Senescence-Independent Anti-Inflammatory Activity of the Senolytic Drugs Dasatinib,Navitoclax, and Venetoclax in Zebrafish Models of Chronic Inflammation

Telomere shortening is the main molecular mechanism of aging, but not the only one. The adaptive immune system also ages, and older organisms tend to develop a chronic pro-inflammatory status with low-grade inflammation characterized by chronic activation of the innate immune system, called inflammaging. One of the main stimuli that fuels inflammaging is a high nutrient intake, triggering a metabolic inflammation process called metainflammation. In this study, we report the anti-inflammatory activity of several senolytic drugs in the context of chronic inflammation, by using two different zebrafish models: (i) a chronic skin inflammation model with a hypomorphic mutation in spint1a, the gene encoding the serine protease inhibitor, kunitz-type, 1a (also known as hai1a) and (ii) a non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) model with inflammation induced by a high-fat diet. Our results show that, although these models do not manifest premature aging, the senolytic drugs dasatinib, navitoclax, and venetoclax have an anti-inflammatory effect that results in the amelioration of chronic inflammation.     

Correlation of Immunological and Histopathological Features with Gene Expression-Based Classifiers in Colon Cancer Patients

The purpose of this study was to evaluate the association between four distinct histopathological features: (1) tumor infiltrating lymphocytes, (2) mucinous differentiation, (3) tumor-stroma ratio, plus (4) tumor budding and two gene expression-based classifiers—(1) consensus molecular subtypes (CMS) plus (2) colorectal cancer intrinsic subtypes (CRIS). All four histopathological features were retrospectively scored on hematoxylin and eosin sections of the most invasive part of the primary tumor in 218 stage II and III colon cancer patients from two independent cohorts (AMC-AJCC-90 and AC-ICAM). RNA-based CMS and CRIS assignments were independently obtained for all patients. Contingency tables were constructed and a χ2 test was used to test for statistical significance. Odds ratios with 95% confidence intervals were calculated. The presence of tumor infiltrating lymphocytes and a mucinous phenotype (>50% mucinous surface area) were strongly correlated with CMS1 (p < 0.001 and p = 0.008) and CRIS-A (p = 0.006 and p < 0.001). The presence of mucus (≥ 10%) was associated with CMS3: mucus was present in 64.1% of all CMS3 tumors (p < 0.001). Although a clear association between tumor-stroma ratio and CMS4 was established in this study (p = 0.006), still 32 out of 61 (52.5%) CMS4 tumors were scored as stroma-low, indicating that CMS4 tumors cannot be identified solely based on stromal content. Higher budding counts were seen in CMS4 and CRIS-B tumors (p = 0.045 and p = 0.046). No other associations of the measured parameters were seen for any of the other CRIS subtypes. Our analysis revealed clear associations between histopathologic features and CMS or CRIS subtypes. However, identification of distinct molecular subtypes solely based on histopathology proved to be infeasible. Combining both molecular and morphologic features could potentially improve patient stratification.     

DeepHP: A New Gastric Mucosa Histopathology Dataset for Helicobacter pylori Infection Diagnosis

Emerging deep learning-based applications in precision medicine include computational histopathological analysis. However, there is a lack of the required training image datasets to generate classification and detection models. This phenomenon occurs mainly due to human factors that make it difficult to obtain well-annotated data. The present study provides a curated public collection of histopathological images (DeepHP) and a convolutional neural network model for diagnosing gastritis. Images from gastric biopsy histopathological exams were used to investigate the performance of the proposed model in detecting gastric mucosa with Helicobacter pylori infection. The DeepHP database comprises 394,926 histopathological images, of which 111 K were labeled as Helicobacter pylori positive and 283 K were Helicobacter pylori negative. We investigated the classification performance of three Convolutional Neural Network architectures. The models were tested and validated with two distinct image sets of 15% (59K patches) chosen randomly. The VGG16 architecture showed the best results with an Area Under the Curve of 0.998%. The results showed that CNN could be used to classify histopathological images from gastric mucosa with marked precision. Our model evidenced high potential and application in the computational pathology field.     

