-HMGCR axis as a central coordinator of PDAC malignancy and position USP20 inhibition as a strategy to suppress oncogenic signaling, perturb metabolic reprogramming, and reverse microenvironmental remodeling.Significance: Targeting USP20 disrupts coevolution of pancreatic ductal adenocarcinoma and the tumor microenvironment and enhances immune checkpoint inhibitor efficacy by blocking mevalonate metabolism rewiring, providing a dual-action therapeutic approach for pancreatic cancer.

Bethesda IV thyroid nodules remain a major diagnostic challenge because cytology cannot reliably distinguish benign from malignant follicular-patterned lesions, often leading to diagnostic surgery for ultimately benign disease. This study evaluated whether ultrasound radiomics combined with machine learning could improve preoperative risk stratification in this setting. We conducted a retrospective monocentric study including 69 surgically treated patients with Bethesda IV thyroid nodules and definitive histopathology. Ultrasound images acquired between 2019 and 2020 were manually segmented, and radiomic features were extracted using LIFEx software. After preprocessing and removal of non-informative features, the dataset was split into training (n = 48) and a held-out test set (n = 21), isolated prior to any modelling procedure. Dimensionality reduction was performed with principal component analysis analysis (20 components, 99.5

The ubiquitin-proteasome system is a fundamental regulatory mechanism that governs protein stability and intracellular signaling in eukaryotic cells. This system relies on a coordinated cascade of enzymatic activities involving activating enzymes, conjugating enzymes, and ligases to assemble distinct ubiquitin signals. These signals are subsequently edited, removed, or interpreted by deubiquitinases and ubiquitin-binding proteins. While E3 ligases have traditionally been recognized as the primary determinants of substrate specificity in the ubiquitination process, recent studies have revealed that the dysregulation of E2 enzymes can also lead to significant pathological outcomes, including chromatin instability, immune dysregulation, metabolic dysfunction, and an elevated risk of cancer. Consequently, E2 enzymes have emerged as promising therapeutic targets for the treatment of various dis-eases. This review provides a comprehensive examination of the roles and mechanisms of the ubiquitin-conjugating enzyme E2T (UBE2T) in cancer initiation, progression, and therapy resistance, highlighting its potential as a compelling target for cancer therapeutics.

CP organoids exhibit more proliferation ability, ECM-like characteristics and activation of inflammatory signaling