Search Results (1,713)

Background/Objectives: Pharmaceutical formulation involves designing a drug product by combining the properties of an active pharmaceutical ingredient (API) with suitable excipients and processing strategies to produce a safe, effective, and manufacturable dosage form. However, data in formulation science are often limited, expensive to generate, and frequently restricted by proprietary and confidentiality constraints. Interactive digital tools can support formulators during early drug product development by improving the structure, transparency, and efficiency of formulation decision-making. While the current system focuses on structured decision support, future extensions may incorporate machine-learning methods for recommendation and knowledge extraction. Methods: In this work, we developed the Formulation tool, an interactive decision-support and visualization system for formulation development based on a hierarchical formulation-strategy framework commonly used in pharmaceutical practice. The tool is designed to prioritize suitable formulation principles and associated processing routes, with oral solid formulation as the initial application domain. The evaluated scenarios also include pathway regions relevant to oral liquid formulations. Its modular architecture also makes it adaptable to other formulation scenarios. To assess practical applicability, the tool was evaluated in a structured expert study involving five expert users across six predefined formulation scenarios (n = 30 runs) , covering three drugs under adult and pediatric conditions. Results: The tool showed agreement with the expected dosage-form families and overall formulation properties, with adult scenarios converging to oral solid regions and pediatric scenarios converging to oral liquid regions. At the downstream formulation-profile level, users converged either to the dominant expected pathway or to alternative feasible pathways within the same formulation region. Variability in full pathway completion was observed and was primarily associated with differences in user interaction behavior and exploratory usage patterns. The median task completion time was 113.5 s. Conclusions: In addition to organizing formulation knowledge, the Formulation tool records user interactions in a structured manner, which may support future learning from usage patterns. Because detailed downstream formulation constraints are often institution-specific and are typically not available in the public domain, the present evaluation focused on agreement at the dosage-form-family level and on overall formulation properties rather than on highly specialized constraint logic. The system is based on a constraint satisfaction problem (CSP) framework, which is well suited for modeling complex decision processes under explicit constraints. CSP has also been widely applied in intelligent scheduling systems, supporting its suitability for structured, constraint-rich decision-making tasks such as pharmaceutical formulation strategy development. Full article

Three-dimensional (3D) bioprinting has rapidly evolved into a controlling platform for the fabrication of patient-specific biomedical implants, with growing importance in advanced drug delivery systems. Beyond structural tissue engineering, bioprinted constructs now function as programmable therapeutic depots capable of localized, sustained, and stimuli-responsive drug release. This review focuses on recent biomaterial design strategies that enable precise control over drug encapsulation, retention, and release kinetics within 3D bioprinted architectures. The physicochemical and mechanical properties of bioinks, including crosslinking density, porosity, degradation behavior, viscoelasticity, and swelling characteristics, directly influence drug loading efficiency and release dynamics under physiological conditions. The rational tuning of these parameters allows the development of constructs that provide spatially controlled and temporally regulated therapeutic delivery. Recent advances in predictive modeling, such as finite element modeling (FEM), data-driven machine learning approaches, and ML, have significantly improved the ability to correlate material composition, printing parameters, and structural geometry with drug diffusion and degradation-mediated release mechanisms. These tools facilitate the optimization of printing variables including extrusion pressure, nozzle diameter, and layer resolution to ensure structural fidelity while maintaining therapeutic functionality. Emerging strategies incorporating multi-material printing, gradient architectures, and stimuli-responsive biomaterials have expanded the potential of 3D bioprinting for combination therapies and personalized medicine. This review discusses key challenges in translating bioprinted drug delivery systems into clinical applications, including the standardization of drug release characterization methods, and long-term stability assessment. Full article

