To analyze the characteristics of adverse drug reaction (ADR) in a specialized stomatology hospital and thus provide references for clinical rational drug use and risk management.

Chemotherapy-induced sensory alterations are common and may negatively affect nutritional status, treatment adherence and quality of life in people with cancer. However, inter-individual variability in these alterations remains poorly understood. This study examined whether personality traits, food neophobia, disgust sensitivity, and sensitivity to reward, contribute to variability in self-reported sensory alterations during chemotherapy.

Echium angustifolium is traditionally valued for its therapeutic properties; yet comprehensive studies on its biological activities are limited. Aerial flowering parts were sequentially extracted with solvents of varying polarity. Extracts were analyzed for yield, phytochemical composition, and total phenolic and flavonoid contents and HPLC. LC-MS/MS analysis in negative ion mode was performed for detailed compound identification. Antioxidant activity was measured using the DPPH assay. Antibacterial activity against Gram-positive and Gram-negative bacteria was evaluated via agar diffusion and MIC/MBC methods. Anti-inflammatory potential was determined in vitro through RBC membrane stabilization (hemolysis) assay. Cytotoxicity and antiviral activity were examined using MTT and cell-based assays on HepG2 and Vero cells. The molecular mechanism of anticancer activity was investigated through qPCR analysis of apoptosis-related genes (Bax, Caspase-3, Caspase-9, and Bcl-2) in HepG2 cells. Antiviral efficacy against Hepatitis A virus (HAV) and Coxsackievirus B4 (CoxB4) was further validated by RT-qPCR quantification of viral RNA copy numbers. The ethanolic extract showed the highest yield (14.23%) among the tested solvents and richest phytochemical profile, with rutin as the predominant compound. LC-MS/MS identified 24 compounds including threonic acid, hypoxanthine, indole-3-carboxylic acid, N-methyllysine, 4-methyl-2-oxovaleric acid, 4-isopropylbenzoic acid, methionine, N-2-fluorenylacetamide, arachidic acid, N-methylanthranilic acid, carbocysteine, fructose-1,6-bisphosphate, lumazine, 5-aminoimidazole-4-carboxamide, and 3-isochromanone. It exhibited significant antioxidant activity (IC50 = 21.08 µg/mL) and antibacterial effects against both Gram-positive and Gram-negative bacteria. It exhibited in vitro anti-inflammatory effects via RBC membrane stabilization (95.5% inhibition at 1000 µg/mL) and dose-dependent cytotoxicity against HepG2 cells (IC50 = 94 µg/mL), while showing low toxicity toward Vero cells (IC50 = 632.24 µg/mL). Mechanistically, qPCR analysis revealed that the extract at IC50 concentration significantly upregulated pro-apoptotic Bax (4.21-fold), Caspase-3 (5.02-fold), and Caspase-9 (4.08-fold), while downregulating anti-apoptotic Bcl-2 (0.33-fold) compared to untreated controls, confirming apoptosis induction through the intrinsic mitochondrial pathway. Antiviral assays revealed significant inhibition of HAV and Coxsackievirus B4 replication at non-toxic concentrations. RT-qPCR quantification demonstrated that the extract at MNTC (250 µg/mL) reduced HAV and CoxB4 viral RNA copies by 50.6% (from 1.22 × 106 to 6.03 × 105 copies/mL for HAV; from 2.47 × 105 to 1.22 × 105 copies/mL for CoxB4), providing direct evidence of viral inhibition. The ethanolic extract of E. angustifolium exhibited multifunctional in vitro bioactivities, including antioxidant, antimicrobial, anti-inflammatory, anticancer, and antiviral effects. LC-MS/MS identified a diverse array of bioactive compounds, while mechanistic studies revealed apoptosis induction via the mitochondrial pathway (upregulation of Bax, Caspase-3, and Caspase-9; downregulation of Bcl-2) and direct antiviral activity through inhibition of viral replication (confirmed by RT-qPCR). These findings validate the traditional medicinal uses of E. angustifolium and highlight its potential as a promising source of bioactive compounds that warrant further in vivo and mechanistic investigations.

Immune checkpoint inhibitor (ICI)-related parkinsonism is an exceedingly rare neurologic immune-related adverse event (irAE).

