Selpercatinib: First approved selective RET inhibitor.

Selpercatinib is a small molecule that binds at the RET kinase active site. It inhibits activity of constitutively dimerized RET fusion proteins and activated point mutants, thereby blocking downstream signals for proliferation and survival. It is the first selective RET inhibitor to be FDA approved for tumor agnostic targeting of oncogenic RET fusion proteins. To view this Bench to Bedside, open or download the PDF.

Long-term stability in the circumpolar foraging range of a Southern Ocean predator between the eras of whaling and rapid climate change.

Assessing environmental changes in Southern Ocean ecosystems is difficult due to its remoteness and data sparsity. Monitoring marine predators that respond rapidly to environmental variation may enable us to track anthropogenic effects on ecosystems. Yet, many long-term datasets of marine predators are incomplete because they are spatially constrained and/or track ecosystems already modified by industrial fishing and whaling in the latter half of the 20th century. Here, we assess the contemporary offshore distribution of a wide-ranging marine predator, the southern right whale (SRW, Eubalaena australis), that forages on copepods and krill from ~30°S to the Antarctic ice edge (>60°S). We analyzed carbon and nitrogen isotope values of 1,002 skin samples from six genetically distinct SRW populations using a customized assignment approach that accounts for temporal and spatial variation in the Southern Ocean phytoplankton isoscape. Over the past three decades, SRWs increased their use of mid-latitude foraging grounds in the south Atlantic and southwest (SW) Indian oceans in the late austral summer and autumn and slightly increased their use of high-latitude (>60°S) foraging grounds in the SW Pacific, coincident with observed changes in prey distribution and abundance on a circumpolar scale. Comparing foraging assignments with whaling records since the 18th century showed remarkable stability in use of mid-latitude foraging areas. We attribute this consistency across four centuries to the physical stability of ocean fronts and resulting productivity in mid-latitude ecosystems of the Southern Ocean compared with polar regions that may be more influenced by recent climate change.

Immunomodulatory Effects of Anadenanthera colubrina Bark Extract in Experimental Autoimmune Encephalomyelitis.

This study aimed to evaluate the efficacy of the ethanolic extract of Anadenanthera colubrina in modulating the immune response in the Experimental Autoimmune Encephalomyelitis (EAE) model. The ethanolic extract of the dried bark was analyzed by ESI (+) Orbitrap-MS to obtain a metabolite profile, demonstrating a wide variety of polyphenols, such as flavonoids and phenolic acids. Various parameters were evaluated, such as clinical signs, cytokines, cellular profile, and histopathology in the central nervous system (CNS). The ethanolic extract of A. colubrina demonstrated significant positive effects attenuating the clinical signs and pathological processes associated with EAE. The beneficial effects of the extract treatment were evidenced by reduced levels of pro-inflammatory cytokines, such as IL1ß, IL-6, IL-12, TNF, IFN-γ, and a notable decrease in several cell profiles, including CD8+, CD4+, CD4+IFN-γ, CD4+IL-17+, CD11c+MHC-II+, CD11+CD80+, and CD11+CD86+ in the CNS. In addition, histological analysis revealed fewer inflammatory infiltrates and demyelination sites in the spinal cord of mice treated with the extract compared to the control model group. These results showed, for the first time, that the ethanolic extract of A. colubrina exerts a modulatory effect on inflammatory processes, improving clinical signs in EAE, in the acute phase of the disease, which could be further explored as a possible therapeutic alternative.

Effects of docetaxel on metastatic prostate (DU-145) carcinoma cells cultured as 2D monolayers and 3D multicellular tumor spheroids.

