Case Report: Successful Use of BRAF/MEK Inhibitors in Aggressive BRAF-mutant Craniopharyngioma.

BACKGROUND: Although a benign intracranial tumor, craniopharyngioma treatment has always been considered a challenging clinical problem. Recently, BRAF V600E mutation in the pathogenesis of papillary craniopharyngioma (PCP) has been further revealed. Thus, BRAF inhibitors (BRAFi) serve as an applicable treatment for patients with PCP. METHODS: Two patients with recurrent PCP were treated with combined BRAFi dabrafenib (150 mg, orally twice daily) and MEK inhibitors (MEKi) trametinib (2 mg, orally twice daily). A follow-up exceeding 2 years was conducted. We meticulously scrutinized the treatment's safety and efficacy profiles by delving into existing literature. RESULTS: One patient harboring a solid tumor achieved a complete tumor response devoid of any adverse events and encountered no recurrence over 2 years subsequent to discontinuation. Moreover, within a mere month of commencing targeted therapy, the tumor demonstrated observable shrinkage. This finding substantiates the considerable potential inherent in targeted therapy for PCP cases marked by the somatic BRAF V600E mutation. CONCLUSIONS: Under specific conditions, individuals diagnosed with PCP can attain a complete tumor response following combined treatment with BRAFi/MEKi.

UPLC-QE-Orbitrap-Based Cell Metabolomics and Network Pharmacology to Reveal the Mechanism of N-Benzylhexadecanamide Isolated from Maca (Lepidium meyenii Walp.) against Testicular Dysfunction.

Testicular dysfunction (TDF) is characterized by testosterone deficiency and is caused by oxidative stress injury in Leydig cells. A natural fatty amide named N-benzylhexadecanamide (NBH), derived from cruciferous maca, has been shown to promote testosterone production. Our study aims to reveal the anti-TDF effect of NBH and explore its potential mechanism in vitro. This study examined the effects of H2O2 on cell viability and testosterone levels in mouse Leydig cells (TM3) under oxidative stress. In addition, cell metabolomics analysis based on UPLC-Q-Exactive-MS/MS showed that NBH was mainly involved in arginine biosynthesis, aminoacyl-tRNA biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, the TCA cycle and other metabolic pathways by affecting 23 differential metabolites, including arginine and phenylalanine. Furthermore, we also performed network pharmacological analysis to observe the key protein targets in NBH treatment. The results showed that its role was to up-regulate ALOX5, down-regulate CYP1A2, and play a role in promoting testicular activity by participating in the steroid hormone biosynthesis pathway. In summary, our study not only provides new insights into the biochemical mechanisms of natural compounds in the treatment of TDF, but also provides a research strategy that integrates cell metabolomics and network pharmacology in order to promote the screening of new drugs for the treatment of TDF.

Screening of the Active Compounds against Neural Oxidative Damage from Ginseng Phloem Using UPLC-Q-Exactive-MS/MS Coupled with the Content-Effect Weighted Method.

The neuroprotective properties of ginsenosides have been found to reverse the neurological damage caused by oxidation in many neurodegenerative diseases. However, the distribution of ginsenosides in different tissues of the main root, which was regarded as the primary medicinal portion in clinical practice was different, the specific parts and specific components against neural oxidative damage were not clear. The present study aims to screen and determine the potential compounds in different parts of the main root in ginseng. Comparison of the protective effects in the main root, phloem and xylem of ginseng on hydrogen peroxide-induced cell death of SH-SY5Y neurons was investigated. UPLC-Q-Exactive-MS/MS was used to quickly and comprehensively characterize the chemical compositions of the active parts. Network pharmacology combined with a molecular docking approach was employed to virtually screen for disease-related targets and potential active compounds. By comparing the changes before and after Content-Effect weighting, the compounds with stronger anti-nerve oxidative damage activity were screened out more accurately. Finally, the activity of the selected monomer components was verified. The results suggested that the phloem of ginseng was the most effective part. There were 19 effective compounds and 14 core targets, and enriched signaling pathway and biological functions were predicted. After Content-Effect weighting, compounds Ginsenosides F1, Ginsenosides Rf, Ginsenosides Rg1 and Ginsenosides Rd were screened out as potential active compounds against neural oxidative damage. The activity verification study indicated that all four predicted ginsenosides were effective in protecting SH-SY5Y cells from oxidative injury. The four compounds can be further investigated as potential lead compounds for neurodegenerative diseases. This also provides a combined virtual and practical method for the simple and rapid screening of active ingredients in natural products.

Expression and clinical significance of VISTA, B7-H3, and PD-L1 in glioma.

Immune checkpoint (IC) therapy has led to a breakthrough in cancer treatment. However, the interaction of ICs is controversial in glioma. We detected features of ICs using transcriptome data and a multicolor immunofluorescence assay. We discovered that B7-H3 increased with grade and age and predicted worse overall survival (OS) at the transcriptional and proteomic levels. VISTA and PD-L1 were associated with OS and grade at the RNA level. At the protein level, VISTA was primarily expressed in tumor cells and TAMs. B7-H3 and VISTA were positively correlated with PD-L1. There was a strong correlation between PD-L1 and CD3 and between VISTA and IBA-1. PD-L1 was coexpressed with T cells. VISTA was coexpressed with TAMs. In T cells, we found a strong correlation in ICs, which worsened in TAMs and tumor cells. In conclusion, B7-H3 is a vital prognostic target for immunotherapy. We provided a potential mechanism for the immunosuppressive microenvironment in glioma.

[Targeted Drug Therapy for Intracranial Tumors].

Intracranial tumors seriously affect the physical and mental health of humans. Due to variations in the nature and the growth site of tumors, individualized and specific treatment of patients with intracranial tumor has become a hotspot topic of research, and targeted drug therapy of intracranial tumors, an important subspecialty of precision medicine, has become a key issue that scientists are working hard to tackle. At present, the rapid development in molecular biology and genomics has provided corresponding targets for precision therapies of tumors. However, the blood-brain barrier and blood-tumor barrier prevent drugs from reaching intracranial targets. Therefore, finding effective ways to elevate the concentration of intracranial drugs has become the key issue concerning existing targeted therapies for intracranial tumors. Herein, we reviewed the current status of targeted drug therapy for different intracranial tumors and discussed their efficacy, intending to provide new perspectives for the treatment of intracranial tumors with targeted drugs in the future.

Predicting the druggability of protein-protein interactions based on sequence and structure features of active pockets.

Protein-protein interactions (PPIs) are becoming highly attractive targets for drug discovery. Motivated by the rapid accumulation of PPI data in public database and the success stories concerning the targeting of PPIs, a machine-learning method based on sequence and structure properties was developed to access the druggability of PPIs. Here, a comprehensive non-redundant set of 34 druggable and 122 less druggable PPIs were firstly presented from the perspective of pockets. When tested by outer 5-fold cross-validation, the most representative model in discriminating the druggable PPIs from the less-druggable ones yielded an average accuracy of 88.24% (sensitivity of 82.38% and specificity of 92.00%). Moreover, a promising result was also obtained for the independent test set. Compared to other methods, the method gives a comparative performance, which is most likely due to the construction of a training set that encompasses less druggable PPIs and also the information of active pockets that have evolved to bind a natural ligand.