Fulzerasib, a KRASG12C inhibitor, has shown clinical activity in previously treated non-small-cell lung cancer (NSCLC). Clinical studies indicate that combining a KRASG12C inhibitor with an anti-EGFR antibody is effective in colorectal cancer; however, its benefit in NSCLC remains to be explored.

Survival discrepancy between male and female patients in lung cancer is a well-known, but still poorly understood phenomenon. Previous studies have used different patient cohorts and clinical covariates and have not included obesity, which is associated with longer lung cancer survival. We evaluated the relationship between survival, obesity, sex and other covariates using comprehensive, harmonized patient cohorts and a federated analysis approach.

Cell reprogramming can be used to short-circuit the cancer-immunity cycle.

Extrachromosomal circular DNA (eccDNA) are molecules that originate from chromosomal DNA but exist independently. While large eccDNA (ecDNA) contributes to tumorigenesis, the role of smaller eccDNA (<100,000 base pairs) in cancer remains unclear. Our analysis of 25 colorectal cancer (CRC) tumors and normal adjacent tissues revealed that eccDNA is significantly more abundant in tumor tissues, correlating strongly with chromosomal amplifications. The presence of whole intact genes on 1.29% of eccDNA was nonrandom. We identified 84 genes that recurred across tumors of multiple patients when present on eccDNA, with 19% of genes being cancer-associated. eccDNA-borne genes were often accompanied by increased expression, and their contribution to expression was much larger than that from linear amplifications and the larger ecDNA. The cytokine gene CXCL5 exemplified this phenomenon, showing substantial copy-number increase and upregulation when present on eccDNA. Functional validation in cell lines showed that CXCL5 eccDNA enhanced transcriptional output and immune cell recruitment function. The recurrence and overexpression of CRC-related genes on eccDNA indicate their selection in tumors, suggest that eccDNA can serve as an additional mechanism for dynamically influencing gene expression and is capable of conferring cancer phenotypes on cells. Analysis of chromatin landscapes revealed that eccDNA preferentially forms at sites of open chromatin and active transcription, with architectural boundaries marked by CTCF protein. Clinically, higher eccDNA levels correlated with poorer relapse-free survival in a small patient cohort. These findings suggest that circular DNA elements across the entire size spectrum participate in cancer evolution and warrant further investigation in larger cohorts.

Loss of DNA methylation is a hallmark of cancer that is proposed to promote carcinogenesis through gene expression alterations, retrotransposon activation and induction of genomic instability. Cancer-associated hypomethylation does not occur across the whole genome but leads to the formation of partially methylated domains (PMDs). However, the mechanisms underpinning PMD formation remain unclear. PMDs replicate late in S-phase leading to the hypothesis that they become hypomethylated due to incomplete re-methylation by the maintenance methyltransferase DNMT1 during cell division. Here we investigate the role of DNMT1 in shaping the cancer methylome by conducting whole genome bisulfite sequencing (WGBS), repli-seq and ChIP-seq on DNMT1 knockout HCT116 colorectal cancer cells (DNMT1 KO cells). We find that DNMT1 loss leads to preferential hypomethylation in late replicating, heterochromatic PMDs marked by the constitutive heterochromatic mark H3K9me3 or the facultative heterochromatic mark H3K27me3. However, we also observe that a subset of H3K9me3-marked PMDs gain methylation in DNMT1 KO cells. We find that, in DNMT1 KO cells, these hypermethylated PMDs remain late replicating but DNMT3A localises to them. This is accompanied by loss of heterochromatic H3K9me3, specific gain of euchromatic H3K36me2 and some gene upregulation. These same domains also have more variable DNA methylation than other PMDs in colorectal tumours in vivo. Our observations suggest that hypermethylated PMDs lose their heterochromatic state, enabling their methylation by DNMT3A and the establishment of a hypermethylated, non-PMD state, despite their late replication timing. More generally, our findings suggest that differential de novo DNMT activity plays a key role in establishing domain level DNA methylation patterns in cancer cells.

