GRP78 Protein Expression in Ovarian Cancer Patients and Perspectives for a Drug-Targeting Approach

Glucose-regulated protein of 78 kD (GRP78) is a chaperone protein mainly located in the endoplasmic reticulum (ER). This protein is normally present at low levels in adult cells but its expression is triggered by ER stress including glucose deprivation and hypoxia. In tumor cells, it is overexpressed with fraction of protein found at the cell surface. This paper presents the physiology of GRP78 in the context of ovarian cancer and its potential use as drug delivery systems targeting ovarian cancer cell

Polymeric Particulates to Improve Oral Bioavailability of Peptide Drugs

Oral administration remains the most convenient way of delivering drugs. Recent advances in biotechnology have produced highly potent new molecules such as peptides, proteins and nucleic acids. Due to their sensitivity to chemical and enzymatic hydrolysis as well as a poor cellular uptake, their oral bioavailability remains very low. Despite sophisticated new delivery systems, the development of a satisfactory oral formulation remains a challenge. Among the possible strategies to improve the absorption of drugs, micro- and nanoparticles represent an exciting approach to enhance the uptake and transport of orally administered molecules. Increasing attention has been paid to their potential use as carriers for peptide drugs for oral administration. This article reviews the most common manufacturing methods for polymeric particles and the physiology of particle absorption from the gastrointestinal (GI) tract. In a second part, the use of polymeric particulate systems to improve the oral absorption of insulin is discussed

Desarrollo de un sistema experto para apoyar el proceso de la orientación vocacional de los estudiantes egresados del nivel secundario

La presente investigación tiene como objetivo el Desarrollo de un Sistema Experto para apoyar el proceso de la orientación vocacional de los estudiantes egresados del nivel secundario. Para lograr dicho objetivo se hizo un estudio a las diferentes instituciones educativas existente en nuestra provincia de Andahuaylas sobre la orientación vocacional y se concluyó que se necesita de una herramienta que brinde apoyo al orientador vocacional en su labor de asesoramiento sobre su futuro profesión. La finalidad de dicho sistema es contar con una herramienta que permita al estudiante identificar la carrera de acuerdo a sus aptitudes e intereses, así como disponer de la información necesaria acerca de las opciones vocacionales existentes, además de mostrarle, de acuerdo a sus resultados obtenidos, la carrera profesional a la que más se orienta. Para la construcción de este sistema se utilizó el híbrido de dos metodologías: Metodología Grover, que se usó para la adquisición de conocimientos y la metodología IDEAL para la construcción del sistema.Tesi

Understanding Tolerance: Measuring and Modeling Human-Black Bear Interaction in Oregon

The social sciences are increasingly used in conservation to describe interactions and relationships between humans, wildlife, and ecosystems. Scientists and policy-makers have concluded that promoting human tolerance for wildlife is critical to the success of conservation efforts. Yet, the concept of tolerance is relatively new in the context of human-wildlife interaction and varies in its interpretation from the theoretical literature to how it is empirically operationalized. Tolerance is defined here as a multidimensional disposition to wildlife and wildlife management action that may or may not manifest itself in human behavior. Grounding tolerance in psychology, this study developed a theoretically informed measure of tolerance, with black bears (Ursus americanus) as the case subject and western Oregon as the context. The results of this exploratory factor analysis identified five hypothesized dimensions of tolerance. Using confirmatory factor analysis (CFA), with a different sample population, we confirmed four of the five interrelated dimensions of tolerance for black bears: antipathy, connection, lethal control (damage), and lethal control (danger to pets). The fifth dimension safety from the exploratory results was not confirmed in the CFA. Results indicated that these four dimensions are not independent constructs, and we may need all of them to explain expressions for tolerating black bears. We then aimed to delineate the psychological determinants of this measure of tolerance. With structural equation modeling analysis, we tested whether direct experience related to the four dimensions of tolerance for black bears both directly and indirectly (via the relationship with risk perception, self-assessed knowledge, and factual knowledge). We found that direct experience related to all tolerance dimensions and that all dimensions were related differently by the other predicted factors. Risk perception was the strongest predictor of antipathy (negative beliefs) and connection (positive beliefs), whereas self-assessed knowledge was a stronger predictor of an individual’s propensity to accept lethal measures to manage black bears (lethal control [damage] and lethal control [danger to pets]). In its entirety, the research helps clarify the meaning, measurement, and psychological determinants of tolerance for wildlife that can provide actionable recommendations to promote tolerance for black bears

