Search Results (190)

The Sam (Sterile alpha motif) domain of the lipid phosphatase Ship2 (Ship2-Sam) is engaged by the Sam domain of the receptor tyrosine kinase EphA2 (EphA2-Sam) and, this interaction is principally linked to procancer effects. Peptides able to hinder the formation of the EphA2-Sam/Ship2-Sam complex could possess therapeutic potential. Herein, by employing the FoldX software suite, we set up an in silico approach to improve the peptide targeting of the so-called Mid Loop interface of Ship2-Sam, representing the EphA2-Sam binding site. Starting from a formerly identified peptide antagonist of the EphA2-Sam/Ship2-Sam association, first, the most stabilizing mutations that could be inserted in each peptide position were predicted. Then, they were combined, producing a list of potentially enhanced Ship2-Sam ligands. A few of the in silico generated peptides were experimentally evaluated. Interaction assays with Ship2-Sam were performed using NMR and BLI (BioLayer Interferometry). In vitro assays were conducted as well to check for cytotoxic effects against both cancerous and healthy cells, and also to assess the capacity to regulate EphA2 degradation. This study undoubtedly enlarges our knowledge on how to properly target EphA2-Sam/Ship2-Sam associations with peptide-based tools and provides a promising strategy that can be used to target any protein–protein interaction. Full article

Despite the use of screening programs, gastric cancer (GC) diagnosis may only be possible at an advanced stage. In this study, we examined the serum levels of C-C chemokine receptor type 5 (CCR5), C-C motif chemokine ligand 5 (CCL5), platelet-derived growth factor (PDGF), and EphrinA7 (EphA7) in patients with gastric carcinoma and healthy controls to investigate the significance and usability of these potential biomarkers in the early diagnosis of GC. The study enrolled 69 GC patients and 40 healthy individuals. CCR5, CCL5, PDGF-BB, and EphA7 levels, which have been identified in the carcinogenesis of many cancers, were measured in the blood samples using the ELISA method. CCR5, CCL5, PDGF-BB, and EphA7 were all correlated with GC diagnosis (CCR5, p < 0.001, r = −0.449; CCL5, p = 0.014, r = −0.234; PDGF-BB, p < 0.001, r = −0.700; EPHA7, p < 0.001, r = −0.617). The serum CCR5, EphA7, and especially the PDGF-BB levels of the patients diagnosed with GC were discovered to be significantly higher compared to the healthy controls. PDGF-BB had the highest positive and negative predictive values when evaluated in ROC analysis to determine its diagnostic significance (cut-off value: 59.8 ng/L; AUC: 0.92 (0.87–0.97)). As far as we know, this is the first study to investigate the potential connection between GC and these four biomarkers. The fact that serum CCR5, CCL5, EphA7, and especially PDGF-BB levels in the patient group were significantly higher compared to healthy controls indicates that they can be used with high accuracy in the early diagnosis of GC. In addition, the levels of CCR5, PDGF-BB, and EphA7 can be used as important indicators to predict the biological behavior and prognosis of GC. Full article

Factsage is a robust thermodynamic calculation software that enables simulation and computation of complex multi-component and multi-phase system reactions. It has a variety of application fields such as metallurgy, energy, and environmental domains. This article elucidates the key functionalities of Factsage’s diverse modules, including Equilib, Viscosity, EpH, Reaction, and Phase Diagram modules. Furthermore, it delineates the present usage and research progress of the software in the realms of air pollution, water pollution, and solid waste treatment. By predicting the thermodynamic properties of pollutants, their chemical reactions, and complex phase changes, Factsage provides a critical scientific foundation for environmental decision-making and optimization of waste treatment processes. It showed its greater contributions to environmental protection and sustainable development. Full article

