Identification of Molecular Subtypes and Potential Small-Molecule Drugs for Esophagus Cancer Treatment Based on m6A Regulators

Background. Esophagus cancer (ESCA) is the sixth most frequent cancer in males, with 5-year overall survival of 15%–25%. RNA modifications function critically in cancer progression, and m6A regulators are associated with ESCA prognosis. This study further revealed correlations between m6A and ESCA development. Methods. Univariate Cox regression analysis and consensus clustering were applied to determine molecular subtypes. Functional pathways and gene ontology terms were enriched by gene set enrichment analysis. Protein-protein interaction (PPI) analysis on differentially expressed genes (DEGs) was conducted for hub gene screening. Public drug databases were employed to study the interactions between hub genes and small molecules. Results. Three molecular subtypes related to ESCA prognosis were determined. Based on multiple analyses among molecular subtypes, 146 DEGs were screened, and a PPT network of 15 hub genes was visualized. Finally, 8 potential small-molecule drugs (BMS-754807, gefitinib, neratinib, zuclopenthixol, puromycin, sulfasalazine, and imatinib) were identified for treating ESCA. Conclusions. This study applied a new approach to analyzing the relation between m6A and ESCA prognosis, providing a reference for exploring potential targets and drugs for ESCA treatment.

Optical spectra and conformation pool of tyrosine kinase inhibitor PD153035 using robust quantum mechanical conformation search

Tyrosine kinase inhibitors (TKIs) based on the quinazoline-aniline scaffold represent a significant class of small molecule drugs for diseases such as cancer. The present study applies the recently developed robust...

Identification of a Novel PPAR Signature for Predicting Prognosis, Immune Microenvironment, and Chemotherapy Response in Bladder Cancer

Background. Mounting evidence has confirmed that peroxisome proliferator-activated receptors (PPARs) played a crucial role in the development and progression of bladder cancer (BLCA). The purpose of this study is to comprehensively investigate the function and prognostic value of PPAR-targeted genes in BLCA. Methods. The RNA sequencing data and clinical information of BLCA patients were acquired from The Cancer Genome Atlas (TCGA). The differentially expressed PPAR-targeted genes were investigated. Cox analysis and least absolute shrinkage and selection operator (LASSO) analysis were performed for screening prognostic PPAR-targeted genes and constructing the prognostic PPAR signature and then validated by GSE13507 cohort and GSE32894 cohort. A nomogram was constructed to predict the outcomes of BLCA patients in combination with PPAR signature and clinical factors. Gene set enrichment analysis (GSEA) and immune cell infiltration were implemented to explore the molecular characteristics of the signature. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to predict the chemotherapy responses of the prognostic signature. The candidate small molecule drugs targeting PPAR-targeted genes were screened by the CMAP database. Results. We constructed and validated the prognostic signature comprising of 4 PPAR-targeted genes (CPT1B, CALR, AHNAK, and FADS2), which was an independent prognostic biomarker in BLCA patients. A nomogram based on the signature and clinical factors was established in the TCGA set, and the calibration plots displayed the excellent predictive capacity. GSEA analysis indicated that PPAR signature was implicated in multiple oncogenic signaling pathways and correlated with tumor immune cell infiltration. Patients in the high-risk groups showed greater sensitivity to chemotherapy than those in the low-risk groups. Moreover, 11 candidate small molecule drugs were identified for the treatment of BLCA. Conclusion. We constructed and validated a novel PPAR signature, which showed the excellent performance in predicting prognosis and chemotherapy sensitivity of BLCA patients.

Polymer Microparticles Prolong Delivery of the 15-PGDH Inhibitor SW033291

As the prevalence of age-related fibrotic diseases continues to increase, novel antifibrotic therapies are emerging to address clinical needs. However, many novel therapeutics for managing chronic fibrosis are small-molecule drugs that require frequent dosing to attain effective concentrations. Although bolus parenteral administrations have become standard clinical practice, an extended delivery platform would achieve steady-state concentrations over a longer time period with fewer administrations. This study lays the foundation for the development of a sustained release platform for the delivery of (+)SW033291, a potent, small-molecule inhibitor of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme, which has previously demonstrated efficacy in a murine model of pulmonary fibrosis. Herein, we leverage fine-tuned cyclodextrin microparticles—specifically, β-CD microparticles (β-CD MPs)—to extend the delivery of the 15-PGDH inhibitor, (+)SW033291, to over one week.

