Breast cancer accounts for a disproportionate share of global cancer-related deaths, with 670,000 fatalities and 2.3 million new diagnoses recorded in women during 2022 alone. Existing treatment modalities carry considerable toxicity burdens, and resistance to available agents remains an unresolved clinical problem. DNA methyltransferase 1 (DNMT1), the enzyme chiefly responsible for maintaining genome-wide methylation patterns during DNA replication, has been mapped out as a high-value target in breast cancer because its dysregulation silences tumour suppressor genes through promoter hypermethylation. The present work involves hierarchical in silico workflow to screen 4549 plant-derived compounds from the PlantCyc database (v16.0.3) against the human DNMT1 catalytic domain (PDB ID: 4WXX). Ten top-scoring compounds were taken forward for molecular docking via AutoDock Vina; Quercetin and Kaempferol both recorded the highest binding affinities at -9.5 kcal/mol, Wogonin (-9.3 kcal/mol) and Xanthohumol (-8.1 kcal/mol) also emerged as strong binders. Pharmacokinetic evaluation using ADMET-AI confirmed that all 10 compounds met Lipinski's rule of five, with human intestinal absorption values at or above 0.98. Wogonin and Xanthohumol were selected for a 100 ns all-atom molecular dynamics (MD) simulation in GROMACS due to their well-rounded ADMET profiles and limited existing data on their specific interactions with DNMT1 in breast cancer. Across all measured trajectory metrics, backbone RMSD, residue fluctuation, radius of gyration, solvent-accessible surface area, and intermolecular hydrogen bond count, Wogonin formed a more stable, compact complex. These findings suggest that Wogonin and Xanthohumol are non-toxic nutraceutical candidates suitable for DNMT1 targeted epigenetic therapy, with computational foundation strong enough to facilitate future in vitro and in vivo validation work.

Organoids are considered a novel modeling platform for studying human biology and advancing health research. With the ability to demonstrate complex 3D structure and multicellular interactions, organoids have advanced studies in all major organs as a reliable model. In this study, we generated an advanced cardiovascular organoid by using a genome-edited human pluripotent stem cell line with inducible SOX17 expression, enabling controlled endothelial specification, adjustable cell-type composition, and human heart-like morphology. Our organoids recapitulated the cardiotoxic phenotypes of FDA-approved chemotherapeutic doxorubicin, manifesting as decreased cell viability and diminished contractile activity. Cryoinjury-induced myocardial infarction in our organoids led to reduced beating, viability, and α-actinin expression, along with increased fibroblast formation, which were mitigated by Captopril. Lastly, isoproterenol treatment increased peak Ca transient amplitude and shortened APD in our organoids, consistent with previously reported β-adrenergic responses. In summary, we established a protocol for generating in vitro 3D cardiovascular organoids with controllable cellular composition and heart-like structures, providing a robust and easy-to-produce platform for future studies of human heart disease.

OBJECTIVE: To review recent evidence on the association between progestin exposure and meningioma risk and to propose practical recommendations for hormonal management in women requiring progestin therapy. METHODS: A narrative review of studies published between 2015 and 2025 evaluating the relationship between exogenous progestins and meningioma development, growth, or progression was performed. Evidence regarding different progestin compounds, cumulative exposure, reversibility after discontinuation, and implications for gynecologic practice was analyzed. RESULTS: Meningiomas account for more than one-third of intracranial tumors and occur two to three times more frequently in women, supporting a potential hormonal influence mediated by progesterone receptors, which are expressed in most tumors. The increasing use of MRI has led to more frequent detection of incidental meningiomas in premenopausal women using progestins for contraception or gynecologic conditions such as endometriosis and heavy menstrual bleeding. Consistent associations with increased meningioma risk were observed for high-dose or prolonged exposure to cyproterone acetate, chlormadinone acetate, nomegestrol acetate, and medroxyprogesterone acetate. Risk appeared to increase with cumulative exposure and decrease after treatment discontinuation. Evidence for other progestins, including desogestrel, dienogest, levonorgestrel, and the levonorgestrel-releasing intrauterine system, remains limited and less conclusive. CONCLUSIONS: Women's health specialists should systematically assess a history of meningioma before prescribing progestins. In patients with incidental meningioma, discontinuation of high-risk progestins should be considered, followed by MRI reassessment within 3-6 months. When hormonal treatment remains necessary, the lowest effective dose and regular neuro-oncologic monitoring are recommended. Increased awareness and individualized counseling are essential to optimize hormonal management in women at risk of meningioma.

