Resistance to Cancer Treatment: The Role of Somatic Genetic Events and the Challenges for Targeted Therapies

Therapeutic resistance remains a major cause of cancer-related deaths. Resistance can occur from the outset of treatment or as an acquired phenomenon after an initial clinical response. Therapeutic resistance is an almost universal phenomenon in the treatment of metastatic cancers. The advent of molecularly targeted treatments brought greater efficacy in patients whose tumors express a particular target or molecular signature. However, resistance remains a predictable challenge. This article provides an overview of somatic genomic events that confer resistance to cancer therapies. Some examples, including BCR–Abl, EML4–ALK, and the androgen receptor, contain mutations in the target itself, which hamper binding and inhibitory functions of therapeutic agents. There are also examples of somatic genetic changes in other genes or pathways that result in resistance by circumventing the inhibitor, as in resistance to trastuzumab and BRAF inhibitors. Yet other examples results in activation of cytoprotective genes. The fact that all of these mechanisms of resistance are due to somatic changes in the tumor’s genome makes targeting them selectively a feasible goal. To identify and validate these changes, it is important to obtain biopsies of clinically resistant tumors. A rational consequence of this evolving knowledge is the growing appreciation that combinations of inhibitors will be needed to anticipate and overcome therapeutic resistance

Proteomic analysis and candidate allergenic proteins in Populus deltoides CL. ‘2KEN8’ mature pollen

Proteomic analysis was used to generate a map of Populus deltoides CL. ‘2KEN8’ mature pollen proteins. By applying 2-D electrophoresis, we resolved 403 protein spots from mature pollen. Using the matrix-assisted laser desorption/ionization time time-of-flight/time-of-flight tandem mass spectrometry method, we identified 178 distinct proteins from 218 protein spots expressed in mature pollen. Moreover, out of these, 28 proteins were identified as putative allergens. The expression patterns of these putative allergen genes indicate that several of these genes are highly expressed in pollen. In addition, the members of profilin allergen family were analyzed and their expression patterns were compared with their homologous genes in Arabidopsis and rice. Knowledge of these identified allergens has the potential to improve specific diagnosis and allergen immunotherapy treatment for patients with poplar pollen allergy

Neurochemical properties of BDNF-containing neurons projecting to rostral ventromedial medulla in the ventrolateral periaqueductal gray

The periaqueductal gray (PAG) modulates nociception via a descending pathway that relays in the rostral ventromedial medulla (RVM) and terminates in the spinal cord. Previous behavioral pharmacology and electrophysiological evidence suggests that brain-derived neurotrophic factor (BDNF) plays an important role in descending pain modulation, likely through the PAG-RVM pathway. However, there still lacks detailed information on the distribution of BDNF, activation of BDNF-containing neurons projecting to RVM in the condition of pain, and neurochemical properties of these neurons within the PAG. Through fluorescent in situ hybridization (FISH) and immunofluorescent staining, the homogenous distributions of BDNF mRNA and protein were observed in the four subregions of PAG. Both neurons and astrocytes expressed BDNF, but not microglias. By combining retrograde tracing methods and formalin pain model, there were more BDNF-containing neurons projecting to RVM being activated in the ventrolateral PAG (vlPAG) than other subregions of PAG. The neurochemical properties of BDNF-containing projection neurons in the vlPAG were investigated. BDNF-containing projection neurons expressed auto receptor Tropomyosin-related kinase B (TrkB) in addition to serotonin (5-HT), neurotensin (NT), substance P (SP), calcitonin gene related peptide (CGRP), nitric oxide synthase (NOS), and parvalbumin (PV) but not tyrosine decarboxylase (TH). It is speculated that BDNF released from projection neurons in the vlPAG might participate in the descending pain modulation through enhancing the presynaptic release of other neuroactive substances (NSs) in the RVM

Metabolomics coupled with multivariate data and pathway analysis on potential biomarkers in cholestasis and intervention effect of Paeonia lactiflora Pall.

Background: The dried root of Paeonia lactiflora Pall. (PLP) is a classical Chinese herbal medicine that has been used to treat hepatic disease for thousands of years. Our previous work suggested that PLP can be used to treat hepatitis with severe cholestasis. This study explored the mechanism by which PLP affects ANIT-induced cholestasis in rats using a metabolomics approach.Methods: The effects of PLP on serum indices (TBIL, DBIL, AST, ALT, ALP and TBA) and the histopathology of the liver were analyzed. Moreover, UHPLC-Q-TOF was performed to identify the possible effect of PLP on metabolites. The pathway analysis was conducted to illustrate the pathways and network by which PLP treats cholestasis. Result: High-dose PLP remarkably down-regulated the serum indices and alleviated histological damage to the liver. Metabolomics analyses showed that the therapeutic effect of high-dose PLP is mainly associated with the regulation of several metabolites, such as glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, L(D)-arginine and L-tryptophan. A pathway analysis showed that the metabolites were related to bile acid secretion and amino acid metabolism. In addition, the significant changes in bile acid transporters also indicated that bile acid metabolism might be involved in the therapeutic effect of PLP on cholestasis. Moreover, a principal component analysis indicated that the metabolites in the high-dose PLP group were closer to those of the control, whereas those of the moderate dose or low-dose PLP group were closer to those of the ANIT group. This finding indicated that metabolites may be responsible for the differences between the effects of low-dose and moderate-dose PLP. Conclusions: The therapeutic effect of high-dose PLP on cholestasis is possibly related to regulation of bile acid secretion and amino acid metabolism. Moreover, these findings may help better understand the mechanisms of disease and provide a potential therapy for cholestasis