Background/Objectives: Combination of antiparasitic drugs with different mechanisms of action has been suggested as an effective strategy to delay the development of parasite resistance. Considering the need to understand the pharmacological basis of drug combinations, the current study evaluated the potential pharmacokinetic (PK) interactions and the clinical efficacy (pharmacodynamic response) occurring after the subcutaneous administration of ivermectin (IVM) and levamisole (LEV), administered either as single treatments or concurrently to different groups of parasitized calves on three commercial farms (A, B and C). Methods: Forty-five (45) male calves naturally infected with gastrointestinal nematodes were randomly allocated into three groups (n = 15): IVM, treated with IVM by subcutaneous injection (0.2 mg/kg); LEV, treated subcutaneously with LEV (8 mg/kg); IVM + LEV, simultaneously treated with IVM and LEV (two subcutaneous injections at the same dose rates). Seven animals from each treated group (farm C) were randomly selected to perform the PK study. Drug concentrations were measured by HPLC. The therapeutic response (efficacy) was determined at 14 days after treatment by the fecal egg reduction test. Results: The mean area under the concentration vs time curve (AUC) for IVM obtained after administration of IVM alone (274 ± 65.1 ng.d/mL) was similar to that obtained when IVM was co-administered with LEV (295 ± 111 ng.d/mL). Likewise, mean LEV AUC values were similar after LEV administration alone (8.90 ± 2.69 µg.h/mL) or combined with IVM (9.11 ± 1.82 µg.h/mL). No adverse PK interactions were observed after the combined treatment, with similar PK parameters (p > 0.05) obtained between the single-drug and the combination-based strategies. On farm A, the overall fecal egg reductions were 38% (IVM), 99% (LEV) and 100% (IVM + LEV). While Cooperia spp. and Haemonchus spp. showed reduced susceptibility to IVM treatment, LEV demonstrated high efficacy against both genera, with only a minimal proportion of Haemonchus spp. remaining after treatment. Similarly, total fecal egg reductions were 42% (IVM), 99% (LEV) and 100% (IVM + LEV) on farm B, and 54% (IVM), 99% (LEV) and 100% (IVM + LEV) on farm C. On those farms, IVM was ineffective against Cooperia spp. and/or Haemonchus spp., while LEV failed to control Ostertagia spp. Remarkably, the combination of both molecules was the only treatment that achieved 100% efficacy against all nematode genera (Cooperia, Ostertagia, Haemonchus and Oesophagostomum spp.). Conclusions: Based on the described PK and pharmacodynamic (PD) assessments, the IVM + LEV combination appears to be a promising pharmacological option for controlling resistant gastrointestinal nematodes in cattle, with the additional potential to delay the progression of nematode anthelmintic resistance. Overall, the study provides original and robust pharmacokinetic and efficacy data that contribute to the optimization of parasite control strategies in cattle. This drug combination strategy may enhance treatment efficacy and contribute to improved parasite control in cattle production systems. Full article

Treatment-refractory rectal cancer liver metastasis represents a major therapeutic challenge, particularly in the absence of actionable genomic biomarkers. Functional precision oncology approaches integrating genomic profiling with patient-derived organoid (PDO) drug testing may provide biologically informed therapeutic prioritization. A 50-year-old female patient with KRAS/TP53-mutant, microsatellite-stable (MSS) rectal adenocarcinoma refractory to FOLFIRINOX was enrolled. A liver metastasis from a treatment-refractory rectal cancer patient was processed to establish three-dimensional patient-derived organoids. Histopathological concordance was assessed using H&E and p53 immunohistochemistry. Comprehensive genomic profiling was performed using a 637-gene targeted next-generation sequencing panel, enabling detection of single-nucleotide variants, indels, copy number variations, microsatellite instability, and tumor mutational burden. Functional drug sensitivity profiling was conducted in parallel 2D and 3D platforms using a customized 17-agent panel, followed by exploratory combinatorial validation. The organoids demonstrated high phenotypic and genomic concordance with the parental tumor, preserving key driver alterations (KRAS^A146T, TP53^R175H, APC frameshifts, CCNE1 amplification), microsatellite stability, and low tumor mutational burden (TMB: 6.37 mut/Mb). Functional screening identified selective sensitivity to bevacizumab (IC₅₀: 0.130 μM), doxorubicin (IC₅₀: 0.570 μM), carboplatin (IC₅₀: 0.950 μM), and topotecan (IC₅₀: 1.600 μM) in the 3D organoid model, with consistent cross-platform validation. An exploratory combination assay further supported enhanced viability suppression under bevacizumab-based regimens. Critically, at the time of manuscript preparation, the patient demonstrated radiological disease stabilization under bevacizumab plus trastuzumab deruxtecan, consistent with the organoid-derived response profile. These findings highlight the capacity of integrated genomic and organoid-based profiling to uncover therapeutic vulnerabilities beyond standard biomarker assessment. This proof-of-concept case report study demonstrates the feasibility and translational relevance of an established organoid-based functional precision oncology platform for therapeutic prioritization in metastatic rectal cancer. Full article

