NSCLC as the Paradigm of Precision Medicine at Its Finest: The Rise of New Druggable Molecular Targets for Advanced Disease

Standard treatment for advanced non-small cell lung cancer (NSCLC) historically consisted of systemic cytotoxic chemotherapy until the early 2000s, when precision medicine led to a revolutionary change in the therapeutic scenario. The identification of oncogenic driver mutations in EGFR, ALK and ROS1 rearrangements identified a subset of patients who largely benefit from targeted agents. However, since the proportion of patients with druggable alterations represents a minority, the discovery of new potential driver mutations is still an urgent clinical need. We provide a comprehensive review of the emerging molecular targets in NSCLC and their applications in the advanced setting.     

Profile of TREM2-Derived circRNA and mRNA Variants in the Entorhinal Cortex of Alzheimer’s Disease Patients

Genetic variants in TREM2, a microglia-related gene, are well-known risk factors for Alzheimer’s disease (AD). Here, we report that TREM2 originates from circular RNAs (circRNAs), a novel class of non-coding RNAs characterized by a covalent and stable closed-loop structure. First, divergent primers were designed to amplify circRNAs by RT-PCR, which were further assessed by Sanger sequencing. Then, additional primer sets were used to confirm back-splicing junctions. In addition, HMC3 cells were used to assess the microglial expression of circTREM2s. Three candidate circTREM2s were identified in control and AD human entorhinal samples. One of the circRNAs, circTREM2_1, was consistently amplified by all divergent primer sets in control and AD entorhinal cortex samples as well as in HMC3 cells. In AD cases, a moderate negative correlation (r = −0.434) was found between the global average area of Aβ deposits in the entorhinal cortex and circTREM2_1 expression level. In addition, by bioinformatics tools, a total of 16 miRNAs were predicted to join with circTREM2s. Finally, TREM2 mRNA corresponding to four isoforms was profiled by RT-qPCR. TREM2 mRNA levels were found elevated in entorhinal samples of AD patients with low or intermediate ABC scores compared to controls. To sum up, a novel circRNA derived from the TREM2 gene, circTREM2_1, has been identified in the human entorhinal cortex and TREM2 mRNA expression has been detected to increase in AD compared to controls. Unraveling the molecular genetics of the TREM2 gene may help to better know the innate immune response in AD.     

Effects of the Treatment with Flavonoids on Metabolic Syndrome Components in Humans: A Systematic Review Focusing on Mechanisms of Action

Diets high in bioactive compounds, such as polyphenols, have been used to mitigate metabolic syndrome (MetS). Polyphenols are a large group of naturally occurring bioactive compounds, classified into two main classes: non-flavonoids and flavonoids. Flavonoids are distributed in foods, such as fruits, vegetables, tea, red wine, and cocoa. Studies have already demonstrated the benefits of flavonoids on the cardiovascular and nervous systems, as well as cancer cells. The present review summarizes the results of clinical studies that evaluated the effects of flavonoids on the components of the MetS and associated complications when offered as supplements over the long term. The results show that flavonoids can significantly modulate several metabolic parameters, such as lipid profile, blood pressure, and blood glucose. Only theaflavin and catechin were unable to affect metabolic parameters. Moreover, only body weight and body mass index were unaltered. Thus, the evidence presented in this systematic review offers bases in support of a flavonoid supplementation, held for at least 3 weeks, as a strategy to improve several metabolic parameters and, consequently, reduce the risk of diseases associated with MetS. This fact becomes stronger due to the rare side effects reported with flavonoids.     

A cytosolic activity distinct from crm1 mediates nuclear export of protein kinase inhibitor in permeabilized cells

The leucine-rich nuclear export signal (NES) is used by a variety of proteins to facilitate their delivery from the nucleus to the cytoplasm. One of the best-studied examples, protein kinase inhibitor (PKI), binds to the catalytic subunit of protein kinase A in the nucleus and mediates its rapid export to the cytoplasm. We developed a permeabilized cell assay that reconstitutes nuclear export mediated by PKI, and we used it to characterize the cytosolic factors required for this process. The two-step assay involves an import phase and an export phase, and quantitation is achieved by digital fluorescence microscopy. During the import phase, a fluorescent derivative of streptavidin is imported into the nuclei of digitonin-permeabilized HeLa cells. During the export phase, biotinylated PKI diffuses into the nucleus, binds to fluorescent streptavidin, and mediates export of the complex to the cytoplasm. Nuclear export of the PKI complex is cytosol dependent and can be stimulated by addition of the purified NES receptor, Crm1. HeLa cell cytosol treated with N-ethylmaleimide (NEM) or phenyl-Sepharose to inactivate or deplete Crm1, respectively, is still fully active in the PKI export assay. Significantly, the export activity can be depleted from cytosol by preadsorption with a protein conjugate that contains a functional NES. These data indicate that cytosol contains an export activity that is distinct from Crm1 and is likely to correspond to an NES receptor.     

