Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.

Microbiological Quality and Safety of Fresh Rabbit Meat with Special Reference to Methicillin-Resistant S. aureus (MRSA) and ESBL-Producing E. coli.

The purpose of this investigation was to evaluate the microbial quality and safety of rabbit meat. A total of 49 rabbit meat samples were taken at the retail level. The mesophiles, staphylococci, Enterobacterales, and Pseudomonas spp. counts were 4.94 ± 1.08, 2.59 ± 0.70, 2.82 ± 0.67, and 3.23 ± 0.76 log CFU/g, respectively. Campylobacter spp. were not detected in any sample. Listeria monocytogenes was isolated from one sample (2.04%) at levels below 1.00 log CFU/g. Multi-resistant S aureus was found in seven samples (14.9%). Methicillin-resistant S. aureus, S. epidermidis, S. haemolyticus, M. caseolyticus, and M. sciuri were found in a sample each (10.20%), and all of them were multi-resistant. Multi-resistant ESBL-producing E. coli were detected in two samples from the same retailer (4.08%). The high resistance found in methicillin-resistant staphylococci and ESBL-producing E. coli is of particular concern, and suggests that special measures should be taken in rabbit meat.

Identifying Ferroptosis Inducers, HDAC, and RTK Inhibitor Sensitivity in Melanoma Subtypes through Unbiased Drug Target Prediction.

The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC and AKT1, across five distinct MM subtypes. These proteins serve as potential drug targets applicable to one or multiple MM subtypes. By analyzing transcriptomic data from 48 publicly accessible melanoma cell lines sourced from Achilles and CRISPR dependency screens, we forecasted 162 potentially targetable genes. We also identified genetic resistance in 260 genes across at least one melanoma subtype. In addition, we employed publicly available compound sensitivity data (Cancer Therapeutics Response Portal, CTRPv2) on the cell lines to assess the correlation of compound effectiveness within each subtype. We have identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype. Remarkably, employing this unbiased approach, we have uncovered compounds targeting ferroptosis, that demonstrate a striking 30x fold difference in sensitivity among different subtypes. This implies that the proteogenomic classification of melanoma has the potential to predict sensitivity to ferroptosis compounds. Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy. Highlights: (1) Proteogenomic subtype classification can define the landscape of genetic dependencies in melanoma (2) Nine proteins from molecular subtypes were identified as potential drug targets for specified MM patients (3) 20 compounds identified that show potential effectiveness in at least one melanoma subtype (4) Proteogenomics can predict specific ferroptosis inducers, HDAC, and RTK Inhibitor sensitivity in melanoma subtypes.

Multiomics Approach Reveals Serum Biomarker Candidates for Congenital Zika Syndrome.

The Zika virus (ZIKV) can be vertically transmitted, causing congenital Zika syndrome (CZS) in fetuses. ZIKV infection in early gestational trimesters increases the chances of developing CZS. This syndrome involves several pathologies with a complex diagnosis. In this work, we aim to identify biological processes and molecular pathways related to CZS and propose a series of putative protein and metabolite biomarkers for CZS prognosis in early pregnancy trimesters. We analyzed serum samples of healthy pregnant women and ZIKV-infected pregnant women bearing nonmicrocephalic and microcephalic fetuses. A total of 1090 proteins and 512 metabolites were identified by bottom-up proteomics and untargeted metabolomics, respectively. Univariate and multivariate statistical approaches were applied to find CZS differentially abundant proteins (DAP) and metabolites (DAM). Enrichment analysis (i.e., biological processes and molecular pathways) of the DAP and the DAM allowed us to identify the ECM organization and proteoglycans, amino acid metabolism, and arachidonic acid metabolism as CZS signatures. Five proteins and four metabolites were selected as CZS biomarker candidates. Serum multiomics analysis led us to propose nine putative biomarkers for CZS prognosis with high sensitivity and specificity.

Pharmacokinetic Profile Evaluation of Novel Combretastatin Derivative, LASSBio-1920, as a Promising Colorectal Anticancer Agent.

LASSBio-1920 was synthesized due to the poor solubility of its natural precursor, combretastatin A4 (CA4). The cytotoxic potential of the compound against human colorectal cancer cells (HCT-116) and non-small cell lung cancer cells (PC-9) was evaluated, yielding IC50 values of 0.06 and 0.07 µM, respectively. Its mechanism of action was analyzed by microscopy and flow cytometry, where LASSBio-1920 was found to induce apoptosis. Molecular docking simulations and the enzymatic inhibition study with wild-type (wt) EGFR indicated enzyme-substrate interactions similar to other tyrosine kinase inhibitors. We suggest that LASSBio-1920 is metabolized by O-demethylation and NADPH generation. LASSBio-1920 demonstrated excellent absorption in the gastrointestinal tract and high central nervous system (CNS) permeability. The pharmacokinetic parameters obtained by predictions indicated that the compound presents zero-order kinetics and, in a human module simulation, accumulates in the liver, heart, gut, and spleen. The pharmacokinetic parameters obtained will serve as the basis to initiate in vivo studies regarding LASSBio-1920's antitumor potential.

