Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review.

Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Oncogenic mutations in the KRAS protein affect cellular proliferation and survival, leading to tumorigenesis through RAS/MAPK pathways. Until recently, only indirect targeting of the pathway had been investigated. There are now several KRAS allele-specific inhibitors in late-phase clinical trials, and many newer agents and targeting strategies undergoing preclinical and early-phase clinical testing. The adequate treatment of KRAS-mutated CRC will inevitably involve combination therapies due to the existence of robust adaptive resistance mechanisms in these tumors. In this article, we review the most recent understanding and findings related to targeting KRAS mutations in CRC, mechanisms of resistance to KRAS inhibitors, as well as evolving treatment strategies for KRAS-mutated CRC patients.

Psychometric Properties of the Reflective Function Questionnaire in Iranian Prisoners.

Reflective functioning is the process of reflecting on the thoughts and feelings of oneself and others and is foundational to healthy human relationships. The 54-item Reflective Function Questionnaire (RFQ) is a self-report measure that assesses reflective functioning, initially developed while studying individuals with borderline personality disorder (BPD) . The purpose of the present study was to translate the RFQ from English to Persian and evaluate its reliability and validity among Iranian prisoners. The sample of this study included 509 (455 men and 54 women) Iranian prisoners. Findings confirm the translated measure had acceptable face and content validity. A confirmatory factor analysis (CFA) confirmed two dimensions of certainty (RFQ-c) and uncertainty (RFQ-u) of reflective functioning. The correlation analysis showed positive relationships between the dimensions of the RFQ and the borderline personality symptoms questionnaire and the emotional dissatisfaction questionnaire. Correlation analysis also showed negative associations between the dimensions of the RFQ and the Toronto Basic Empathy Scale (BES) and the Kentucky Inventory of Mindfulness Skills (KIMS) questionnaire, confirming the concurrent validity of the RFQ. The Cronbach's alphas of the RFQ-c and RFQ-u subscales were .69 and .7 respectively, which demonstrated relatively acceptable internal consistency. The results of the analysis demonstrated that the translated RFQ had desirable psychometric properties for evaluating reflective function among Iranian prisoners.

Biological Effects of Gyrophoric Acid and Other Lichen Derived Metabolites, on Cell Proliferation, Apoptosis and Cell Signaling pathways.

Secondary metabolites from fungi, algae and lichens have remarkable biological activities as antibiotics, fungicides, antiviral drugs, and cancer therapeutics. This review focuses on the lichen-derived metabolite gyrophoric acid and other select secondary metabolites (e.g., usnic acid, salazinic acid, physodic acid, vulpinic acid ceratinalone, flavicansone, ramalin, physciosporin, tumidulin, atranorin, parmosidone) that modulate a number of cellular pathways relevant to several biomedical diseases and disorders, including cancer, diabetes and cardiovascular disease. We discuss the chemical structure and biochemical activities of gyrophoric acid and other compounds relative to the molecular mechanisms and cellular processes that these metabolites target in a distinct human and rodent cell types. The therapeutic promise of gyrophoric acid and similar lichen derived metabolites is associated with the chemical versatility of these compounds as polyaromatic depsides with functional carboxyl and hydroxyl side-groups that may permit selective interactions with distinct enzymatic active sites. Gyrophoric acid has been examined in a series of studies as an effective anticancer drug because it impinges on topoisomerase 1 activity, as well as causes cell cycle arrest, comprises cell survival, and promotes apoptosis. Because gyrophoric acid has cytostatic properties, its biological roles and possible medicinal utility may extend beyond effects on cancer cells and be relevant to any process that is controlled by cell growth and differentiation.

Lichenochemicals: extraction, purification, characterization, and application as potential anticancer agents.

Introduction: To date, over 1,000 lichen secondary metabolites have been identified. Despite their promising cytotoxic properties, the number of literature reports on anticancer evaluation of lichenochemicals is limited. As cancer prevalence among the human population increases, there is growing interest in lichens as a natural source of secondary metabolites for anti-cancer drug discovery and development.Areas covered: The lack of significant progress in lichen anticancer research is due to the low levels of cytotoxic compounds contained in lichens, the technical difficulties associated with their isolation and characterization, and the insufficient understanding of their mechanism of action on different cancer cell lines. In this review, the authors discuss these challenges and provide systematically organized information on the limitations and advantages of commonly used and newly developed methods for lichen exploration and screening of lichen secondary metabolites for their anticancer potential.Expert opinion: Recent research activities have demonstrated that lichen secondary metabolites possess chemotherapeutic properties. A systematic and multidisciplinary approach is required to advance lichen research and improve our understanding of the mechanisms responsible for the potent cytotoxic properties of lichenochemicals. More efforts need to focus on screening and discovery of new lichen-derived compounds with unique anticancer properties.

Feasibility study of sucrose and fat replacement using inulin and rebaudioside A in cake formulations.