A cost-effective, selective, sensitive, and operational TLC-densitometric approach has been adapted for the concurrent assay of Hydroxyzine Hydrochloride (HYX), Ephedrine Hydrochloride (EPH), and Theophylline (THP) in their pure powder and pharmaceutical forms. In the innovative TLC-densitometric approach, HYX, EPH, and THP were efficaciously separated and quantified on a 60F₂₅₄ silica gel stationary phase with chloroform–ammonium acetate buffer (9.5:0.5, v/v) adjusted to pH 6.5 using ammonia solution as a mobile liquid system and UV detection at 220 nm. The novel TLC method validation has been performed in line with the international conference for harmonization (ICH) standards and has been effectively used for the estimation of the researched medicines in their pharmaceutical formulations without intervention from excipients. Additionally, parameters affecting the chromatographic analysis have been investigated. The new TLC approach’s functionality and greenness were appraised using three modern and automated tools, namely the Blue Applicability Grade Index (BAGI), the Analytical Greenness metric (AGREE), and the Green Analytical Procedure Index (GAPI) tools. In short, the greenness characteristics were not achieved as a result of using mandatory, non-ecofriendly solvents such as ammonia and chloroform. On the contrary, the applicability and usefulness of the novel TLC approach were attained via concurrent estimation for the three drugs using simple and straightforward procedures. Moreover, the novel TLC method outperforms previously published HPLC ones in terms of the short run time per sample and moderate pH value for the liquid system. According to the conclusions of comparisons with previously recorded TLC methods, our novel HPTLC method has the highest AGREE score, so it is the greenest HPTLC strategy. Moreover, its functionality and applicability are very appropriate because of the simultaneous assessment of three drugs in one TLC run. Furthermore, no tedious and complicated extraction and evaporation processes are prerequisites. Full article

Osteosarcoma is an aggressive bone cancer affecting both humans and dogs, often leading to pulmonary metastasis. Despite surgery and chemotherapy being the primary treatment modalities, survival rates remain low in both species, underscoring the urgent need for more efficacious therapeutic options. Accumulating evidence indicates numerous biological and clinical similarities between human and canine osteosarcoma, making it an ideal choice for comparative oncological research that should benefit both species. The EphA2 receptor has been implicated in controlling invasive responses across different human malignancies, and its expression is associated with poor prognosis. In this study, we utilized a comparative approach to match EphA2 functions in human and canine osteosarcoma models. Our objectives were to assess EphA2 levels and its pro-malignant action in osteosarcoma cells of both species. We found that EphA2 is overexpressed in most of both canine and human osteosarcoma cell lines, while its silencing significantly reduced cell viability, migration, and invasion. Moreover, EphA2 silencing enhanced the sensitivity of osteosarcoma cells to cisplatin, a drug commonly used for treating this cancer. Furthermore, inhibition of EphA2 expression led to a significant reduction in tumor development capability of canine osteosarcoma cells. Our data suggest that these EphA2 effects are likely mediated through various signaling mechanisms, including the SRC, AKT, and ERK–MAPK pathways. Collectively, our findings indicate that EphA2 promotes malignant behaviors in both human and canine osteosarcoma and that targeting EphA2, either alone or in combination with chemotherapy, could offer potential benefits to osteosarcoma patients. Full article

The magnetic field range in which a magnetic sensor operates is an important consideration for many applications. Elliptical planar Hall effect (EPHE) sensors exhibit outstanding equivalent magnetic noise (EMN) on the order of pT/Hz, which makes them promising for many applications. Unfortunately, the current field range in which EPHE sensors with pT/Hz EMN can operate is sub-mT, which limits their potential use. Here, we fabricate EPHE sensors with an increased field range and measure their EMN. The larger field range is obtained by increasing the uniaxial shape-induced anisotropy parallel to the long axis of the ellipse. We present measurements of EPHE sensors with magnetic anisotropy which ranges between 12 Oe and 120 Oe and show that their EMN at 10 Hz changes from 800 pT/Hz to 56 nT/Hz. Furthermore, we show that the EPHE sensors behave effectively as single magnetic domains with negligible hysteresis. We discuss the potential use of EPHE sensors with extended field range and compare them with sensors that are widely used in such applications. Full article