Conformational stability of SARS-CoV-2 glycoprotein spike variants.

The severe acute respiratory syndrome spread worldwide, causing a pandemic. SARS-CoV-2 mutations have arisen in the spike, a glycoprotein at the viral envelope and an antigenic candidate for vaccines against COVID-19. Here, we present comparative data of the glycosylated full-length ancestral and D614G spike together with three other transmissible strains classified by the World Health Organization as variants of concern: beta, gamma, and delta. By showing that D614G has less hydrophobic surface exposure and trimer persistence, we place D614G with features that support a model of temporary fitness advantage for virus spillover. Furthermore, during the SARS-CoV-2 adaptation, the spike accumulates alterations leading to less structural stability for some variants. The decreased trimer stability of the ancestral and gamma and the presence of D614G uncoupled conformations mean higher ACE-2 affinities compared to the beta and delta strains. Mapping the energetics and flexibility of variants is necessary to improve vaccine development.

Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones.

Sulfonylhydrazones are privileged structures with multifaceted pharmacological activity. Exploring the hypoglycemic properties of these organic compounds, we previously revealed a new series of N-sulfonylhydrazones (NSH) as antidiabetic drug candidates. Here, we evaluated the microsomal metabolism, chemical stability, and permeability profile of these NSH prototypes, focusing on the pharmacokinetic differences in N-methylated and non-N-methylated analogs. Our results demonstrated that the N-methylated analogs (LASSBio-1772 and LASSBio-1774) were metabolized by CYP, forming three and one metabolites, respectively. These prototypes exhibited chemical stability at pH 2.0 and 7.4 and brain penetration ability. On the other hand, non-N-methylated analogs (LASSBio-1771 and LASSBio-1773) were hydrolyzed in acid pH and could not cross the artificial blood-brain barrier. The cyano group in LASSBio-1771 was postulated as a possible site of interaction with the heme group, potentially inhibiting CYP enzymes. Moreover, prototypes with the methyl ester group were metabolized by carboxylesterase, and non-N-methylated analogs did not show oxidative metabolism. The prototypes (except LASSBio-1774) showed excellent gastrointestinal absorption. Altogether, our data support the idea that the methyl effect on NSH strongly alters their pharmacokinetic profile, enhances the recognition by CYP enzymes, promotes brain penetration, and plays a protective effect upon acid hydrolysis.

The oldest unvaccinated Covid-19 survivors in South America.

BACKGROUND: Although older adults are at a high risk of severe or critical Covid-19, there are many cases of unvaccinated centenarians who had a silent infection or recovered from mild or moderate Covid-19. We studied three Brazilian supercentenarians, older than 110 years, who survived Covid-19 in 2020 before being vaccinated. RESULTS: Despite their advanced age, humoral immune response analysis showed that these individuals displayed robust levels of IgG and neutralizing antibodies (NAbs) against SARS-CoV-2. Enrichment of plasma proteins and metabolites related to innate immune response and host defense was also observed. None presented autoantibodies (auto-Abs) to type I interferon (IFN). Furthermore, these supercentenarians do not carry rare variants in genes underlying the known inborn errors of immunity, including particular inborn errors of type I IFN. CONCLUSION: These observations suggest that their Covid-19 resilience might be a combination of their genetic background and their innate and adaptive immunity.

Effect of the Presence of Antibiotic Residues on the Microbiological Quality and Antimicrobial Resistance in Fresh Goat Meat.

