Triple-negative breast cancer (TNBC), particularly when associated with breast cancer susceptibility gene 1/2 (BRCA1/2) alterations or homologous recombination deficiency (HRD), remains therapeutically challenging because DNA repair vulnerabilities coexist with molecular heterogeneity, resistance, and toxicity constraints. This narrative review synthesizes mechanistic, preclinical, clinical, and translational evidence on DNA damage response (DDR)-targeted and synthetic lethality-based strategies in TNBC. We summarize TNBC biological heterogeneity, current biomarker-guided treatment options, mechanisms of poly(ADP-ribose) polymerase (PARP) inhibition and resistance, and emerging DDR targets, including ataxia telangiectasia and Rad3-related/checkpoint kinase 1 (ATR/CHK1), WEE1, DNA-dependent protein kinase (DNA-PK), RAD51, DNA polymerase theta (POLQ), neddylation-related pathways, and targeted protein degradation. The review highlights that PARP inhibitors and platinum agents provide clinically validated examples of exploiting HRD in selected populations, whereas most next-generation DDR inhibitors remain preclinical, investigational, or in early clinical trials. Resistance mechanisms, including BRCA reversion, homologous recombination restoration, replication fork stabilization, and checkpoint adaptation, limit durable benefit. Safety, target selectivity, overlapping toxicities, and the lack of standardized functional biomarkers further constrain translation. Future progress will require prospective biomarker validation, dynamic HRD assessment, rational scheduling of combinations, and medicinal chemistry approaches that improve therapeutic index rather than a broad application of DDR inhibition across all TNBC.

Survivin (BIRC5) is a key inhibitor of apoptosis that is highly overexpressed in many cancers, where it promotes tumour cell survival, mitotic progression, and resistance to therapy. Because survivin is largely absent from normal adult tissues, it represents a selective and promising target for cancer treatment. Antisense oligonucleotides (ASOs) provide a precise approach to silence survivin by targeting its transcripts. Preclinical studies have shown that ASO-mediated reduction of survivin is associated with increased cancer cell death, inhibition of tumour growth, and enhanced sensitivity to other treatments. Early-phase clinical trials of survivin-targeting ASOs have shown evidence of target engagement but ultimately failed to demonstrate consistent clinical benefit and/or encountered dose-limiting toxicities, which hindered their further development. This review outlines survivin's central role in cancer biology, the principles of ASO therapeutics (sequence design, mechanisms of action, chemical modifications, and delivery strategies), and the progress in preclinical and clinical development of survivin-targeting ASOs, while also discussing key challenges that may contribute to their clinical limitations, including inefficient delivery, off-target effects, and systemic toxicities. Collectively, the current status of survivin-targeting ASOs underscores the need for synergistic optimization of delivery platforms and molecular chemistry to improve efficacy and safety, thereby enabling their use in personalised and combination cancer treatment approaches.

