Drug-tolerant persister (DTP) cells are a major cause of cancer treatment failure and tumor relapse. This review provides a systematic summary of recent advances in research on DTP cells in cancer, including their biological features, model systems, and targeting strategies. Current studies show that formation of DTP cells is a complex and dynamic process, involving cell cycle arrest, epigenetic remodeling, and extensive transcriptional and metabolic reprogramming. The drug tolerance of DTP cells arises from a cooperative molecular network that integrates metabolic adaptation, reactivation of key signaling pathways, and resistance to cell death programs. To investigate the DTP state, researchers have developed a variety of in vitro and in vivo models, including patient-derived xenograft (PDX) models, drug-treated cancer cell lines, and organoid systems. These models have become essential tools for identifying vulnerabilities in DTP cells, such as sensitivity to ferroptosis induction, dependence on specific metabolic pathways, and expression of distinct surface antigens. However, the field still faces important challenges. Existing models have limitations in mimicking the complex tumor microenvironment and in capturing the transient nature of DTP cells. In addition, the clinical value of targeting strategies identified with experimental models remains to be validated in large-scale trials. The high level of heterogeneity of DTP cells and the lack of standardized research protocols also hinder the comparison and integration of findings across studies. The future development of more physiologically relevant models, the use of advanced technologies to better characterize DTP cells, and the design of clinical trials aimed at eliminating DTP cells are critical steps in the transition from tumor control to durable cure.

Radiotherapy failure remains a major challenge in glioblastoma (GBM), yet the stress-adaptive programs that enable tumor cells to survive irradiation-induced lethal injury remain incompletely defined. This study investigated whether serpin family E member 1 (SERPINE1) contributes to GBM radioresistance by modulating ferroptosis-associated lipid peroxidation, a process linked to iron-dependent oxidative injury.

Radiotherapy-treated GBM cohorts from TCGA (n = 93; 56 radiosensitive and 37 radioresistant cases), the Chinese Glioma Genome Atlas (CGGA)-325 (n = 100), and CGGA-693 (n = 193), as well as Clinical Proteomic Tumor Analysis Consortium (CPTAC) protein data and the Gene Expression Omnibus (GEO) single-cell RNA sequencing (scRNA-seq) dataset GSE131928, were analyzed using differential gene expression, weighted gene co-expression network analysis (WGCNA), machine-learning feature selection, FerrDb annotation, survival analysis, pathway enrichment, scRNA-seq, and tumor microenvironment (TME) signature profiling. Radiosensitive disease was defined as a complete or partial response after radiotherapy, whereas radioresistant disease was defined as stable or progressive disease. Statistical analyses included Wilcoxon rank-sum tests, Spearman correlations, log-rank tests, multivariable Cox regression for overall survival (OS), and time-dependent receiver operating characteristic (ROC) analysis. Functional validation was performed in two GBM cell lines (U87 and U251) using SERPINE1 knockdown or overexpression, X-ray irradiation, ferrostatin-1 (Fer-1), and RAS-selective lethal 3 (RSL3).

Integrative screening identified SERPINE1 as a ferroptosis-associated mediator of radioresistance and poor survival. SERPINE1 expression was elevated in primary GBM tumors (n = 199) compared with normal tissues (n = 18). SERPINE1-high tumors showed enrichment of ferroptosis driver, suppressor, and marker gene signatures, consistent with a ferroptosis-stressed but ferroptosis-defensive state. Single-cell analysis localized SERPINE1 mainly to mesenchymal-like malignant cells, where high expression co-occurred with hypoxia, extracellular matrix remodeling, radioresistance, and ferroptosis-defense programs. In U87 cells, SERPINE1 knockdown enhanced radiosensitivity and increased irradiation-induced lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe²⁺ accumulation, whereas SERPINE1 overexpression in U251 cells attenuated ferroptosis-associated lipid peroxidation and iron accumulation and improved post-irradiation cell survival. Fer-1 partially rescued the radiosensitizing effect of SERPINE1 depletion, whereas RSL3 weakened SERPINE1-mediated radioprotection.

SERPINE1 appears to link mesenchymal adaptation, redox stress regulation, and ferroptosis-associated lipid peroxidation defense in GBM radioresistance. These findings support further evaluation of SERPINE1-guided ferroptosis-based radiosensitization strategies. Public datasets were obtained from TCGA, CGGA, CPTAC, and GEO (GSE131928).

Pancreatic cancer ranks among the leading causes of cancer-related death worldwide, and novel therapeutic strategies are urgently needed for advanced or metastatic disease states. Notably, targeted therapy remains a particularly promising approach. The transcription factor FOS-like antigen 1 (FOSL1) is overexpressed in refractory pancreatic cancers and drives tumor progression, correlating with unfavorable clinical outcomes. Thus, this study aimed to investigate the molecular mechanisms through which FOSL1 and proliferating cell nuclear antigen (PCNA) promote pancreatic cancer progression by regulating DNA repair, invasion, and migration.