Cancer drug response (CDR) prediction is crucial for advancing precision medicine. Advanced computational predictors extracted CDR patterns from multimodal features of cell lines and drugs under the guidance of known CDRs. However, most existing methods struggle to extract biologically meaningful and generalizable CDR representations due to insufficient semantic alignment among the multimodal features. In addition, semantic inconsistencies between multimodal and topological features further hinder the predictive accuracy of CDRs. To address the challenges, a novel Reinforcement Learning-driven Adaptive Synergistic Optimization Network-CDR (RLASON-CDR) is put forward for CDR prediction. RLASON-CDR first constructs multimodal CDR representations aligned within and across drugs and cell lines. Next, it captures high-order topological representations of CDRs from the cell line-drug response network. Finally, a reinforcement learning-based network is proposed to adaptively explore potential CDR patterns by synergistically optimizing these representations instead of semantic fusion. Extensive evaluations demonstrate that RLASON-CDR consistently outperforms existing methods and is robust for predicting unknown CDRs. Gradient attribution analysis further reveals that RLASON-CDR identifies key modality contributions and uncovers biologically response patterns. Furthermore, biological significance analysis indicates that RLASON-CDR can effectively reveal mechanisms of drug response and provide valuable guidance for precision therapy in clinical applications.

The current study devised and synthesized a novel class of pyrazole derivatives based on indole as possible inhibitors of cyclin-dependent kinase-2 (CDK-2). 1H NMR, 13C NMR, NOESY, HMQC, and elemental analysis were used to confirm the structural integrity of the synthesized compounds. Promising CDK-2 inhibitory activity was observed in biological assays, and numerous compounds exhibited sub-micromolar IC50 values. Compound 5 d outperformed the reference inhibitor Roscovitine (IC50 = 0.716 µM) as the most potent inhibitor (IC50 = 0.536 µM), followed by compound 9 g (IC50 = 0.675 µM). SAR analysis showed that the observed activity was significantly influenced by the electronic nature of the added substituents as well as the orientation of the indole bond, with brominated derivatives exhibiting greater potency. The antiproliferative activity of the most potent compounds against the cancer cell lines HepG2, HCT-116, and MCF-7 was further assessed. In addition to having an enhanced selectivity index for normal MCF-10A cells (SI = 8.00 vs. 4.96 for Roscovitine), compound 5 d had the greatest activity against MCF-7 cells (IC50 = 6.78 µM), surpassing Roscovitine (IC50 = 8.11 µM). According to mechanistic investigations, compound 5 d significantly reduced the S-phase population, markedly promoted apoptosis, and caused G1 and G2/M cell-cycle arrest. Additionally, the consistent binding of compound 5 d within the ATP-binding pocket of CDK-2 was confirmed by molecular docking and molecular dynamics simulations, and attractive drug-like and pharmacokinetic features, similar to those of Roscovitine, were demonstrated by in silico ADMET predictions. All of these results point to compound 5 d as a promising lead scaffold for developing potent CDK-2-targeted anticancer agents.

Metastasis is the primary cause of mortality across gastrointestinal (GI) cancers, including colorectal, gastric, pancreatic, biliary and esophageal cancers. Cancer-associated fibroblasts (CAFs) constitute the dominant stromal component of the desmoplastic GI tumor microenvironment (TME) and regulate every stage of metastatic progression. This review systematically summarizes CAF-mediated pro-metastatic mechanisms in GI tumors, including extracellular matrix (ECM) remodeling, paracrine oncogenic signaling, immune exclusion, angiogenesis, lymphangiogenesis, pre-metastatic niches (PMNs) construction and therapeutic resistance. Notably, CAFs are heterogeneous populations with context-dependent dual functions: certain myofibroblastic CAF (myCAF) subsets restrain tumor progression in pancreatic ductal adenocarcinoma (PDAC), while inflammatory CAFs (iCAFs) drive metastasis and immune suppression. Antigen-presenting CAFs (apCAFs) exert divergent immunomodulatory effects depending on tumor context. Rather than acting as uniformly tumor-promoting stromal cells, CAFs represent heterogeneous and plastic populations whose functions vary by tumor type, spatial niche, and metastatic stage. We further discuss why broad CAF depletion has shown limited clinical success and emphasize the need for subtype-specific, context- aware CAF-targeted strategies.

PD-1 blockade has yet to achieve broad clinical success in colorectal cancer (CRC), with microsatellite-stable tumors proving especially resistant. At the same time, ferroptosis has emerged as a mechanistic link between redox control in tumor cells and the antitumor immune response. GPR39 is overexpressed in CRC, but its functional role in ferroptosis and immunotherapy resistance is currently unclear.

