Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, largely because of late-stage diagnosis, limited therapeutic options, and frequent treatment resistance. Ras homolog family member V (RHOV), a member of the Rho family of small GTPases, has been demonstrated in tumorigenesis in several cancer types. However, its role in PDAC remains undefined. This study aimed to evaluate the clinical significance and functional contribution of RHOV in PDAC progression. The association between RHOV expression and PDAC patient outcomes was assessed using the Human Protein Atlas database and validated in an independent cohort of 114 PDAC specimens by immunohistochemistry. The biological functions of RHOV were interrogated using in vitro cell proliferation, migration, and invasion assays, as well as in vivo xenograft models. Mechanistic investigations focused on RHOV-mediated signaling alterations. High RHOV expression correlated with significantly reduced overall and recurrence-free survival in patients with PDAC. RHOV overexpression enhanced PDAC cell proliferation and motility, whereas RHOV knockout suppressed these phenotypes in vitro. Mechanistically, RHOV overexpression activated key components of the mitogen-activated protein kinase signaling pathway, promoting cell growth, and induced epithelial-mesenchymal transition, facilitating increased migration and invasion. The xenograft studies confirmed that RHOV drives tumor growth and elevates tumor burden in vivo. These findings identify RHOV as a previously unrecognized oncogenic driver in PDAC and suggest its potential utility as a prognostic biomarker and therapeutic target.

Precision-guided therapy is imperative in the battle against pancreatic ductal adenocarcinoma (PDAC), one of the most lethal solid malignancies with limited improvements in survival despite advances in molecular profiling and systemic therapy. While oncogenic drivers such as KRAS, TP53, CDKN2A, and SMAD4 are nearly ubiquitous, their translation into effective targeted therapies has been constrained by profound tumor heterogeneity, a therapy-resistant tumor microenvironment (TME), and a paucity of predictive biomarkers. In parallel, clinical outcomes are increasingly shaped by extrinsic modifiers, including metabolic disease, chronic inflammation, and microbiome dysregulation, which remain under-integrated into current treatment paradigms. Recent progress in precision oncology has enabled regulatory approval of biomarker-defined therapies for select PDAC subsets, including immune checkpoint inhibitors for mismatch repair-deficient tumors, PARP inhibitors for BRCA1/2-mutant disease, and combination cytotoxic regimens such as NALIRIFOX in the metastatic setting. However, these advances benefit only a minority of patients, underscoring the urgent need for improved patient stratification and rational combination strategies. Emerging clinical and translational studies highlight the promise of integrating multi-omic profiling, liquid biopsies, functional precision models (organoids and patient-derived xenografts), and artificial intelligence-driven analytics to uncover actionable vulnerabilities, monitor response, and guide adaptive trial design. In this review, we critically evaluate the clinical relevance of molecular, metabolic, and microenvironmental determinants of PDAC progression and therapeutic resistance. We focus on translational bottlenecks that have limited clinical success to date and highlight biomarker-driven strategies, ongoing clinical trials, and emerging technologies poised to shift treatment from uniform algorithms toward biologically informed, patient-specific therapeutic approaches in pancreatic cancer.

Supplementary Table S2. Representativeness of Study Participants

Purpose: Metastatic castration-resistant prostate cancer with homologous recombination (HR) deficiency (HRD) is sensitive to PARP inhibitors (PARPi). PI3K inhibitors (PI3Ki) sensitize to PARPi by disrupting HR in preclinical models. This phase Ib/II study investigated copanlisib (Copa; pan–class I PI3Ki) and rucaparib (R). Patients and Methods: Eligible patients had metastatic castration-resistant prostate cancer treated with ≥1 androgen receptor inhibitor and taxanes. Phase I followed a standard 3 + 3 dose-escalation design (rucaparib 400–600 mg orally twice a day; Copa 45–60 mg i.v. on days 1, 8, and 15). Primary goal of phase I was to establish MTD and the recommended phase II dose. The primary endpoint of phase II was PSA50 response rate. Results: Thirteen patients enrolled had a median age of 64 (55–78) years and PSA was 11.7 ng/mL (0.018–2,101). Seven patients received taxanes, and one patient received PARPi. Eight patients had HRD+ tumors [BRCA2 (four), BRCA1 (one), RAD51C (one), CDK12 (one), and FANCA (one)] and three had PTEN loss. There were two dose-limiting toxicities in dose level 1 (rucaparib 400 mg twice a day; Copa 45 mg on days 1, 8, and 15): grade 3 rash and aspartate aminotransferase/alanine aminotransferase elevation. Treatment-related adverse events ≥ grade 2 included leukopenia (54%), anemia (38%), rash (30%), fatigue (23%), and neutropenia (23%). Six patients were treated at dose level –1 without dose-limiting toxicities, which was established as the recommended phase II dose (rucaparib 400 mg twice a day + Copa 45 mg on day 1/15). Among patients with HRD+, one had confirmed partial response and three had stable disease by RECIST, including one patient treated with prior PARPi, and three patients had PSA50 responses (23%). Conclusions: Copa/R had an acceptable safety profile with a signal of efficacy supporting future studies of PARPi with PI3Ki. Significance: Gene alterations in the PI3K and HR pathways are common in prostate cancer. Based on preclinical studies, the inhibition of PI3K disrupts HR, and PARP blockade induces AKT activation, supporting the combination of PI3Ki and PARPi. Herein, we investigated the safety and preliminary efficacy of the PI3Ki copanlisib and the PARPi rucaparib in patients with or without alterations in HR repair pathway genes.

