Quercetin alleviates imatinib-induced premature ovarian insufficiency by regulating mitophagy via the ROS/JNK/c-JUN pathway.

Precision-cut tissue slice culture is an innovative exvivo approach for studying fibrosis pathogenesis. Here, we report for the first time the use of human precision-cut bladder slices (PCBS) to investigate fibrotic changes and evaluate anti-fibrotic compounds. Fresh bladder tissue was obtained from 16 patients undergoing surgery for non-fibrotic conditions and 7 patients with documented bladder fibrosis. PCBS were cultured and stimulated with transforming growth factor β (TGF-β) to induce fibrotic changes. Viability was assessed by ATP quantification. The anti-fibrotic efficacy of pirfenidone (PFD), relaxin-2 (RLN), bone morphogenetic protein 7 (BMP-7), imatinib (IMA), and galunisertib (GAL) was evaluated. Fibrosis was quantified using qPCR analysis of collagen 1 (COL1A1), fibronectin (FN1), and cellular communication network factor 2 (CCN2) gene expression. PCBS remained viable over 48 h, with stable ATP levels. TGF-β stimulation significantly increased COL1A1 and CCN2 expression, confirming induction of a fibrotic response. Treatment with PFD, IMA, and GAL effectively attenuated TGF-β-induced upregulation of fibrosis markers. At baseline, PCBS derived from fibrotic bladders exhibited elevated COL1A1 expression compared to non-fibrotic tissue, while FN and CCN2 levels remained unchanged. PFD treatment notably reduced CCN2 expression in fibrotic PCBS. This study demonstrates that PCBS provide a viable and reproducible platform for modeling bladder fibrosis and screening anti-fibrotic therapies. PFD, IMA, and GAL showed promising anti-fibrotic effects, supporting further investigation into their therapeutic potential.

Mast cell tumours (MCTs) are common in dogs. Treatment options include surgery, radiation therapy, and cytotoxic chemotherapy; however, in cases of inoperable or metastatic tumours, tyrosine kinase inhibitors (TKIs) can be used. Imatinib mesylate has been used in the treatment of solid tumours in both human and veterinary medicine. Previous studies have shown some efficacy in dogs with MCTs; however, additional data are needed to better define the optimal dosage, toxicity profile, and clinical outcomes associated with its use. Dogs with a cytological or histopathological diagnosis of mucosal, cutaneous or subcutaneous MCTs were included. Medical records from 2017 to 2024 were reviewed for clinical presentation, results of staging procedures, diagnostic tests, and treatment. Inclusion required the presence of macroscopic disease and administration of imatinib, either as a sole treatment or in combination with surgery. Thirty-five cases were included, all receiving medical treatment with or without surgical excision. Imatinib was administered as first-line treatment in 8 dogs (22.8%) and as a rescue treatment in 27 dogs (77.1%), achieving an overall clinical benefit, including complete response, partial response, and stable disease of 77%. Median progression-free survival was 37 days (range 13-770 days), while the overall median survival time (MST) was 270 days (range 83-1396 days). Following imatinib treatment, the MST was 105 days (range 22-1145 days). Gastrointestinal and haematological adverse events were recorded in 2 (5.7%) and 3 (8.6%) dogs, respectively, and were self-limiting. Imatinib treatment was generally well tolerated, with measurable clinical responses observed and only a limited spectrum of toxicities. Further studies are warranted to better characterise its safety and efficacy in dogs with MCTs.