Docetaxel (DTX) is one of the chemotherapeutic drugs indicated as a first-line treatment against metastatic prostate cancer (mPCa). This study aimed to compare the impact of DTX on mPCa (DU-145) tumor cells cultured as 2D monolayers and 3D multicellular tumor spheroids (MCTS) in vitro. The cells were treated with DTX (1-96 µM) at 24, 48, or 72 hr in cell viability assays (resazurin, phosphatase acid, and lactate dehydrogenase). Cell death was assessed with fluorescent markers and proliferation by clonogenic assay (2D) and morphology, volume, and integrity assay (3D). The cell invasion was determined using transwell (2D) and extracellular matrix (ECM) (3D). Results showed that DTX decreased cell viability in both culture models. In 2D, the IC50 (72 hr) values were 11.06 µM and 14.23 µM for resazurin and phosphatase assays, respectively. In MCTS, the IC50 values for the same assays were 114.9 µM and 163.7 µM, approximately 10-fold higher than in the 2D model. The % of viable cells decreased, while the apoptotic cell number was elevated compared to the control in 2D. In 3D spheroids, only DTX 24 µM induced apoptosis. DTX (≥24 µM at 216 hr) lowered the volume, and DTX 96 µM completely disintegrated the MCTS. DTX reduced the invasion of mPCa cells to matrigel (2D) and migration from MCTS to the ECM. Data demonstrated significant differences in drug response between 2D and 3D cell culture models using mPCa DU-145 tumor cells. MCTS resembles the early stages of solid tumors in vivo and needs to be considered in conjunction with 2D cultures when searching for new therapeutic targets.

Population Pharmacokinetic of the Diterpenes ent-Polyalthic Acid and Dihydro-ent-Agathic Acid from Copaifera Duckei Oil Resin in Rats.

Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.

Accuracy of acute hyperglycemia as a biomarker of severe brain damage in children with traumatic brain injury.

PURPOSE: Biomarkers are substances measured at the systemic level to evaluate organic responses in certain situations, establishing diagnoses, disease staging, and prognosis. Blood glucose is a biomarker recognized as a predictor of prognosis in children victims of traumatic brain injury (TBI). The scope of this study was to identify the accuracy of blood glucose as a biomarker of severe brain injury. METHODS: A retrospective analytical study was conducted through the consecutive review of medical records of children and teenage victims of TBI who underwent neurological surgery between 2016 and 2023 in a level 1 trauma center. Two groups were compared: children with Glasgow Coma Scale (GCS) score ≤ 8 and children with GCS > 8. We calculated the predictive values to define the accuracy of blood glucose as a biomarker of brain injury. RESULTS: Ninety-two medical records were included for analysis. Hyperglycemia predominated in cases with GCS ≤ 8 (48% vs 3%; p < 0.0001; OR, 30; 95% CI, 5.9902-150.2448). The glycemic measurement considering the cutoff point of 200 mg/dL or 11.1 mmol/L showed a specificity of 97%, a positive predictive value of 86%, an accuracy of 84%, and a likelihood ratio for a positive test of 16. CONCLUSION: Victims with GCS ≤ 8 are 16 times more likely to develop acute hyperglycemia after TBI when compared to those with GCS > 8. Blood glucose is a biomarker with an accuracy of 84% to predict severe brain injury, considering the cutoff point of 200 mg/dL or 11.1 mmol/L.

In Situ Preparation of Dehydrodieugenol-Loaded Silver Nanoparticles and their Antischistosomal Activity.

Schistosomiasis is a major neglected disease that imposes a substantial worldwide health burden, affecting approximately 250 million people globally. As praziquantel is the only available drug to treat schistosomiasis, there is a critical need to identify new anthelmintic compounds, particularly from natural sources. To enhance the activity of different natural products, one potential avenue involves its combination with silver nanoparticles (AgNP). Based on this approach, a one-step green method for the in situ preparation of dehydrodieugenol (DHDG) by oxidation coupling reaction using silver and natural eugenol is presented. AgNP formation was confirmed by UV-Vis spectroscopy due to the appearance of the surface plasmon resonance (SPR) band at 430 nm which is characteristic of silver nanoparticles. The nanoparticles were spherical with sizes in the range of 40 to 50 nm. Bioassays demonstrated that the silver nanoparticles loaded with DHDG exhibited significant anthelmintic activity against Schistosoma mansoni adult worms without toxicity to mammalian cells and an in vivo animal model (Caenorhabditis elegans), contributing to the development of new prototypes based on natural products for the treatment of schistosomiasis.

In Vitro and In Silico Evaluation of the Leishmanicidal and Trypanocidal Activities of Lignan Methylpiperitol Isolated from Persea Fulva.