We evaluated the role of FOSL1 in pancreatic cancer cell proliferation, DNA repair, stemness, invasion, and migration, and identified downstream targets and pathways through transcriptomic analysis. Mechanistically, we validated the FOSL1-PCNA interaction, FOSL1 binding to the PCNA promoter, and the role of FOSL1 in regulating PCNAubiquitination. Finally, we assessed whether FOSL1 functions through PCNA and explored the effects of combined FOSL1 knockdown and PCNA inhibition.

FOSL1 depletion altered cell proliferation, steady-state DNA damage, stemness-associated markers, invasion, and migration. PCNA overexpression partially rescued the reduction in colony formation caused by FOSL1 knockdown. Mechanistically, FOSL1 binds the PCNA promoter, and FOSL1 knockdown reduced PCNA mRNA expression. Moreover, chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) showed that FOSL1 occupies the PCNA promoter region. Conversely, PCNA knockdown suppressed pancreatic cancer cell proliferation and impaired the expression of genes involved in DNA repair, stemness, and epithelial-mesenchymal transition (EMT)-mediated invasion and migration.

Our findings indicate that FOSL1 promotes pancreatic cancer progression, at least in part by upregulating PCNA expression. We hypothesize that combined inhibition of FOSL1 and PCNA may represent a therapeutic strategy for advanced pancreatic cancer.

Chronic myeloid leukaemia (CML), a distinct myeloproliferative neoplasm, results from the malignant reprogramming of haematopoietic stem cells (HSCs) into leukaemia stem cells (LSCs), primarily driven by breakpoint cluster region and Abelson (BCR-ABL1) fusion oncogene. Although the advent of tyrosine kinase inhibitors (TKIs) has significantly transformed clinical management, leading to improved patient survival and quality of life, sustained treatment-free remission (TFR) remains achievable in only a minority of patients. This limitation is largely attributable to the persistence of LSCs and the development of resistance mechanisms. Emerging evidence indicates that LSCs evade TKI-induced apoptosis through aberrant expression of specific cell-surface markers, dysregulated intracellular signalling pathways, and extensive epigenetic alterations. This review examines recent advancements in CML therapy, with a focus on these novel therapeutic targets. It highlights the pivotal role of LSCs in disease progression and relapse, evaluates potential molecular and epigenetic regulators as new targets for intervention, and supports the development of combination treatment strategies to improve TFR rates and move towards curative outcomes.

Recent data show that there are direct relationships between mitochondrial activity, cancer progression, and chemoresistance. Venetoclax (Ven) is a mitochondria-targeted chemotherapeutic drug, which facilitates apoptosis by selectively inhibiting the antiapoptotic protein Bcl-2. Ven exhibits a dual effect, affecting not only mitochondria but also the cell drug resistance system. There is also evidence indicating that cancer cells develop resistance to Ven, which is mediated by the upregulation of antiapoptotic proteins, simultaneous activation of multiple signaling pathways, an alteration in the cellular and mitochondrial metabolism, and other defensive mechanisms. The influence of Ven on the opening of the mitochondrial permeability transition pore (mPTP), a key event in the induction of mitochondria-dependent cell death, has not been previously studied.

The effect of Ven on calcium-induced mPTP opening, respiration, and reactive oxygen species (ROS) production was examined in isolated rat liver mitochondria, using cation-selective electrodes, as well as fluorescent and chemiluminescent methods.

Ven was found to have a protective effect against the Ca²⁺-induced mPTP opening, increasing the threshold calcium concentrations and the calcium load that activate pore opening. A comparison with the known mPTP inhibitors ADP, bongkrekic acid (BA), cyclosporine A (Cs), oligomycin, used separately and in combination with Ven, showed a similarity of the effect of Ven (at a concentration of 50 µM) to the effect of BA (20 µM). The effects of both were prevented by carboxyatractyloside (CATR). Also, the protective effect of Ven, as well as that of BA, was completely eliminated by 2-thenoyltrifluoroacetone (TTFA), an inhibitor of the ubiquinone-binding site of succinate dehydrogenase complex at low concentrations (5 µM and 50 µM under the oxidation of succinate and NAD-dependent substrates, respectively). Simultaneously, Ven decreased the ROS production induced by TTFA under the same conditions.

Ven shows two protective activities, namely, the inhibition of mPTP opening and the suppression of ROS production in mitochondria, which may be additional causes of the development of drug resistance. The results of the TTFA test are consistent with the data on the dependence of Ven resistance on the state of the respiratory chain.