Ten-eleven translocation (TET) enzymes are critical epigenetic regulators, which oxidize the methylated cytosine nucleobase 5-methyl-dC (mdC) in the genome to 5-hydroxymethyl-dC (hmdC) in an α-ketoglutarate-dependent manner. Because the presence of mdC in the promoter region of a given gene silences its expression, this oxidation goes in hand with the reactivation of such silenced genes. In different highly aggressive cancers such as acute myeloid leukemia (AML) and glioblastoma, loss of TET enzyme function, and therefore reduced hmdC levels pave the way for tumor development. Impairment of TET activity can occur through metabolic inhibition, through loss-of-function mutations in TET genes themselves, and finally through suppression of TET-expression via epigenetic silencing. Reactivation of TET enzyme expression represents a major aim of epigenetic cancer therapy. Here we show that the carbocyclic antimetabolite 5-aza-2'deoxycytidine (cAzadC), which is supposed to suppress the methylation of DNA during replication, leads to a substantial increase of TET2 expression and strongly increasing hmdC levels. We show that the treatment with cAzadC goes in hand with the broad reactivation of the cellular antitumor responses. With patient-derived xenograft AML-mouse models, we show that this translates into a strongly improved anticancer effect in vivo.

Sustained human papillomavirus (HPV) infection induces cervical intraepithelial neoplasia (CIN), a well-established precursor lesion and risk factor for cervical cancer. However, the specific long noncoding RNAs (lncRNAs) that regulate CIN progression remain poorly characterized. Herein, we identified a novel lncRNA, designated CIN-related lncRNA (CRL), and explored its role in CIN pathogenesis. Clinically, reduced CRL expression was significantly associated with advanced CIN stages, suggesting a potential correlation with disease severity. HPV oncoproteins E6 and E7 suppressed CRL expression through KDM2B-mediated modification of histone H3 lysine 4 trimethylation (H3K4me3). CRL repressed CIN progression and cell death in vitro. Further mechanistic investigations revealed that CRL exerted this inhibitory effect by suppressing ferroptosis. Importantly, CRL accelerated the degradation of transferrin receptor (TFRC) mRNA by interacting with the iron-sensing protein iron-responsive element-binding protein 2 (IREB2). Collectively, our findings highlight the functional importance of lncRNA CRL in HPV-induced CIN progression, specifically through its regulation of ferroptosis via the IREB2-TFRC axis. This study provides new insights into the molecular mechanisms underlying CIN development and identifies CRL as a potential candidate for CIN diagnosis or intervention.

OBJECTIVES: Pneumonectomy is associated with substantial perioperative morbidity and long-term cardiopulmonary function impairment. Therefore, avoiding pneumonectomy whenever oncologically feasible is an important goal in managing centrally located non-small cell lung cancer. This study evaluated the feasibility and oncologic outcomes of induction chemoradiotherapy administered to avoid pneumonectomy. METHODS: We retrospectively reviewed patients with centrally located non-small cell lung cancer initially considered candidates for pneumonectomy but underwent induction chemoradiotherapy to reduce surgical margins between April 2010 and December 2025. Induction treatment comprised concurrent chemoradiotherapy with platinum-based doublet chemotherapy and thoracic radiotherapy. Radiological responses, surgical procedures, perioperative outcomes, pathological responses, and survival rates were analyzed. RESULTS: Eleven patients received induction chemoradiotherapy; nine underwent surgical resection, and two declined surgery. Pneumonectomy was avoided and complete resection (R0) was achieved in all patients. Sleeve lobectomy was performed in four patients and extended sleeve lobectomy in four patients. Pulmonary artery plasty was performed in three patients, two sleeve plasty and one wedge plasty. Postoperative complications occurred in four patients (44.4%), with no perioperative mortality. A major pathological response was achieved in eight patients (88.9%), including a pathological complete response in seven patients (77.8%). At a median follow-up of 30 months, the 3-year overall survival was 100%, the recurrence-free survival was favorable, and no locoregional recurrence occurred. CONCLUSIONS: Induction chemoradiotherapy may facilitate lung-sparing surgery in selected patients with centrally located non-small cell lung cancer. However, the small retrospective nature of this study and potential selection bias warrant cautious interpretation.