GRP78-targeted nanotherapy against castrate-resistant prostate cancer cells expressing membrane GRP78

Glucose-regulated protein 78, GRP78, is a chaperone protein mainly located in the endoplasmic reticulum (ER) of normal cells. In stress conditions, GRP78 is overexpressed and in different cancer cell types, it is expressed at the cell surface, whereas it stays intracellular in non-cancerous cells. Therefore, it appears as a strategic target to recognize malignant cells. Prostate cancer is one of the most diagnosed cancers in men. The development of castrate resistant tumors and the resistance to chemotherapy frequently occur. The carboxy-terminal ER retention domain is defined by the KDEL amino acid sequence. We developed anti-KDEL functionalized polymeric nanoparticles (NPs) loaded with paclitaxel (Tx) to specifically target prostate cancer cells expressing GRP78. The sensitivity to Tx in different formulations was compared in three prostate cell lines: PNT1B, a normal cell line, PC3, a cancer cell line faintly expressing GRP78 at its surface, and DU145, a cancer cell line expressing GRP78 at its cell surface. Our results show that the targeted formulation significantly increases Tx sensitivity of cell line expressing GRP78 at its surface compared to other treatments suggesting the added value of GRP78 targeted therapy for castrate resistant tumor which expresses GRP78 at its cell surfac

Development of resiquimod-loaded modified PLA-based nanoparticles for cancer immunotherapy: A kinetic study

Resiquimod (R848), a member of the imidazoquinoline family, is a Toll-like receptor 7/8 agonist with high potency for cancer immunotherapy. However, tolerance induction and adverse effects limit its development as a drug. Encapsulation in a polymer matrix can circumvent these limitations, as shown in our formerly published approach where R848 was loaded into polylactic acid (PLA)-based nanoparticles (NP). Although the results were encouraging, low rates of encapsulation and rapid release of the drug were observed. In this study, we present a new strategy using mixed NP from modified linear PLA in order to improve the encapsulation and modulate the release profile of R848. Modified PLA polymers were designed and synthesized by microwave-assisted ring opening polymerization of d,l-lactide, using polyethylene glycol as initiator to increase the hydrophilic properties of the polymer or linear saturated aliphatic chains (C8 or C20) to increase the affinity with hydrophobic R848. NP were prepared by solvent evaporation method, leading to particles of 205–288 nm loaded with either R848 or DiO as a tracking agent. The release profile showed longer retention of R848 at both neutral and acidic pH for NP from grafted polymers. Upon exposure to phagocytic immune cells, NP were actively taken up by the cells and no impact on cell viability was observed, independently of the constitutive polymer. All R848-loaded NP activated macrophages to secrete interleukin-6, demonstrating that the drug cargo was immunologically active. Importantly, macrophage activation by NP- delivered R848 was slower than with free R848, in accordance with the in vitro release profiles. Thus, NP prepared from modified PLA polymers showed no signs of toxicity to immune cells and efficiently delivered their immunoactive cargo in a delayed manner. This delivery strategy may enhance the efficacy and safety of small-molecule immunostimulants

Cadmium accumulation and interactions with zinc, copper, and manganese, analysed by ICP-MS in a long-term Caco-2 TC7 cell model

