Pancreatic cancer, characterized by its highly aggressive malignancy and suboptimal clinical outcomes, remains a formidable global health challenge. Focal adhesion kinase (FAK) functions as a pivotal modulator of diverse cellular pathways, representing a well-established therapeutic target. In this study, using the clinically advanced FAK inhibitor defactinib as a reference compound, a series of novel N1-linked indole-pyrimidine derivatives were designed via a cyclization strategy. Distinct from conventional aminopyrimidine-based FAK inhibitors bearing flexible linkers, these compounds feature a conformationally constrained N1-cyclized indole-aminopyrimidine framework developed via a scaffold-hopping strategy. Among them, compound DF4 exhibited kinase inhibitory activity (IC50 = 2.23 nM), demonstrating improved enzymatic potency over the reference inhibitor defactinib. It also showed enhanced antiproliferative activity against PANC-1 cells and improved selectivity toward normal HUVECs, highlighting the therapeutic potential of the conformationally constrained N1-cyclized scaffold. DF4 also displayed favorable stability in PBS and serum, together with moderate metabolic stability in liver microsomes, supporting its preliminary drug-like properties. Biological evaluation revealed that DF4 suppresses FAK phosphorylation and downstream ERK signaling in PANC-1 cells. DF4 treatment was also associated with changes in apoptosis-related proteins, reduced wound closure, and an increased G2/M phase cell population. Collectively, DF4 emerges as a potent FAK inhibitor with notable in vitro anticancer activity in pancreatic cancer models, supporting its further evaluation as a lead compound.

Traditional Chinese medicines are based on complex mixtures of natural products and their multi-target mechanism of action. Therefore the discovery and validation of targets and mechanisms have always been challenging. In previous studies, using transcriptomic methods and Compound Kushen Injection (CKI) as a model drug, we identified multiple pathways and candidate target genes for validation, through which CKI exerts its pharmacological effects.

NAMI-A (ImH)[trans-RuCl4(dmso-S)(Im)], where dmso-S = sulfur-bonded dimethyl sulfoxide and Im = imidazole emerged as a promising alternative to approved Pt(II) anticancer drugs, offering high antimetastatic activity and low toxicity. However, its development was discontinued due to insufficient activity against primary tumors. In this work, we synthesized 12 new pyridine NAMI derivatives and evaluated their anticancer activity against three cancer cell lines: lung adenocarcinoma A549, melanoma MeWo and bladder cancer T24, and compared with the nonmalignant keratinocyte HaCaT cells. Among them, two complexes exhibited potent cytotoxicity and selectivity while retaining the characteristic antimetastatic activity of the NAMI scaffold. The Ru(III) complex (CHO-PyH)[trans-Ru(CHO-Py)Cl4 (dmso-S)], where CHO-Py = pyridine-3-aldehyde, displayed an IC50 of 34 μM and a selectivity index of 7.60 against A549 cells. Additionally, (NCS-PyH)[trans-RuCl4(dmso-S)(NCS-Py)], where NCS-Py = 3-(isothiocyanatomethyl)pyridine, showed an IC50 of 240 nM and a selectivity index of 5.2 against T24 cells.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting side effect of taxane-based chemotherapy used in breast cancer treatment. Despite its prevalence, no FDA-approved therapies exist for CIPN prevention or treatment, highlighting the need for target prioritzation studies. Using label-free liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), we examined the effects of four doses of paclitaxel (8 mg/kg) on the lumbar (L4-L6) spinal cord proteome in MMTV-PyMT-derived breast cancer bearing C57BL/6J mice. Breast cancer altered the expression of 551 proteins relative to naïve mice, while paclitaxel treatment in tumor-bearing mice altered 112 proteins relative to vehicle-treated cancer controls. Thirty-eight proteins were commonly affected by both conditions. Gene ontology enrichment and STRING protein-protein interaction analyses identified pathways linked to mitochondrial metabolism, ion transport, and neurotransmitter signaling. Pathway mapping further revealed convergent effects of breast cancer and paclitaxel on neuronal activation, neurotransmitter uptake, and mitochondrial dysfunction. Together, these findings define spinal cord proteomic alterations associated with acute paclitaxel-induced peripheral neuropathy and identify pain-relevant pathways for future mechanistic studies.