Abstract Cancer poses a serious global health problem, responsible for the deaths of millions of people annually. In this context, the design of drug delivery systems has attracted notable interest due to minimizing the adverse effects of cancer drugs on living cells. This study aims to synthesize an efficient carrier for the anticancer agent imatinib mesylate (IM) through the synthesis of a composite material combining mesoporous silica with reduced graphene oxide (rGO@ms) via green synthesis. The release behavior of IM was systematically assessed under different pH conditions (5.0, 6.0 and 7.4) to simulate diverse environments. IM-loaded and unloaded rGO@ms were characterized using UV–Vis spectroscopy, X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and field emission scanning electron microscopy (FESEM) analysis methods. The drug loading capacity of rGO@ms was calculated as 27.79%. Over a 50-h period, IM-loaded rGO@ms was found to have released approximately 80% at pH 5.0, 58% at pH 6.0 and 19% at neutral pH (7.4). The release was significantly higher at pH 5.0, which is attributed to the easier breakdown of the bond between the drug and carrier in an acidic environment. The synthesized composite, which shows favorable release characteristics at lower pH levels, has great potential for cancer treatment. Moreover, the drug release mechanism of the composite was found to closely follow the Korsmeyer–Peppas kinetic model.

The year 2024 witnessed significant advancements in cancer therapy, with the U.S. Food and Drug Administration (FDA) approving 56 anticancer drugs for various malignancies. These approvals encompass 36 organic small molecules and 20 macromolecular monoclonal antibody conjugates, each with distinct mechanisms of action targeting key oncogenic pathways. Among the small molecules, kinase inhibitors such as Ribociclib, Imatinib Mesylate, and Nilotinib Hydrochloride Dihydrate modulate critical signaling cascades, while antimetabolites like Fluorouracil and Pemetrexed Disodium disrupt nucleotide biosynthesis. Other classes include DNA-damaging agents (Mitomycin, Gemcitabine Hydrochloride), immune modulators (Pomalidomide, Lenalidomide), and hormonal antagonists (Abiraterone Acetate, Erleada). The macromolecular therapeutics primarily consist of monoclonal antibody-based agents, such as Keytruda, Tecentriq, and Imfinzi, which enhance immune checkpoint inhibition, and antibody-drug conjugates like Enhertu and Elahere, which deliver cytotoxic payloads with high specificity. This review systematically examines the chemical synthesis, mechanisms of action, and therapeutic indications of these FDAapproved agents, emphasizing their role in improving patient outcomes. By analyzing their structural frameworks and biological targets, we aim to provide insights into current trends in anticancer drug development and potential future directions.

Rationale:Chordoma is a malignant bone tumor that typically affects structures along the midline. Soft tissue chordoma of the right thigh is an extremely rare entity but significant, as it can create diagnostic challenges and increases the risk of misdiagnosis, making accurate identification essential. This report introduces a diagnostic strategy of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for a huge chordoma.Patient concerns:A 45-year-old man presented with a painless, gradually growing mass on his right thigh for 6 years without weight loss. Imaging studies revealed a huge mass in his soft tissue of the right thigh, raising concerns about pathology.Diagnoses:Magnetic resonance imaging demonstrated a mass with cystic mixed components, in the middle of the right thigh region with irregular shape and a poorly defined local boundary, measured 267 × 119 × 102 mm, leading to a presumptive diagnosis of malignancy.Interventions:18F-FDG PET/CT showed a huge area of heterogeneously increased 18F-FDG uptake (SUVmax, 4.4), and pathology and immunohistochemistry confirmed the diagnosis of conventional chordoma.Outcomes:He was treated with Imatinib Mesylate (400 mg) orally twice daily. There was no recurrence during the 6-month follow-up, with plans for continued long-term surveillance.Lessons:This case highlights the diagnostic challenge posed by chordoma of the soft tissue in the thigh, as its radiological appearance can closely resemble other soft tissue tumors. Clinicians should ensure exhaustive assessment including CT, magnetic resonance imaging, and 18F-FDG PET/CT imaging. Pathological confirmation is essential. Despite the rarity of soft tissue chordoma, careful treatment planning including consideration of targeted therapy and long-term follow-up is important to address the risk of late recurrence.

