The role of S100 proteins and their receptor RAGE in pancreatic cancer

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is a devastating disease with low survival rates. Current therapeutic treatments have very poor response rates due to the high inherent chemoresistance of the pancreatic-cancer cells. Recent studies have suggested that the receptor for advanced glycation end products (RAGE) and its S100 protein ligands play important roles in the progression of PDAC. We will discuss the potential role of S100 proteins and their receptor, RAGE, in the development and progression of pancreatic cancer

The role of S100 proteins and their receptor RAGE in pancreatic cancer

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is a devastating disease with low survival rates. Current therapeutic treatments have very poor response rates due to the high inherent chemoresistance of the pancreatic-cancer cells. Recent studies have suggested that the receptor for advanced glycation end products (RAGE) and its S100 protein ligands play important roles in the progression of PDAC. We will discuss the potential role of S100 proteins and their receptor, RAGE, in the development and progression of pancreatic cancer

The S100B/RAGE Axis in Alzheimer's Disease

Increasing evidence suggests that the small EF-hand calcium-binding protein S100B plays an important role in Alzheimer's disease. Among other evidences are the increased levels of both S100B and its receptor, the Receptor for Advanced Glycation Endproducts (RAGEs) in the AD diseased brain. The regulation of RAGE signaling by S100B is complex and probably involves other ligands including the amyloid beta peptide (Aβ), the Advanced Glycation Endproducts (AGEs), or transtheyretin. In this paper we discuss the current literature regarding the role of S100B/RAGE activation in Alzheimer's disease

Using Tumor-Like Spheroids to Study the Effect of Anti-Cancer Drugs <em>in vitro</em>

Cell culture techniques have evolved in the last decades and allow now testing anti-cancer drugs using tumor-like spheroids. We describe here issues and trouble-shooting solutions when generating spheroids from three human melanoma cell lines (A375, WM115 and WM266). A375 cells generated irregular shape spheroids that were difficult to study due to their fragility. Spheroids generated from all cell lines initially reduced their diameter and increased compacity before increasing in size overtime. Cells present at the periphery of the spheroids showed higher metabolic activity than cells present in the core of the spheroids. When grown as spheroids, a smaller fraction of the A375 and WM115 cells was sensitive to the chemotherapeutic agent temozolomide as compared to cells grown on flat surface. However, this difference was not observed with WM266 cells. Although the presence of spheroids resulted in a smaller fraction of WM155 cells sensitive to the anti-cancer agent vemurafenib, the opposite was observed with A375 cells. Among the cells, WM266 cells were the most resistant to vemurafenib. In conclusion, our study suggests that cell lines behave differently in terms of spheroid formation, and that the effect of the 3D cellular architecture on drug effect is cell type and drug dependent

Virtual Reality Human-Human Interface to Deliver Psychotherapy to People Experiencing Auditory Verbal Hallucinations: Development and Usability Study

BACKGROUND Digital technologies have expanded the options for delivering psychotherapy, permitting for example, the treatment of schizophrenia using Avatar Therapy. Despite its considerable potential, this treatment method has not been widely disseminated. As a result, its operability and functionality remain largely unknown. OBJECTIVE We aimed to study the usability of a therapeutic virtual reality human-human interface, created in a game engine. METHODS Participants were psychiatric hospital staff who were introduced to the therapeutic platform in a hands-on session. The System Usability Scale (SUS) was employed for evaluation purposes. Statistical evaluation was conducted using descriptive statistics, the chi-square test, analysis of variance, and multilevel factor analysis. RESULTS In total, 109 staff members were introduced to the therapeutic tool and completed the SUS. The mean SUS global score was 81.49 (SD 11.1). Psychotherapists (mean 86.44, SD 8.79) scored significantly higher (F$_{2,106}$=6.136; P=.003) than nursing staff (mean 79.01, SD 13.30) and administrative personnel (mean 77.98, SD 10.72). A multilevel factor analysis demonstrates a different factor structure for each profession. CONCLUSIONS In all professional groups in this study, the usability of a digital psychotherapeutic tool developed using a game engine achieved the benchmark for an excellent system, scoring highest among the professional target group (psychotherapists). The usability of the system seems, to some extent, to be dependent on the professional background of the user. It is possible to create and customize novel psychotherapeutic approaches with gaming technologies and platforms. TRIAL REGISTRATION Clinicaltrials.gov NCT04099940; http://clinicaltrials.gov/ct2/show/NCT04099940

Kinetic regulation of multi-ligand binding proteins

Background: Second messengers, such as calcium, regulate the activity of multisite binding proteins in a concentration-dependent manner. For example, calcium binding has been shown to induce conformational transitions in the calcium-dependent protein calmodulin, under steady state conditions. However, intracellular concentrations of these second messengers are often subject to rapid change. The mechanisms underlying dynamic ligand-dependent regulation of multisite proteins require further elucidation. Results: In this study, a computational analysis of multisite protein kinetics in response to rapid changes in ligand concentrations is presented. Two major physiological scenarios are investigated: i) Ligand concentration is abundant and the ligand-multisite protein binding does not affect free ligand concentration, ii) Ligand concentration is of the same order of magnitude as the interacting multisite protein concentration and does not change. Therefore, buffering effects significantly influence the amounts of free ligands. For each of these scenarios the influence of the number of binding sites, the temporal effects on intermediate apo- and fully saturated conformations and the multisite regulatory effects on target proteins are investigated. Conclusions: The developed models allow for a novel and accurate interpretation of concentration and pressure jump-dependent kinetic experiments. The presented model makes predictions for the temporal distribution of multisite protein conformations in complex with variable numbers of ligands. Furthermore, it derives the characteristic time and the dynamics for the kinetic responses elicited by a ligand concentration change as a function of ligand concentration and the number of ligand binding sites. Effector proteins regulated by multisite ligand binding are shown to depend on ligand concentration in a highly nonlinear fashion

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

The bii4africa dataset of faunal and floral population intactness estimates across Africa’s major land uses

Sub-Saharan Africa is under-represented in global biodiversity datasets, particularly regarding the impact of land use on species’ population abundances. Drawing on recent advances in expert elicitation to ensure data consistency, 200 experts were convened using a modified-Delphi process to estimate ‘intactness scores’: the remaining proportion of an ‘intact’ reference population of a species group in a particular land use, on a scale from 0 (no remaining individuals) to 1 (same abundance as the reference) and, in rare cases, to 2 (populations that thrive in human-modified landscapes). The resulting bii4africa dataset contains intactness scores representing terrestrial vertebrates (tetrapods: ±5,400 amphibians, reptiles, birds, mammals) and vascular plants (±45,000 forbs, graminoids, trees, shrubs) in sub-Saharan Africa across the region’s major land uses (urban, cropland, rangeland, plantation, protected, etc.) and intensities (e.g., large-scale vs smallholder cropland). This dataset was co-produced as part of the Biodiversity Intactness Index for Africa Project. Additional uses include assessing ecosystem condition; rectifying geographic/ taxonomic biases in global biodiversity indicators and maps; and informing the Red List of Ecosystems

Hypoxia and the Receptor for Advanced Glycation End Products (RAGE) Signaling in Cancer

Hypoxia is characterized by an inadequate supply of oxygen to tissues, and hypoxic regions are commonly found in solid tumors. The cellular response to hypoxic conditions is mediated through the activation of hypoxia-inducible factors (HIFs) that control the expression of a large number of target genes. Recent studies have shown that the receptor for advanced glycation end products (RAGE) participates in hypoxia-dependent cellular adaptation. We review recent evidence on the role of RAGE signaling in tumor biology under hypoxic conditions