Auranofin (AF), an FDA-approved drug for rheumatoid arthritis, exhibits strong antibacterial activity against Gram-positive bacteria, while Gram-negative species remain largely tolerant. This study assessed the antimicrobial activity of AF and three analogues against clinically relevant Gram-negative pathogens and explored tolerance mechanisms in Pseudomonas aeruginosa. Broth microdilution assays were performed on reference strains and clinical isolates of Escherichia coli, Klebsiella pneumoniae, and P. aeruginosa. Synergy studies with the most active analogue, PEt₃AuCl (AF-Cl), were conducted against P. aeruginosa using polymyxin B (PMB), two efflux-pump inhibitors, and two glutathione (GSH) depletors. Gold compounds showed MICs between 4 and >64 µg/mL, with AF-Cl displaying the highest activity. AF-Cl activity was markedly enhanced by PMB and efflux-pump inhibitors, indicating that outer membrane permeability and efflux contribute to tolerance. Additionally, GSH depletion significantly potentiated AF-Cl, implicating redox homeostasis in resistance. Overall, AF-Cl shows potential against Gram-negative bacteria when combined with agents targeting membrane integrity, efflux systems, or redox balance, supporting combinatorial strategies to overcome resistance in P. aeruginosa and related pathogens. Full article

Pre-made dishes have drawn growing attention because of their convenience and rapid market expansion. Their food safety risks, however, are shaped not only by products themselves, but also by the gap between public perception, reported incidents, and inspection records. This study develops a three-stage analytical approach by combining Weibo public opinion data, news media reports, and food inspection records from Gansu Province. First, ERNIE and BERTopic are used to identify public sentiment and discussion topics. The results show that negative sentiment slightly exceeds positive sentiment, with school meals, additives, and food safety as the main concerns. Second, 11,110 pre-made dish-related food safety reports from Food Partner Network are clustered and assessed for incident severity. The results point to drug residues in aquatic products, microbial contamination in egg products, authenticity disputes over meat ingredients, and quality issues in frozen composite foods. Third, based on the 2024 official definition, 12,121 inspection records are screened, and 2783 definition-constrained pre-made dish-associated products are retained. Six imbalanced classification models are then constructed. The Weight + RF model performs relatively well for starch and starch products, with a Precision of 0.7857, an AUC-ROC of 0.7778, and an MCC of 0.4429. The study provides a reference for risk identification and inspection resource optimization under limited pre-made dish inspection data. Full article