In this study, a new series of (E)-4-((2-(2-(4-amino-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetyl)hydrazono)methyl)phenyl 4-halogenobenzenesulfonates (3a-3d), where 3a = F, 3b = Cl, 3c = Br, and 3d = I, were successfully synthesized via a straightforward synthetic route. The structures of the obtained compounds were fully characterized and confirmed by spectroscopic techniques, including FT-IR, ¹H NMR, and ¹³C NMR, as well as LC-MS/MS analysis. 1,2,4-triazole-based hydrazone derivatives (3a-3d) were investigated using IR and NMR spectroscopy and DFT calculations. Intermolecular interactions, HOMO-LUMO, dipole moment, polarization, first-order hyperpolarizability, and molecular electrostatic potential studies on the molecules were examined. The HOMO and LUMO energy gap study supports the charge transfer probability in the molecules. These were conducted to investigate the reactivity and stability of heterocyclic molecules in bioactivity analysis. Electron density mapping within the molecular electrostatic potential plot and electrostatic potential representation within the iso-surface plot evaluated the concept of charge distribution in the molecule as nucleophilic reactions and electrophilic regions. The predicted nonlinear optical (NLO) properties of the molecules are much greater than those of urea. The results obtained from these investigations collectively provide evidence that the molecules possess nonlinear optical applications. Novel triazole-hydrazone-functionalized aryl sulfonate derivatives (3a-3d) were evaluated for their anticancer potential against a panel of brain and non-brain cancer cell lines. Compound 3b exhibited the most favorable overall biological profile, displaying potent activity against SH-SY5Y neuroblastoma (GI = 7.59 μM) and U87MG glioblastoma cells (GI = 13.85 μM), together with the lowest toxicity toward normal FL fibroblasts (GI = 62.02 μM). Compounds 3c and 3d demonstrated remarkable potency against IDHmut-U87 glioma cells (GI = 3.87 and 3.27 μM, respectively), although their selectivity toward cancer cells was limited. DNA degradation studies revealed substantial fragmentation, particularly in C6 and SH-SY5Y cells, while migration assays indicated reduced cellular motility. Molecular docking studies identified compound 3b as the strongest PI3Kα binder, supporting a possible. In addition, the antimicrobial activities of compounds 3a-3d were evaluated against selected Gram-positive and Gram-negative bacteria as well as Candida species using the broth microdilution method. The compounds exhibited measurable antimicrobial effects with MIC values ranging from 156 to 625 µg/mL, showing moderate growth inhibition against the tested microorganisms. Although the observed activity was lower than that of the reference antimicrobial agents, the results indicate that these triazole-hydrazone derivatives possess a detectable level of antimicrobial activity and provide a basis for further structural optimization. Collectively, the results suggest that compound 3b represents the most promising lead structure due to its balanced combination of potency, selectivity, and predicted target engagement. Molecular docking was performed to evaluate the binding potential of newly synthesized triazole derivatives (3a-3d) against PI3Kα. The docking protocol was validated by re-docking alpelisib, yielding an RMSD of 0.64 Å. Among the tested compounds, 3b showed the most favorable binding energy (-9.94 kcal/mol) and estimated Ki value (52.13 nM), consistent with its superior in vitro activity. Its interactions with key PI3Kα residues, including Val851, Ser854, Met922, and Asp933, support a stable binding mode within the ATP-binding pocket. In silico ADME and toxicity analyses suggested acceptable drug-likeness characteristics, absence of major hepatotoxic, mutagenic, and carcinogenic liabilities, and moderate predicted acute toxicity profiles. These findings suggest that 3b is the most promising derivative for further validation.

Multifunctional drugs represent an emerging strategy for treating complex skin disorders and melanoma. A series of benzothiazole-based hybrids incorporating gallic and syringic acid moieties was synthesized and evaluated as multifunctional agents for skin-related applications. Six hydrazone (GAHYDR1-3) and acyl-hydrazone (GACIN1-3) derivatives were obtained and fully characterized. Hydroxylated compounds showed the strongest antioxidant activity, with GAHYDR1 and GACIN1 displaying low DPPH IC₅₀ values and high FRAP reducing power. UV-Vis studies revealed strong UVA-UVB absorption, with molar extinction coefficients comparable to or exceeding those of PBSA. Photoprotective evaluation showed SPF values up to 10.09 (GACIN2) and broad-spectrum behavior for selected derivatives. Antioxidant activity remained substantially stable over 3 months in solution. Antiproliferative assays against Colo38, A375, and HaCaT cell lines indicated generally low cytotoxicity toward non-tumor cells. Notably, GAHYDR3 exhibited selective activity against A375 melanoma cells (IC₅₀ = 8.75 µM; SI = 8.12). Overall, phenolic substitution emerged as a key determinant of biological activity, highlighting hydroxylated benzothiazole hybrids as promising antioxidant and photoprotective agents, with GAHYDR3 representing a potential lead for anti-melanoma development.

Chronic atrophic gastritis (CAG) is a pivotal precancerous condition in gastric carcinogenesis, with progression typically following the classic Correa cascade. Although Helicobacter pylori (H. pylori) infection is widely recognized as the principal etiological factor, the persistence of gastric cancer (GC) risk in a subset of patients after successful eradication suggests that gastric microbiota dysbiosis may also contribute to CAG progression. In recent years, high-throughput sequencing technologies have revealed distinct microbial restructuring in patients with CAG, characterized by decreased microbial diversity, depletion of commensal taxa, and enrichment of opportunistic pathogens. These compositional changes are accompanied by metabolic dysfunction, activation of inflammatory signaling pathways, and disruption of immune homeostasis, which may contribute to a microenvironment permissive for precancerous transformation of the gastric mucosa. Probiotics and related microbiome-based therapeutics, including prebiotics, synbiotics, and postbiotics, have emerged as promising adjunctive strategies for H. pylori eradication and disease management. Their beneficial effects are mediated through multiple mechanisms, including remodeling of the microbial community, inhibition of pathogen colonization, modulation of host immune responses, and restoration of mucosal barrier integrity. However, whether these interventions can reverse established atrophic or metaplastic lesions remains unclear. In addition, how strain specificity, dose dependency, and interindividual heterogeneity influence clinical efficacy has yet to be fully elucidated. In this review, we summarize the compositional and functional features of gastric microbiota dysbiosis in patients with CAG, as well as the mechanisms and clinical applications of microbiome-based interventions. We further highlight current limitations in the field and discuss future directions for precision microecological therapies integrating multi-omics approaches, engineered probiotics, and artificial intelligence. These advances may provide a theoretical framework and practical guidance for the diagnosis and management of CAG and the prevention of GC.

