Hypercholesterolemia in Cancer and in Anorexia Nervosa: A Hypothesis for a Crosstalk

The relationship between cholesterol and cancer has been widely demonstrated. Clinical studies have shown changes in blood cholesterol levels in cancer patients. In parallel, basic research studies have shown that cholesterol is involved in the mechanisms of onset and progression of the disease. On the other hand, anorexic patients have high cholesterol levels and a high susceptibility to cancer. In this review, we first present a brief background on the relations among nutrition, eating disorders and cancer. Using several notable examples, we then illustrate the changes in cholesterol in cancer and in anorexia nervosa, providing evidence for their important relationship. Finally, we show a new possible link between cholesterol disorder in cancer and in anorexia nervosa.     

Design,dynamic modelling and experimental validation of a 2DOF flexible antenna sensor

A two-degree-of-freedom flexible antenna sensor platform was designed to physically simulate the ability of a robotic arm, which rapidly reorients and targets itself towards specific surfaces from different approachable angles. An accurate antenna model involves non-linear expressions that represent the system dynamics. Therefore, a comprehensive study along with experimental work has been carried out in order to achieve accurate system identification and validate the dynamic model. The model developed has proven useful in controlling the antenna tip, minimising the effects of the non-linear flexural dynamics and the Coulomb friction. The system was driven by servo motors. Algebraic controllers were developed for the antenna tip to track the reference trajectory. The platform system used encoders to measure the joint angles and a loadcell sensor to obtain the flexible link tip position. To validate the sensory information, the results obtained by the integrated sensors were compared to that of an external camera system.     

Formulations for an inventory routing problem

In this paper, we present and compare formulations for the inventory routing problem (IRP) where the demand of customers has to be served, over a discrete time horizon, by capacitated vehicles starting and ending their routes at a depot. The objective of the IRP is the minimization of the sum of inventory and transportation costs. The formulations include known and new mathematical programming formulations. Valid inequalities are also presented. The formulations are tested on a large set of benchmark instances. One of the most significant conclusions is that the formulations that use vehicle‐indexed variables are superior to the more compact, aggregate formulations.     

Chronic Hyperkaliemia in Chronic Kidney Disease: An Old Concern with New Answers

Increasing potassium intake ameliorates blood pressure (BP) and cardiovascular (CV) prognoses in the general population; therefore the World Health Organization recommends a high-potassium diet (90–120 mEq/day). Hyperkalaemia is a rare condition in healthy individuals due to the ability of the kidneys to effectively excrete dietary potassium load in urine, while an increase in serum K⁺ is prevalent in patients with chronic kidney disease (CKD). Hyperkalaemia prevalence increases in more advanced CKD stages, and is associated with a poor prognosis. This scenario generates controversy on the correct nutritional approach to hyperkalaemia in CKD patients, considering the unproven link between potassium intake and serum K⁺ levels. Another concern is that drug-induced hyperkalaemia leads to the down-titration or withdrawal of renin-angiotensin system inhibitors (RASI) and mineralocorticoids receptors antagonists (MRA) in patients with CKD, depriving these patients of central therapeutic interventions aimed at delaying CKD progression and decreasing CV mortality. The new K⁺-binder drugs (Patiromer and Sodium-Zirconium Cyclosilicate) have proven to be adequate and safe therapeutic options to control serum K⁺ in CKD patients, enabling RASI and MRA therapy, and possibly, a more liberal intake of fruit and vegetables.     

The β2-Subunit (AMOG) of Human Na+, K+-ATPase Is a Homophilic Adhesion Molecule

The β₂ subunit of Na⁺, K⁺-ATPase was originally identified as the adhesion molecule on glia (AMOG) that mediates the adhesion of astrocytes to neurons in the central nervous system and that is implicated in the regulation of neurite outgrowth and neuronal migration. While β₁ isoform have been shown to trans-interact in a species-specific mode with the β₁ subunit on the epithelial neighboring cell, the β₂ subunit has been shown to act as a recognition molecule on the glia. Nevertheless, none of the works have identified the binding partner of β₂ or described its adhesion mechanism. Until now, the interactions pronounced for β₂/AMOG are heterophilic cis-interactions. In the present report we designed experiments that would clarify whether β₂ is a cell–cell homophilic adhesion molecule. For this purpose, we performed protein docking analysis, cell–cell aggregation, and protein–protein interaction assays. We observed that the glycosylated extracellular domain of β₂/AMOG can make an energetically stable trans-interacting dimer. We show that CHO (Chinese Hamster Ovary) fibroblasts transfected with the human β₂ subunit become more adhesive and make large aggregates. The treatment with Tunicamycin in vivo reduced cell aggregation, suggesting the participation of N-glycans in that process. Protein–protein interaction assay in vivo with MDCK (Madin-Darby canine kidney) or CHO cells expressing a recombinant β₂ subunit show that the β₂ subunits on the cell surface of the transfected cell lines interact with each other. Overall, our results suggest that the human β₂ subunit can form trans-dimers between neighboring cells when expressed in non-astrocytic cells, such as fibroblasts (CHO) and epithelial cells (MDCK).     