A total of 11 fresh goat legs were collected at the retail level. Mesophiles, Pseudomonas spp., Enterobacteriaceae, staphylococci, enterococci, Clostridium perfringens, Campylobacter spp., and Listeria monocytogenes counts were determined. Nine samples were free of antibiotic residues, while in the other two samples the presence of sulfadiazine and doxycycline was detected. The antimicrobial resistance of E. coli, staphylococci, Macrococcus spp., and enterococci isolates was also evaluated. Clostridium perfringens was found in two samples. Methicillin-resistant Staphylococcus aureus was detected in one sample. S. epidermidis isolated from one sample containing doxycycline residues showed resistance to mupirocin. Moreover, multi-resistant S. epidermidis and M. caseolyticus were found. Most of the isolated Enterococcus faecium were multi-resistant. Neither extended-spectrum ß-lactamase -producing E. coli nor vancomycin-resistant enterococci were detected in any sample. The presence of doxycycline or sulfadiazine could affect the goat meat microbiota since less microbial diversity was found in these samples compared to those free of antibiotics. The presence of antibiotic residues could increase the antimicrobial resistance of enterococci in fresh goat meat. The presence of multidrug-resistant bacteria in goat meat could be considered a potential threat and should be monitored. Special measures should be taken at the farm level and during slaughter to reduce antimicrobial resistance.

First evaluation of the anxiolytic-like effects of a bromazepam­palladium complex in mice.

A significant fraction of patients are affected by persistent fear and anxiety. Currently, there are several anxiolytic drug options, however their clinical outcomes do not fully manage the symptoms. Here, we evaluated the effects of a bromazepam­palladium derivative [2-{(7-bromo-2-oxo-1,3-dihydro-2H-1,4-benzodiazepin-5-il)pyridinyl-κ2-N,N}chloropalladium(II)], [(BMZ)PdCl2], on fear/anxiety and memory-related behavior in mice. For this, female Swiss mice were treated intraperitoneally (i.p.) with saline (NaCl 0.9%) or [(BMZ)PdCl2] (0.5, 5.0, or 50 µg/kg). After 30 min, different tests were performed to evaluate anxiety, locomotion, and memory. We also evaluated the acute toxicity of [(BMZ)PdCl2] using a cell viability assay (neutral red uptake assay), and whether the drugs mechanism of action involves the γ-aminobutyric acid type A (GABAA) receptor complex by pre-treating animals with flumazenil (1.0 mg/kg, i.p., a competitive antagonist of GABAA-binding site). Our results demonstrate that [(BMZ)PdCl2] induces an anxiolytic-like phenotype in the elevated plus-maze test and that this effect can be blocked by flumazenil. Furthermore, there were no behavioral alterations induced by [(BMZ)PdCl2], as evaluated in the light-dark box, open field, and step-down passive avoidance tests. In the acute toxicity assay, [(BMZ)PdCl2] presented IC50 and LD50 values of 218 ± 60 µg/mL and 780 ± 80 mg/kg, respectively, and GSH category 4. Taken together, our results show that the anxiolytic-like effect of acute treatment with [(BMZ)PdCl2] occurs through the modulation of the benzodiazepine site in the GABAA receptor complex. Moreover, we show indications that [(BMZ)PdCl2] does not promote sedation and amnesia and presents the same toxicity as the bromazepam prototype.

Plasma metabolome study reveals metabolic changes induced by pharmacological castration and testosterone supplementation in healthy young men.

Testosterone is a hormone that plays a key role in carbohydrate, fat, and protein metabolism. Testosterone deficiency is associated with multiple comorbidities, e.g., metabolic syndrome and type 2 diabetes. Despite its importance in many metabolic pathways, the mechanisms by which it controls metabolism are not fully understood. The present study investigated the short-term metabolic changes of pharmacologically induced castration and, subsequently, testosterone supplementation in healthy young males. Thirty subjects were submitted to testosterone depletion (TD) followed by testosterone supplementation (TS). Plasma samples were collected three times corresponding to basal, low, and restored testosterone levels. An untargeted metabolomics study was performed by liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) to monitor the metabolic changes induced by the altered hormone levels. Our results demonstrated that TD was associated with major metabolic changes partially restored by TS. Carnitine and amino acid metabolism were the metabolic pathways most impacted by variations in testosterone. Furthermore, our results also indicated that LH and FSH might strongly alter the plasma levels of indoles and lipids, especially glycerophospholipids and sphingolipids. Our results demonstrated major metabolic changes induced by low testosterone that may be important for understanding the mechanisms behind the association of testosterone deficiency and its comorbidities.

Comparative chemical and biological hydrolytic stability of homologous esters and isosteres.

Esters are one of the major functional groups present in the structures of prodrugs and bioactive compounds. Their presence is often associated with hydrolytic lability. In this paper, we describe a comparative chemical and biological stability of homologous esters and isosteres in base media as well as in rat plasma and rat liver microsomes. Our results provided evidence for the hydrolytic structure lability relationship and demonstrated that the hydrolytic stability in plasma and liver microsome might depend on carboxylesterase activity. Molecular modelling studies were performed in order to understand the experimental data. Taken together, the data could be useful to design bioactive compounds or prodrugs based on the correct choice of the ester subunit, addressing compounds with higher or lower metabolic lability.

