Peipei Shan

Histone deacetylases (HDACs) are attractive therapeutic targets due to their established role in tumorigenesis. In this study, a series of naphthalene-based hydroxamate derivatives were designed and synthesized as novel HDAC inhibitors. Among them, compound 6e showed excellent inhibitory activities against HDAC1 and 4T1 cancer cell line, and it also increased the levels of acetylated histones H3 and H4. Moreover, 6e induced significant cell apoptosis and cycle arrest. Importantly, 6e exhibited significant antitumor activity in the 4T1 orthotopic autograft mouse model. Collectively, these results identify the naphthalene-hydroxamate scaffold as a promising template for the development of novel HDAC-targeted anticancer agents.

Background: General anesthesia may counteract the neuroprotective effects of S-ketamine, so previous trials may have underestimated the efficacy of S-ketamine to reduce postoperative delirium (POD). The authors hypothesized that administration of S-ketamine in a non–general anesthesia setting would reduce the risk of POD. Methods: This study was conducted at a high-volume arthroplasty referral center where standardized, evidence-based perioperative protocols are implemented with high fidelity. This study included 372 elderly patients undergoing total hip or knee arthroplasty under neuraxial anesthesia. Patients were enrolled from November 2023 to October 2024, and in-person follow-up assessments were conducted from admission to 3 days after surgery. Patients were randomized to receive either S-ketamine (n = 186) or normal saline placebo (n = 186). The primary outcome was risk of POD within 3 days after surgery. Secondary outcomes were number of POD episodes, POD onset time and duration, POD severity, POD subtype, pain score (numeric rating scale), opioid consumption, number of patients requiring rescue analgesia, sleep quality, clinical outcomes, and harms. Results: Within 3 days after surgery, 15 patients in the S-ketamine group (8.06%) developed POD, compared to 38 patients (20.43%) in the placebo group (adjusted odds ratio, 0.29; 95% CI, 0.14 to 0.63; P = 0.002). On postoperative day 1, patients in the S-ketamine group experienced significantly less pain during exercise and physical therapy and had a lower incidence of rescue analgesia use compared to the placebo group. The incidence of hallucinations, dizziness, and nightmares was higher in the S-ketamine group than in the placebo group. The incidence of other complications was low in both groups, with no statistically significant differences. Conclusions: S-ketamine can reduce risk of POD in elderly patients undergoing total hip or knee arthroplasty under neuraxial anesthesia. However, generalizability of these findings may be limited due to the study’s setting.

Immunotherapy has revolutionized cancer treatment; however, only 10–30% of patients experience durable survival benefits, while most malignancies remain resistant. In melanoma, vitiligo‐like depigmentation is a frequent and generally mild immune‐related adverse event, whose presence correlates positively with enhanced antitumor immune responses and prolonged patient survival. By performing comparative analyses between vitiligo and melanoma, we established a biomarker panel—designated the vitiligo signature (VGS)—that differentiates “cold” from “hot” tumors with high accuracy. Leveraging a deep learning–based efficacy prediction system (DLEPS), we identified and validated Fulvestrant as a candidate capable of enhancing anti–programmed cell death ligand 1 (PD L1) therapy in preclinical models. Single cell RNA sequencing revealed that Fulvestrant expanded cytotoxic T cell populations, while immunofluorescence and flow cytometry confirmed markedly increased CD8⁺ T cell infiltration into tumor tissue. Mechanistic investigations demonstrated that Fulvestrant activates the C─C motif chemokine 5 (CCL5), major histocompatibility complex class I (MHC I), and type II interferon (IFN II) signaling pathways, thereby potentiating antitumor immunity. Collectively, our study introduces a precision approach for patient stratification in immunotherapy and highlights Fulvestrant as a promising component of immunotherapy based combination strategies warranting clinical evaluation.

Microtubules, critical to diverse cellular processes, represent a clinically validated target for anticancer therapeutics. In this study, a virtual screening of the Specs library, consisting of 200,340 compounds, was conducted to target the taxane and colchicine binding sites on tubulin, resulting in the identification of 93 promising candidates for further analysis. Subsequent characterization revealed a nicotinic acid derivative (compound 89) as a potent tubulin inhibitor, demonstrating significant anti-tumor efficacy in vitro and in vivo, with no observable toxicity at therapeutic doses in mice. Notably, compound 89 also exhibited robust antitumor activity in patient-derived organoids. Mechanistic studies, including EBI competitive binding assays and molecular docking, confirmed its inhibition toward tubulin polymerization via selective binding to the colchicine site. Furthermore, compound 89 disrupted tubulin assembly dynamics through modulation of the PI3K/Akt signaling pathway. This work presents a novel tubulin-inhibiting scaffold with potential for advancing next-generation microtubule-targeted chemotherapies.

Background: Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized. Methods: A substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B. Results: We synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice. Conclusions: Our findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.

Small extracellular vesicles (sEVs) hold considerable promise for drug delivery due to their natural origin and inherent qualities. However, their clinical application is impeded by two main challenges: low yield and potential side effects. Therefore, it is crucial to obtain substantial quantities of sEVs that adhere to rigorous biosafety standards to ensure successful translation into clinical practice. To address this need, we propose exploring optimized methods for sourcing and separating sEVs, taking inspiration from clinical blood transfusion. In particular, we have identified blood sEVs as a viable alternative and developed a novel separation technique for their isolation. Our approach involves incubating dopamine solution with serum, resulting in the formation of polydopamine (PDA) nanoparticles on the surface of blood sEVs. These nanoparticles have minimal impact on blood sEVs, facilitating their easy separation under standard centrifugal conditions with high purity. This innovative technique enables the development of nanocarriers using blood sEVs with efficient drug-loading capabilities and enhanced pharmacokinetics. Additionally, the incorporation of PDA nanoparticles imparts a photothermal effect to the nanomedicines, enabling the integration of chemotherapy and photothermal therapy. Moreover, the photothermal effect holds the potential to facilitate the membrane fusion of sEVs and cells. In summary, our straightforward surface functionalization technique utilizing PDA effectively isolates blood sEVs and enables chemo-thermal tumor therapy. This approach significantly enhances the feasibility of translating sEV-based nanomedicines into clinical applications.

In the realm of colon carcinoma, significant genetic and epigenetic diversity is observed, underscoring the necessity for tailored prognostic features that can guide personalized therapeutic strategies. In this study, we explored the association between the type 2 bitter taste receptor (TAS2Rs) family-related genes and colon cancer using RNA-sequencing and clinical datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Our preliminary analysis identified seven TAS2Rs genes associated with survival using univariate Cox regression analysis, all of which were observed to be overexpressed in colon cancer. Subsequently, based on these seven TAS2Rs prognostic genes, two colon cancer molecular subtypes (Cluster A and Cluster B) were defined. These subtypes exhibited distinct prognostic and immune characteristics, with Cluster A characterized by low immune cell infiltration and less favorable outcomes, while Cluster B was associated with high immune cell infiltration and better prognosis. Finally, we developed a robust scoring system using a gradient boosting machine (GBM) approach, integrated with the gene-pairing method, to predict the prognosis of colon cancer patients. This machine learning model could improve our predictive accuracy for colon cancer outcomes, underscoring its value in the precision oncology framework.

The discovery and development of small molecule methuosis inducers and their modes of action were summarized for the first time.