We aimed to establish and evaluate a method for measuring the cardiac implantable electronic devices (CIEDs) dose of radiotherapy patients using radiophotoluminescence glass dosimeters (RPLDs). Thirty-two treatment courses of thirty patients were analyzed. The relationships between the CIEDs dose and the treatment site locations were analyzed, and the RPLD doses were compared to the treatment planning system (TPS) doses for head and neck or chest cases (n = 18). A phantom study was conducted in five cases wherein the dose discrepancies between RPLD and TPS in all fractions were more than double and 5 cGy or more, and filter of energy dependence correction of RPLDs was evaluated. The longer the distance between the irradiation field and the CIEDs, the lower the doses, and it was approximated by a function of the power law of distance from the field edge. In eighteen cases where TPS and RPLD doses could be compared, the dose discrepancies per prescribed dose between RPLD measurements and TPS calculations were within 1.15%, with a 95% confidence limit of 0.6%. In the phantom study, the dose discrepancies between the RPLD and TPS were decreased using filters for all five cases. In conclusion, in vivo dosimetry using RPLD was very useful as a means of avoiding the following risks: when planning CT did not include the CIED for dose calculation-based assessment; unintended direct exposure of the CIED to the treatment beam; furthermore, TPS dose calculation accuracy outside of the irradiated field remains an issue.

Near-infrared (NIR) and red light photobiomodulation (PBM) has gained increasing interest as a non-invasive therapeutic approach for a variety of medical conditions including ocular diseases. The eye represents a particularly suitable target for light-based therapies owing to its optical accessibility and the high mitochondrial demand of various tissues such as the retina and optic nerve. Ocular aging and several ophthalmic disorders are associated with mitochondrial dysfunction, oxidative stress, and chronic inflammation, providing a biological rationale for the use of PBM as a potential adjunctive approach. This narrative review provides an evidence-weighted, indication-specific synthesis of NIR and red-light PBM in ophthalmology, emphasizing device- and protocol-dependence, differences between multiwavelength PBM and repeated low-level red-light therapy, study-design limitations, safety considerations, and clinical translation gaps. A structured literature search was conducted using major scientific databases to identify relevant experimental studies, clinical trials, and observational reports. The review focuses on proposed mitochondria-centered mechanisms of action, including cytochrome c oxidase-mediated signaling, nitric oxide release, reactive oxygen species-driven hormetic responses, and downstream anti-inflammatory effects. Particular emphasis is reserved to dry age-related macular degeneration, for which literature is more relevant, and to dry eye disease owing to meibomian gland dysfunction and myopia, for which a body of evidence is progressively growing. For other ocular indications, data remain preliminary or exploratory. Overall, available data support biological plausibility and suggest possible functional or anatomical signals in selected ocular diseases, but the clinical evidence remains heterogeneous, with substantial variability in devices, wavelengths, dosimetry, treatment protocols, and study design, and remains insufficient to define PBM as established therapy for most indications. However, the clinical evidence remains heterogeneous, with substantial variability in devices, wavelengths, dosimetry, and treatment protocols. Although available studies generally report favorable short-term tolerability, long-term safety and the role of PBM in routine ophthalmic practice remain insufficiently defined. Well-designed, adequately randomized controlled trials with standardized treatment parameters are required to determine efficacy, optimal protocols, and long-term clinical relevance.

BACKGROUND: The impact of progesterone receptor (PR) status on the prognosis of breast cancer after isolated locoregional recurrence (ILRR) remains unclear. This study assessed the prognostic impact of the PR status of ILRR tumors in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. METHODS: The study utilized data from the Japanese National Clinical Database (2004-2015), including 1,625 patients with ER+/HER2- ILRR. All participants were patients aged between 20 and 75 years at diagnosis who underwent curative surgery for ER+/HER2- primary breast cancer. Patients were classified into three groups based on the PR status of primary (p) and recurrent (r) tumors. We compared the overall survival (OS) and breast cancer-specific survival (BCSS) among the three groups using the Kaplan-Meier method with the log-rank test. ER and PR were considered positive if immunohistochemistry staining was positive in > 1% of tumor cells. For the ER expression levels in ILRR tumors, 1-10% were considered as ER-low positive. RESULTS: Patients with PR- ILRR (pPR-/rPR- and pPR+/rPR-) had significantly worse OS and BCSS than those with PR+ ILRR (pPR+/rPR+). Factors associated with worse outcomes included lymph node metastasis, a shorter disease-free interval, ER-low positivity, and no surgery for ILRR tumor. CONCLUSIONS: This study highlights PR-negativity in ER+/HER2- ILRR tumors as a poor prognostic factor after ILRR, independent of the PR status of the primary breast cancer, emphasizing the need for tailored treatment strategies.

