ABSTRACT
Deciphering cell-intrinsic mechanisms of metastasis progression in vivo is essential to identify novel therapeutic approaches. Here we elucidate cell-intrinsic drivers of metastatic prostate cancer progression through analyses of genetically engineered mouse models (GEMM) and correlative studies of human prostate cancer. Expression profiling of lineage-marked cells from mouse primary tumors and metastases defines a signature of de novo metastatic progression. Cross-species master regulator analyses comparing this mouse signature with a comparable human signature identifies conserved drivers of metastatic progression with demonstrable clinical and functional relevance. In particular, nuclear receptor binding SET Domain Protein 2 (NSD2) is robustly expressed in lethal prostate cancer in humans, while its silencing inhibits metastasis of mouse allografts in vivo. We propose that cross-species analysis can elucidate mechanisms of metastasis progression, thus providing potential additional therapeutic opportunities for treatment of lethal prostate cancer.
Subject(s)
Histone-Lysine N-Methyltransferase/metabolism , Prostatic Neoplasms/metabolism , Repressor Proteins/metabolism , Animals , Cell Line, Tumor , Disease Progression , Gene Expression Regulation, Neoplastic , Gene Silencing , Histone-Lysine N-Methyltransferase/genetics , Humans , Male , Mice , Mice, Nude , Neoplasm Metastasis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Repressor Proteins/geneticsABSTRACT
PURPOSE OF REVIEW: An important number of newly identified molecular alterations in prostate cancer affect gene encoding master regulators of chromatin biology epigenetic regulation. This review will provide an updated view of the key epigenetic mechanisms underlying prostate cancer progression, therapy resistance, and potential actionable mechanisms and biomarkers. RECENT FINDINGS: Key players in chromatin biology and epigenetic master regulators has been recently described to be crucially altered in metastatic CRPC and tumors that progress to AR independency. As such, epigenetic dysregulation represents a driving mechanism in the reprograming of prostate cancer cells as they lose AR-imposed identity. SUMMARY: Chromatin integrity and accessibility for transcriptional regulation are key features altered in cancer progression, and particularly relevant in nuclear hormone receptor-driven tumors like prostate cancer. Understanding how chromatin remodeling dictates prostate development and how its deregulation contributes to prostate cancer onset and progression may improve risk stratification and treatment selection for prostate cancer patients.
ABSTRACT
The study of adverse drug reactions (ADRs) constitutes a challenge in the area of Medicine. Drugs generate a large number of the total registered hypersensitivity reactions, where penicillins are responsible for more than half of them. In vitro tests in the market are not efficient enough since they lack in sensitivity and specificity. This is the reason why in vivo tests are carried out, with the subsequent danger to the patient's life. It is essential to discover new ß-lactam antigenic determinants to develop more effective detection systems and thus, obtain better explanations of the allergic mechanisms related to these drugs. We propose a strategy based on the use of "peptide probes", small labeled and chemical active peptides which have been structurally modified for reacting with the ß-lactam moiety at different conditions. The probes also contain a biotin group for application in an immunoassay format. Three different amoxicillin adducts have been obtained, purified and characterized by HPLC-MS and NMR techniques. These results have helped us to elucidate and propose a new antigenic determinant for ß-lactams, named the "penamidyl" epitope. All the adducts have been validated and evaluated with sera from different penicillin allergic patients by means of a Magneto-ELISA, immunochemical technique that has allowed us to detect specific IgEs in a very high percentage of the serum samples. An immunoassay has been developed, validated and applied as a diagnostic tool for the detection of specific IgEs in the sera of penicillin allergic patients using a new antigenic determinant.
Subject(s)
Anti-Bacterial Agents/immunology , Epitopes/immunology , Hypersensitivity, Immediate/immunology , Penicillins/immunology , Amoxicillin/immunology , Drug-Related Side Effects and Adverse Reactions/immunology , Humans , Immunoassay/methods , Immunoglobulin E/immunology , Sensitivity and Specificity , beta-Lactams/immunologyABSTRACT
With the worldwide use of penicillin antibiotics comes the need for tighter controls. Bacterial resistance is a genuine problem and governmental and international bodies, for example the European Medicines Agency (EMA) and the World Health Organization (WHO), have designed strategies to overcome this unfortunate consequence of antibiotic use. Foodstuffs are monitored to ensure they contain very low quantities of antibiotics, so they are not prejudicial to health and the environment. Detection is based on chromatographic methods. However, screening can be performed by use of simpler, rapid methods of detection, e.g. microbial inhibition test, lateral flow assays, immunoassays, and use of biosensors, to reduce the final number of samples to be analyzed by chromatography. In this review, we have gathered information regarding all such screening methods for the penicillins and have critically assessed their capability and specificity for detection of penicillins.