As part of our ongoing bioprospecting program targeting endophytic fungi, the strain Talaromyces pinophilus J6 was isolated from Euphorbia umbellata. The endophyte metabolic potential was evaluated through a combined metabolomics-dereplication workflow based on an in-house high-resolution mass spectrometry (HRMS) database of Talaromyces metabolites. The strategy enabled rapid annotation of seven metabolites (a-g), allowing rapid characterization of the fungal metabolome and guiding the isolation of potentially new specialized metabolites. Chromatographic fractionation of the crude extract from T. pinophilus J6 cultivated on potato dextrose agar supplemented with ammonium sulfate afforded two polyketides: the new (-)-R-talaropinophiloic acid (1) and the known 3-O-methylfunicone (2). Their chemical structures were determined by Nuclear Magnetic Resonance (NMR), Circular Dichroism (CD), and HRMS analyses. The cytotoxic activities were assessed against the muscle-invasive bladder cancer cell line T24 by MTT assay, yielding IC₅₀ values of 204.70 µM for 1 and 59.68 µM for 2, compared with 6.4 µM for the positive control cisplatin. Assays against the non-tumor RPE-1 cell line showed that 2 displayed a CC₅₀ of 16.62 µM, whereas 1 was non-toxic, highlighting 1 as highly selective for cancer cells. Overall, our results expand knowledge of the chemical diversity of the Talaromyces genus and underscore its potential as a promising source of new bioactive polyketides.

The discovery of epidermal growth factor receptor (EGFR) mutations has deeply reshaped the treatment of non-small cell lung cancer (NSCLC). Throughout the last years, third-generation tyrosine kinase inhibitor (TKI) osimertinib in monotherapy has been the standard of care; however, resistance limits durable responses, necessitating novel combinations and sequencing strategies.

Type-I photodynamic therapy (PDT) is a promising strategy for treating hypoxic tumors because it overcomes the oxygen dependence of traditional PDT. However, the rational design of a potent Type-I photosensitizer that simultaneously achieves subcellular organelle targeting and activates the pyroptotic cell-death pathway remains a formidable challenge. Herein, we report the development of a "Swiss-army-knife" iridium(III) complex, termed Mito-Ir, that concurrently integrates mitochondria targeting, phosphorescence imaging, Type-I/II reactive oxygen species generation, photocatalytic oxidation of 1,4-dihydronicotinamide adenine dinucleotide (NADH) and pyroptosis induction, offering a "one-for-all" platform for high-performance breast-cancer PDT. Upon light irradiation, Mito-Ir triggers severe mitochondrial dysfunction, activating the caspase-3/GSDME pathway to induce pronounced pyroptosis. This pathway not only overcomes apoptosis resistance but also elicits immunogenic cell death through the release of cytokines and damage-associated molecular patterns, thereby activating antitumor immunity. Both in vitro and in vivo studies confirmed its potent antitumor efficacy, underscoring its potential as a pioneering pyroptosis-based therapeutic strategy for breast cancer.

The role of DNA topoisomerase II beta (TOP2B) in cardiomyocyte differentiation is poorly understood. To address this, human induced pluripotent stem cells (hiPSC) were differentiated into cardiomyocytes (CM) that were wild type (WT) or contained a genomic deletion of Topoisomerase 2B (BKO). Both WT and BKO hiPSC could be induced to differentiate into sheets of beating cardiomyocytes. BKO hiPSC take slightly longer to differentiate into sheets of beating CM than WT iPSC. RNA was prepared from both undifferentiated and differentiated WT and BKO hiPSC. RNA-seq was used to examine gene expression changes when the WT and BKO hiPSC were differentiated into CM. Gene expression changes following differentiation of BKO cells were largely similar to those in WT cells. In addition, the differentiated WT CM were treated with dexrazoxane (ICRF-187), a TOP2 catalytic inhibitor that targets both TOP2A and TOP2B, or topobexin, a new TOP2B selective catalytic inhibitor. Topobexin inhibition partially phenocopied a TOP2B deletion and thereby providing an alternative to TOP2B gene knockout in many cell lines. In future, hiPSC derived CM with and without TOP2B and inhibition by topobexin ex vivo CM could be used to study anthracycline-induced cardiotoxicity and to screen for cardioprotectants.