This study systematically analyzed misdiagnosis classification, incidence and root causes of pediatric peripheral neurogenic tumors on high-frequency ultrasound among diagnostically ambiguous cases, and summarized core diagnostic pitfalls.

We retrospectively collected clinical and ultrasonographic data from 44 children with superficial soft tissue masses treated between January 2022 and June 2026. Final diagnoses were confirmed via surgical pathology, pathogenic genetic testing combined with typical multimodal imaging, or multidisciplinary consensus after a minimum 12-month clinical and MRI follow-up. Only atypical lesions with initial ultrasound suspicion of neurogenic origin were enrolled; all cases with classic definitive sonographic signs were excluded. Using final pathological or follow-up diagnosis as the gold standard, we quantified misdiagnosis proportions and categorized misdiagnosis patterns.

Of the 44 enrolled children, 31 (70.5%) were confirmed to have peripheral neurogenic tumors, and 13 (29.5%) carried non-neurogenic lesions. A total of 15 misdiagnoses occurred (34.1% of the cohort). Thirteen misdiagnoses represented source misjudgment, in which all non-neurogenic lesions were incorrectly categorized as neurogenic; these predominantly included five lipogenic tumors, four fibrogenic lesions, and four other miscellaneous soft tissue masses. Two misdiagnoses were subtype misjudgments of confirmed neurogenic tumors (6.5% of all neurogenic cases). Importantly, this cohort only included atypical confusing lesions without classic imaging features; the 0% specificity of the combined ultrasound criteria only reflects ultrasound performance in difficult cases and cannot be extended to routine pediatric superficial masses. The rat-tail sign yielded 100% specificity (95% confidence interval (CI): 75.3%-100%) and 100% positive predictive value (95% CI: 73.5%-100%) for identifying neurogenic lesions, while its sensitivity was only 38.7% (12/31; 95% CI: 21.8%-57.8%).

The rat-tail sign achieves 100% specificity and positive predictive value for neurogenic lesions within this atypical cohort, yet shows only 38.7% sensitivity. Major pitfalls include pseudo-rat-tail artifacts and mimicking lesions. Integrating patient age, growth velocity, and dynamic multiplanar tracing into a standardized stepwise workflow can reduce false-positive misdiagnoses in daily practice.

Systemic inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), are established prognostic biomarkers in melanoma, particularly in advanced disease. However, their utility in predicting early metastatic spread, such as sentinel lymph node (SLN) involvement, remains unclear. To evaluate the relative contributions of systemic inflammatory indices and tumor microenvironment (TME) features in predicting SLN metastasis in cutaneous melanoma. In this retrospective, single-center study, clinicopathological parameters, peripheral blood-derived inflammatory indices (NLR, PLR, lymphocyte-to-leukocyte ratio, lymphocyte-to-monocyte ratio, and neutrophil-to-eosinophil ratio), and TME features, including tumor-infiltrating lymphocytes (TILs) and tumor regression, were analyzed. Multivariable analyses and nested predictive models were constructed to identify independent predictors and to assess the incremental predictive value of each parameter group. SLN positivity was strongly associated with established histopathological markers, including Breslow thickness, ulceration, mitotic rate, and lymphovascular invasion (all P < 0.001). In contrast, systemic inflammatory indices showed no significant association with SLN involvement (all P > 0.05). TME-related features demonstrated significant associations; higher TIL density showed a dose-dependent inverse relationship with SLN positivity (P = 0.001), while tumor regression was linked to reduced nodal metastasis (P = 0.031). In addition, lower platelet counts were also associated with SLN positivity (P = 0.03). Incorporation of TME features improved model performance, whereas systemic inflammatory markers did not provide additional predictive value. Early nodal metastasis in melanoma appears to be driven by local tumor-immune interactions rather than systemic inflammation. These findings support the limited predictive value of circulating inflammatory markers and highlight the importance of TME features in risk stratification and clinical decision-making.

BACKGROUND Zinner syndrome is a rare congenital anomaly of the male genitourinary system, characterized by the classic triad of features: a seminal vesicle cyst, unilateral renal agenesis, and vas deferens obstruction. This article presents a clinical case of a 36-year-old patient with this rare condition and describes the results of his successful laparoscopic surgical treatment. CASE REPORT A 36-year-old man with a 2-year history of infertility and chronic pelvic pain received a diagnosis of Zinner syndrome, characterized by the triad of left renal agenesis, ipsilateral ureteral atresia, and a large seminal vesicle cyst. He underwent successful laparoscopic excision of the cyst. The cyst contents (approximately 120 mL of light-brown fluid) were aspirated, followed by meticulous enucleation. The cyst, remnant seminal vesicle tissue, and distal atretic ureter (3 cm) were completely resected. Histopathological examination confirmed a benign, multilocular cyst lined by columnar epithelium with glandular metaplasia and chronic inflammation, with no evidence of malignancy. The postoperative course was uneventful. At 3-month follow-up, the patient reported complete resolution of pain and normalized urination. Semen analysis showed significant improvement: ejaculate volume increased to 1.6 mL, sperm concentration to 1.4×10⁷/mL, and progressive motility to 35%, indicating partial recovery of ejaculatory function. The case demonstrates that laparoscopic surgery is an effective treatment for Zinner syndrome, alleviating symptoms and potentially improving fertility parameters. CONCLUSIONS This case highlights the importance of timely recognition of Zinner syndrome, especially in patients with unilateral renal agenesis and pelvic pain, and demonstrates the effectiveness of the laparoscopic approach as a method of choice in the symptomatic course of this pathology.