Population pharmacokinetic (PK) and exposure-response analyses were performed to characterize the PK and exposure-response relationships of vepdegestrant, a first-in-class, oral PROteolysis-TArgeting Chimera estrogen receptor degrader. Population PK and exposure-response analyses for safety utilized data from the first-in-human study (ARV-471-mBC-101, NCT04072952) and the registrational VERITAC-2 study (NCT05654623), which included patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Safety endpoints of clinical interest were evaluated using logistic regression and included grade ≥3 treatment-emergent adverse events (TEAEs) and TEAEs of any grade (arthralgia, fatigue, nausea, aspartate aminotransferase or alanine aminotransferase elevations, anemia, and neutrophil count decreased). Exposure-efficacy analysis included patients with estrogen receptor-1 (ESR1)-mutated, ER-positive, HER2-negative advanced breast cancer from the VERITAC-2 vepdegestrant arm only. Progression-free survival (PFS) as assessed by blinded independent central review, the primary efficacy endpoint in VERITAC-2, was assessed via Cox proportional hazards modeling. Vepdegestrant PK was described by a two-compartment model with linear elimination and sequential zero-, first-order absorption. None of the evaluated covariates significantly influenced the disposition of vepdegestrant. There was no statistically significant relationship between vepdegestrant exposure and any of the evaluated safety endpoints across 30-500 mg total daily doses. In patients with ESR1-mutated, ER-positive, HER2-negative advanced breast cancer treated with vepdegestrant 200 mg once daily in the VERITAC-2 study, exposure was not a statistically significant predictor of PFS. Overall, integrated analyses adequately characterized the PK of vepdegestrant, with no clinically meaningful covariate effects. No exposure-response relationships were identified between vepdegestrant exposure and efficacy or safety outcomes.

Glucuronide prodrug strategies may enhance target specificity and reduce the toxicity of PARP inhibitors, but no clinical evaluation has been performed. We evaluated TSL-1502, a novel glucuronide prodrug of a PARP inhibitor, in a randomized, open-label, phase 2 study at 28 sites in China (NCT05420779). Eligible patients were women aged 18-75 years with HER2-negative locally advanced or metastatic breast cancer and germline BRCA mutations. Patients were assigned randomly (2:2:1) to receive TSL-1502 at 350 mg or 500 mg once daily or the investigator's choice of chemotherapy (eribulin, capecitabine, or vinorelbine) in 3-week cycles. Sixty-three patients were enrolled between August 18, 2022, and March 5, 2024. According to the Independent Review Committee assessment, the objective response rates were 36.0% (95% CI, 18.0-57.5) in the 350 mg group, 55.6% (95% CI, 35.3-74.5) in the 500 mg group, and 40.0% (95% CI, 12.2-73.8) in the chemotherapy group. The median progression-free survival times were 5.6 (95% CI, 4.0-8.2), 8.8 (95% CI, 5.7-not assessable [NA]), and 9.2 (95% CI, 1.38-NA) months, respectively, and the overall survival times were 17.4 months (95% CI, 9.1-NA), not reached (95% CI, 16.9-NA), and 19.8 months (95% CI, 9.2-NA), respectively. Grade ≥3 treatment-related adverse events occurred in 60.0%, 59.3%, and 80.0% of patients, with anemia most common in the TSL-1502 group and neutropenia most common with chemotherapy. No treatment-related deaths occurred. TSL-1502 at 500 mg showed promising antitumor activity and a manageable safety profile, supporting further clinical development.

The development of novel antimicrobial and anticancer agents remains a priority due to rising drug resistance and high systemic toxicity of current treatments. A series of novel pyrazole (2-6), pyrimidine (7-10), and pyridine/oxazinone (11-14) derivatives were synthesized from a chalcone scaffold (1). They were evaluated for antimicrobial, antibiofilm (Pseudomonas aeruginosa), and cytotoxic (HepG2 cells) activities. Molecular docking and qRT-PCR were performed to study their mechanism. Pyrazoles 3-5 and oxazinone 13 showed potent antibacterial activity against S. aureus (MIC = 2-3.12 µg/mL). Compounds 4 and 13 effectively eradicated P. aeruginosa biofilms, achieving a ≥ 5 log10 reduction within 4 h at 0.8 × MIC, driven by disruption of the bacterial respiratory chain. For anticancer activity, compounds 10 and 13 selectively reduced HepG2 cell viability to 35-40% via oxidative stress-mediated apoptosis. Mechanistically, compound 4 reduced gyrB expression in E. coli by approximately 4.6-fold, while molecular docking supported its interaction with the ATP-binding pocket of DNA gyrase. Overall, the functionalized heterocycles, particularly compounds 4 and 13, represent promising dual-acting candidates with potent antibacterial, antibiofilm, and selective anticancer activities.