PURPOSE: To assess the concordance of CT-based radiological, surgical, and histopathological determination of vascular invasion in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: This retrospective single-center study included 103 treatment-naive PDAC patients (median age 68 years, male 61%) with arterial-/portal venous-contrast enhanced CT undergoing successful primary resection. Three radiologists independently assessed tumor-vessel contact according to NCCN criteria. Radiological vascular invasion was operationally defined as > 180° or contour irregularity versus no invasion defined as no contact or contact ≤ 180° without contour irregularity, to compare to binary intraoperative and histological reference. Intraoperatively, venous and arterial invasion were defined as tumor adherence to or invasion of the vessel wall. Histopathologically, venous invasion (V0/1) was defined according to UICC-TNM. Additionally, as major arteries were not resected, microscopically seen periarterial perineural invasion (Pn) served as a surrogate marker for arterial invasion (Pn0/Pn1), intermodal concordance of CT-to-surgery ≤/ > 4 weeks) was compared, Cohen's kappa and McNemar's-tests were used. RESULTS: Median CT-to-surgery was 17 days (81% within 4 weeks). CT-based interobserver agreement was κ = 0.8 for venous, κ = 0.6 for arterial invasion determination. Intraoperatively, 35% patients showed venous, 5% arterial involvement. Histopathologically, 14% showed venous invasion, 3% Pn1-status. CT-surgery venous invasion concordance was 75%, arterial 96%. CT-histopathology venous invasion concordance was 81%, 96% for Pn-status. CT-to-surgery interval ≤4 weeks showed higher CT-surgery (77% vs 65%) and CT-histopathology venous invasion concordance (84% vs 60%) compared to > 4 weeks interval. CONCLUSION: NCCN-derived, threshold-based radiological venous invasion determination was similar to binary intraoperative and histopathological findings and decreased with longer CT-to-surgery intervals. CRITICAL RELEVANCE STATEMENT: NCCN-derived, threshold-based CT venous-invasion determination in PDAC is concordant with binary intraoperative and histopathological invasion, but depends on the selected threshold and decreases with longer CT-to-surgery interval, underlining the clinical need for standardized staging intervals in patients undergoing surgery. KEY POINTS: Comparison between CT vascular assessment and surgical/histopathological findings in PDAC remains highly complex, and current guidelines lack CT-to-surgery interval recommendations. Threshold-based CT venous invasion agreed moderately with surgery and strongly with histopathology, while CT-based arterial status correlated strongly with surgery, albeit in markedly low overall incidence. CT-vascular assessment precision decreases with longer time intervals, showing the need for establishing timeframes for preoperative imaging.

PURPOSE: Ovarian cancer is frequently associated with gBRCA1/2 mutations, which also confer a high lifetime risk of breast cancer in non-affected patients. While risk-reducing salpingo-oophorectomy (RRSO) is established in hereditary breast and ovarian cancer prevention, the recommendation for risk-reducing bilateral mastectomy (RRBM) remains unclear in gBRCA1/2mutovarian cancer patients due to high recurrence rates and limited survival. This study evaluates the preventive strategies of these patients in a real-world setting. METHODS: This retrospective study included 49 patients with gBRCA1/2mut HGSC treated at the Hereditary Breast and Ovarian Cancer Centre, University Hospital Erlangen, between 2012 and 2024. Clinical, pathological, treatment-related, and genetic data were collected and analyzed from electronic records. RESULTS: Among 49 patients with gBRCAmut HGSC, 44 out of 49 did not undergo a RRBM during follow-up. Intensified breast cancer surveillance was recommended to 33 patients. Although 19 out of 49 patients were formally recommended a RRBM, only two proceeded with the preventive option. Three additional patients chose the surgery driven by the diagnosis of metachronous breast cancer. 80% of the operations occurred > 60 months after ovarian cancer diagnosis. CONCLUSIONS: In patients with gBRCA1/2mut and a history of HGSC, RRBM is rarely chosen. Most patients prefer an intensified surveillance program. Due to low metachronous breast cancer rate in follow up care, RRBM seems to be an option just for long-term survivors. Individual patient preferences play a crucial role in the management strategy.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are rare tumors comprising both neuroendocrine and non-neuroendocrine components, with each component constituting at least 30% of the tumor. MiNEN of the extrahepatic bile duct is particularly uncommon and is often associated with a poor prognosis. We report the case of a 63-year-old male with jaundice, who was diagnosed with cholangiocarcinoma at the confluence of the cystic duct. Imaging and endoscopic cholangiography revealed perihilar-to-distal bile duct involvement, accompanied by bulky lymph node metastases. Endoscopic biliary drainage was performed, and biopsy revealed adenocarcinoma. The patient received four cycles of neoadjuvant chemotherapy with gemcitabine, cisplatin, and durvalumab. The tumor and lymph nodes decreased in size, enabling curative pancreatoduodenectomy. Pathological examination revealed adenocarcinoma with small-cell neuroendocrine components, confirming MiNEN. The therapeutic response was grade 2, and curative resection was achieved. Four months after surgery, the patient developed para-aortic lymph node recurrence, prompting chemotherapy resumption; however, he died 2 years after treatment initiation. MiNENs with neuroendocrine carcinoma components are associated with a poor prognosis. Despite the initial response to neoadjuvant chemotherapy and curative resection, early recurrence indicates tumor aggressiveness. Additional case reports and further research exploring optimal treatment strategies are required to improve outcomes.