High-risk human papillomavirus (HR-HPV; HPV-16) and cigarette smoking are associated with cervical cancer (CC); however, the underlying mechanism(s) remain unclear. Additionally, the carcinogenic components of tobacco have been found in the cervical mucus of women smokers. Here, we determined the effects of cigarette smoke condensate (CSC; 3R4F) on human ectocervical cells (HPV-16 Ect/E6E7) exposed to CSC at various concentrations (10⁻⁶–100 μg/mL). We found CSC (10⁻³ or 10 μg/mL)-induced proliferation, enhanced migration, and histologic and electron microscopic changes consistent with EMT in ectocervical cells with a significant reduction in E-cadherin and an increase in the vimentin expression compared to controls at 72 h. There was increased phosphorylation of receptor tyrosine kinases (RTKs), including Eph receptors, FGFR, PDGFRA/B, and DDR2, with downstream Ras/MAPK/ERK1/2 activation and upregulation of common EMT-related genes, TGFB SNAI2, PDGFRB, and SMAD2. Our study demonstrated that CSC induces EMT in ectocervical cells with the upregulation of EMT-related genes, expression of protein biomarkers, and activation of RTKs that regulate TGFB expression, and other EMT-related genes. Understanding the molecular pathways and environmental factors that initiate EMT in ectocervical cells will help delineate molecular targets for intervention and define the role of EMT in the initiation and progression of cervical intraepithelial neoplasia and CC. Full article

Recurrent pregnancy loss (RPL) affects around 2% of women of reproductive age. Primary RPL is defined by ≥2 pregnancy losses and no normal birth delivery. In secondary RPL, the losses are after a normal pregnancy and delivery. Most cases have no clear aetiology, although primary cases are the most complex. Several gene single nucleotide polymorphisms (SNPs) have been associated with RPL. The frequency of some SNPs is increased in women suffering from RLP from Asian or Caucasian races; however, in admixed populations, the information on possible genetic links is scarce and contradictory. This study aimed to assess the frequency of two SNPs present in two different enzymes involved in medical conditions observed during pregnancy. It is a case–control study. Microsomal epoxy hydrolase (mEPH) is involved in detoxifying xenobiotics, is present in the ovaries, and is hormonally regulated. The endothelial nitric oxide synthase (NOS3) that forms nitric is involved in vascular tone. Two SNPs, rs1051740 (mEPH) and rs1799983 (NOS3), were assessed. The study included 50 controls and 63 primary RPL patients. The frequency of mutated alleles in both SNPs was significantly higher in patients (p < 0.05). Double-mutated homozygotes were encountered only in RPL patients (p < 0.05). Genetic polymorphisms rs1051740 and rs1799983 may be involved in primary RPL in the Venezuelan admix population. Genetic studies could provide crucial information on the aetiology of primary RPL. Full article

Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell–cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell–cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway’s intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges. Full article

Breast cancer (BCA) remains the leading cause of cancer-related mortality among women worldwide. This review delves into the therapeutic challenges of BCA, emphasizing the roles of interleukin-13 receptor α2 (IL-13Rα2) and erythropoietin-producing hepatocellular receptor A2 (EphA2) in tumor progression and resistance. Highlighting their overexpression in BCA, particularly in aggressive subtypes, such as Her-2-enriched and triple-negative breast cancer (TNBC), we discuss the potential of these receptors as targets for chimeric antigen receptor T-cell (CAR-T) therapies. We examine the structural and functional roles of IL-13Rα2 and EphA2, their pathological significance in BCA, and the promising therapeutic avenues their targeting presents. With an in-depth analysis of current immunotherapeutic strategies, including the limitations of existing treatments and the potential of dual antigen-targeting CAR T-cell therapies, this review aims to summarize potential future novel, more effective therapeutic interventions for BCA. Through a thorough examination of preclinical and clinical studies, it underlines the urgent need for targeted therapies in combating the high mortality rates associated with Her-2-enriched and TNBC subtypes and discusses the potential role of IL-13Rα2 and EphA2 as promising candidates for the development of CAR T-cell therapies. Full article