Optimised Electroporation for Loading of Extracellular Vesicles with Doxorubicin

The clinical use of chemotherapeutics is limited by several factors, including low cellular uptake, short circulation time, and severe adverse effects. Extracellular vesicles (EVs) have been suggested as a drug delivery platform with the potential to overcome these limitations. EVs are cell-derived, lipid bilayer nanoparticles, important for intercellular communication. They can transport bioactive cargo throughout the body, surmount biological barriers, and target a variety of tissues. Several small molecule drugs have been successfully incorporated into the lumen of EVs, permitting efficient transport to tumour tissue, increasing therapeutic potency, and reducing adverse effects. However, the cargo loading is often inadequate and refined methods are a prerequisite for successful utilisation of the platform. By systematically evaluating the effect of altered loading parameters for electroporation, such as total number of EVs, drug to EV ratio, buffers, pulse capacitance, and field strength, we were able to distinguish tendencies and correlations. This allowed us to design an optimised electroporation protocol for loading EVs with the chemotherapeutic drug doxorubicin. The loading technique demonstrated improved cargo loading and EV recovery, as well as drug potency, with a 190-fold increased response compared to naked doxorubicin.

Targeted siRNA nanotherapeutics against breast and ovarian metastatic cancer: a comprehensive review of the literature

Metastasis is considered the major cause of unsuccessful cancer therapy. The metastatic development requires tumor cells to leave their initial site, circulate in the blood stream, acclimate to new cellular environments at a remote secondary site and endure there. There are several steps in metastasis, including invasion, intravasation, circulation, extravasation, premetastatic niche formation, micrometastasis and metastatic colonization. siRNA therapeutics are appreciated for their usefulness in treatment of cancer metastasis. However, siRNA therapy as a single therapy may not be a sufficient option for control of metastasis. By combining siRNA with targeting, functional agents or small molecule drugs have shown potential effects that enhance therapeutic effectiveness. This review addresses multidrug resistance and metastasis in breast and ovarian cancers and highlights drug delivery strategies using siRNA therapeutics.

Exploration and Identification of Potential Therapeutic Targets and Biomarkers for Docetaxel Resistant Prostate Cancer

Background: Prostate cancer has become the third most common cancer, and the death rate of advanced patients due to metastasis and invasion is high. Approximately 40% to 50% of castration resistant prostate cancer responding to docetaxel did not show a substantial and sustained prostate specific antigen decline, and the median response duration was limited to 6 to 9 months.Objective: To understand the pathogenesis of docetaxel-resistant prostate cancer (DRPC), and to search for prognostic markers and new therapeutic targets.Methods: RNA sequencing data of GSE36135 and GSE33455 from the Gene Expression Synthesis Database were used to search for co-expressed genes. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors, which were validated by expression and survival analyses. Subsequently, their ability to jointly predict patient prognosis was evaluated. Then, the lasso Cox regression model was established to evaluate the correlation of DEGs with immune score, ferroptosis, methylation, and OCLR score. And predicted for targeted small molecule drugs and validated the effect of small molecule drugs.Results: EZH2 and SRC were identified as potential therapeutic targets and effective prognostic markers for docetaxel-resistant prostate cancer, and were found to be significantly associated with the immune score, ferroptosis, methylation, and OCLR score. Targeted small molecule drugs were predicted and validated for EZH2 and SRC.Conclusions: This study helps to fully explain the mechanism of docetaxel-resistant prostate cancer formation and provides new immune-related therapeutic targets and biomarkers for it. Preliminary exploration of the effects of docetaxel in combination with urapidil or roxithromycin in prostate cancer cells