Background/Objectives: BPC-157 (body protection compound 157) is a synthetic pentadecapeptide derived from a gastric protein fragment with reported cytoprotective and regenerative properties across multiple organ systems. Despite over three decades of preclinical research demonstrating consistent biological activity, its pharmaceutical development remains rudimentary, with no approved formulation, no validated dosing regimen, and no completed Phase II clinical trial. This review critically evaluates BPC-157 from a biopharmaceutical and drug development perspective, examining its physicochemical and pharmacokinetic properties, formulation challenges across routes of administration, the pharmacokinetic–pharmacodynamic disconnect that characterizes its preclinical profile, and the regulatory and translational barriers that currently preclude clinical advancement. Methods: A narrative review of the literature was conducted using PubMed/MEDLINE, Embase, and Cochrane Library from database inception to April 2026. Search terms included “BPC-157”, “BPC157”, “body protection compound 157”, “pentadecapeptide”, and “GEPPPGKPADDAGLV”, each combined with “pharmacokinetics”, “formulation”, “biopharmaceutics”, “drug delivery”, “clinical trial”, “toxicology”, and “regulatory”. Patent databases (Espacenet, Google Patents) and regulatory agency websites (FDA, EMA, WADA) were searched independently. Searches were supplemented by forward and backward citation tracking of key references. Articles were selected based on relevance to biopharmaceutical characterization, pharmacokinetics, formulation science, clinical evidence, and regulatory status; pharmacodynamic studies were included insofar as they inform translational development. Evidence was synthesized with emphasis on pharmaceutical characterization, formulation science, and translational feasibility; no formal quality assessment instrument was applied, consistent with the narrative review design. Results: BPC-157 exhibits unusual stability in gastric juice and demonstrates activity via oral, parenteral, and topical routes, yet its human pharmacokinetic profile remains critically undercharacterized despite a recently published formal preclinical ADME study in two species confirming a sub-30-min plasma half-life, linear dose-proportional kinetics, and intramuscular bioavailability of 14–51% depending on species. A plasma half-life of under 30 min—confirmed preclinically and in a preliminary two-subject human pilot—contrasts with prolonged biological effects lasting hours to days—a disconnect with significant implications for dosing strategy and formulation design. No pharmaceutical-grade formulation has been developed or validated. The peptide lacks bcs classification data, permeability characterization, and formal excipient compatibility studies. Available clinical data derive from fewer than 30 subjects across three uncontrolled pilot studies, none of which employed standardized pharmaceutical preparations. Conclusions: BPC-157 presents a compelling but pharmaceutically underdeveloped profile. The primary barrier to clinical translation is not the absence of biological activity, but the absence of fundamental pharmaceutical science: characterized formulations, validated pharmacokinetics, and a coherent drug development strategy. Addressing these biopharmaceutical gaps is a prerequisite for any meaningful clinical program. Full article

Polymer-based nanoparticle systems have emerged as a versatile platform for advancing precision medicine by enabling controlled, targeted, and multifunctional drug delivery. This narrative review synthesizes recent progress in the design, functionalization, and clinical translation of polymer-based nanoparticles, with a focused scope on drug delivery, diagnostics, theranostics, nanosponges, and regenerative medicine. Specifically, it highlights three key insights: (i) surface engineering strategies, including ligand conjugation and stealth coatings, substantially enhance targeting specificity and reduce off-target toxicity; (ii) stimulus-responsive polymers enable spatiotemporally controlled drug release, improving therapeutic outcomes in complex disease microenvironments; and (iii) integration with artificial intelligence (AI) supports the rational design of personalized nanomedicines based on patient-specific molecular profiles. The innovative nature of this review lies in its comprehensive approach, which combines material design parameters with clinical outcomes and the barriers to implementation. Despite significant progress, serious challenges remain, including scalable and reproducible manufacturing, regulatory harmonization, and comprehensive long-term biosafety assessment. In the future, the priority should be to develop reliable manufacturing processes, a harmonized regulatory framework, and data-driven, clinically validated design methodologies. Overall, polymer-based nanoparticles are poised to redefine targeted therapy, but their clinical impact will depend on bridging the gap between laboratory innovation and scalable, safe, and personalized medical applications. Full article

The occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related to intestinal flora imbalance, intestinal barrier damage, and gut-liver axis dysfunction. Due to their multi-target regulatory effects and advantages in intestinal microecological intervention, Chinese herbal monomers have shown promising application prospects in the prevention and treatment of MASLD. However, basic research on their toxicity still lags behind, and issues related to safety and clinical translation urgently need attention. This article systematically reviews the research progress on how flavonoids, triterpenoids, alkaloids, and polysaccharides improve hepatic steatosis, inflammatory responses, and metabolic disorders from a toxicological perspective by reshaping the intestinal microbiota, repairing the intestinal mucosal barrier, regulating short-chain fatty acid and bile acid metabolism, and synergistically acting on signaling pathways such as TLR4/NF-kB, FXR, TGR5, SIRT1, and the NLRP3 inflammasome. Furthermore, by combining methods such as 16S rRNA sequencing, metagenomics, metabolomics, and multi-omics integration, the article analyzes their application value and limitations in toxicological mechanism research, and discusses the translational bottlenecks faced by Chinese herbal monomers in pharmacokinetics, bioavailability, quality standardization, targeted delivery, and toxicological safety. Existing evidence indicates that Chinese herbal monomers have a three-in-one intervention advantage of microecological remodeling-metabolic regulation-inflammation inhibition, but their long-term medication safety, toxic target organs, dose-effect/toxicity relationships, and potential drug interactions still need further clarification. This article aims to provide a systematic reference for the safety evaluation and clinical translational research of Chinese herbal monomers in the prevention and treatment of MASLD. Full article

Cataract remains the preeminent cause of reversible blindness globally, with cataract extraction and intraocular lens (IOL) implantation serving as the definitive surgical intervention. Nevertheless, its long-term efficacy is undermined by formidable postoperative complications, specifically posterior capsule opacification (PCO) and endophthalmitis, which necessitate effective prophylactic strategies. IOL modification has emerged as a pivotal paradigm to effectively mitigate these complications. Current approaches encompass surface modification, drug delivery IOLs, and photo-responsive IOLs. Driven by the rapid interdisciplinary convergence of materials science, ophthalmology and pharmacology, the field has also evolved to have combined modification strategies and multifunctional systems. This review provides a comprehensive overview of the recent progress in IOL modification for postoperative complication prophylaxis. By categorizing recent advancements into three major types—surface modification, drug delivery systems, and photo-responsive IOLs—we critically evaluate their mechanisms, advantages, and limitations. Furthermore, we offer strategic insights to accelerate the development of IOL modification and bridge the gap between innovation and clinical translation. Full article

Manganese-based nanomaterials have been novel multifunctional platforms in tumor immunotherapy because of their tunable multivalent states, biocompatibility, and multi-stimulus responsiveness. Current cancer treatments are insufficient and cause severe side effects; therefore, manganese-based nanomaterials are proposed in combination with immunotherapy to mitigate adverse effects. This review outlines the antitumor effects mediated by four key mechanisms: (1) activation of the cGAS-STING immune signaling pathway, (2) direct activation of immune cells, (3) induction of immunogenic cell death (ICD), and (4) modulation of the tumor microenvironment. These approaches are broadly categorized into two types: monotherapy and multimodal combination therapy. Monotherapy encompasses three specific modalities: (1) direct use as a Stimulator of Interferon Genes (STING) agonist, (2) vector-mediated targeted drug delivery, and (3) mediation of chemodynamic therapy to generate reactive oxygen species, thereby inducing ICD. Multimodal combination therapy involves synergistic integration with traditional or emerging treatment modalities, including chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy, and low-level light therapy, as well as multimodal combination treatment methods. It significantly enhances the antitumor efficacy of traditional therapies through immunostimulation, thus achieving synergistic breakthroughs in treatment efficiency and survival rate. Collectively, the multifunctional integration of manganese-based materials is a novel strategy for developing “self-adjuvant” immunotherapeutic platforms and investigating the clinical translation potential. Full article