PURPOSE: Triple-negative breast cancer (TNBC), the subtype with the poorest prognosis, shows treatment outcomes closely tied to the response to neoadjuvant chemotherapy. Patients with residual disease post-treatment face a higher recurrence risk. In this subgroup, adjuvant capecitabine has been shown to improve disease-free and overall survival. Although concurrent use of capecitabine and radiotherapy (RT) is considered safe in gastrointestinal cancers, data on its safety in breast cancer are limited. This study aimed to evaluate toxicity outcomes associated with concurrent capecitabine and RT in TNBC. METHODS: This retrospective multicenter study included 95 patients with TNBC treated with concurrent adjuvant capecitabine and RT between 2018 and 2024 across eight medical centers. Toxicity was graded according to CTCAE v5.0. Univariable comparisons were adjusted for multiple testing using the Benjamini-Hochberg false discovery rate. Multivariable analyses were performed using forward stepwise logistic regression for grade 2-3 dermatitis and Firth's penalized likelihood logistic regression for grade 3 dermatitis. Statistical analyses were performed using Jamovi 2.6.44, JASP 0.19.3, and Python 3.11. RESULTS: The median follow-up was 25.3 months, and the median age was 49 years (range 29-81). Comorbidities were present in 33.7% of patients. RT was interrupted in 5.3% of patients; capecitabine was dose-reduced in 5 patients and discontinued in 2. Skin toxicity occurred in 86.3% of patients (grade 1, 44.2%; grade 2, 33.7%; grade 3, 8.4%), while 13.7% experienced no skin toxicity. Hematologic toxicity (any grade) was observed in 26.3% of patients and gastrointestinal toxicity in 8.4%, with no significant differences across skin toxicity strata. After multiplicity adjustment, clinical T3-4 stage, post-neoadjuvant ypT3-4 and ypN2-3 stage, and bolus application were significantly associated with higher-grade dermatitis (all q < 0.05). On multivariable analysis, advanced clinical T stage was the sole independent predictor of grade 2-3 dermatitis (OR 4.62, 95% CI 1.80-11.91, p = 0.002). For grade 3 dermatitis, Firth penalized regression identified total lymphatic irradiation (OR 9.93, p = 0.006) and bolus application (OR 7.08, p = 0.036) as independent predictors. CONCLUSION: Concurrent capecitabine and RT in TNBC demonstrated a manageable acute toxicity profile in this retrospective multicenter cohort. Further prospective studies are needed to validate these findings.