Neglected Tropical Diseases are a significant concern as they encompass various infections caused by pathogens prevalent in tropical regions. The limited and often highly toxic treatment options for these diseases necessitate the exploration of new therapeutic candidates. In the present study, the lignan methylpiperitol was isolated after several chromatographic steps from Persea fulva L. E. Koop (Lauraceae) and its leishmanicidal and trypanocidal activities were evaluated using in vitro and in silico approaches. The chemical structure of methylpiperitol was defined by NMR and MS spectral data analysis. The antiprotozoal activity of methylpiperitol was determined in vitro and indicated potency against trypomastigote forms of Trypanosoma cruzi (EC50 of 4.5±1.1 mM) and amastigote forms of Leishmania infantum (EC50 of 4.1±0.5 mM), with no mammalian cytotoxicity against NCTC cells (CC50>200 mM). Molecular docking studies were conducted using six T. cruzi and four Leishmania. The results indicate that for the molecular target hypoxanthine phosphoribosyl transferase in T. cruzi and piteridine reductase 1 of L. infatum, the methylpiperitol obtained better results than the crystallographic ligand. Therefore, the lignan methylpiperitol, isolated from P. fulva holds potential for the development of new prototypes for the treatment of Neglected Tropical Diseases, especially leishmaniasis.

Transcutaneous Electric Nerve Stimulation in Animal Model Studies: From Neural Mechanisms to Biological Effects for Analgesia.

OBJECTIVE: This systematic and meta-analysis review evaluated the transcutaneous electrical nerve stimulation (TENS)-induced action mechanisms for animal analgesia. MATERIALS AND METHODS: Two independent investigators identified relevant articles published until February 2021 through a literature review, and a random-effects meta-analysis was performed to synthesize the results. RESULTS: Of the 6984 studies found in the data base search, 53 full-text articles were selected and used in the systematic review. Most studies used Sprague Dawley rats (66.03%). High-frequency TENS was applied to at least one group in 47 studies, and most applications were performed for 20 minutes (64.15%). Mechanical hyperalgesia was analyzed as the primary outcome in 52.83% of the studies and thermal hyperalgesia in 23.07% of studies using a heated surface. More than 50% of the studies showed a low risk of bias on allocation concealment, random housing, selective outcome reporting, and acclimatization before the behavioral tests. Blinding was not performed in only one study and random outcome assessment in another study; acclimatization before the behavioral tests was not performed in just one study. Many studies had an uncertain risk of bias. Meta-analyses indicated no difference between low-frequency and high-frequency TENS with variations among the pain models. CONCLUSIONS: This systematic review and meta-analysis suggests that TENS has presented a substantial scientific foundation for its hypoalgesic effect in preclinical studies for analgesia.

Searching for bacteria able to metabolize polycyclic aromatic sulfur compounds in 12-years periodically fed bioreactor.

Biodesulfurization is a promising alternative for removing sulfur molecules from the polycyclic aromatic sulfur compounds (PASC) found in petroleum. PASC consists of recalcitrant molecules that can degrade fuel quality and cause a range of health and environmental problems. Therefore, identifying bacteria capable of degrading PASC is essential for handling these recalcitrant molecules. Microorganisms in environments exposed to petroleum derivatives have evolved specific enzymatic machinery, such as the 4S pathway associated with the dszABC genes, which are directly linked to sulfur removal and utilization as nutrient sources in the biodesulfurization process. In this study, bacteria were isolated from a bioreactor containing landfarm soil that had been periodically fed with petroleum for 12 years, using a medium containing dibenzothiophene (DBT), 4.6-dimethylbenzothiophene, 4-methylbenzothiophene, or benzothiophene. This study aimed to identify microorganisms capable of degrading PASC in such environments. Among the 20 colonies isolated from an inoculum containing DBT as the sole sulfur source, only four isolates exhibited amplification of the dszA gene in the dszABC operon. The production of 2-hydroxybiphenyl (HPB) and a decrease in DBT were detected during the growth curve and resting cell assays. The isolates were identified using 16S rRNA sequencing belonging to the genera Stutzerimonas and Pseudomonas. These isolates demonstrated significant potential for biodesulfurization and/or degradation of PASC. All isolates possessed the potential to be utilized in the biotechnological processes of biodesulfurization and degradation of recalcitrant PASC molecules.

Influence of COVID-19 pandemic on molar pregnancy and postmolar gestational trophoblastic neoplasia: An observational study.