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that recapitulate tumor architecture, proliferation, angiogenesis, metastasis, and PD-L1 expression. Methods: Tumor specimens from two renal cell carcinoma (RCC) patients were expanded subcutaneously in NOD/SCID mice, transduced with luciferase/red fluorescent protein (Luc/RFP), and orthotopically implanted into mouse kidneys (KiCa-Pt58: sarcomatoid RCC, pT3aN1M1, Fuhrman grade 4; KiCa-Pt118: clear cell RCC with sarcomatoid component, pT3aNxM0, Fuhrman grade 4, respectively). Tumor growth and metastasis were monitored weekly by bioluminescence imaging (BLI). Mice were randomized into vehicle control or four sequential treatment groups (Everolimus→Sunitinib [E→S], Sunitinib→Everolimus [S→E], Pazopanib→Sunitinib [P→S], Pazopanib→Everolimus [P→E]). Drugs were administered orally three times weekly until resistance (>200% BLI increase), with one switch. At necropsy, tumor burden, ex vivo BLI metastasis, weights, H&E histology, and immunohistochemistry (Ki67, CD44, CD31, PD-L1) were assessed. Results: Two independent experiments were performed. In dosing optimization, PDOX tumors recapitulated parental histology and proliferative indices, mirroring patient trajectories. KiCa-Pt58 (metastatic sarcomatoid RCC; deceased 1-month post-nephrectomy) showed aggressive features: rapid engraftment at low doses, early growth (week 2), and lung metastases in 78% of mice (sacrifice day 34), reflecting a fulminant course. KiCa-Pt118 (non-metastatic; patient recurrence-free >8 years post nephrectomy) exhibited indolent behavior: delayed engraftment requiring higher doses plus lymph node stromal (HK) support, slower growth (week 4), no metastases, and later sacrifice (day 78), consistent with remission. In sequential therapy evaluation, for KiCa-Pt58, P→E yielded greatest reductions in tumor weight (p < 0.01), lung metastases (p < 0.01), Ki67+ proliferation, CD31+ angiogenesis, and PD-L1 expression versus control; E→S and S→E were also effective. For KiCa-Pt118, S→E and P→E reduced tumor burden (p < 0.01) and Ki67⁺ proliferation; S→E lowered CD31 and PD-L1. Conclusions: This RCC PDOX platform faithfully preserves patient-specific biology—including metastatic propensity, engraftment efficiency, growth kinetics, and stromal dependency—while enabling real-time evaluation of sequential targeted therapies. Given the limited number of models tested, these findings provide proof-of-concept for individualized treatment exploration in advanced RCC and support future investigation of rational combinations with immune checkpoint blockade in humanized or immunocompetent systems. Full article

At present, there is still a lack of effective treatments to slow the progression of Parkinson’s disease. Naturally derived active substances, valued for their safety and multi-target potential, have become an important direction in anti-PD drug development, with marine organisms representing a valuable source of bioactive peptides. This study aimed to isolate and identify anti-PD peptides from Rapana venosa protein hydrolysates. Through bioactivity-guided screening combined with an MPTP-induced zebrafish PD model, three novel active peptides—KSTELLI, FLVKLPMFM, and SDSLSEILIS—were successfully identified. The study showed that these peptides significantly alleviated dopaminergic neuron loss, improved the cerebral vascular system, restored motor and sensory function, and alleviated oxidative stress. Molecular docking confirmed their stable binding to key PD targets (DDC, α-synuclein, and MAO-B). Further transcriptomic and gene expression analyses revealed that their neuroprotective effects involve the regulation of pathways related to metabolism, oxidative stress, inflammation, and apoptosis, with the three peptides exhibiting distinct mechanistic emphases. The research demonstrates that these marine-derived peptides exert neuroprotective effects through a synergistic multi-target mechanism, laying a foundation for the development of novel lead compounds against Parkinson’s disease. Full article