Short-Term Effect of Induced Alterations in Testosterone Levels on Fasting Plasma Amino Acid Levels in Healthy Young Men.

Long term effect of testosterone (T) deficiency impairs metabolism and is associated with muscle degradation and metabolic disease. The association seems to have a bidirectional nature and is not well understood. The present study aims to investigate the early and unidirectional metabolic effect of induced T changes by measuring fasting amino acid (AA) levels in a human model, in which short-term T alterations were induced. We designed a human model of 30 healthy young males with pharmacologically induced T changes, which resulted in three time points for blood collection: (A) baseline, (B) low T (3 weeks post administration of gonadotropin releasing hormone antagonist) and (C) restored T (2 weeks after injection of T undecanoate). The influence of T on AAs was analyzed by spectrophotometry on plasma samples. Levels of 9 out of 23 AAs, of which 7 were essential AAs, were significantly increased at low T and are restored upon T supplementation. Levels of tyrosine and phenylalanine were most strongly associated to T changes. Short-term effect of T changes suggests an increased protein breakdown that is restored upon T supplementation. Fasting AA levels are able to monitor the early metabolic changes induced by the T fluctuations.

Chloroquine analogs as antimalarial candidates with potent in vitro and in vivo activity.

In spite of recent efforts to eradicate malaria in the world, this parasitic disease is still considered a major public health problem, with a total of 216 million cases of malaria and 445,000 deaths in 2016. Artemisinin-based combination therapies remain effective in most parts of the world, but recent cases of resistance in Southeast Asia have urged for novel approaches to treat malaria caused by Plasmodium falciparum. In this work, we present chloroquine analogs that exhibited high activity against sensitive and chloroquine-resistant P. falciparum blood parasites and were also active against P. berghei infected mice. Among the compounds tested, DAQ, a chloroquine analog with a more linear side chain, was shown to be the most active in vitro and in vivo, with low cytotoxicity, and therefore may serve as the basis for the development of more effective chloroquine analogs to aid malaria eradication.

Perfil sociodemográfico e de adoecimento de idosos residentes em Instituição de Longa Permanência: estudo observacional / Sociodemographic profile and advice of elderly residents in a Long-Stay Institution: observational study / Perfil sociodemográfico y de enfermería de ancianos residentes en Institución de Larga Permanencia: estudio observacional

Foi objetivo identificar o perfil sociodemográfico e o de adoecimento de idosos residentes em uma Instituição de Longa Permanência. Estudo epidemiológico, descritivo e transversal. A maioria dos idosos era do gênero feminino, possuía baixo índice de escolaridade e renda familiar de um salário mínimo. Considerando-se o gênero, houve prevalência de doença renal crônica e osteoporose entre mulheres e hipertensão arterial sistêmica e acidente vascular cerebral entre os homens.

The objective was to identify the sociodemographic and illness profile of elderly residents in a long - term institution. Epidemiological, descriptive and crosssectional study. The majority of the elderly were of the female gender, had a low level of education and family income of a minimum wage. Considering the gender, there was prevalence of chronic kidney disease and osteoporosis among women and systemic arterial hypertension and stroke among men.

Fue objetivo identificar el perfil sociodemográfico y de enfermo de ancianos residentes en una Institución de Larga Permanencia. Estudio epidemiológico, descriptivo y transversal. La mayoría de los ancianos era del género femenino, poseía bajo índice de escolaridad y renta familiar de un salario mínimo. En vista del género, hubo prevalencia de enfermedad renal crónica y osteoporosis entre mujeres e hipertensión arterial sistémica y accidente cerebrovascular entre los hombres.

Efeitos deletérios da ventilação mecânica invasiva em prematuros: revisão sistemática / Deleterial effects of invasive mechanical ventilation in prematures: sistematic review