OBJECTIVE: To assess whether the incidence and aggressiveness of molar pregnancy (MP) and postmolar gestational trophoblastic neoplasia (GTN) changed during the COVID-19 pandemic. DESIGN: Observational study with two separate designs: retrospective multicentre cohort of patients with MP/postmolar GTN and a cross-sectional analysis, with application of a questionnaire. SETTING: Six Brazilian Reference Centres on gestational trophoblastic disease. POPULATION: 2662 patients with MP/postmolar GTN treated from March-December/2015-2020 were retrospectively evaluated and 528 of these patients answered a questionnaire. METHODS: Longitudinal retrospective multicentre study of patients diagnosed with MP/ postmolar GTN at presentation and a cross-sectional analysis, with application of a questionnaire, exclusive to patients treated during the period of study, to assess living and health conditions during the COVID-19 pandemic compared with previous years. MAIN OUTCOME MEASURES: The incidence of MP/postmolar GTN. RESULTS: Compared with the last 5 pre-pandemic years, MP/postmolar GTN incidence remained stable during 2020 (COVID-19 pandemic). Multivariable logistic regression, adjusted for the patient age, showed that during 2020, presentation with MP was more likely to be >10 weeks of gestation (adjusted odds ratio [aOR] 2.50, 95% confidence interval [CI] 1.90-3.29, P < 0.001), have a pre-evacuation hCG level ≥100 000 iu/l (aOR 1.77, 95% CI 1.38-2.28, P < 0.001) and time to the initiation of chemotherapy ≥7 months (aOR 1.86, 95% CI 1.01-3.43, P = 0.047) when compared with 2015-2019. CONCLUSIONS: Although the incidence of MP/postmolar GTN remained stable during the COVID-19 pandemic in Brazil, the pandemic was associated with greater gestational age at MP diagnosis and more protracted delays in initiation of chemotherapy for postmolar GTN.

Tropical grass silages with spineless cactus in diets of Holstein × Zebu heifers in the semiarid region of Brazil.

One of the factors that limit ruminant production in the semiarid region is the lack of roughage in the dry season. The management of forage plants adapted to edaphoclimatic conditions is a strategy to improve animal production. This study was conducted to examine the effects of biomass sorghum silage (BSS; Sorghum bicolor (L.) Moench) and BRS capiaçu grass silage (CGS; Pennisetum purpureum Schum) with or without spineless cactus (Opuntia spp.) in crossbred Holstein × Zebu heifers' diets on the intake, apparent digestibility of the nutrients and animal performance (e.g., final weight, daily weight gain) (experiment 1). Also, to evaluate the ruminal kinetics of dry matter (DM) and neutral detergent fiber (NDF) of roughages used in diets using two animals cannulated in the rumen (experiment 2). In experiment 1, ten heifers with an initial body weight of 200 ± 2.74 kg (mean ± standard deviation) and a mean age of 10 months were used. The animals were distributed in an experimental design in two simultaneous 5 × 5 Latin squares. Five experimental diets were used: diet 1, Volumax sorghum silage (VSS); diet 2, biomass sorghum silage (BSS); diet 3, BRS capiaçu silage (CGS); diet 4, biomass sorghum silage (60%) with spineless cactus (40%) (BSS + SC); and diet 5, BRS capiaçu grass silage (60%) with spineless cactus (40%) (CGS + SC). The diets were formulated with sorghum silage or BRS capiaçu grass silage with or without spineless cactus (roughage) and a maize- and soybean-based concentrate (75:25 roughage-to-concentrate ratio) on DM basis. The experiment lasted 105 days, divided into five periods of 21 days (17 days for the adaptation of the animals to the diets and management and 4 for data collection and samples). The diets containing CGS and CGS + SC resulted in lower dry matter intake (DMI; 5.61 kg day-1; P < 0.01), which was 19.4% lower than the diets with VSS, BSS, and BSS + SC (7.00 kg day-1). The BSS + SC and CGS + SC diets showed higher crude protein digestibility (P < 0.01) at 21.9% than the other treatments (Volumax, BSS, CGS). The different diets did not change the final weight or the daily weight gain of the heifers. The BRS 716 biomass sorghum silage and BRS capiaçu grass combined with spineless cactus increased (P < 0.05) the intake of nonfibrous carbohydrates and did not interfere (P > 0.05) with the final weight or average daily gain of the crossbred Holstein × Zebu heifers. The standardized potentially degradable fraction (Bp) of the NDF was 13.91% higher (P < 0.01) for BSS and BSS + SC (61.6%) compared to the others (53.0%). A diet based on BSS + SC is recommended for feeding crossbred heifers in the growing phase.