Chronic Myeloid Leukemia (CML) is characterized by a specific genetic anomaly. Imatinib mesylate serves as the primary treatment for CML at Patan Hospital in Nepal which was initiated as compassionate use program under Novartis Pharmaceuticals. In this retrospective 20-year study involving 431 CML patients enrolled in the Max Access Program, it was observed that 64.7% achieved optimal treatment responses, 11.6% had suboptimal outcomes, and 14.6% experienced treatment failure. The survival rate for CML patients was 89.1%. Some patients exhibited genetic mutations like T315I and were subsequently treated with a 3rd generation TKI known as ponatinib. The increased detection of mutations can be attributed to expanded testing practices, aligning with trends observed elsewhere. In summary, the research suggests that TKIs have had a beneficial impact on CML treatment, leading to improved survival rates, on par with those in developed countries.

ABSTRACT Therapeutic drug monitoring (TDM) of imatinib (IMT) is critical for the effective treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). Herein, a surface‐enhanced Raman scattering (SERS)‐based microfluidic biosensor integrated with a pretreatment function was developed for the highly sensitive TDM of IMT. Experimentally, a three‐dimensional carbon framework decorated with silver nanoparticles (Ag NPs) was first synthesized as the SERS substrate to ensure high uniformity and sensitivity. Specifically, a gelatin/AgNO 3 mixed solution was spin‐coated onto a silicon substrate, followed by high‐temperature annealing to form a carbon skeleton lightly decorated with Ag NPs. Subsequently, the density of Ag NPs was further optimized via additional silver sputtering, and optimal SERS performance with the detect limit of 10 −10 M (R6G) was achieved. Meanwhile, a triple‐channel microfluidic system was fabricated using a mold casting method, with a serpentine mixing channel section designed for on‐chip deproteinization pretreatment. Thereafter, the aforementioned SERS substrate was cascaded with the prepared microfluidic system to serve as the sensing module. By leveraging the system's on‐chip pretreatment capability and high sensitivity, the novel biosensor achieves a broad detection range of 10 2 –10 6 ng/mL, which covers the IMT entire therapeutic window (1000–3200 ng/mL) and paves the way for its future application in point‐of‐care testing (POCT).

Gastrointestinal stromal tumor (GIST) frequently develops resistance to imatinib (IM). This study identifies AOC3 downregulation as a critical contributor to IM resistance. Analyzing clinical samples and IM-sensitive/resistant GIST cell lines, we found AOC3 significantly decreased in resistant states. Functionally, AOC3 knockdown promoted IM resistance, enhanced glycolytic activity, and increased lactate production. Mechanistically, AOC3 loss attenuated ubiquitin-mediated degradation of HK2, stabilizing this glycolytic enzyme and boosting lactate generation. Subsequent histone lactylation, notably at H3K18, enriched at the Myc promoter and stimulated its transcription. Crucially, HK2 overexpression reversed AOC3's suppressive effects on glycolysis, lactylation, Myc expression, and IM resistance. In vivo xenograft models confirmed these findings. We conclude that AOC3 acts as a tumor suppressor by promoting HK2 degradation; its loss triggers a HK2/glycolysis/lactylation/Myc axis driving IM resistance, positioning AOC3 as a promising prognostic biomarker and therapeutic target in GIST.

Genotoxic impurities (GTIs) in pharmaceutical products represent a critical safety concern because they can induce DNA damage and may lead to mutagenic and carcinogenic effects even at trace concentrations. Consequently, regulatory authorities such as EMA, FDA, and ICH require a risk-based and impurity-specific control strategy, as defined in ICH M7, for active pharmaceutical ingredients (APIs) and finished dosage forms. Due to their structural and physicochemical diversity, GTIs cannot be adequately monitored using a single analytical technique, and method selection must be tailored to the characteristics of each impurity. In this study, impurity-specific analytical methods were developed and validated to demonstrate the practical application of this regulatory approach in different pharmaceutical matrices. GC-MS method was optimized for the determination of volatile alkylating agents, namely methyl, ethyl, and isopropyl methanesulfonate in imatinib mesylate API. LC-MS/MS method was established for the quantification of 5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole, a polar and thermolabile azido impurity in valsartan formulations. Both methods were validated in accordance with ICH Q2(R1) guidelines, demonstrating excellent specificity, linearity (R2 > 0.999), accuracy, and precision, with detection limits sufficient to meet regulatory requirements. Application to commercial products confirmed the robustness of methods and their suitability for routine quality control supporting effective GTI risk management.