PURPOSE: Late-onset fetal growth restriction (FGR) presents clinical management challenges, often requiring frequent in-hospital fetal surveillance. Telemedicine-based computerized cardiotocography (cCTG) performed at home may offer a viable remote monitoring addition. METHODS: This single-center, open-label, a pilot randomized controlled pragmatic trial (COSMOS) was conducted in Warsaw, Poland, between 2022 and 2025. A total of 120 women with late-onset FGR, defined according to the Delphi criteria, were randomly assigned (1:1) to either a cCTG-based monitoring approach with protocol-mandated safety Doppler assessments or to standard hospital-based Doppler surveillance. The primary outcome was neonatal condition at birth (Apgar score at 5 min, umbilical artery pH). Secondary outcomes included emergency cesarean section for fetal compromise, maternal anxiety, measured using the Generalized Anxiety Disorder 7-item scale (GAD-7), number of antenatal visits, and a composite of adverse neonatal outcomes. The study protocol was registered at ClinicalTrials.gov (NCT05034861). RESULTS: There were no significant differences between groups in Apgar scores, umbilical cord arterial pH, or need for neonatal resuscitation. The rate of emergency cesarean delivery was lower in the cCTG-based group. Women in the cCTG-based group also reported significantly lower anxiety levels at delivery and required fewer antenatal visits, with no increase in adverse neonatal outcomes. CONCLUSIONS: Home-based computerized CTG within a pragmatic real-world framework appears feasible in pregnancies complicated by late-onset FGR. These findings support the potential of this approach to reduce hospital-based monitoring, maternal anxiety and in-person visits; however, these results should be considered hypothesis-generating and not indicative of clinical effectiveness. CLINICAL TRIALS REGISTRATION: Date 13.08.2021 NCT Number NCT05034861.

BACKGROUND: Despite advances in multimodal therapy, high-risk neuroblastoma (HR-NB) continues to have poor outcomes. Response to induction chemotherapy is a key predictor of long-term survival, yet intensive multi-agent regimens have not substantially improved prognosis. OBJECTIVES: This study aims to evaluate the efficacy and safety of adding bevacizumab to conventional induction chemotherapy in HR-NB. METHODS: This prospective, multicenter, randomized controlled trial will enroll newly diagnosed high-risk neuroblastoma patients, randomized to receive either conventional induction chemotherapy alone (control) or bevacizumab plus conventional induction chemotherapy (intervention). Response to induction therapy will be assessed according to standard criteria, and patients achieving a complete or good partial response will proceed to autologous stem cell transplantation (ASCT). All participants will be followed for at least 2 years to evaluate event-free survival (EFS) and overall survival (OS). The primary outcome, response rate, will be reported as a proportion, and EFS and OS will be analyzed using Kaplan-Meier plots and log-rank tests. The secondary outcomes (toxicity and minimal residual disease) will be reported as proportions. Prognostic factors will be evaluated with univariate and multivariate Cox regression analyses. EXPECTED OUTCOMES: The study aims to demonstrate that adding bevacizumab to conventional induction chemotherapy improves response rates, increases the proportion of patients eligible for autologous stem cell transplantation (ASCT), and improves survival outcomes, with manageable toxicities. TRIAL REGISTRATION: This study is registered with the Clinical Trials Registry of India (CTRI/2024/09/074065, dated: 19/09/2024).

Sarcomas are rare, highly heterogeneous malignancies, with soft tissue sarcomas (STS) comprising nearly 80 histological subtypes. Localized STS is generally treated with surgery and radiotherapy, whereas metastatic disease relies largely on chemotherapy, which offers limited benefit. Although inflammation influences tumor development, treatment response, and prognosis, immune checkpoint inhibitors have shown minimal efficacy in sarcoma. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is linked to mutational burden, genomic instability, immune cell infiltration, and therapeutic response across multiple cancer types. However, its role in sarcoma remains unclear. In a newly established cohort of STS patients, we found that STING expression in primary tumors correlates with immune cell infiltration. Using a lipid nanoparticle (LNP)-mediated delivery of CRISPR activation mRNA components, we restored STING expression in STS cells, thereby reactivating cGAS-STING signaling. This promoted T‑cell recognition and tumor cell killing in both 2D and 3D patient-derived models and enhanced responses to anti-PD-1 treatment. Together, our results show that controlled epigenetic activation of STING in STS enhances immune infiltration and tumor cell killing. Targeting STING through CRISPR activation may therefore represent a promising therapeutic strategy for STS.