From the moment a cell is on the path to malignant transformation, its interaction with other cells from the microenvironment becomes altered. The flow of molecular information is at the heart of the cellular and systemic fate in tumors, and various processes participate in conveying key molecular information from or to certain cancer cells. For instance, the loss of tight junction molecules is part of the signal sent to cancer cells so that they are no longer bound to the primary tumors and are thus free to travel and metastasize. Upon the targeting of a single cell by a therapeutic drug, gap junctions are able to communicate death information to by-standing cells. The discovery of the importance of novel modes of cell–cell communication such as different types of extracellular vesicles or tunneling nanotubes is changing the way scientists look at these processes. However, are they all actively involved in different contexts at the same time or are they recruited to fulfill specific tasks? What does the multiplicity of modes mean for the overall progression of the disease? Here, we extend an open invitation to think about the overall significance of these questions, rather than engage in an elusive attempt at a systematic repertory of the mechanisms at play. Full article

Periodontal defects’ localization affects wound healing and bone remodeling, with faster healing in the upper jaw compared to the lower jaw. While differences in blood supply, innervation, and odontogenesis contribute, cell-intrinsic variances may exist. Few studies explored cell signaling in periodontal ligament stem cells (PDLSC), overlooking mandible-maxilla disparitiesUsing kinomics technology, we investigated molecular variances in PDLSC. Characterization involved stem cell surface markers, proliferation, and differentiation capacities. Kinase activity was analyzed via multiplex kinase profiling, mapping differential activity in known gene regulatory networks. Upstream kinase analysis identified stronger EphA receptor expression in the mandible, potentially inhibiting osteogenic differentiation. The PI3K-Akt pathway showed higher activity in lower-jaw PDLSC. PDLSC from the upper jaw exhibit superior proliferation and differentiation capabilities. Differential activation of gene regulatory pathways in upper vs. lower-jaw PDLSC suggests implications for regenerative therapies. Full article

Runs of Homozygosity (ROH) are continuous homozygous DNA segments in diploid genomes, which have been used to estimate the genetic diversity, inbreeding levels, and genes associated with specific traits in livestock. In this study, we analyzed the resequencing data from 10 local goat breeds in Yunnan province of China and five additional goat populations obtained from a public database. The ROH analysis revealed 21,029 ROH segments across the 15 populations, with an average length of 1.27 Mb, a pattern of ROH, and the assessment of the inbreeding coefficient indicating genetic diversity and varying levels of inbreeding. iHS (integrated haplotype score) was used to analyze high-frequency Single-Nucleotide Polymorphisms (SNPs) in ROH regions, specific genes related to economic traits such as coat color and weight variation. These candidate genes include OCA2 (OCA2 melanosomal transmembrane protein) and MLPH (melanophilin) associated with coat color, EPHA6 (EPH receptor A6) involved in litter size, CDKAL1 (CDK5 regulatory subunit associated protein 1 like 1) and POMC (proopiomelanocortin) linked to weight variation and some putative genes associated with high-altitude adaptability and immune. This study uncovers genetic diversity and inbreeding levels within local goat breeds in Yunnan province, China. The identification of specific genes associated with economic traits and adaptability provides actionable insights for utilization and conservation efforts. Full article

The lipid phosphatase Ship2 interacts with the EphA2 receptor by forming a heterotypic Sam (sterile alpha motif)–Sam complex. Ship2 works as a negative regulator of receptor endocytosis and consequent degradation, and anti-oncogenic effects in cancer cells should be induced by hindering its association with EphA2. Herein, a computational approach is presented to investigate the relationship between Ship2-Sam/EphA2-Sam interaction and cancer onset and further progression. A search was first conducted through the COSMIC (Catalogue of Somatic Mutations in Cancer) database to identify cancer-related missense mutations positioned inside or close to the EphA2–Sam and Ship2–Sam reciprocal binding interfaces. Next, potential differences in the chemical–physical properties of mutant and wild-type Sam domains were evaluated by bioinformatics tools based on analyses of primary sequences. Three-dimensional (3D) structural models of mutated EphA2–Sam and Ship2–Sam domains were built as well and deeply analysed with diverse computational instruments, including molecular dynamics, to classify potentially stabilizing and destabilizing mutations. In the end, the influence of mutations on the EphA2–Sam/Ship2–Sam interaction was studied through docking techniques. This in silico approach contributes to understanding, at the molecular level, the mutation/cancer relationship by predicting if amino acid substitutions could modulate EphA2 receptor endocytosis. Full article

Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer. Full article