Background: The introduction of tyrosine kinase inhibitors has revolutionised the treatment of gastrointestinal stromal tumours (GISTs), yet the role of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal GISTosis remains controversial. Methods: A retrospective analysis was conducted on patients with peritoneal GISTosis who underwent CRS plus HIPEC in an 18-year period. We analysed the clinicopathological characteristics and evaluated the perioperative and long-term outcomes based on the extent of disease (peritoneal cancer index, PCI), the resection (completeness of cytoreduction score) and the IM-administration. The survival factors were also analysed and the Kaplan-Meier estimator to model and estimate overall (OS) and progression-free survival (PFS). The median follow-up period was 72 months (range, 12-146). Results: A total of 25 patients (M:F = 15:10) with a median age of 57 years (range, 32-69) underwent CRS with HIPEC for peritoneal GIST metastases, detected either synchronously (n = 11) or metachronously (n = 14). The media PCI score was 9 (range, 4-20) and complete cytoreduction was achieved in 80%. Grade III complications were observed in two patients, whereas there was no postoperative mortality. Neoadjuvant imatinib-mesylate (IM) therapy was administered in 60% of patients who detected with metachronous metastases (n = 8/14), whereas adjuvant IM therapy was administered in 19 of 25 patients. Median OS was 62 months (95% CI = 22.8-101.2). Median OS and DFS for patients with PCI scores ≤ 10 were significantly longer compared to those with PCI scores > 10 (p = 0.009 and p = 0.024, respectively). Patients with CC scores of 0-1 had a significantly longer OS compared to those with CC scores of 2 (p = 0.005) and 3 (p = 0.002) and longer PFS compared to those with CC scores of 3 (p = 0.005). The need for imatinib did not significantly impact OS (p = 0.240) or PFS (p = 0.243). Conclusions: CRS combined with HIPEC shows promising results in peritoneal GISTosis, especially in patients with lower PCI and CC scores. Until larger studies validate its safety and efficacy, it should be primarily performed in expert hands in specialised peritoneal surface oncology centres.

Cannabidiol modulates exosomal miRNA networks to enhance Imatinib mesylate response in chronic myelogenous leukemia.

Crystallization process design and workflow for a polymorphic system.

Objective: To investigate the effect of CYP3A4 polymorphisms rs2740574 and rs2242480 on the response to Imatinib Mesylate in treatment-naïve patients with chronic myeloid leukaemia (CML). Methods: It was a prospective, non-interventional observational genetic association study involving 106 treatment-naive CML patients genotyped for rs2740574 and rs2242480. According to the Helsinki Declaration, the study was conducted in compliance with current good clinical practices and was approved by the Ethical Review Committee. Blood samples and clinical data were collected in the pathology department between March 2018 and March 2020. Informed consent was obtained from all participants. Treatment response was evaluated at 3 months based on complete hematologic response (CHR) and plasma Imatinib levels. Results: Patients with wild-type homozygous genotypes for both polymorphisms exhibited higher CHR rates (75% vs. 50% and 30% for rs2740574; 80% vs. 55% and 35% for rs2242480). Conclusions: CYP3A4 polymorphisms rs2740574 and rs2242480 predict Imatinib response. Early detection of non-responders based on polymorphism analysis before treatment initiation allows timely initiation of second-generation Tyrosine Kinase Inhibitors (e.g., dasatinib, nilotinib), thereby avoiding ineffective Imatinib therapy and facilitating earlier achievement of treatment-free remission. Keywords: Tyrosine Kinase Inhibitors, Leukaemia, Imatinib Mesylate, Cytochrome P-450 Cyp3A4, Pharmacogenetics