Breast cancer is the most frequently diagnosed cancer in women and remains a leading cause of cancer-related mortality worldwide. Recently, bacteria-based delivery systems have emerged as promising strategies for targeted cancer therapy due to their biocompatibility, low systemic toxicity, and ability to overcome drug resistance. In this study, bacterial ghosts (BGs) derived from Escherichia coli DH5-α were successfully prepared using a modified sponge-like reduced protocol, achieving approximately 92% reduction in optical density and releasing 246.3 ± 5.46 µg/mL DNA and 2.5 ± 0.054 mg/mL proteins, confirming efficient cytoplasmic evacuation. Heat-killed E. coli (HKEc) was prepared via thermal inactivation. Ethanolic extract of fenugreek seeds (Trigonella foenum-graecum) was obtained with a yield of 14% and characterized by GC-MS, identifying 26 bioactive compounds, including linoleic acid ethyl ester (19.39%) and β-sitosterol (14.14%). LC-MS/MS analysis further confirmed the presence of key metabolites such as trigonelline, diosgenin, orientin, and vitexin. The extract was successfully loaded into BGs and HKEc with loading capacities of 14 µg/mg and 11.6 µg/mg, and entrapment efficiencies of 21% and 13.4%, respectively. In vitro release studies demonstrated sustained release behavior from BGs, with only 14% released after 4 h at pH 7.4 compared to 90% for free extract, indicating effective controlled delivery. Cytotoxicity analysis using the WST-1 assay revealed enhanced anticancer activity of FEE-loaded BGs, with IC₅₀ values of 1.2 mg/mL in MDA-MB-231 and 0.87 mg/mL in ZR-75-1 cells, compared to 2.2 and 1.74 mg/mL for free extract, respectively. Mechanistically, treatment resulted in significant downregulation of STAT3, mTOR, and β-catenin, alongside upregulation of STAT5, and a twofold increase in caspase-3 activity, confirming apoptosis induction. Overall, these findings highlight E. coli-derived bacterial ghosts as an effective and low-cost delivery platform for plant-derived anticancer compounds, offering enhanced therapeutic efficacy and controlled release for breast cancer treatment. KEY POINTS: • Escherichia coli ghosts are safe, versatile carriers with high drug-loading capacity. • E. coli ghosts enhance natural extract delivery, improving anticancer efficacy and targeting. • Fenugreek extract-loaded E. coli ghosts modulate key cancer pathways.

Artificial intelligence accelerates anticancer peptides (ACPs) discovery. However, existing computational methods lack integration of identification with activity-based candidate prioritization. Here, we present DeepACPred, a three-stage pipeline encompassing ACP binary classification model, ACP multilabel classification model, and ACP IC50 prediction model, leveraging multimodal features from ESM2 protein language model embeddings, AAindex physicochemical descriptors, and sequence composition. On 5712 benchmark sequences, the binary classifier achieved 95.10% accuracy (AUC = 0.9913), with performance remaining stable under CD-HIT cluster-aware splitting at 40%-90% identity thresholds. Multilabel cancer-type prediction yielded macro-F1 = 0.9124 across seven cancer types, and log10(IC50) regression achieved Spearman ρ = 0.8602 under 5-fold cross-validation. Ablation experiments showed task-dependent feature contributions rather than uniformly additive multimodal effects. Applied to 260 000 motif-enriched 18-mer candidates, DeepACPred selected 12 peptides predicted to be active against breast cancer cells, all of which showed measurable in vitro cytotoxic activity against murine 4T1 cells in OD-derived dose-response assays (IC50: 0.88-36.83 μg/ml). Although prospective IC50 ranking showed limited fine-grained resolution, these results support the use of the regression module for coarse candidate enrichment. In conclusion, DeepACPred provides a systematic framework for ACP candidate enrichment and prioritization.