Introdução: O recém-nascido é considerado pré-termo pela Organização Mundial da Saúde (OMS) quando nascido com menos de 37 semanas de gestação. A prematuridade acarreta consigo diversos problemas devido a imaturidade biológica, dentre as complicações mais graves relacionadas à prematuridade está o subdesenvolvimento do sistema respiratório. Objetivos: reexaminar a literatura dos últimos 5 anos sobre os efeitos deletérios da VM em prematuros. Materiais e métodos: Foi realizada uma revisão sistemática de estudos em bases de dados Medical Literature Analysis and Retrieval System Online (PubMed/Medline) e Literatura Latino- Americana e do Caribe em Ciências da Saúde (LILACS ) e SciELO. Foram excluídos os artigos de revisão narrativa e os demais artigos que não correspondessem aos critérios de inclusão: Artigos que abordassem em seu desfecho primário ou secundário os efeitos deletérios da ventilação mecânica em prematuros, nos idiomas inglês, português ou espanhol. Resultados: Foram selecionados 20 artigos, 12 de intervenção, 3 observacionais, 3 revisões sistemáticas e 2 meta-análise, que obtiveram pontuação entre 8 e 25 segundo critérios utilizados por Vieira e colaboradores e pontuação máxima na versão adaptada do instrumento AMSTAR, respectivamente, em sua qualificação metodológica. Foram encontrados 15 tipos de efeitos deletérios associados ao uso de ventilação mecânica invasiva. Conclusão: Demonstrou a ocorrência de 15 tipos diferentes de efeitos deletérios associados ao uso de ventilação mecânica em prematuros e dentre estes o efeito com maior incidência é a broncodisplasia pulmonar seguido pela lesão pulmonar induzida pela ventilação mecânica. [AU]

Introduction: The newborn is considered preterm by the World Health Organization (WHO) when born with less than 37 weeks of gestation. Prematurity brings with it several problems due to biological immaturity, among the most serious complications related to prematurity is the underdevelopment of the respiratory system. Objectives: This study aims to review the literature of the last 5 years on the deleterious effects of MV in preterm infants. Materials and methods: A systematic review of the Medical Literature Analysis and Retrieval System Online (PubMed / Medline) and Latin American and Caribbean Literature in Health Sciences (Lilacs) and Scielo databases was carried out. Narrative review articles and other articles that did not correspond to the inclusion criteria were excluded: Articles that addressed the deleterious effects of mechanical ventilation in premature infants in the English, Portuguese or Spanish languages in their primary or secondary outcome. Results: Twenty articles, 12 intervention, 3 observational, 3 systematic reviews and 2 meta-analysis were selected, which scored between 8 and 25 according to criteria used by Vieira and collaborators and maximum score in the adapted version of the AMSTAR instrument, respectively. methodological qualification. We found 15 types of deleterious effects associated with the use of invasive mechanical ventilation. Conclusion: It demonstrated the occurrence of 15 different types of deleterious effects associated with the use of mechanical ventilation in premature infants and among these the effect with a higher incidence is pulmonary bronchodysplasia followed by mechanical ventilation-induced lung injury. [AU]

Synthesis and evaluation of the antibiotic and adjuvant antibiotic potential of organotin(IV) derivatives.

A series of organotin(IV) derivatives was investigated in vitro for their antibiotic and adjuvant antibiotic properties (efflux pump inhibitors) against Staphylococcus aureus strains that overexpress efflux pump proteins for norfloxacin (SA-1199B), erythromycin (RN-4220) and tetracycline (IS-58). Most organotin(IV) compounds showed significant antibacterial activity with small Minimum Inhibitory Concentration (MIC) values, some of which were close to 1.0µg/mL (3.1µM), but this feature was also associated with substantial cytotoxicity. Nevertheless, the cytotoxicity of these organotin(IV) compounds can be overcome when they are used as antibiotic adjuvants. Their remarkable adjuvant antibiotic properties allow potentiation of the action of tetracycline (against IS-58 strain) by up to 128-fold. This likely indicates that they can act as putative inhibitors of bacterial efflux pumps. These results reinforce organotin(IV) complexes as promising antibacterial agents, and many of these complexes, if associated with antibiotics, can act as potential adjuvant antibiotic candidates.

Emprego de metodologias ativas na área da saúde nos últimos cinco anos: revisão integrativa / Use of active methodologies in the health area in the last five years: an inetegrative review

Este estudo teve por objetivo conhecer a produção científica brasileira sobre metodologias ativas utilizadas na área da saúde nos últimos cinco anos. Trata-se de uma revisão integrativa da literatura. As bases de dados utilizadas foram a BVS e SCIELO. Foi utilizada a seguinte estratégia de busca: metodologias ativas AND ensino AND Brasil. Os critérios de inclusão foram: texto completo disponível, idioma português, com publicação entre 2014 a 2018. Totalizaram nove artigos para amostra. Destes, cinco são da enfermagem e quatro da odontologia. Percebe-se que a temática ainda não atingiu a dimensão de destaque a qual deveria tomar, preparando não apenas o estudante para esta nova forma de ensino-aprendizagem, mas também o professor, para que este, apesar de não assumir mais o papel central dos processos educativos, ainda mantenha o interesse pela sala de aula, sem medos, preconceitos e tabus sobre as novas formas de ensinar.