Three-dimensional segmentation and growth-rate estimation of small pulmonary nodules in helical CT images

Small pulmonary nodules are a common radiographic finding that presents an important diagnostic challenge in contemporary medicine. While pulmonary nodules are the major radiographic indicator of lung cancer, they may also be signs of a variety of benign conditions. Measurement of nodule growth rate over time has been shown to be the most promising tool in distinguishing malignant from nonmalignant pulmonary nodules. In this paper, we describe three-dimensional (3-D) methods for the segmentation, analysis, and characterization of small pulmonary nodules imaged using computed tomography (CT). Methods for the isotropic resampling of anisotropic CT data are discussed. 3-D intensity and morphology-based segmentation algorithms are discussed for several classes of nodules. New models and methods for volumetric growth characterization based on longitudinal CT studies are developed. The results of segmentation and growth characterization methods based on in vivo studies are described. The methods presented are promising in their ability to distinguish malignant from nonmalignant pulmonary nodules and represent the first such system in clinical use.     

Fighting the Huntington’s Disease with a G-Quadruplex-Forming Aptamer Specifically Binding to Mutant Huntingtin Protein: Biophysical Characterization,In Vitro and In Vivo Studies

A set of guanine-rich aptamers able to preferentially recognize full-length huntingtin with an expanded polyglutamine tract has been recently identified, showing high efficacy in modulating the functions of the mutated protein in a variety of cell experiments. We here report a detailed biophysical characterization of the best aptamer in the series, named MS3, proved to adopt a stable, parallel G-quadruplex structure and show high nuclease resistance in serum. Confocal microscopy experiments on HeLa and SH-SY5Y cells, as models of non-neuronal and neuronal cells, respectively, showed a rapid, dose-dependent uptake of fluorescein-labelled MS3, demonstrating its effective internalization, even in the absence of transfecting agents, with no general cytotoxicity. Then, using a well-established Drosophila melanogaster model for Huntington’s disease, which expresses the mutated form of human huntingtin, a significant improvement in the motor neuronal function in flies fed with MS3 was observed, proving the in vivo efficacy of this aptamer.     

Leptin Signaling in Obesity and Colorectal Cancer

Obesity and colorectal cancer (CRC) are among the leading diseases causing deaths in the world, showing a complex multifactorial pathology. Obesity is considered a risk factor in CRC development through inflammation, metabolic, and signaling processes. Leptin is one of the most important adipokines related to obesity and an important proinflammatory marker, mainly expressed in adipose tissue, with many genetic variation profiles, many related influencing factors, and various functions that have been ascribed but not yet fully understood and elucidated, the most important ones being related to energy metabolism, as well as endocrine and immune systems. Aberrant signaling and genetic variations of leptin are correlated with obesity and CRC, with the genetic causality showing both inherited and acquired events, in addition to lifestyle and environmental risk factors; these might also be related to specific pathogenic pathways at different time points. Moreover, mutation gain is a crucial factor enabling the genetic process of CRC. Currently, the inconsistent and insufficient data related to leptin’s relationship with obesity and CRC indicate the necessity of further related studies. This review summarizes the current knowledge on leptin genetics and its potential relationship with the main pathogenic pathways of obesity and CRC, in an attempt to understand the molecular mechanisms of these associations, in the context of inconsistent and contradictory data. The understanding of these mechanisms linking obesity and CRC could help to develop novel therapeutic targets and prevention strategies, resulting in a better prognosis and management of these diseases.     

Targeting CD10 on B-Cell Leukemia Using the Universal CAR T-Cell Platform (UniCAR)

Chimeric antigen receptor (CAR)-expressing T-cells are without a doubt a breakthrough therapy for hematological malignancies. Despite their success, clinical experience has revealed several challenges, which include relapse after targeting single antigens such as CD19 in the case of B-cell acute lymphoblastic leukemia (B-ALL), and the occurrence of side effects that could be severe in some cases. Therefore, it became clear that improved safety approaches, and targeting multiple antigens, should be considered to further improve CAR T-cell therapy for B-ALL. In this paper, we address both issues by investigating the use of CD10 as a therapeutic target for B-ALL with our switchable UniCAR system. The UniCAR platform is a modular platform that depends on the presence of two elements to function. These include UniCAR T-cells and the target modules (TMs), which cross-link the T-cells to their respective targets on tumor cells. The TMs function as keys that control the switchability of UniCAR T-cells. Here, we demonstrate that UniCAR T-cells, armed with anti-CD10 TM, can efficiently kill B-ALL cell lines, as well as patient-derived B-ALL blasts, thereby highlighting the exciting possibility for using CD10 as an emerging therapeutic target for B-cell malignancies.