BACKGROUND AND AIMS: Lung adenocarcinoma (LUAD) treatment is challenging process. and the function of PIEZO1, a mechanically sensitive ion channel has not been systematically determined. In this study we aimed to explore the expression, potential associations, and clinical significance of PIEZO1 in LUAD. METHODS AND AIMS: A comprehensive bioinformatics analysis was performed using data from the Cancer Genome Atlas (TCGA) database, the Gene Expression Omnibus (GEO) database and other databases. Experimental validation was performed to confirm the expression patterns and preliminarily examine the associations of PIEZO1 in LUAD cell lines. RESULTS: PIEZO1 expression was significantly lower in LUAD tissues than in normal lung tissues (P < 0.05). Its expression was correlated with advanced pathological stage, lymph node involvement, and distant metastasis. High PIEZO1 expression was associated with a distinct immune-related tumor microenvironment, characterized by correlations with the expression levels of multiple immune checkpoint molecules, and was identified as an independent factor associated with poor overall survival (HR = 1.49; 95% CI 1.11-2; P < 0.007). In vitro experiments confirmed the downregulated PIEZO1 expression in LUAD cell lines, and functional knockdown experiments revealed its association with cell migration and PD-L1 expression. CONCLUSION: This exploratory study revealed that PIEZO1 expression in LUAD cell lines correlated with the expression of immune-related features and EMT-related genes, as well as poor prognosis. In vitro, PIEZO1 knockdown is associated with reduced cell migration and decreased PD-L1 expression. These findings provide a basis for future investigations into the potential role of PIEZO1 in LUAD.

The lymphatic system in the liver has long been regarded as a passive transport route responsible for interstitial fluid drainage. However, recent research has redefined it as a "new frontier in hepatology," playing active and multifaceted roles in liver disease progression, ascites formation, and tumor immune responses. In malignancies such as liver cancer, lymphatic vessels function as conduits for lymph node metastasis, while simultaneously serving as pathways for tumor antigens and tumor-induced inflammatory cells, potentially contributing to the modulation of the immune microenvironment. This review first outlines the latest findings regarding the lymphatic system in non-neoplastic tissues. Next, we examine recent studies investigating the impact of lymphatic vessels on cancer progression. Furthermore, we focus specifically on the hepatic lymphatic system in both non-neoplastic and cancerous states. Finally, we conclude by discussing the potential role of hepatic lymphatic vessels in regulating the tumor microenvironment in liver cancer.

BACKGROUND: Globally, lung cancer is the most common malignancy among males, with higher incidence and mortality rates than in females. Sex chromosome analyses may provide insights into these disparities. KDM5D, located on the Y chromosome, is recognized as a tumor suppressor. Ongoing studies explore KDM5D's role in malignancies and therapeutic pathways. We evaluated the association of immunohistochemical expression with clinicopathologic parameters and survival. METHODS: A total of 102 male lung carcinoma patients who underwent trucut or resection procedures between June 1, 2014, and October 31, 2023, at a tertiary care center were analyzed. Evaluated parameters included age, tumor type, TNM stage, tumor-infiltrating lymphocytes, and KDM5D expression. Additional parameters were also assessed for resections. The JAD1D (KDM5D) antibody was applied to unstained slides, expression levels were quantified using the Q score method, and a cut-off was determined by the ROC curve. RESULTS: A cut-off value of 8 was calculated for mortality, but no significant value was found for recurrence or progression. Patients with high expression (>8) had significantly lower overall survival. Higher levels were associated with increased maximum tumor diameter, involvement of pN1, M1 and above, stage IVA-IVB disease, and mild to moderate tumor-infiltrating lymphocytes. These features and elevated KDM5D were significantly higher in the exitus group. CONCLUSION: KDM5D expression showed an unadjusted association with mortality in univariate Cox regression. However, this association was not significant after adjusting for clinicopathological variables or correcting for multiple comparisons. Given conflicting findings in the literature, further studies, methodological standardization, and deeper exploration of KDM5D and the KDM5 family are warranted.

INTRODUCTION: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide, largely due to late-stage diagnosis and limited availability of reliable biomarkers. Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells that carry nucleic acids, proteins, and lipids reflective of their cellular origin. Their stability and accessibility through minimally invasive sampling make them promising liquid biopsy biomarkers. AREAS COVERED: This review summarizes current evidence supporting EVs as diagnostic and prognostic biomarkers in NSCLC. We discuss the clinical relevance of EV-associated molecular signatures, including miRNAs, other non-coding RNAs, and proteins, in early detection, disease stratification, and outcome prediction. Recent advances in EV isolation and characterization technologies, particularly microfluidic and high-throughput platforms, are highlighted. We also examine key barriers to clinical translation, including biological heterogeneity, methodological variability, and the lack of standardized protocols. EXPERT OPINION: EVs have the potential to transform NSCLC management by enabling minimally invasive diagnosis, real-time disease monitoring, and personalized treatment strategies. However, widespread clinical implementation requires standardized methodologies, improved tumor-specific EV enrichment, and large-scale validation studies. Future integration of multi-omics, artificial intelligence, and advanced detection technologies is expected to enhance biomarker performance and facilitate the incorporation of EV-based liquid biopsy approaches into precision oncology.