Cake is a popular food around the world, however, it is considered as unhealthy due to its high fat and sucrose content. To satisfy customers' demand for a low fat and sucrose cake, in this research both sucrose and fat content of the cake were reduced by using rebaudioside A (Reb A; as a natural sucrose replacer) and inulin (as a natural fat replacer) at 0%, 25%, 50%, 75%, and 100%. The water content of different formulation was adjusted to obtain a constant batter viscosity similar to the control (3,757 cP). By reducing sucrose and fat content up to 50%, water activity increased and the cakes became more asymmetrical. However, other physical properties including baking weight loss, height, volume, crust color, and texture were similar to those of the control. Higher levels of replacement (75% and 100%) resulted in remarkable loss of different quality attributes. These samples showed higher water activity and baking loss, lower volume, harder texture, darker color, and highly asymmetrical shape. Thus, successful reduction of both fat and sucrose in cakes is possible by using inulin and Reb A at replacement levels no more than 50%. PRACTICAL APPLICATIONS: Customers' demand for healthy and yet tasty and high-quality foods is increasing around the world. Therefore, finding applicable and safe methods to produce such products is of great interest in the food manufacturing to satisfy customers. Health conscious customers avoid consumption of cakes because it contains high sucrose and fat content. Many studies have been performed to reduce either fat or sucrose content, while a few studies are available to show the reduction of both fat and sucrose in the same product. This study indicates the results of an applicable method to reduce fat and sucrose content of cakes simultaneously. Using rebaudioside A (as a natural sucrose replacer) and inulin (as a natural fat replacer) up to 50% of sucrose and fat content of cakes were reduced and the resulting cake had very similar physical properties to the control.

Effect of PEO coating on bubble behavior within a polycarbonate microchannel array: A model for hemodialysis.

Obstruction of fluid flow by stationary bubbles in a microchannel hemodialyzer decreases filtration performance and increases damage to blood cells through flow maldistribution. A polyethylene oxide (PEO)-polybutadiene (PB)-polyethylene oxide surface modification, previously shown to reduce protein fouling and water/air contact angle in polycarbonate microchannel hemodialyzers, can improve microchannel wettability and may reduce bubble stagnation by lessening the resistive forces that compete with fluid flow. In this study, the effect of the PEO-PB-PEO coating on bubble retention in a microchannel array was investigated. Polycarbonate microchannel surfaces were coated with PEO-PB-PEO triblock polymer via radiolytic grafting. Channel obstruction was measured for coated and uncoated microchannels after injecting a short stream of air bubbles into the device under average nominal water velocities of 0.9 to 7.2 cm/s in the channels. The presence of the PEO coating reduced obstruction of microchannels by stationary bubbles within the range of 1.8 to 3.6 cm/s, average nominal velocity. Numerical simulations based on the lattice Boltzmann method indicate that beneficial effects may be due to the maintenance of a lubricating, thin liquid film around the bubble. The determined effective range of the PEO coating for bubble management serves as an important design constraint. These findings serve to validate the multiutility of the PEO-PB-PEO coating (bubble lubrication, biocompatibility, and therapeutic loading). © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 941-948, 2016.

The Role of Contact Line (Pinning) Forces on Bubble Blockage in Microchannels.

This paper highlights the influence of contact line (pinning) forces on the mobility of dry bubbles in microchannels. Bubbles moving at velocities less than the dewetting velocity of liquid on the surface are essentially dry, meaning that there is no thin liquid film around the bubbles. For these "dry" bubbles, contact line forces and a possible capillary pressure gradient induced by pinning act on the bubbles and resist motion. Without sufficient driving force (e.g., external pressure), a dry bubble is brought to stagnation. For the first time, a bipartite theoretical model that estimates the required pressure difference across the length of stagnant bubbles with concave and convex back interfaces to overcome the contact line forces and stimulate motion is proposed. To validate our theory, the pressure required to move a single dry bubble in square microchannels exhibiting contact angle hysteresis has been measured. The working fluid was deionized water. The experiments have been conducted on coated glass channels with different surface hydrophilicities that resulted in concave and convex back interfaces for the bubbles. The experimental results were in agreement with the model's predictions for square channels. The predictions of the concave and convex back models were within 19% and 27% of the experimental measurements, respectively.

Experimental Techniques for Bubble Dynamics Analysis in Microchannels: A Review.

Experimental studies employing advanced measurement techniques have played an important role in the advancement of two-phase microfluidic systems. In particular, flow visualization is very helpful in understanding the physics of two-phase phenomenon in microdevices. The objective of this article is to provide a brief but inclusive review of the available methods for studying bubble dynamics in microchannels and to introduce prior studies, which developed these techniques or utilized them for a particular microchannel application. The majority of experimental techniques used for characterizing two-phase flow in microchannels employs high-speed imaging and requires direct optical access to the flow. Such methods include conventional brightfield microscopy, fluorescent microscopy, confocal scanning laser microscopy, and micro particle image velocimetry (micro-PIV). The application of these methods, as well as magnetic resonance imaging (MRI) and some novel techniques employing nonintrusive sensors, to multiphase microfluidic systems is presented in this review.