Assessment of hepatic functional reserve is critically important for preventing serious complications after hepatectomy such as liver failure. While the indocyanine green clearance test (ICG) is a liver-specific test that is not affected by other organs and is commonly used to evaluate liver reserve capacity. We lack knowledge regarding what test should be performed for patients with jaundice, portal shunts, or intolerance whose liver function cannot be accurately assessed by ICG. To close this gap, we focused on changes in amino acid metabolism associated with impaired liver function. The branched-chain amino acid-to-tyrosine ratio (BTR) reflects the severity of liver disease. The research objectives are to evaluate whether BTR is useful as an alternative test to ICG. The primary endpoint of this study is to clarify the correlation between BTR and ICG. The secondary endpoints are to provide pathological confirmation of liver fibrosis and clarify the relationship with short- and long-term outcome and to examine whether it is clinically significant as a marker of preoperative liver reserve capacity. This retrospective single-center cohort study included patients who underwent hepatectomy for HCC between January 2011 and December 2016. In this study, 235 patients were enrolled, with a median BTR of 5.58. The BTR and indocyanine green stagnation rates at 15 min (ICG-R15) showed a significant correlation (r = -0.57, p < 0.001), whereas 1/BTR showed an even stronger correlation (r = 0.66, p < 0.0001). Conversion formulas that is a regression equation predicting ICG test results with BTR as an explanatory variable were analyzed. In addition to its correlation with ICG-R15, BTR was significantly associated with liver fibrosis in the background liver pathology of resected specimens, demonstrating higher sensitivity for detecting cirrhosis compared to ICG. The high BTR group exhibited significantly longer survival than the low BTR group (p = 0.020). The results indicate that BTR and ICG are significantly correlated. Comparable to ICG, BTR is a predictor of liver fibrosis and a prognostic factor for postoperative outcomes in patients with HCC. Although 99mTc-GSA scintigraphy has been reported to correlate with IGC, the correlation coefficient and number of cases in this study are equivalent. BTR can be tested through routine blood sampling. The results of this study demonstrate the potential for clinically evaluating preoperative hepatic reserve capacity in a less invasive, more cost-effective without facility limitations.

Glioblastoma (GBM) remains a significant therapeutic challenge. While GBM-derived extracellular vesicles (EVs) are known to remodel the normal blood-brain barrier (BBB) into a blood-tumour barrier (BTB), the underlying mechanism is largely not understood. Here, we reveal that nucleolin (NCL) is transferred via GBM-derived EVs to the surface of brain endothelial cells, where it promotes BTB formation. Furthermore, the NCL-specific aptamer AS1411 exploits this pathway, crossing the BTB through receptor-mediated transcytosis and selectively entering GBM cells in an NCL-dependent manner. Proteolysis-targeting chimeras (PROTACs), heterobifunctional molecules that recruit E3 ligases to degrade target proteins, show therapeutic potential but are hindered by inefficient brain penetration in GBM. Capitalizing on the BTB-penetrating capability of AS1411 and our prior finding that AS1411 can intracellularly recruit the E3 ligase MDM2 via employing NCL as a molecular bridge, we engineered AS1411-based PROTACs against VEGFR2 and EGFR. These PROTACs induced NCL- and MDM2-dependent ubiquitination and degradation of VEGFR2 or EGFR in GBM cells, demonstrating potent anti-tumour activity. Collectively, our findings identify EV-transferred NCL as a key mediator of BTB formation and a functional transcytosis receptor for AS1411, providing a promising strategy for developing BTB-permeable, targeted therapy for GBM.

BTK inhibitors (BTKi) have reshaped the therapeutic algorithm of lymphoproliferative diseases, but class-specific adverse events (AEs) have emerged. Dose adjustment (DA) is often attempted to mitigate AEs, particularly with ibrutinib, the first BTKi approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients. We described ibrutinib DA in 226 consecutive R/R MCL who started ibrutinib between 2016 and 2023. We assessed DA rate and calculated single patient's relative ibrutinib dose as a percentage of the expected full dose during the entire treatment period, grouping patients into 4 dose levels (DL1a 95%-100%, DL1b 75%-94%, DL2a 50%-74%, DL2b < 50%). We evaluated changes in response, progression free survival (PFS), overall survival (OS) and time to next treatment (TTNT) between groups. Thirty-four percent of patients started ibrutinib at reduced dose, mainly due to age/comorbidities. Overall, 44% of patients reduced ibrutinib dose, mostly due to AEs. Thirty-five percent of patients interrupted treatment, predominantly for AEs, and 65% of patients discontinued ibrutinib, most often due to progressive disease (70%). No statistically significant differences in response rates/PFS/OS were observed across DLs. Interestingly, patients on the lowest dose tended to remain on treatment longer. This is the first real-life report evaluating ibrutinib DA in MCL. We showed that DA is common, particularly in older comorbid patients, and doesn't compromise efficacy, making it a feasible strategy for managing ibrutinib-related toxicities.