Retinopathy of prematurity (ROP) is a sight-threatening vascular disorder driven by pathological neovascularization. Silibinin (SIL), a major flavonolignan from milk thistle, possesses antioxidant and anti-inflammatory properties. Mechanistically, its therapeutic effect arises from attenuated oxidative stress, which suppresses mitogen-activated protein kinase (MAPK) signaling upstream. This study employed an integrated network pharmacology and experimental strategy to elucidate SIL's antiangiogenic mechanism. Network analysis identified the MAPK pathway as a key target, and topological analysis highlighted core associated proteins (KDR, ABCB1, and MMP2). Subsequent in vitro experiments using human umbilical vein endothelial cells (HUVECs) showed that SIL (at concentrations of 10 and 20 µM) significantly inhibited hypoxia-induced MAPK pathway activation (reducing phosphorylation of p38, ERK, and JNK) and downregulated KDR expression. SIL treatment dose-dependently suppressed endothelial cell proliferation, migration, and tube formation under hypoxic conditions. In an oxygen-induced retinopathy (OIR) mouse model, in vivo administration of SIL (at a dose of 100 mg/kg) reduced pathological retinal neovascularization (RNV) by ∼57.6% and the avascular area by ∼27.2%. (p < 0.01 and p < 0.05, respectively). These findings demonstrate that SIL inhibits pathological retinal angiogenesis primarily by modulating the MAPK pathway, providing mechanistic insight and highlighting its potential as a multi-target therapeutic candidate for ROP.

The chemical composition and biological activities of Malus domestica 'Ak Sakı' fruits cultivated in Erzincan, Türkiye, were analyzed. The aroma profile of the fruits was investigated for the first time. This study aimed to identify the major volatile and phenolic compounds and determine their antioxidant, antimicrobial, and cytotoxicity properties to investigate the potential health benefits of this cultivar. GC-MS analysis identified major volatile compounds, including 1-hexanol (20.54%), benzaldehyde (13.49%), and 1-octanol (6.68%). LC-MS/MS analysis of phenolic compounds in the ethyl acetate fraction revealed high levels of chlorogenic acid (12 802.67 µg/g), catechin (8601.52 µg/g), and quercetin (805.96 µg/g). Among the tested extracts, the ethyl acetate extract exhibited the highest antioxidant activity (47.18 ± 0.92 µg/mL), total phenolic content (70.17 ± 0.28 mg GAE/g extract), and reducing power (90.17 ± 0.71 mg TE/g extract), followed by butanol and diethyl ether extracts. Antimicrobial tests demonstrated varying inhibition zones, with volatile oil being the most effective. In addition, extracts exhibit cytotoxicity potential. The diethyl ether fraction shows the most potent selective cytotoxicity against A549 lung cancer cells. The findings indicate that the 'Ak Saki' cultivar contains diverse bioactive compounds with strong antioxidant, cytotoxicity, and antimicrobial properties. This fruit may contribute to the nutritional and health value of the daily diet.

Systematic phytochemical investigation of whole plant of Salvia kiangsiensis led to the isolation of three undescribed abietane diterpenoids (1-3) and 24 known analogues (4-27), while compounds 2 and 3 belong to the 20-norabietane skeleton. Four derivatives (24a-24d) were also obtained through structural optimization. Their structures were elucidated by a combination of spectroscopic data, chemical methods, and x-ray diffraction. Cytotoxicity screening indicated that 24c, an oxime ester derivative of 24, exerted the most potent activity against the non-small-cell lung cancer (NSCLC) cell line H1975, with higher potency than the positive control cisplatin. Mechanism study revealed that 24c could promote cell-cycle arrest in S phase and induce cell apoptosis.

ISA-2011B is a phosphatidylinositol-4-phosphate 5-kinase-α (PIP5K1α) inhibitor that has been reported to be selective in suppressing the growth of prostate, breast and hepatic cancer cells. Here, cell viability of 2-dimensional (2D) cultures and 3-dimensional (3D) spheroids of four colorectal cancer (CRC) cell lines with different mutations were evaluated after treatment with the drug ISA-2011B.

The combination of enfortumab vedotin and pembrolizumab (EV+P) has revolutionized advanced urothelial carcinoma treatment, yet their combined real-world safety profile remains insufficiently characterized. This study aimed to quantitatively compare the adverse event (AE) landscapes of EV+P and EV monotherapy using the FAERS data.

Systemic administration of immunotherapy via intravenous injection is frequently associated with off-target toxicity throughout the body. In contrast, intratumoral injection has emerged as a promising strategy to mitigate systemic adverse effects. However, data regarding the safety of CT-guided intratumoral immunotherapy remain limited.

Nearly half of patients with melanoma do not respond to immune checkpoint inhibitors (CPIs) and many develop immune-related adverse events (irAEs), often forcing treatment discontinuation, and underscoring the need to predict and monitor outcomes. Responses may depend on both B cell and T cell activity.