Immunomodulatory effect of vitamin D on the STATs and transcription factors of CD4+ T cell subsets in pregnant women with preeclampsia.

This study evaluated the in vitro modulatory effect of vitamin D (VD) on T cells, by determining the expression of STATs and the transcription factors of each CD4+ T cell subsets. Twenty women with preeclampsia (PE) and 20 normotensive pregnant women were studied. Peripheral blood mononuclear cells were cultured with or without VD to analyse the STATs and transcription factors by flow cytometry, and cytokines production by ELISA. The plasma levels of VD were lower in the PE group. Treatment of cells with VD decreased STAT1/STAT4/T-bet, STAT3/RORγt, and increased STAT6/GATA-3 and STAT5/FoxP3 in preeclamptic women. Treatment with VD also decreased the levels of inflammatory cytokines and increased IL-10 and TGF-ß. This hormone exerts immunomodulatory effects on the STAT signalling pathway, shifting the inflammatory profiles, Th1/Th17 cells to Th2/Treg profiles, and it can be suggested as a promising strategy to regulate the systemic inflammatory response in PE.

Anti-inflammatory effect, antibiotic potentiating activity against multidrug-resistant strains of Escherichia coli and Staphylococcus aureus, and evaluation of antibiotic resistance mechanisms by the ibuprofen derivative methyl 2-(-4-isobutylphenyl)propanoate.

The prevalence of multidrug-resistant (MDR) bacteria and the limited efficacy of current available antibiotics cause every year approximately 700 000 deaths per year. This study aimed to evaluate the anti-inflammatory effect and antibacterial potential of the ibuprofen derivative Methyl 2-(-4-isobutylphenyl)propanoate (MET-IBU). The molecular structure of MET-IBU was confirmed by Nuclear Magnetic Resonance (NMR) and, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) spectroscopy. Our in vivo study using adult zebrafish model demonstrated that the ibuprofen derivative MET-IBU also possesses anti-inflammatory effect, and in vitro antibacterial activity assays showed that in the association of ampicillin, norfloxacin, and gentamicin with MET-IBU occurred reduction in the minimum inhibitory concentration (MIC) for MDR bacterial strains of Escherichia coli 06 and Staphylococcus aureus 10, indicating a potentiating in the growth inhibition of these pathogenic bacteria. Regarding the strain of Staphylococcus aureus K2068 (overexpressing mepA gene), a potentiation of ethidium bromide was found in the association with MET-IBU, indicating the action of this compound on the efflux pump mechanism present in this strains. This result corroborates the molecular docking study that indicated a high affinity of the MET-IBU with the MepA efflux pump. It was also noticed an antibiotic potentiating activity in the association MET-IBU with norfloxacin against strains of Staphylococcus aureus 1199B (overexpressing norA gene) when compared to the norfloxacin control. This enhanced antibiotic effect of MET-IBU is associated with a second resistance mechanism, which is due to the modification in the topoisomerase enzyme. These results bring attention to the ibuprofen derivative MET-IBU as possible candidate for the development of new options for the treatment of bacterial infections with protective anti-inflammatory action.

Phylogenomic Discordance in the Eared Seals is best explained by Incomplete Lineage Sorting following Explosive Radiation in the Southern Hemisphere.