Antitumor effect of plant lectins

BACKGROUND: Staff development experts in a tertiary-care hospital were searching for a holistic approach to facilitating improved outcomes. METHOD: Staff development experts, clinical nurse specialists, and clinical managers developed a model that provides a framework for educators to integrate their energies with those of other leaders in order to create a holistic approach to the goal of achieving excellence. RESULTS: The model that is proposed links strategies for change with outcome evaluation. CONCLUSIONS: The model provides a conceptual lens that helps nurse leaders focus on organizational assessment, strategies to improve the work environment, and the evaluation of outcomes. The model is useful for guiding practice as well as research.     

List partitions

By definition, apartition of a list is a division of that list into nonempty contiguous segments. Many programming and operations research problems can be specified in terms of list partitions, and we present a hierarchy of theorems for deriving programs from such specifications. Throughout, reasoning is conducted in an equational style using the calculus for program synthesis developed by Bird and Meertens.Supported by a BP research studentship.     

A new look at British graduate students.

Discusses findings of a survey of British graduate students in psychology conducted in late 1972 and 1973. Responses were obtained from 34 of the 89 British departments offering advanced courses or supervision for research leading to the PhD in psychology or one of its subspecialties. The total enrollment of all postbaccalaureate students in psychology was 1,112, but only 277 of these were in PhD programs; the number is almost 8 times higher in the US. UK postgraduate training in psychology seems to be conducted on a much smaller scale than in the US, the students enter doctoral training at an earlier age than American students, and females and non-White minority students are well represented in UK doctoral training programs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A Second Life for MAP,a Model Amphipathic Peptide

Cell-penetrating peptides (CPP) have been shown to be efficient in the transport of cargoes into the cells, namely siRNA and DNA, proteins and peptides, and in some cases, small therapeutics. These peptides have emerged as a solution to increase drug concentrations in different tissues and various cell types, therefore having a relevant therapeutic relevance which led to clinical trials. One of them, MAP, is a model amphipathic peptide with an α-helical conformation and both hydrophilic and hydrophobic residues in opposite sides of the helix. It is composed of a mixture of alanines, leucines, and lysines (KLALKLALKALKAALKLA). The CPP MAP has the ability to translocate oligonucleotides, peptides and small proteins. However, taking advantage of its unique properties, in recent years innovative concepts were developed, such as in silico studies of modelling with receptors, coupling and repurposing drugs in the central nervous system and oncology, or involving the construction of dual-drug delivery systems using nanoparticles. In addition to designs of MAP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy, this review will be focused on unique molecular structure and how it determines its cellular activity, and also intends to address the most recent and frankly motivating issues for the future.     

Molecular Dynamics of CYFIP2 Protein and Its R87C Variant Related to Early Infantile Epileptic Encephalopathy

The CYFIP2 protein (cytoplasmic FMR1-interacting protein 2) is part of the WAVE regulatory complex (WRC). CYFIP2 was recently correlated to neurological disorders by the association of the R87C variant with early infantile epileptic encephalopathy (EIEE) patients. In this set of syndromes, the epileptic spasms and seizures since early childhood lead to impaired neurological development in children. Inside the WRC, the variant residue is at the CYFIP2 and WAVE1 protein interface. Thus, the hypothesis is that the R87C modification weakens this interaction, allowing the WRC complex’s constant activation. This work aimed to investigate the impacts of the mutation on the structure of the WRC complex through molecular dynamics simulation. For that, we constructed WRC models containing WAVE1-NCKAP1 proteins complexed with WT or R87C CYFIP2. Our simulations showed a flexibilization of the loop comprising residues 80–110 due to the loss of contacts between internal residues in the R87C CYFIP2 as well as the key role of residues R/C87, E624, and E689 in structural modification. These data could explain the mechanism by which the mutation impairs the stability and proper regulation of the WRC.