Bevacizumab (BEV) is pivotal for anti-angiogenic therapy in recurrent ovarian cancer (ROC), but its real-world bleeding risk profile and standardized management remain to be refined, demanding tailored pharmacovigilance data for clinical decision-making.

This study evaluates the effectiveness and safety of combining radiotherapy with first-line chemotherapy and immune checkpoint inhibitors in patients with locally advanced or metastatic urothelial carcinoma (la/mUC).

Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) across multiple organ systems. Although inflammatory central nervous system irAEs (CNS inflammatory irAEs) are uncommon, they are often severe. Primary CNS tumors and brain metastases have distinct immune microenvironments, yet the heterogeneity of ICI-related inflammatory CNS irAE reporting signals across tumor phenotypes remains poorly understood.

Chemotherapy-induced oral mucositis (CIOM) is a prevalent toxic side effect of cancer treatment, severely compromising patients' quality of life, nutritional intake, and treatment adherence. Its pathogenesis has evolved from the traditional model of simple epithelial damage to a complex pathological process involving the interplay of chemotherapy toxicity, host immunity, and oral microbiota. Research indicates that chemotherapy can disrupt the oral microbiota, promoting the proliferation of pathogenic bacteria and exacerbating damage to the mucosal barrier and local inflammatory responses. Current clinical interventions, such as mouth rinses and cryotherapy, have limited efficacy and lack standardized protocols. In recent years, modulating the oral microbiota has emerged as a promising therapeutic strategy. Probiotic preparations have demonstrated potential in clinical studies to alleviate CIOM severity through mechanisms including competitive colonization, metabolic regulation, and immunomodulation. This review systematically summarizes the clinical manifestations, epidemiological characteristics, pathogenesis, and existing treatment strategies of CIOM. It highlights the critical role of the oral microbiota in CIOM pathogenesis and further outlines the promising application prospects of microbiome-targeted interventions, particularly probiotic preparations, aiming to provide novel insights for CIOM prevention and treatment.

Zebrafish patient-derived xenografts (zPDX) are a powerful emerging platform for personalized oncology, offering a rapid in vivo system for high-throughput chemoprofiling. Recent studies have demonstrated a strong predictive correlation between drug response in zPDX and patient clinical outcomes. However, current protocols show significant variability in drug concentrations, which can hinder comparison across studies. We aimed to establish toxicity profiles for commonly used clinical chemotherapeutic agents in wild-type Tübingen (TU) and Casper (CSP) zebrafish (ZF) strains. Embryos aged 48-72 hours post-fertilization (hpf) were exposed to a clinically relevant chemotherapeutic panel, including standard combination regimens, for 72 hours. Toxicity was assessed using two parameters: mortality rate and any adverse effects (AAE), defined as embryos exhibiting either mortality or morphological abnormalities. Screening of single agents was similar between the two strains, but the combination regimes revealed toxicity disparities, with AAE proving to be the more sensitive endpoint. Highly toxic agents, such as paclitaxel, caused rapid, dose-dependent lethality, whereas antimetabolites like 5-fluorouracil (5-FU) showed high safety margins. Multi-agent protocols demonstrated synergistic toxicity, with more complex regimens correlating with increased adverse effects, particularly in the CSP strain. This study establishes a toxicological framework for standardizing chemotherapy dosing in ZF larvae and recommends AAE as the primary metric for defining non-toxic concentrations. Our results also underscore the necessity of testing the exact clinical drug formulation, due to potential excipient effects, and of screening multi-agent protocols for synergistic toxicity. We hope these findings will contribute to the further standardization of zPDX models for clinical applications.