Lung cancer remains a significant cause of cancer-relateddeathsglobally. The effective cancer treatment aims to deliver drugs thatspecifically target cancer cells at the optimal dose. Imatinib (IMB),a selective kinase inhibitor, has demonstrated therapeutic efficacyagainst lung cancer. However, its use is often limited because oflow solubility in water. This study investigated water-soluble IMB/cyclodextrin(CD) inclusion complex formation. IMB demonstrated a high affinityfor γCD and HPγCD, as evidenced by phase-solubility studies,solid- and solution-state characterizations, and molecular dockingstudy. IMB/CD complex-loaded niosomes in the presence and absenceof D-alpha-tocopheryl polyethylene glycol succinate (TPGS) were fabricatedusing a thin-film hydration method. The prepared niosomal formulationsshowed nanoscale particle sizes (126–163 nm) with a low polydispersityindex (<0.2), a negative zeta potential value (−3.65 to−13.67 mV), and % entrapment efficiency of 59–78%. Thenovel TPGS-based niosomes loaded with the IMB/CD complex significantlyenhanced cellular uptake and induced apoptosis in A549 cells, exhibitingpotent cytotoxicity with an IC50 value of 5 μM. Theseresults indicate that our developed IMB/CD complex-loaded niosomescould be promising for efficient IMB delivery to nonsmall cell lungcancer A549 cells and potentially contributing to future lung cancertherapy.

Currently, many scientific studies investigate the role of receptor tyrosine kinases in mechanisms of tumor cell resistance to targeted therapies and chemotherapies. Activation of FGFR and VEGR signaling pathways through fibroblast growth factors (FGF) and vascular endothelial growth factors (VEGF) is seen in many malignant neoplasms. The literature review was addressed to describe the role of FGFR and VEGFR signaling pathways in the secondary (acquired) resistance of gastrointestinal stromal tumors to the targeted drugs – tyrosine kinase receptor inhibitors (imatinib mesylate, sunitinib, regorafenib). The review describes the molecular mechanisms of activation of FGFR and VEGR signaling pathways in tumor cells, as well as their structural and functional relationship between aforementioned pathways. Multiple studies, including our own, illustrate the activation of FGFR and VEGFR pathways in gastrointestinal stromal tumors. The review also describes the clinical effectiveness of FGFR and VEGFR inhibition for advanced and metastatic gastrointestinal stromal tumors, thereby providing a rationale to utilize activation of the aforementioned signaling pathways as the markers for gastrointestinal stromal tumors progression.