BACKGROUND Pancreatic cancer remains one of the most aggressive malignancies, characterized by late diagnosis, limited treatment options, and a dismal prognosis, with a 5-year survival rate consistently below 13%. The molecular mechanisms driving its progression are incompletely understood, highlighting the need to identify novel regulators of oncogenic pathways. This study focused on keratin 13 (KRT13), a cytoskeletal protein, and investigated its role in pancreatic cancer pathogenesis, particularly its regulatory effect on peroxisome proliferator-activated receptor gamma (PPARG) through the PI3K/AKT signaling axis. MATERIAL AND METHODS We integrated in vitro cellular assays with molecular biology approaches and bioinformatic analyses to systematically examine KRT13 expression and function. Pancreatic cancer cell lines were used for functional studies, including proliferation, migration, and pathway modulation experiments. Gene expression levels were assessed via quantitative PCR. Expression of KRT13 was further validated via immunohistochemistry on tissue sections from 85 patients. Public transcriptomic datasets (eg, TCGA) were interrogated to evaluate clinical correlations. Mechanistic insights were gained through pharmacological inhibition and genetic silencing of key pathway components. Further in vitro investigation of drug sensitivity was performed with patient-derived organoids (PDOs). RESULTS KRT13 expression was markedly upregulated in pancreatic tumor tissues compared to adjacent normal samples. This result was also confirmed in a set of 85 clinical samples, showing a strong positive correlation with PPARG levels. Clinically, elevated KRT13 was significantly associated with reduced overall survival (log-rank P<0.001). Importantly, analysis of The Cancer Genome Atlas (TCGA) database revealed that KRT13 expression was significantly associated with tumor TNM stage and other clinical parameters. Functional experiments demonstrated that KRT13 activates the PI3K/AKT signaling cascade, leading to subsequent upregulation of PPARG. This activation promoted pancreatic cancer cell proliferation and migration, effects that were attenuated upon PI3K/AKT pathway inhibition. Drug sensitivity assays using patient-derived organoids (PDOs) demonstrated that KRT13 significantly enhanced the sensitivity of pancreatic cancer to Navitoclax. CONCLUSIONS Our findings establish KRT13 as a critical contributor to pancreatic cancer progression, via the PI3K/AKT-PPARG regulatory axis. These results underscore the potential of KRT13 as a prognostic biomarker and a candidate therapeutic target, offering new insights into the molecular pathogenesis of this lethal disease.

Nimotuzumab is an anti-epidermal growth factor receptor antibody. This Phase I study evaluated the pharmacokinetics and safety of nimotuzumab plus irinotecan in Chinese patients with advanced solid tumors. At single ascending dosage (SAD) stage, four cohorts (100, 200, 400, and 600 mg) of patients received nimotuzumab intravenously on Day 1, alongside irinotecan 180 mg/m² on Day 8. Three weeks later, all patients in the four cohorts transferred to multiple ascending dosage (MAD) stage: nimotuzumab was administrated weekly for 6 weeks, alongside irinotecan (Days 1, 15, 29, 43, and 57, 180 mg/m²). Primary objective was pharmacokinetics, safety and tolerability was also examined. From December 2012 to October 2014, in SAD and MAD stages, there were 28 and 39 patients with Stage IV solid tumors. The area under the concentration curve (AUC_0-∞) for a single dose of nimotuzumab was 10.2 ± 2.7 (100 mg), 37.6 ± 10.0 (200 mg), 114.8 ± 35.5 (400 mg), 197.6 ± 32.0 (600 mg) (×100 h µg/mL), and for multiple dose, it was 26.7 ± 3.4 (100 mg), 87.1 ± 12.0 (200 mg), 193.4 ± 46.9 (400 mg) and 446.3 ± 100.7 (600 mg) (×100 h µg/mL). There was low incidence of rash and no dose-limiting toxicities occurred. This study indicated that nimotuzumab at doses ranging from 100 to 600 mg exhibited a manageable and tolerable safety profile.