Background: Cancer-related cachexia is primarily characterized by systemic inflammation and progressive muscle wasting, which is why a high-protein diet (from 1.2 to 1.5 g/kg/day) is commonly recommended. However, concerns remain that an excessive supply of amino acids could promote tumor growth due to the metabolic flexibility of cancer cells, thereby favoring proliferation and survival. Systematic evidence addressing these concerns under controlled conditions for various types of cancer cells remains limited and inconclusive. Methods: We investigated the short-term effects of all 20 amino acids at both moderate (2×) and high (10×) concentrations to evaluate three key oncological endpoints in four human cancer cell lines: MDA-MB-231 (breast), HT29 (colorectal), PC3 (prostate), and PANC-1 (pancreatic). Cell proliferation was assessed by BrdU incorporation, metabolic activity by WST-1 assay, and apoptosis signaling by caspase-3/7 activity measurement. Results: Amino acid supplementation was not associated with a significant change in proliferation at either concentration across all four cell lines studied. Metabolic activity showed only minor variations throughout, with PC3 cells exhibiting slightly greater variability, although this did not reach statistical significance. Caspase-3/7 activity remained largely unchanged under all conditions; however, high-concentration lysine induced an approximately 2.5-fold increase in PANC1 cells, which was not statistically significant. Conclusions: These findings suggest that short-term exposure to individual amino acids, even at supraphysiological conditions, does not acutely enhance proliferative activity in the cancer cell lines studied, supporting the rationale for adequate protein and amino acid intake in patients with cancer cachexia.

The tumor microbiome has been implicated in pancreatic ductal adenocarcinoma (PDAC)'s poor response to treatment, demanding new methods for understanding host-microbe interactions in therapy. Traditional 2D systems, while widely used, fail to adequately recapitulate human PDAC due to insufficient representation of structural, immunological and stromal components. Differences in cancer-specific microbiomes, microbe-immune interactions, and the unique physiological and immunosuppressive features unique to PDAC have hindered the clinical translation of immune therapies. Reproducible 3D culture systems that integrate the human microbe-tumor-immune (MTI) axis represent a promising avenue for treatment research, yet they remain underexplored in PDAC. In this narrative review, we discuss the key microbial determinants of therapy resistance, explore the current 3D multicellular modeling approaches in other cancer types, and provide a path forward for similar integrative translational models in PDAC.

Objectives: Polycystic ovary syndrome (PCOS) is a widespread and complex endocrine disorder affecting women of childbearing potential, characterized by reproductive dysfunction, hyperandrogenism, and metabolic disorders, including insulin resistance. Insulin resistance is a key pathogenetic factor contributing to ovarian dysfunction and reduced fertility. Myo-inositol (MI), a ubiquitous polyol, has earned a reputation as a promising dietary supplement due to its vital role in insulin signaling pathways. This scoping review aimed to map the available scientific literature on the effects of MI supplementation in women with PCOS, with particular emphasis on fertility and ovarian function, and to identify gaps in the current evidence base. Methods: This scoping review was conducted in accordance with the methodology developed by the Joanna Briggs Institute (JBI) and presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines. A literature search was conducted against six electronic databases: PubMed, Scopus, Web of Science, EBSCO (MEDLINE Complete), Cochrane Library and Google Scholar. Searches were conducted between 10 January and 20 February 2026. Eligibility sources included original articles (observational and randomized controlled trials), meta-analyses, systematic and narrative reviews, published in English with full text available, focusing on adult women with PCOS. Data extraction was performed independently by two reviewers using the Population-Concept-Context (PCC) framework. In accordance with the scope review methodology, no formal critical appraisal of study quality and no quantitative synthesis were performed. This is consistent with JBI methodology, which does not require critical appraisal for scoping reviews unless explicitly justified. Results: Of the 77 records initially identified, 13 studies were included in the review, and no duplicates were found. These potential benefits should be interpreted cautiously, as the available evidence is heterogeneous and varies across study designs. Potential benefits were also reported for hormonal and metabolic parameters, including reductions in hyperandrogenism and the improvement of insulin sensitivity. Some studies suggest benefits for oocyte and embryo quality, but results remain inconsistent. Conclusions: MI supplementation may support PCOS management, particularly in fertility-related outcomes. Its ability to improve ovulation, increase pregnancy rates, optimize ART outcomes, and mitigate the risk of OHSS highlights its clinical utility. However, the evidence remains heterogeneous, and some outcomes, particularly oocyte and embryo quality, remain inconclusive.