Fine-needle aspiration biopsy (FNAB) and core-needle biopsy (CNB) are common methods to evaluate the pathology of an abnormal tissue mass. However, both methods have their limitations, e.g., FNAB samples often remain inadequate, and CNB is more invasive. A novel device, ultrasound-enhanced fine-needle aspiration biopsy (USeFNAB), can collect samples with greater cellular content quantitatively without compromising tissue quality. The purpose of this prospective study was to evaluate USeFNAB for the first time in humans in vivo.

Mutations in PIK3CA are one of several actionable mutations for patients with hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer. Alpelisib in combination with fulvestrant was the first approved PI3K inhibitor and was introduced in clinical practice in 2019. A lack of evidence for the use of alpelisib in the context of current treatment options like cyclin-dependent 4/6 inhibitor (CDK4/6i), highlights the importance of this analysis. We provide a real-world analysis of the use of alpelisib with the prospective German PRAEGNANT registry (NCT02338167).

Activation of the T cell receptor (TCR) complex is fundamental to initiating adaptive immune responses, particularly in CD8⁺ cytotoxic T lymphocytes that mediate anti-tumor immunity. However, the immunosuppressive tumor microenvironment often impairs TCR signaling, limiting the efficacy of T cell-based cancer immunotherapies. Here, we report the identification of rosmarinic acid (RA), a naturally occurring polyphenolic compound, as a potent small molecule enhancer of TCR signaling. RA significantly augments IL-2 and IFN-γ production, promotes T cell proliferation, and enhances cytotoxicity of CD8⁺ T cells in vitro. Mechanistically, RA directly binds to MEK1, a key kinase in the MAPK/ERK pathway, with high affinity, leading to reduced MEK1 phosphorylation and downstream signaling activation. Transcriptomic and metabolic profiling of RA-treated CD8⁺ T cells revealed upregulation of genes associated with TCR signaling, calcium flux, PPAR signaling, and oxidative phosphorylation, indicating a broad remodeling of T cell effector function and metabolism. In vivo, RA treatment significantly suppressed tumor growth, increased tumor-infiltrating lymphocyte (TIL) frequency, and improved survival in MC38 tumor-bearing mice. These effects were abrogated upon CD8⁺ T cell depletion, confirming their central role. Furthermore, RA synergized with anti-PD-1 therapy and enhanced the efficacy of adoptively transferred OT-I T cells in colorectal tumor-bearing hosts. Collectively, our findings reveal RA as a novel immunomodulatory agent that boosts CD8⁺ T cell responses via MEK1-mediated TCR signaling enhancement, providing a promising strategy for drug repurposing in cancer immunotherapy.

Immune checkpoint inhibitor-related myocarditis (ICI-M) is increasingly recognized, but real-world data in thymic epithelial tumors (TET) remain limited.

Natural language processing (NLP, artificial intelligence) can enable automated identification of records in large datasets. The purpose of this study was to evaluate the feasibility of NLP in identifying breast cancer-associated lung metastases and to understand the clinical characteristics and challenges of this common site of breast cancer recurrence.

Higher concentrations of human epidermal growth receptor 2 (HER2) may cause chronic kidney disease. We sought to determine if trastuzumab (a HER2 inhibitor) may be kidney protective.

Triple-negative breast cancer (TNBC) lacks effective targeted treatments, rendering γδ T cell immunotherapy a promising therapeutic strategy. However, the function of these immune cells is often limited by exhaustion and immunosuppression. This study investigated whether metformin can enhance γδ T cell-mediated immunity against TNBC. Results demonstrated that metformin increased the cytotoxicity, proliferation, and cytokine production of γδ T cells while reducing their exhaustion markers. It differentially modulated cellular metabolism by enhancing oxidative phosphorylation (OXPHOS) and glycolysis in γδ T cells while suppressing these pathways in cancer cells through AMPK-HIF1-α signaling. Metformin also upregulated stress ligands on tumor cells, thereby improving immune recognition. In chemoresistant models, metformin restored γδ T cell function. Clinical data further showed that high AMPK activity and increased γδ T cell infiltration were associated with improved patient survival. These findings indicate that metformin remodels immunometabolism and enhances tumor immunogenicity, supporting its potential as a combinatory agent in γδ T cell-based immunotherapy for TNBC.