Background and Aims: The formation of 5-hydroxymethylcytosine catalyzed by the ten-eleven translocation (TET) methylcytosine dioxygenases is related to DNA demethylation and has been found decreased in human chronic liver diseases, including the metabolic dysfunction-associated steatotic liver disease (MASLD). However, the underlying mechanisms by which these enzymes are involved in MASLD progression are not clear. We aimed to determine how TET dioxygenases affect MASLD progression. We investigated the impacts of hepatic TET1 on MASLD. Approaches: Two strains of whole body TET1 knockout (KO) mice were generated and challenged with a high-fat diet (HFD). RNA sequencing (RNA-Seq) was used to clarify the TET1-mediated signaling cascades involved in MASLD. Liver specific TET1 KO mice were used to determine the role of hepatic TET1 in MASLD. A TET1 small molecule inhibitor was adopted to investigate the impacts of targeting TET1 in a preclinical MASLD model. Results: Whole body TET1 KO using two different strategies both substantially alleviated MASLD progression in a MASLD murine model induced with HFD feeding. Besides, TET1 KO led to reduced hepatic cholesterols, triglycerides, and circulating cholesterols in MASLD mice. However, fed glucose levels were not significantly impacted by TET1 KO. The RNA-Seq results revealed that CD36 and IGFBP2 were among the most significantly altered hepatic genes in TET1 KO mice fed with HFD. Inhibiting TET1 in human hepatocytes validated that CD36 is downregulated upon TET1 knockdown. Using the liver specific TET1 KO (TET1 LKO) mice, it was found that depleting hepatic TET1 protects mice from MASLD progression. The molecular mechanism studies determined that TET1 promoted CD36 expression through transcriptional up-regulation via binding to the CD36 enhancer regions. TET1 enzymatic function is required for CD36 upregulation. The effects of TET1 knockdown on fatty acid uptake were rescued by CD36 overexpression in human hepatocytes. More importantly, suppressing TET1 function with a small molecule inhibitor significantly improved MASLD progression in a preclinical MASLD model. Conclusions: Hepatic TET1 is likely involved in exacerbating MASLD progression, suggesting the potential of targeting TET1 signaling cascade in treating MASLD patients. R01DK135664 R21AA028576 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background and Aims Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by diagnosis at advanced stages, limited therapeutic options, and frequent resistance to therapies. Although oncogenic KRAS mutations are central drivers of PDAC, alternative pathways indisputably contribute to its tumorigenesis and progression. RhoV, a member of the Rho family of small GTPases, has been implicated in tumor development in other cancer types, such as breast cancer and lung adenocarcinoma; however, its role in PDAC remains unclear. Methods In this study, we investigated the expression and functional impact of RhoV on PDAC. Analysis of publicly available datasets and immunohistochemical profiling of 114 PDAC patient specimens were used to evaluate the expression of RhoV in PDAC and its prognostic impact. Overexpression and CRISPR-Cas9-mediated knockout of RhoV were established in three pancreatic cancer cell lines. Functional analyses, such as cell proliferation, migration, invasion, colony formation, spheroid growth, and mouse xenograft, were used to evaluate the role of RhoV in PDAC cells. Results RhoV overexpression was associated with reduced overall and recurrence-free survival in public datasets and our own patient cohort. Functional assays demonstrated that RhoV overexpression promoted PDAC cell proliferation, colony formation, and spheroid growth, whereas knockout of RhoV suppressed these changes. Moreover, RhoV enhanced PDAC cell migration and invasion in vitro , accompanied by downregulation of E-cadherin and upregulation of N-cadherin and vimentin, indicating induction of epithelial–mesenchymal transition. Mechanistically, RhoV overexpression activated key MAPK pathway components, including phosphorylation of ERK, JNK, and p38. In vivo , xenograft models confirmed that RhoV drives tumor growth and increases tumor burden. Conclusion These results establish RhoV as a novel oncogenic factor in PDAC progression and highlight its potential as a biomarker and therapeutic target, warranting further investigation into combinatorial targeting strategies to overcome KRAS inhibitor resistance. ### Competing Interest Statement The authors have declared no competing interest. General Research Fund from Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, ;0 Startup Fund from Department of Pathology and Laboratory Medicine, Tulane University School of Medicine