Background: Apoptosis is a fundamental process for maintaining tissue homeostasis, and its dysregulation is closely linked to the development of numerous diseases, including colorectal cancer. In recent years, dietary polyphenols have gained interest due to their antioxidant, pro-apoptotic, and chemopreventive properties. Artichoke (Cynara scolymus L.) by-products are rich source of hydroxycinnamic acids and flavonoids, making them promising source of bioactive compounds. Methods: In this study we evaluated the cytotoxic and pro-apoptotic activity of four aqueous extracts obtained from artichoke bract by-products, including one commercial hybrid (CAPB) and three local Apulian varieties (BriB, VaMB, LMTB), in human colorectal adenocarcinoma cell lines (Caco-2 and HT29). The extracts were characterized according to their total polyphenol content and phenolic profile. Results: The selected artichoke by-product extracts exhibited significant cytotoxic effects both in a concentration- and time-dependent manner, with concentrations ≥ 2 mg/mL significantly reducing cell viability and nearly abolishing it at 4 mg/mL after 48 h. Moreover, treatment with the extracts modulated the expression of apoptosis-related proteins, characterized by an increase in pro-apoptotic markers (Bax, caspase-9, caspase-3) and a decrease in the anti-apoptotic protein Bcl-2, suggesting activation of the mitochondrial apoptotic pathway. In particular, the BriB extract was able to induce an apoptosis rate higher than 80% in Caco-2 cells and achieved comparable rates in HT29 cells at concentrations of 2-3 mg/mL. Conclusions: Overall, these findings demonstrate that artichoke by-product extracts exert significant pro-apoptotic effects in colorectal cancer cells and highlight their potential as sustainable sources of bioactive compounds for nutraceutical or adjuvant anticancer applications.

Background: The Semipalatinsk Nuclear Test Site (SNTS) represents a unique example of long-term population exposure to ionizing radiation. This study aimed to assess the health status of individuals from three generations permanently residing in territories affected by radioactive contamination resulting from nuclear weapons testing at the SNTS, based on the findings of a population screening examination. Materials and Methods: A cross-sectional screening study was conducted among 2802 adults aged 18 years and older. The exposed group consisted of residents of the Abay and Beskaragai districts of the Abay Region and their descendants (n = 1358). The control group included residents of Arshaly village in the Akmola Region with no history of radiation exposure (n = 1444). All participants underwent a structured questionnaire survey, clinical examination, biochemical and hematological testing, and assessment of thyroid function. Individual radiation doses were obtained from the State Scientific Automated Medical Registry of Persons Exposed to Radiation (SSAMR). Results: Arterial hypertension (p < 0.001), chronic ischemic heart disease (p < 0.001), thyroid disorders (p < 0.001), malignant neoplasms (p = 0.003), renal diseases, and respiratory diseases were significantly more prevalent in the exposed population than in the control group. Exposed individuals also demonstrated significantly higher levels of total cholesterol, triglycerides, and the triglyceride-glucose (TyG) index, indicating increased insulin resistance. After adjustments, the only outcome that retained a statistically significant association with radiation dose was thyroid disorders (adjusted OR per 10 mSv increase = 1.017; 95% CI: 1.009-1.025; p < 0.001). ROC analysis demonstrated a moderate discriminative ability of radiation dose with respect to arterial hypertension (AUC = 0.715), chronic ischemic heart disease (AUC = 0.735), and ischemic stroke (AUC = 0.711). Conclusions: The findings suggest long-term adverse health effects associated with radiation exposure among populations residing near the SNTS. Continued epidemiological surveillance and medical monitoring of exposed individuals and their descendants are warranted.