The phylogeny and systematics of fur seals and sea lions (Otariidae) have long been studied with diverse data types, including an increasing amount of molecular data. However, only a few phylogenetic relationships have reached acceptance because of strong gene-tree species tree discordance. Divergence times estimates in the group also vary largely between studies. These uncertainties impeded the understanding of the biogeographical history of the group, such as when and how trans-equatorial dispersal and subsequent speciation events occurred. Here, we used high-coverage genome-wide sequencing for 14 of the 15 species of Otariidae to elucidate the phylogeny of the family and its bearing on the taxonomy and biogeographical history. Despite extreme topological discordance among gene trees, we found a fully supported species tree that agrees with the few well-accepted relationships and establishes monophyly of the genus Arctocephalus. Our data support a relatively recent trans-hemispheric dispersal at the base of a southern clade, which rapidly diversified into six major lineages between 3 and 2.5 Ma. Otaria diverged first, followed by Phocarctos and then four major lineages within Arctocephalus. However, we found Zalophus to be nonmonophyletic, with California (Zalophus californianus) and Steller sea lions (Eumetopias jubatus) grouping closer than the Galapagos sea lion (Zalophus wollebaeki) with evidence for introgression between the two genera. Overall, the high degree of genealogical discordance was best explained by incomplete lineage sorting resulting from quasi-simultaneous speciation within the southern clade with introgresssion playing a subordinate role in explaining the incongruence among and within prior phylogenetic studies of the family. [Hybridization; ILS; phylogenomics; Pleistocene; Pliocene; monophyly.].

Vitamin D decreases cell death and inflammation in human umbilical vein endothelial cells and placental explants from pregnant women with preeclampsia cultured with TNF-α.

This study evaluated the impact of vitamin D on Human Umbilical Vein Endothelial Cells (HUVEC) and inflammation in placental explants from women with preeclampsia (PE). HUVEC and explants from 10 late-onset PE (LOPE), 10 early-onset (EOPE), and 10 normotensive (NT) pregnant women were cultured with/without tumor necrosis factor (TNF-α) and VD. Interleukin-1ß (IL-1ß), 18 (IL-18), TNF-α, and TNF-related apoptosis-inducing ligand (TRAIL) were detected by ELISA. High mobility group box 1 (HMGB1) was determined by qPCR/Western blotting, and cell death by flow cytometry. Statistical significance was accepted at p < .05. Compared to the NT group, the endogenous levels of IL-1ß, TNF-α, and IL-18 were higher in the PE group. The stimulus with TNF-α increased cytokines in NT, TNF-α in EOPE/LOPE, IL-18 in LOPE, and all cytokines in HUVEC. TNF-α+VD treatment decreased cytokines in explant and HUVEC supernatants. TRAIL was higher in EOPE versus NT, while TNF-α increased this receptor in NT versus control. In HUVEC, TNF-α increased TRAIL versus control, and TNF-α+VD decreased levels compared to only TNF-α stimulus. Protein expression of HMGB1 was higher in explant cultures treated with TNF-α and decreased after TNF-α+VD treatment in all groups, and gene/protein expression in HUVEC. Gene expression was elevated in EOPE versus NT and LOPE, and TNF-α increased HMGB1 in NT versus control, while TNF-α+VD decreased mRNA levels in EOPE. TNF-α stimulus increased late apoptosis in HUVEC, while VD increased viability. These in vitro observations suggest that VD administration to women with preeclampsia may be beneficial in reducing placental inflammation and cell death.

Anticancer effects of carboxymethylated (1→3)(1→6)-ß-D-glucan (botryosphaeran) on multicellular tumor spheroids of MCF-7 cells as a model of breast cancer.

Breast cancer is the most common cancer worldwide among the female population. The fungal exopolysaccharide botryosphaeran is a (1→3)(1→6)-ß-D-glucan with limited solubility in water that can be promoted through carboxymethylation. Thus, the aim of this study was to examine in-vitro anticancer effects of carboxymethylated-botryosphaeran (CM-BOT) on breast cancer MCF-7 cells cultivated in multicellular tumor spheroids (MCTS). CM-BOT (≥ 600 µ/ml) decreased the viability (resazurin assay) of MCF-7 grown in monolayers after 24 hr incubation. Although CM-BOT did not markedly alter viability of MCTS in the resazurin assay after 24, 48 or 72 hr, CM-BOT ≥ 600 µg/ml produced cell-death by apoptosis after 72 hr utilizing the triple staining assay and labeling dead cells with propidium iodide, which can also be visualized on the architecture of MCTS. CM-BOT (1000 µg/ml) inhibited cell proliferation, which resulted in MCTSs with smaller diameters than controls. CM-BOT at all concentrations examined decreased the ability of MCF-7 to form colonies and to migrate in the extracellular matrix. This is the first report using MCTS-architecture to study anti-tumor effects of ß-glucans. Our findings are important in the search for compounds for use in breast cancer therapy, or as adjuvants in reducing the adverse effects of mammary tumor chemotherapy.