The influence of long-term exposure to cadmium (Cd) on essential minerals was investigated using a Caco-2 TC7 cells and a multi-analytical tool: microwave digestion and inductively coupled plasma mass spectrometry. Intracellular levels, effects on cadmium accumulation, distribution, and reference concentration ranges of the following elements were determined: Na, Mg, Ca, Cr, Fe, Mn, Co, Ni, Cu, Zn, Mo, and Cd. Results showed that Caco-2 TC7 cells incubated long-term with cadmium concentrations ranging from 0 to 10 lmol Cd/l for 5 weeks exhibited a significant increase in cadmium accumulation. Furthermore, this accumulation was more marked in cells exposed long-term to cadmium compared with controls, and that this exposure resulted in a significant accumulation of copper and zinc but not of the other elements measured. Interactions of Cd with three elements: zinc, copper, and manganese were particularly studied. Exposed to 30 lmol/l of the element, manganese showed the highest inhibition and copper the lowest on cadmium intracellular accumulation but Zn, Cu, and Mn behave differently in terms of their mutual competition with Cd. Indeed, increasing cadmium in the culture medium resulted in a gradual and significant increase in the accumulation of zinc. There was a significant decrease in manganese from 5 lmol Cd/l exposure, and no variation was observed with copper. Abbreviation: AAS – Atomic absorption spectrometry; CRM– Certified reference material; PBS – Phosphate buffered saline without calcium and magnesium; DMEM – Dubelcco’s modified Eagle’s medium

Trend of adherence to iron supplementation during pregnancy among Ethiopian women based on Ethiopian demographic and health surveys: A Multivariable decomposition analysis

BackgroundIron deficiency is one of the significant factors of anemia during pregnancy. Iron supplementation is the main method of prevention and control of iron deficiency anemia, and its effectiveness depends on adherence to the iron supplementation.MethodsThis study was based on a secondary analysis of 2005, 2011, and 2016 EDHS data. After the data was weighted using sampling weight, 696, 1,282, and 3,096 in 2005, 2011, and 2016 EDHS data, respectively, were used for the final analysis. The data were edited, cleaned, coded, managed, and analyzed using StataCorp version 16 software. A logit-based multivariable decomposition analysis was used to identify variables significantly associated with the change in the adherence level during pregnancy.ResultsAdherence levels increased from 1.1% (95% CI; 0.4, 2.7) in 2005 EDHS to 12.4% (95% CI; 10.9, 14.1) in 2016 EDHS. About 30.9% of the overall change in the adherence level to iron supplement use during pregnancy was due to the difference in women's sociodemographic-related variables. After adjusting for these compositional changes, ~69.1% of the change in the adherence level was because of the difference in the coefficients (behavior-related variables). Among the behavioral characteristics, women's age-group, rich wealth index, and secondary and above-secondary educational status of their husbands had a statistically significant effect on the positive change in the adherence level of pregnant mothers.ConclusionThe adherence level to iron supplement use during pregnancy has increased significantly over the last decade in Ethiopia. Both the compositional and behavioral characteristics of women play a major role in the increasing trend of adherence levels

Polymer-based nanoparticles loaded with a TLR7 ligand to target the lymph node for immunostimulation

Small-molecule agonists for the Toll-like receptors (TLR) 7 and 8 are effective for the immunotherapy of skin cancer when used as topical agents. Their systemic use has however been largely unsuccessful due to dose-limiting toxicity. We propose a polymer-based nanodelivery system to target resiquimod, a TLR7 ligand, to the lymph node in order to focus the immunostimulatory activity and to prevent a generalized inflammatory response. We demonstrate successful encapsulation of resiquimod in methoxypoly(ethylene glycol)-b-poly(DL-lactic acid) (mPEG-PLA) and mixed poly(DL- lactic-co-glycolic acid) (PLGA)/mPEG-PLA nanoparticles. We show that these particles are taken up mainly by dendritic cells and macrophages, which are the prime initiators of anticancer immune responses. Nanoparticles loaded with resiquimod activate these cells, demonstrating the availability of the immune-stimulating cargo. The unloaded particles are non-inflammatory and do not have cytotoxic activity on immune cells. Following subcutaneous injection in mice, mPEG-PLA and PLGA/mPEG-PLA nanoparticles are detected in dendritic cells and macrophages in the draining lymph nodes, demonstrating the targeting potential of these particles. Thus, polymer-based nanoparticles represent a promising delivery system that allows lymph node targeting for small-molecule TLR7 agonists in the context of systemic cancer immunotherapy