BACKGROUND: HER2-positive (HER2+) breast cancer (BC) accounts for 15-20% of all BC. Mutations in the PIK3CA gene are found in 25-30% of HER2 + BC cases and have been implicated in tumor progression and endocrine therapy resistance. Recent evidence suggests that a somatic PIK3CA mutation (PIK3CAm) may serve as a marker of early progression in HER2 + metastatic BC. However, its precise prognostic significance across various lines of therapy and disease stages is not fully understood. We therefore aimed to evaluate the impact of PIK3CAm status on clinical outcomes in HER2 + BC patients. METHODS: We conducted a retrospective cohort study using data from the American Association for Cancer Research (AACR) Project GENIE Biopharma Collaborative (BPC). Overall survival (OS), Distant Recurrence-Free Survival (DRFS), and progression-free survival (PFS) were the primary outcomes. We compared patients with and without PIK3CAm and performed survival analysis using Kaplan-Meier methods and Cox proportional hazards models. RESULTS: We identified 212 HER2 + patients (150 early-stage and 62 Stage IV), of which 58 had a PIK3CAm. The median OS for the overall cohort was 125.1 months from treatment. Among early-stage patients, PIK3CAm was associated with a longer DRFS from diagnosis (37.7 months [95% CI 28.6-62.6] vs. 22 months [95% CI 16.8-32.8], p = 0.04). In contrast, among patients with Stage IV disease receiving first-line therapy, PIK3CAm was associated with a shorter median PFS (5.5 [95% CI 1.6-32.2] vs. 14.9 months [95% CI 7.2-22.0], p = 0.04). PIK3CAm was not identified as an independent predictor of OS, DRFS, or PFS in univariable or multivariable regression analyses. Within the PIK3CAm subgroup, not having received hormone therapy was the only factor associated with worse survival on multivariable analysis (aHR = 4.51, 95% CI 1.77-11.5). CONCLUSION: PIK3CAm was not found to be associated with worse OS, however it was associated with a shorter PFS among patients receiving first-line therapy, suggesting PIK3CAm could be explored as a predictive biomarker for identifying HER2 + Stage IV patients at higher risk of disease progression. These findings underscore the need for enhanced surveillance and personalized treatment strategies to manage disease progression in this patient subgroup.

BACKGROUND: While cancer treatment efficacy exhibits circadian differences, the role of circadian rhythms in photodynamic therapy (PDT) remains unclear. Understanding this relationship is crucial for treatment optimization. METHODS: Using B16F10 and 4T1 tumor-bearing mice, PDT was administered at different Zeitgeber times (ZT). Immune cell infiltration was analyzed using flow cytometry and immunofluorescence. We also compared the effects of PDT treatment between NSG mice and CD11c-DTR mice. Transcriptomic profiling of sorted CD11c⁺MHCII⁺ DCs was performed via RNA-seq. In vitro assays measured immunogenic cell death (ICD) markers and dendritic cells (DC) maturation. A PDT vaccine model was also evaluated. RESULTS: PDT efficacy showed strong circadian dependence, optimal at ZT10 and weakest at ZT22 in immunocompetent mice-a rhythm maintained in constant darkness but inverted with light-cycle reversal, confirming endogenous control. The effect was abrogated in immunodeficient NSG mice, pinpointing an immune-mediated mechanism. Further analysis revealed circadian oscillations in the infiltration of CD4⁺, and CD8⁺ T cells into tumors and spleens, peaking at ZT10. Crucially, the rhythmic abundance and function of CD11c⁺MHCII⁺ DCs were identified as the pivotal regulator. Specific DC ablation eliminated both the circadian efficacy of PDT and the rhythmic T-cell infiltration. Transcriptomics revealed ZT10 DCs were polarized toward adaptive immunity, while ZT22 DCs favored pro-tumorigenic pathways. PDT-induced ICD promoted DC maturation in vitro and enhanced antitumor responses in vivo. CONCLUSION: The intrinsic circadian rhythm of DCs is a master regulator of PDT efficacy, rhythmically governing adaptive antitumor immunity. These findings advocate chrono-immunotherapy through precise treatment timing to maximize clinical benefits.