Metabolic reprogramming relying on abnormal glycolysis fuels tumor growth, rendering the rate-limiting glycolytic enzyme PFKL a potential anticancer target; yet no PFKL inhibitor has entered clinical trials. Herein, we synthesized a series of S-benzylisothiourea imidazolium salt derivatives and identified compound 10w, which potently inhibited breast cancer cell proliferation, suppressed glycolysis, and induced apoptosis. Drug Affinity Responsive Target Stability (DARTS) assays revealed PFKL as the direct cellular target of 10w. Surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and molecular docking studies confirmed the binding of 10w to PFKL. Enzymatic activity assays further demonstrated that 10w inhibited PFKL activity. Notably, 10w exerted no obvious effects on glycolysis or glycolytic capacity in PFKL-knockdown breast cancer cells. In vivo assays showed that 10w exerted significant antitumor efficacy and enhanced the efficacy of anti-PD-L1 immunotherapy. In conclusion, compound 10w targets PFKL as a promising therapeutic agent for breast cancer.

Older adults constitute more than 50% of newly diagnosed cancer cases and polypharmacy is highly prevalent in this population. The Anticholinergic Burden (ACB) score quantifies the cumulative anticholinergic effects of all medications. Few studies link high ACB to adverse health outcomes in this population, and its effect on treatment outcomes remains largely unknown.

Streptomyces species are widely recognized as valuable sources of secondary metabolites with diverse biological activities. In this study, the isolate GH53 was identified as Streptomyces paradoxus based on morphological characteristics and partial 16 S rRNA gene sequence analysis. Fermentation conditions were optimized to enhance metabolite production, and the crude ethyl acetate extract was chemically characterized using GC-MS, FT-IR, and UV-Vis spectroscopy. The analytical profile suggested the presence of a chemically complex mixture containing fatty acids, fatty acid derivatives, hydrocarbons, and terpenoid-related constituents. The IC₅₀ values of the crude extract were 0.175 ± 0.013 and 0.097 ± 0.006 mg/mL for the DPPH and ABTS radical scavenging assays, respectively. Because the calculated DPPH IC₅₀ value was slightly below the lowest tested concentration, it should be interpreted as a fitted estimate derived from the dose-response curve rather than as a directly measured concentration point. It also showed cytotoxic activity against HePG-2 and MCF-7 cell lines, with IC₅₀ values of 19.50 ± 1.5 and 28.81 ± 2.0 µg/mL, respectively. To provide a preliminary molecular interpretation of these extract-level bioactivities, selected representative metabolites tentatively identified by GC-MS were evaluated individually as defined ligands using molecular docking, molecular dynamics simulation, and ADMET prediction. The modeled compounds showed favorable predicted interactions with selected antimicrobial-, antioxidant-, and anticancer-related protein targets, and the corresponding protein-ligand complexes generally maintained stable interaction profiles during simulation. However, ADMET analysis indicated potential limitations for some high-molecular-weight lipophilic constituents, including poor drug-likeness, limited predicted solubility, and possible toxicity liabilities. Overall, these findings suggest that S. paradoxus GH53 represents a promising source of bioactive metabolites for future fractionation, purification, structural confirmation, and compound-level biological evaluation. The results should be interpreted as preliminary screening evidence and not as confirmation of therapeutic efficacy or direct systemic drug suitability.

Immune-mediated liver injury from checkpoint inhibitors develops in up to 10% of treated patients. The aim of this study was to describe the relationship between standard liver histopathological findings and clinical presentation and outcomes in a cohort of 67 adult patients.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. The absence of effective targeted therapies and endocrine treatment options leads to limited therapeutic options, which remains one of the major clinical challenges in TNBC management. Drug discovery is typically a lengthy and costly process that could be significantly improved through drug repurposing. However, the biological complexity and insufficient repurposing strategies hinder the reuse. This study aims to develop a deep learning-based framework to accelerate drug discovery for TNBC, identify novel therapeutic candidates, and uncover potential drug targets. We developed a deep neural network framework to predict the anticancer efficacy, toxicity profiles, and structural similarities of compounds. By applying this platform to screen over 6,000 compounds from the Drug Repurposing Hub, we identified promising candidates with potential therapeutic efficacy and safety profiles against TNBC. The top-predicted compounds were subsequently validated through comprehensive in vitro and in vivo functional assays. Furthermore, we employed transcriptomic sequencing and mass spectrometry-based proteomics to elucidate the molecular mechanisms underlying the anti-TNBC activity. We identified emodepside, a structurally unique molecule diverging from conventional anticancer agents that exhibited potent antitumor efficacy across multiple TNBC cell lines. Significantly, emodepside administration (5 mg/kg) inhibited tumor growth in xenograft models. Integrated multiomics analyses (RNA-seq/CETSA-MS) identified NAMPT as the primary target. This study demonstrates the viability of our deep learning models to discover structurally novel anticancer agents that are distinct from conventional drugs, thereby expanding the therapeutic arsenal for TNBC patients. Emodepside emerges as a promising TNBC therapeutic candidate, with a possible mechanism of promoting TNBC cell apoptosis via NAMPT inhibition.