Hepatocyte nuclear factor 4 alpha (HNF4α) is a conserved nuclear receptor that governs epithelial identity and metabolic homeostasis across endoderm-derived tissues. In cancer, HNF4α can function as either an oncogene or a tumor suppressor. In colorectal and hepatocellular carcinoma, reduced HNF4α activity accompanies loss of differentiation and tumor progression, consistent with tumor-suppressive functions. In contrast, in pancreatic ductal adenocarcinoma, invasive mucinous adenocarcinoma, and other lineage-defined epithelial tumors, HNF4α can also participate in transcriptional programs that sustain malignant identity, metabolic adaptation, and therapeutic resistance. However, these effects are highly context-dependent and do not imply a uniformly oncogenic role in these tumor types. These divergent functions are shaped by isoform usage, chromatin state, epigenetic regulation, metabolic cues, and transcription factor networks. Rather than acting as a classical oncogene or tumor suppressor in all settings, HNF4α is better understood as a context-dependent regulator of lineage state whose activity may either restrain tumor progression or support tumor maintenance. This mini review highlights the molecular mechanisms that shape HNF4α activity, including isoform biology and epigenetic control, and discusses emerging strategies for selectively inhibiting HNF4α in dependency states or restoring its differentiation-promoting functions in tumors where it is lost.

To evaluate whether 7-T susceptibility-weighted imaging (SWI) can predict glioma's histological grade, Ki-67 labeling index (LI), isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q co-deletion, telomerase reverse transcriptase (TERT) promoter mutation, and O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status of gliomas.

Using the well-studied two-stage model of skin carcinogenesis, the first transgenic mouse with targeted expression of a polyamine metabolic enzyme was generated 30 years ago. Ornithine decarboxylase (ODC), a key regulating enzyme of polyamine biosynthesis, was constitutively expressed in the outer root sheath cells of hair follicles near the bulge stem cell niche using a keratin 6 promoter in K6/ODC mice. Early studies using K6/ODC mice demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis. Treatment with inhibitors of ODC activity blocked the formation of skin tumors and caused the rapid regression of existing tumors. We review how use of the K6/ODC mouse has shown that elevated polyamines in epithelial cells stimulate proliferation and invasiveness, recruit stem cells, alter chromatin remodeling and cell signaling leading to metabolic reprogramming, increase vascularization, activate underlying fibroblasts, and have powerful effects on immune cell function, all contributing to the development and progression of tumors.

The Muscleblind-like (MBNL) family comprises evolutionarily conserved RNA-binding proteins that interact with target RNAs via zinc finger domains. MBNLs orchestrate RNA processing, particularly alternative splicing, driving the developmental fetal-to-adult isoform switch across numerous target transcripts. This transition is a cornerstone in the process of MBNL-maintained cellular homeostasis and fails in many pathological conditions associated with deregulated expression or function of specific MBNL paralogs. This review provides current insights into the roles of MBNL genes and proteins in both health and disease. We examine their genomic architecture and protein organization and synthesize key insights from animal models to delineate the selective and compensatory functions of individual MBNL paralogs in physiology. To illustrate the roles of MBNLs in disease, we outline nucleotide repeat expansion disorders marked by their functional depletion, with a primary focus on myotonic dystrophy (DM). We also highlight selected cancer studies that have demonstrated the dual roles of MBNLs in tumorigenesis, encompassing both pro-oncogenic and tumor suppressive functions. Finally, using DM as a model, we review evidence for the therapeutic potential of endogenous MBNL gene modulation and argue that analogous strategies could be adapted and tailored to restore MBNL homeostasis in other disorders involving their dysregulation.

Non-small cell lung cancer (NSCLC) is a malignant tumor characterized by high morbidity and mortality, as well as metabolic reprogramming. Enhanced serine synthesis plays a crucial role in the aberrant metabolism of NSCLC. Among the three key enzymes involved in serine synthesis, phosphoserine aminotransferase 1 (PSAT1) requires further investigation to elucidate its regulatory mechanisms in NSCLC.