Evaluation of the condylar position in younger and older adults with or without temporomandibular symptoms by using cone beam computed tomography.

STATEMENT OF PROBLEM: Recent studies in young adults have questioned the influence of discrepancies between central and maximal intercuspal positions in temporomandibular disorders (TMDs). However, whether this finding was because this type of etiologic agent requires time for the development of changes in the condylar position is unclear. PURPOSE: The purpose of this clinical study was to use cone beam computed tomography (CBCT) to evaluate the presence or absence of discrepancies between the centric relation (CR) and maximum intercuspation (MI) in younger and older adults in populations with or without TMDs. MATERIAL AND METHODS: The sample was composed of 80 volunteers, 40 younger individuals aged 18 to 25 years (27 women and 13 men), half with and half without TMD symptoms, and 40 older participants aged 35 to 50 years (30 women and 10 men), half with and half without TMD symptoms. The TMD symptoms were diagnosed by using the diagnostic (standard) criteria for TMD research (RDC/TMD). Two CBCT scans were performed on each participant, one in MI and another in CR. Measurements of the joint space were performed in coronal and sagittal cuts of the temporomandibular joints, and the collected data were statistically analyzed by using the Mann-Whitney U test (α=.05). RESULTS: No significant differences were found when the CR and MI positions and the presence or absence of TMD symptoms were compared in the younger and older groups. However, when the younger and older groups were compared, significant differences were found in all measures used in this study. CONCLUSIONS: The condyle and mandibular fossa do not seem to be influenced by the CR or MI positions or by the presence or absence of TMD symptoms, but age seems to lead to a quantitative increase in the relationship between these structures.

Solar radiation limits the use of paddocks by laying hens raised in the free-range system.

Laying hens on the free-range systems are susceptible to challenging situations in relation to the rearing environment. Therefore, this work evaluated how solar radiation influences the behavior of laying hens raised in a free-range system, in the Brazilian Savanna. The activities included data collection of meteorological variables and behavioral analysis of 300 commercial laying hens in relation to the frequency of use of indoor and outdoor areas of rearing housing. The solar radiation is the main factor that directly affects the heat gain of production animals, in this experiment had a high amplitude during all day, going from 33.42 to 756.98 W m-2. It was observed that the highest frequency of 79% and 91% use of the barn areas by the hens was at 8 am and 4 pm, respectively. The internal area of the housing was more used by hens 87% and 68% at 12 h and 14 h, respectively. Hens were not observed in the paddocks at noon and 2 pm. Hens spend more than 6 h of the day inside the housing to provide shelter from solar radiation. Which the conclusion the solar radiation influences the behavior of laying hens, at times of the day of the higher incidence of radiation, and high air and global temperatures, it was not observed the presence of hens in the external areas of the housing, especially with the use of the paddocks; at these times the hens seek shelter inside the housing to get away from the incidence of direct solar radiation.

Antitrypanosomal Lactones from Nectandra barbellata.

Twigs of Nectandra barbellata were extracted using a solution of the ionic liquid 1-butyl-3-methylimidazolium bromide (BMImBr) in H2O, assisted by microwave (MAE). After successive chromatographic steps, one sesquiterpene, costic acid, and three new related lactones, (R)-3(7)-Z-3-hexadec-21-enylidene-5-(hydroxymethyl)tetrahydrofuran-2-one (1), (R)-3(7)-Z-3-hexadecylidene-5-(hydroxymethyl)tetrahydrofuran-2-one (2), and (R)-3(7)-Z-3-docosylidene-5-(hydroxymethyl)tetrahydrofuran-2-one (3), were isolated. After structural elucidation using IR, UV, HRESIMS, NMR, ECD, and VCD, compounds 1-3 were tested against trypomastigote forms of Trypanosoma cruzi. The mechanism of action of bioactive isolated compounds was studied using different fluorescent-based approaches to investigate alterations of the plasma membrane, permeability/electric potential (ΔΨp), reactive oxygen species levels, mitochondria (electric membrane potential, ΔΨm/ATP levels), Ca2+ levels, and pH of the acidocalcisomes. In addition, in silico studies predicted no resemblance to pan assay interference compounds (PAINS).