Introduction. ABC transporters (ATP-binding cassette transporters) are a class of membrane transporter proteins that play a crucial role in various physiological processes, including nutrient uptake, the secretion of signaling molecules, and the elimination of toxins. In addition to the above physiological functions, these proteins play a crucial role in the development of multidrug resistance in malignant neoplasms, thereby contributing to the progression of the disease. The main types of ABC transporters, for which their clinical significance in the development of drug resistance to chemotherapy and targeted therapy in many malignant neoplasms has been proven, include P-glycoprotein (P-gp, MDR1), BCRP and MRP1. However, the role of these proteins in the pathogenesis of gastrointestinal stromal tumors (GIST) and the formation of their resistance to chemotherapy is poorly understood. Aim. To assess the expression of ABC transporters (ABCB1/MDR1, ABCC1/MRP1, and ABCG2/BCRP), the intracellular content of their fluorescent substrates, and stemness markers in imatinib mesylate (IM) sensitive and resistant GIST cell lines, and their role in resistance to chemotherapy. Materials and methods. The study was conducted using GIST cell lines sensitive (GIST T-1) and resistant (GIST T-1R and GIST 430) to IM. As a positive control for the overexpression of ABC transporters in tumor cell lines, we utilized the previously obtained subline of triple-negative breast cancer HCC 1806 Tx-R, which has been proven to exhibit overexpression of ABC transporters. Results. We observed the increased expression of some ABC transporters (MRP1, ABCG2, and MDR1) in the IM-resistant GIST 430 cell line. This resulted in a significant increase in the excretion of their fluorescent substrate rhodamine 123 compared to the IM-resistant GIST T-1R cell line. At the same time, in the presence of P-gp inhibitors (cyclosporine A and tariquidar), as well as MRP1 (MK-571), there was a significant increase in the number of rhodamine-positive cells. A similar pattern was observed for some chemotherapeutic agents exhibiting autofluorescent activity, specifically an increase in the intensity of their fluorescence in the presence of corresponding ABC transporter inhibitors, indicating an increase in their intracellular concentration in GIST 430. Moreover, for doxorubicin, its excretion from GIST cells was proven exclusively by MRP1 protein, while mitoxantrone was “pumped out” from cells mainly through P-gp. The result of hyperexpression of these transporters in GIST 430 cells was their resistance to the drugs mentioned above, as evidenced by a 4- and 5-fold increase in the values of half-maximal inhibitory concentrations (IC50) for doxorubicin and mitoxantrone, respectively, in relation to GIST 430 cells compared to the GIST T-1R cell line. Based on the results of expression of stemness markers (CD44 and CD133) and colony formation, no evidence of the presence of a pool of cells with a stemness phenotype in the GIST 430 cell line was obtained. Conclusion. One of the mechanisms of secondary resistance of GIST 430 cells to chemotherapy is the hyperexpression of ABC transporters (MRP1, ABCG2, and MDR1), which is not associated with the presence of cells with a stemness phenotype in this cell line.

This case report describes a diagnostically and therapeutically challenging instance of spindle cell neoplasm located in the sacroiliac region of a 16-year-old male. The patient presented with numbness in the right hip and radiating pain in the lower extremities. Diagnostic imaging and laboratory tests localized the disease to a sacroiliac tumor; however, accurate identification of the tumor type remained difficult. Following tumor excision and curettage, RNA sequencing revealed the presence of the COL1A1::PDGFB fusion, which is considered characteristic of dermatofibrosarcoma protuberans (DFSP). Although DFSP is typically a superficial, low-grade tumor with low metastatic potential, this case exhibited aggressive clinical features. Consequently, it was recommended to classify it as a "sacroiliac spindle cell tumor with COL1A1::PDGFB fusion," which may represent a variant within the broader spectrum of DFSP. Following recurrence and metastasis, the patient was treated with imatinib mesylate and radiotherapy, resulting in a sustained major partial response. This report presents a rare case of aggressive sacroiliac spindle cell sarcoma with COL1A1::PDGFB fusion, expands the clinicopathologic spectrum of DFSP and its variants, and underscores the importance of molecular studies for definitive diagnosis, as well as the potential for targeted therapies in managing complex sarcoma cases.

Acute lymphoblastic leukemia (ALL) in children and adolescents is one of high curable malignancy with long-term survival rate 91 %. Nevertheless, patients with high risk of relapse / refractory ALL have event-free survival not exceed 55 %. For therapeutic efficacy improvement in patients with high risk ALL, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used. Improvement of ALL therapy by targeted and molecular oriented drugs (imatinib mesylate, dasatinib, blinatumomab, inotuzumab ozogamycin), extension of therapeutic options for patient care in the post-transplant period are changed indications for allo-HSCT. In the current issue a modern indications for allo-HSCT in patients with primary diagnosed ALL, based on cytogenetic, molecular biologic, and clinical characteristics by the leading research groups AIEOP / BFM (Italy / Germany), St. Jude (USA), COG (USA) are presented. In spite of presented differences, common indications for allo-HSCT are minimal residual disease persistence in postinduction period in combination with cytogenetic, molecular and biologic factors of unfavorable prognosis.

Neurotoxic potential of imatinib in aquatic vertebrates: Behavioral and biochemical disruptions in zebrafish.