Novel CDK19-Targeted Radiotracers: A Potential Design Strategy to Improve the Pharmacokinetics and Tumor Uptake.

Cyclin-dependent kinase 19 (CDK19) is overexpressed in prostate cancer, making it an attractive target for both imaging and therapy. Since little is known about the optimized approach for radioligands of nuclear proteins, linker optimization strategies were used to improve pharmacokinetics and tumor absorption, including the adjustment of the length, flexibility/rigidity, and hydrophilicity/lipophilicity of linkers. Molecular docking was conducted for virtual screening and followed by IC50 determination. Both BALB/c mice and P-16 xenografts were used for tissue distribution and PET/CT imaging. The ligand 68Ga-10c demonstrated high absorption in tumor 5 min after injection and sustains long-term imaging within 3 h. Furthermore, 68Ga-10c exhibited slow clearance within the tumor and was predominantly metabolized in both the liver and kidneys, showing the potential to alleviate metabolic pressure and enhance tissue safety. Therefore, the linker optimization strategy is well suited for CDK19 and provides a reference for the radioactive ligands of other nuclear targets.

Functional Screenings Identify Regulatory Variants Associated with Breast Cancer Susceptibility.

Genome-wide association studies (GWAS) have identified more than 2000 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, most of which are located in the non-coding region. However, the causal SNPs functioning as gene regulatory elements still remain largely undisclosed. Here, we applied a Dinucleotide Parallel Reporter sequencing (DiR-seq) assay to evaluate 288 breast cancer risk SNPs in nine different breast cancer cell lines. Further multi-omics analysis with the ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing), DNase-seq (DNase I hypersensitive sites sequencing) and histone modification ChIP-seq (Chromatin Immunoprecipitation sequencing) nominated seven functional SNPs in breast cancer cells. Functional investigations show that rs4808611 affects breast cancer progression by altering the gene expression of NR2F6. For the other site, rs2236007, the alteration promotes the binding of the suppressive transcription factor EGR1 and results in the downregulation of PAX9 expression. The downregulated expression of PAX9 causes cancer malignancies and is associated with the poor prognosis of breast cancer patients. Our findings contribute to defining the functional risk SNPs and the related genes for breast cancer risk prediction.

Anti-depressant effect of curcumin-loaded guanidine-chitosan thermo-sensitive hydrogel by nasal delivery.

Curcumin, a polyphenol compound extracted from the roots of turmeric plants, possesses anti-depressant effect by regulating the levels of neuroendocrine immunological factors. The purpose of this study was to investigate the anti-depressant effect of curcumin through nasal delivery. The results of phase solubility, Fourier transform infrared spectra, Differential scanning calorimetry, X-ray powder diffractometry and 1H NMR spectra assays showed that curcumin/hydroxypropyl-ß-cyclodextrin complex had been obtained. The viscosity of hydrogel increased rapidly at the temperature range of 29-30 °C through the test of rheological property of Guanidine-Chitosan thermo-sensitive hydrogel. And the hydrogel had good mucoadhesion properties. The cumulative release rate of curcumin was 55% in 10 h in vitro drug release test. Curcumin-loaded (14.6, 29.2, or 58.4 µg/kg) thermo-sensitive hydrogel could reduce the immobility time of mice in force swimming test and tail suspension test, while could not increase the independent behavioral activity of mice. In addition, curcumin-loaded (14.6, 29.2, or 58.4 µg/kg) thermo-sensitive hydrogel could increase the concentration of Norepinephrine, Dopamine, 5-Hydroxytryptamine and their metabolites in hippocampus and striatum. In conclusion, thermo-sensitive hydrogel delivery system can be seen as a promising formulation of curcumin for the treatment of depression through nasal delivery.

Therapeutic effect of liposomal prostaglandin E1 in acute lower limb ischemia as an adjuvant to hybrid procedures.

Prostaglandin E1 (PGE1) is widely used in the treatment of limb ischemia for its potent vasodilatory and antiplatelet effects. In order to assess the curative effect of liposomal PGE1 (lipo-PGE1) as an adjuvant to surgery in patients with acute lower limb ischemia (ALLI), 204 patients who underwent hybrid procedures (operative thromboembolectomy or bypass and necessary endovascular interventions) for ALLI were randomly divided into a blank control group and a lipo-PGE1 group (intravenous infusion of 20 µg/day for 12-14 consecutive days following surgery). Patients were followed-up for 6 months after surgical revascularization for clinical events. The primary study endpoint, which was the combined incidence of perioperative (30 days) mortality (POM) and major adverse limb events (MALE; amputation or major intervention), was significantly reduced in patients treated with lipo-PGE1 (5.1% compared with 13.2% in the control group). The overall incidence of clinical events, including POM, MALE and major adverse cardiovascular events, was significantly reduced in patients receiving lipo-PGE1 (8.2%) compared with the controls (20.8%). Hybrid procedures are an improved method for treating ALLI and may remedy underlying lesions of vessels following thromboembolectomy.