Global hepatic DNA methylation change has been linked to human patients with metabolic dysfunction-associated steatotic liver disease (MASLD). DNA demethylation is regulated by the TET family proteins, whose enzymatic activities require 2-oxoglutarate (2-OG) and iron that both are elevated in human MASLD patients. We aimed to investigate liver TET1 in MASLD progression. Depleting TET1 using two different strategies substantially alleviated MASLD progression. Knockout (KO) of TET1 slightly improved diet induced obesity and glucose homeostasis. Intriguingly, hepatic cholesterols, triglycerides, and CD36 were significantly decreased upon TET1 depletion. Consistently, liver specific TET1 KO led to improvement of MASLD progression. Mechanistically, TET1 promoted CD36 expression through transcriptional upregulation via DNA demethylation control. Overexpression of CD36 reversed the impacts of TET1 downregulation on fatty acid uptake in hepatocytes. More importantly, targeting TET1 with a small molecule inhibitor significantly suppressed MASLD progression. Conclusively, liver TET1 plays a deleterious role in MASLD, suggesting the potential of targeting TET1 in hepatocytes to suppress MASLD.

Purpose: In this study, we use large language models (LLMs) to integrate information from multi-source medical reports to enhance the accuracy of automated diagnostic classification and prognosis for brain tumors. Materials and methods: Brain MRI reports from a cohort of 426 brain tumor patients were manually labeled for tumor presence and stability. Pathology reports from the same cohort were incorporated as an additional information source. A pre-trained LLM was used to extract features from the multi-source reports, and a Multi-layer perceptron (MLP) was trained for classification tasks. Model performance was evaluated on the test set using Micro F1 scores and AUROCs. The model’s zero-shot prognostic capability was validated on an independent cohort of 33 glioblastoma patients. Results: Micro F1-score 0.849 (95%CI: 0.814, 0.880) for tumor presence classification and 0.929 (95%CI: 0.904, 0.954) for tumor stability classification are reached. Compared to using solely radiology reports, the developed model showed improvements on Micro F1 of 10.4 ​% for tumor presence and 5.6 ​% for stability classification. Log-rank tests confirmed significant distinction between the high- and low-risk patient groups stratified by model-predicted “Tumor Stability” label (p-value ​= ​0.017), confirming the prognostic value of the model-generated labels. Conclusion: This study developed a multi-source integration model based on LLMs for automated diagnostic classification and zero-shot prognosis of brain tumors. The integration of multi-source reports improved classification accuracy compared to single-source reports. Predicted tumor stability labels demonstrated survival prognostic capabilities. These findings confirm the potential of LLMs in brain tumor research, supporting precision diagnostics and prognosis.

Supplementary Table S1. Dose-escalation Schema

Mitochondrial fission is mediated by dynamin-related protein 1 (gene name DNM1L) and fusion by mitofusins (MFN1 and MFN2) and optic atrophy 1. The role of mitochondrial dynamics in liver disease and cancer remains poorly understood. We analyzed single, double, and triple liver-specific KO mice lacking mitochondrial fission and fusion proteins using systematic analyses of mitochondrial morphology, untargeted metabolomics, RNA-seq, hydrodynamic tail vein injection of oncogenes, and human hepatocellular carcinoma samples. Liver-specific Dnm1l-KO (L-Dnm1l-KO) mice showed increased alanine aminotransferase levels and hepatic fibrosis, with spontaneous liver tumors developing by 12 to 18 months of age. L-Mfn1- and L-Mfn2-KO mice showed no significant liver damage or tumor development, although a small percentage of L-Mfn1, Mfn2 double KO mice developed tumors. Dnm1l, Mfn1, and Mfn2 triple KO (TKO) mice experienced significantly reduced liver injury and fibrosis, along with decreased spontaneous and oncogene-induced tumorigenesis. L-Dnm1l-KO mice showed increased activation of the cGAS/STING/interferon pathway and pyrimidine metabolism, which were significantly normalized in TKO mice. Deletion of hepatic cGas reduced both basal and oncogene-induced liver injury and tumor development in L-Dnm1l-KO mice. These findings indicate that mitochondrial dynamics are crucial for maintaining hepatic pyrimidine metabolism and regulating the cGAS/STING-mediated immune response to prevent liver tumorigenesis.

Kimura's disease (KD) is a rare chronic inflammatory disorder of unknown etiology prevalent in middle-aged Asian males. Kimura's disease transforming to T-cell lymphoma or coexisting with T-cell lymphoma have not been reported in the scientific literature except two cases of Kimura's disease resembling peripheral T-cell lymphoma morphologically. There was no corresponding entity included in the current WHO classification (5th ed., 2022). It might be a new variant of peripheral T-cell lymphoma. Here, we present the first reported case of coexisting KD and indolent peripheral T-cell lymphoma in a 55-year-old Chinese man.