Cisplatin (cis-diammineplatinum (II) dichloride [CDDP]) induces acute kidney injury (AKI), and repeated dosing may lead to incomplete recovery and progression to chronic kidney disease (CKD). However, the quantitative dynamics underlying the AKI-to-CKD transition remain unclear. This study aimed to develop a mathematical model to characterize the CDDP-induced AKI-to-CKD transition during repeated administration. Rats received three cycles of CDDP at 21-d intervals under different dosing regimens, but with an identical cumulative dose (9 mg/kg). Plasma creatinine (Cr) was measured longitudinally as a marker of renal function, and values from Days 15 to 21 after each dosing cycle were used to evaluate the extent of recovery following AKI. A toxicodynamic model based on Cr mass balance was developed. The model incorporated a Hill-type function to describe CDDP-induced toxic effects and evaluated alternative structural assumptions in which toxicity progression across cycles was modeled as either additive or multiplicative. Renal function progressively decreased in a dose-dependent manner across cycles. Although Cr profiles differed among regimens during individual cycles, Cr levels converged by the end of the third cycle. The additive toxicity model, in which CDDP accumulates in a virtual kidney compartment and the toxic signal decays slowly (half-life: 79 d), best described the data (CDDP dose per body weight producing 50% inhibition: 5.11 mg/kg). To our knowledge, this study presents the first mathematical model describing the dynamics of the AKI-to-CKD transition following repeated CDDP administration. The proposed modeling approach may facilitate prediction of the AKI-to-CKD transition and support the optimization of safer CDDP treatment strategies.

Pharmaceutical residues in aquatic environments are a growing concern. Global surveillance has detected these residues in nearly a quarter of the world's rivers, with anticancer drugs drawing particular attention due to their high bioactivity. Olaparib (Ola), a poly(ADP-ribose) polymerase (PARP) inhibitor, is widely used to treat breast and ovarian cancers, but its developmental toxicity to aquatic vertebrates remains unclear. We exposed zebrafish embryos to Ola (5-15 mg/L) from 6 to 120 h post-fertilization (hpf). Ola exposure caused dose-dependent craniofacial cartilage malformations and behavioral abnormalities. Mechanistically, Ola induced DNA damage (Comet assay) and mitochondrial depolarization (JC-10), as well as oxidative stress evidenced by elevated reactive oxygen species (ROS) levels and impaired antioxidant defenses. Ola exposure impaired cranial neural crest cell (CNCC) migration, as shown by reduced sox10:GFP⁺ fluorescence and altered expression of pax3a, dlx2a, and dlx5a. It also reduced chondrogenic differentiation, with lower expression of sox9a and col2a1, and increased apoptosis, as indicated by more TUNEL-positive cells. Ola also altered Wnt/β‑catenin pathway gene expression. Pharmacological rescue experiments showed that the antioxidant astaxanthin (60 μg/L) and the Wnt inhibitor C59 (3.79 μg/L) both attenuated craniofacial malformations. Together, these results indicate that Ola induces DNA damage and oxidative stress, impairs CNCC function, and disrupts Wnt signaling, leading to craniofacial cartilage deformities. This study underscores the developmental toxicity of PARP inhibitors as emerging environmental contaminants and offers insights into the mechanisms underlying craniofacial cartilage malformations.