Introduction: In the treatment of hormone receptor-positive (HR+), HER2-negative (HER2−) metastatic breast cancer (MBC), the current guidelines recommend endocrine therapy combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as the preferred first-line treatment to preserve quality of life. Ribociclib is a CDK4/6 inhibitor that has been used in combination with aromatase inhibitors or fulvestrant in patients with HR+, HER2− metastatic breast cancer. Various adverse drug reactions associated with ribociclib have been reported, including cutaneous reactions, hepatotoxicity, and hematologic toxicity. In this study, we aimed to evaluate the clinical manifestations and risk factors of dermatologic toxicities in patients with metastatic breast cancer treated with ribociclib. Methods: This retrospective study included patients with metastatic/recurrent breast cancer who were prescribed ribociclib from April 2021 to December 2024 at a single institution. We retrospectively reviewed the medical records of these patients to identify the frequency of cutaneous adverse events, the time of onset, and the clinical characteristics of skin reactions. Logistic regression analysis was performed on several clinical factors, including body surface area (BSA) and concomitant medications, to identify risk factors associated with the occurrence of cutaneous adverse events. Results: A total of 110 patients with MBC were enrolled during the study period. The median age was 53 years (range, 28–82); all 110 patients (100.0%) were female; the median BSA was 1.56 m² (range, 1.29–2.07); and 32 patients (29.1%) were premenopausal. Ribociclib plus letrozole was administered in 48 patients (43.6%) and ribociclib plus fulvestrant in 29 patients (26.4%). An additional 33 patients (30.0%) received ribociclib plus letrozole with a gonadotropin-releasing hormone (GnRH) agonist. Cutaneous adverse events occurred in 29 patients (26.4%), and the median time to onset was 84 days (range, 3–498). The cutaneous adverse event patterns included pruritus, erythematous macular rash, eczematous rash/contact dermatitis, vitiligo, urticarial reactions, polymorphous light eruption, toxic epidermal necrolysis (TEN), and desquamation. Grade 1 or 2 cutaneous adverse events occurred in 93.1% of patients; Grade 3 toxicity occurred in one patient; and Grade 4 toxicity, namely toxic epidermal necrolysis (TEN), was reported in one patient. Dose reduction was required in three patients (10.3%), and permanent discontinuation of ribociclib occurred in one patient. Clinical improvement was achieved in the majority of patients (86.2%) with cutaneous adverse events following supportive care. Logistic regression analysis revealed that age, Eastern Cooperative Oncology Group (ECOG) performance status, body surface area (BSA), treatment regimen, and use of cholesterol-lowering medications were not independently associated with the development of cutaneous adverse events. Conclusion: CDK4/6 inhibitors represent one of the most important treatment options for HR+/HER2− metastatic breast cancer. Regardless of their clinical efficacy, cutaneous adverse events remain a common source of patient discomfort. Therefore, careful clinical attention and appropriate supportive care are essential to improve patients' quality of life. Full article

Maternal consumption of alcohol and drugs during pregnancy can compromise neural development with long-lasting impact on individuals’ health. The inhibitor of growth (ING) family of proteins is an epigenetic regulator that plays a central role in fetal brain development, contributing to neural stem cell maintenance, neuronal differentiation, and the regulation of genes involved in brain morphogenesis. Given the susceptibility of the developing nervous system to epigenetic dysregulation induced by alcohol and drugs, this narrative study aims to summarize literature evidence with the hypothesis that ING proteins may represent a critical but understudied mechanistic link between maternal substance dependence and adverse neurodevelopmental outcomes in newborns. We conducted a comprehensive literature search across three databases (PubMed, Scopus, and Web of Science) up to February 2026 to identify relevant studies. Search terms included combinations of “ING proteins”, “neural development”, “alcohol”, “drugs”, “epigenetic”, “oxidative stress” and “neuroinflammation”. The inclusion criteria were limited to original studies published in English that examined neural development in newborns; the exclusion criteria encompassed non-English publications, letters, editorials, and case reports, and those not directly addressing the specified topics. We identified 55 papers; six were excluded per the exclusion criteria, leaving 49 works discussed in this review. ING proteins are epigenetic regulators essential for embryonic and neural development, including neural stem cell fate and neurogenesis, while substances of abuse are disruptors of the essential pathways necessary for the right fetal brain development. Furthermore, substance abuse creates oxidative stress environments and activates pathways that require ING-mediated chromatin regulation. ING proteins likely act as mediators linking oxidative stress, neuroinflammation, and transcriptional reprogramming in the developing brain. Meanwhile, alcohol and drugs induce epigenetic reprogramming that may disrupt ING-mediated chromatin control. There is little evidence directly linking prenatal exposure (e.g., alcohol and drugs) to ING changes during fetal development. However, we hypothesize that ING proteins function as epigenetic stress response regulators whose disruption by oxidative stress, inflammation, and chromatin alterations induced by prenatal alcohol or drug exposure may contribute to impaired fetal neurodevelopment. Although direct experimental evidence remains limited, this could be a promising and relatively unexplored research area. Full article