Olfactory neuroblastoma: literature review and presentation of two clinical cases with different tumour infiltrations and different approaches.

The olfactory neuroblastoma is a rare malignant neoplasm derived from the olfactory neuroepithelium. It can metastasize to cervical lymph node chains and distant organs through hematogenous or lymphatic routes. Two clinical cases are presented: the first, a 56-year-old man with no pathological history, exhibited symptoms evolving over 2 months, characterized by persistent rhinorrhea with frequent epistaxis, ipsilateral proptosis, left hemicranial pain, anosmia, and dysgeusia.

Longitudinal transcriptional changes reveal genes from the natural killer cell-mediated cytotoxicity pathway as critical players underlying COVID-19 progression.

Patients present a wide range of clinical severities in response severe acute respiratory syndrome coronavirus 2 infection, but the underlying molecular and cellular reasons why clinical outcomes vary so greatly within the population remains unknown. Here, we report that negative clinical outcomes in severely ill patients were associated with divergent RNA transcriptome profiles in peripheral immune cells compared with mild cases during the first weeks after disease onset. Protein-protein interaction analysis indicated that early-responding cytotoxic natural killer cells were associated with an effective clearance of the virus and a less severe outcome.

Negative association of steroids with immunotherapy efficacy in a multi-tumor cohort: time and dose-dependent.

Previous studies have suggested a negative impact of steroids on the efficacy of immune checkpoint inhibitors (ICI), but how this effect is modulated by the dosage and time of administration is yet to be clarified. We have performed a retrospective analysis of 475 patients with advanced solid tumors treated with ICI as monotherapy from 2015 to 2022. Data regarding immune-related adverse events (irAEs) and clinical outcomes were collected.

Interlaboratory Study on Zebrafish in Toxicology: Systematic Evaluation of the Application of Zebrafish in Toxicology's (SEAZIT's) Evaluation of Developmental Toxicity.

Embryonic zebrafish represent a useful test system to screen substances for their ability to perturb development. The exposure scenarios, endpoints captured, and data analysis vary among the laboratories who conduct screening. A lack of harmonization impedes the comparison of the substance potency and toxicity outcomes across laboratories and may hinder the broader adoption of this model for regulatory use.

Validation of a zebrafish developmental defects assay as a qualified alternative test for its regulatory use following the ICH S5(R3) guideline.

Zebrafish is a popular toxicology model and provides an ethically acceptable small-scale analysis system with the complexity of a complete organism. Our goal is to further validate this model for its regulatory use for reproductive and developmental defects by testing the compounds indicated in the "Guideline on detection of reproductive and developmental toxicity for human pharmaceuticals" (ICH S5(R3) guideline.) To determine the embryotoxic and developmental risk of the 32 reference compounds listed in the ICH S5(R3) guideline, the presence of morphological alterations in zebrafish embryos was analyzed at two different stages to calculateLC50 and EC50 values for each stage.

Bioremediation of an industrial soil contaminated by hydrocarbons in microcosm system, involving bioprocesses utilizing co-products and agro-industrial wastes.

The present study describes practical implication of bioaugmentation and biostimulation processes for bioremediation of an industrial soil chronically contaminated by hydrocarbons. For this purpose, biomass production of six autochthonous hydrocarbon-degrading bacteria were evaluated as inoculum of bioaugmentation strategy, by testing carbon and nitrogen sources included co-products and agro-industrial waste as sustainable and low-cost components of the growth medium. Otherwise, biostimulation was approached by the addition of optimized concentration of nitrogen and phosphorus.

Optimization of biomass production by autochthonous sp MT1A3 as strategy to apply bioremediation in situ in a chronically hydrocarbon-contaminated soil.

Unlabelled: These days, petroleum hydrocarbon pollution has become a global problem, because of this, bioremediation is presented as a strategy for cleaning up sites contaminated with organic pollutants, and it has an increasing role in relation to the potential it presents as a non-invasive and cost-effective technology. The aim of this study is to optimize the biomass production of sp. MT1A3 strain as a soil bioremediation approach for petroleum hydrocarbon polluted environments.

Trace element fixation in sediments rich in organic matter from a saline lake in tropical latitude with hydrothermal inputs (Sochagota Lake, Colombia): The role of bacterial communities.

We studied the relationships between the trace element concentration in sediments from a saline lake at a tropical latitude (Sochagota Lake, Colombia) containing hydrothermal and anthropic inputs with the organic matter content, the mineral assemblage composition and the activity of the bacterial communities of the sediments. Organic matter-poor sediments (TOC < 0.7%) with quartz and kaolinite near the southern entrance of the lake were enriched in Zr (up to 603 mg/kg) and some major detrital elements (Na, Ti, Al and Si).

Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family.

We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors.

Computational approach for collection and prediction of molecular initiating events in developmental toxicity.

Developmental toxicity is defined as the occurrence of adverse effects on the developing organism as a result from exposure to a toxic agent. These alterations can have long-term acute effects. Current in vitro models present important limitations and the evaluation of toxicity is not entirely objective.

Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds.

The gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein-protein interactions. We have refined crystallization conditions for KRAS-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein-protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein-protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds).

Detection and Prioritization of Developmentally Neurotoxic and/or Neurotoxic Compounds Using Zebrafish.

The standard methods for toxicity testing using rodent models cannot keep pace with the increasing number of chemicals in our environment due to time and resource limitations. Hence, there is an unmet need for fast, sensitive, and cost-effective alternate models to reliably predict toxicity. As part of Tox21 Phase III's effort, a 90-compound library was created and made available to researchers to screen for neurotoxicants using novel technology and models.

[Phosphorus delivered to surface waters resulting from the use of powder detergents: environmental and public health aspects].

This article addresses the social and environmental aspects related to the presence of phosphorus in surface water bodies, assessing the impacts caused by the utilization of powder detergents on the quality and availability of water resources, with particular respect to the occurrence of eutrophication. Based on data concerning the composition and consumption of the products currently sold in Brazil, the evolution of this phenomenon leading to the current situation is reported. Indications are that Brazilian detergents have a low phosphorus content, thus it is possible to infer that these products offer a small risk of impacting the trophic levels of surface waters.

Toxicity profiling of flame retardants in zebrafish embryos using a battery of assays for developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity toward human relevance.

Following the voluntary phase-out of brominated flame retardants (BFRs) due to their environmental persistence and toxicity, the organophosphorus flame retardants (OPFRs) are emerging replacements. However, there is limited information on the potential human health effects of the OPFRs. Zebrafish embryos are a viable vertebrate model organism with many advantages for high throughput testing toward human hazard assessment.

Automated Morphological Feature Assessment for Zebrafish Embryo Developmental Toxicity Screens.

Detection of developmental phenotypes in zebrafish embryos typically involves a visual assessment and scoring of morphological features by an individual researcher. Subjective scoring could impact results and be of particular concern when phenotypic effect patterns are also used as a diagnostic tool to classify compounds. Here we introduce a quantitative morphometric approach based on image analysis of zebrafish embryos.

Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment.

Targeting specific protein-protein interactions (PPIs) is an attractive concept for drug development, but hard to implement since intracellular antibodies do not penetrate cells and most small-molecule drugs are considered unsuitable for PPI inhibition. A potential solution to these problems is to select intracellular antibody fragments to block PPIs, use these antibody fragments for target validation in disease models and finally derive small molecules overlapping the antibody-binding site. Here, we explore this strategy using an anti-mutant RAS antibody fragment as a competitor in a small-molecule library screen for identifying RAS-binding compounds.

BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions.

The RAS family of proteins is amongst the most highly mutated in human cancers and has so far eluded drug therapy. Currently, much effort is being made to discover mutant RAS inhibitors and in vitro screening for RAS-binding drugs must be followed by cell-based assays. Here, we have developed a robust set of bioluminescence resonance energy transfer (BRET)-based RAS biosensors that enable monitoring of RAS-effector interaction inhibition in living cells.

Intracellular immunization against HIV infection with an intracellular antibody that mimics HIV integrase binding to the cellular LEDGF protein.

Preventing the protein-protein interaction of the cellular chromatin binding protein Lens Epithelium-Derived Growth Factor (LEDGF) and human immunodeficiency virus (HIV) integrase is an important possible strategy for anti-viral treatment for AIDS. We have used Intracellular Antibody Capture technology to isolate a single VH antibody domain that binds to LEDGF. The crystal structure of the LEDGF-VH complex reveals that the single domain antibody mimics the effect of binding of HIV integrase to LEDGF which is crucial for HIV propagation.

Influence of the detergent formulation on the concentration of phosphorus in the sewage inflows to the WWTPs: the Brazilian experience.

This work seeks to discuss the presence of phosphorus in raw sewage considering the formulation of the powder detergent for cleaning fabrics currently sold in Brazil. Based on the results of laboratory analyses performed in the sewage inflows to three wastewater treatment plants (WWTPs) located in São Paulo state, it evaluates the different fractions of this element and sizes the impact caused by the product. The average concentration of total phosphorus (total-P) in sewage inflows has shown a reduction trend over the years, and it is currently between 5.

Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family.

The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved.

An Effective Approach for Clustering InhA Molecular Dynamics Trajectory Using Substrate-Binding Cavity Features.

Protein receptor conformations, obtained from molecular dynamics (MD) simulations, have become a promising treatment of its explicit flexibility in molecular docking experiments applied to drug discovery and development. However, incorporating the entire ensemble of MD conformations in docking experiments to screen large candidate compound libraries is currently an unfeasible task. Clustering algorithms have been widely used as a means to reduce such ensembles to a manageable size.

Clustering molecular dynamics trajectories for optimizing docking experiments.

Molecular dynamics simulations of protein receptors have become an attractive tool for rational drug discovery. However, the high computational cost of employing molecular dynamics trajectories in virtual screening of large repositories threats the feasibility of this task. Computational intelligence techniques have been applied in this context, with the ultimate goal of reducing the overall computational cost so the task can become feasible.