Hyperthermia Enhances Doxorubicin Therapeutic Efficacy against A375 and MNT-1 Melanoma Cells

Melanoma is the deadliest form of skin cancer, and its incidence has alarmingly increased in the last few decades, creating a need for novel treatment approaches. Thus, we evaluated the combinatorial effect of doxorubicin (DOX) and hyperthermia on A375 and MNT-1 human melanoma cell lines. Cells were treated with DOX for 24, 48, and 72 h and their viabilities were assessed. The effect of DOX IC10 and IC20 (combined at 43 °C for 30, 60, and 120 min) on cell viability was further analyzed. Interference on cell cycle dynamics, reactive oxygen species (ROS) production, and apoptosis upon treatment (with 30 min at 43 °C and DOX at the IC20 for 48 h) were analyzed by flow cytometry. Combined treatment significantly decreased cell viability, but not in all tested conditions, suggesting that the effect depends on the drug concentration and heat treatment duration. Combined treatment also mediated a G2/M phase arrest in both cell lines, as well as increasing ROS levels. Additionally, it induced early apoptosis in MNT-1 cells, while in A375 cells this effect was similar to the one caused by hyperthermia alone. These findings demonstrate that hyperthermia enhances DOX effect through cell cycle arrest, oxidative stress, and apoptotic cell death.     

Ficolin-2 Plasma Level Assesses Liver Fibrosis in Non-Alcoholic Fatty Liver Disease

Fibrosis is the strongest predictor for disease-specific mortality in non-alcoholic fatty liver diseases (NAFLD), but the need for liver biopsy limits its diagnosis. We assessed the performance of plasma ficolin-2 (FCN-2) as a biomarker of fibrosis identified by an in silico discovery strategy. Two hundred and thirty-five morbidly obese (MO) subjects with biopsy-proven NAFLD stratified by fibrosis stage (F0, n = 44; F1, n = 134; F2, n = 46; F3/F4, n = 11) and 40 cirrhotic patients were enrolled. The cohort was subdivided into discovery (n = 76) and validation groups (n = 159). The plasma level of FCN-2 and other candidate markers was determined. FCN-2 was inversely correlated with the stage of liver fibrosis (ρ = −0.49, p < 0.001) independently of steatosis (p = 0.90), inflammation (p = 0.57), and ballooning (p = 0.59). In the global cohort, FCN-2 level decreased significantly in a stepwise fashion from F0/F1 (median 4753 ng/mL) to F2–F3–F4 (2760 ng/mL) and in cirrhotic subjects (1418 ng/mL). The diagnostic performance of FCN-2 in detecting F ≥ 2 was higher than other indexes (APRI, FIB-4) (AUROC 0.82, 0.68, and 0.6, respectively). The accuracy improved when combined with APRI score and HDL values (FCNscore, AUROC 0.85). Overall, the FCN-2 plasma level can accurately discriminate liver fibrosis status (minimal vs. moderate/advanced) significantly improving the fibrosis diagnostic algorithms.     

An XRD study of the effect of the SiO2/Na2O ratio on the alkali activation of fly ash

Soluble silica has a very significant effect on the microstructural and mechanical development of the cementitious materials produced as a result of the alkali activation of fly ash. In this study, four different alkaline solutions with different soluble silica contents were used to activate fly ash. The primary reaction product was a sodium aluminosilicate gel, while different types of zeolites appeared as minority phases. The percentage and composition of these reaction products were found to depend on both the soluble silica content present in the activating solutions and the thermal curing time. In addition, the amount of gel was observed to have a decisive effect on the mechanical strength developing in the material.     

Evaluating the effectiveness of photocatalysts based on titanium dioxide in the degradation of the dye Ponceau 4R

The performance of different titanium dioxide (TiO₂) catalysts and a composite based on the association between TiO₂ P25 and Zinc Phthalocyanine (TiO₂/ZnPc 1.6%) was evaluated in the photocatalytic degradation of the dye Ponceau 4R (C.I. 16255). The results show that the composite presents a better performance than the other, reaching about 50% mineralization of the dye in 120 min of reaction, around three times higher than that observed under the action of pure TiO₂ P25, although this catalyst presents a quantum yield of hydroxyl radical generation about three times higher than that estimated for the composite. This result seems to be a consequence of the synergism between the electronically excited ZnPc aggregates and the TiO₂ surface.A parallel study, based on methods from quantum mechanics also suggested the most feasible routes for the photodegradation of the dye in the absence of the catalyst.     

Electrochemical sensor for measuring magnesium content in molten aluminium

Design, construction, and tests of magnesium electrochemical sensors using molten salt electrolytes and pure magnesium metal reference are described. Alumina as well as magnesia membrane thimbles were synthesized to use as the supporting matrixes for the liquid electrolytes. Binary as well as ternary salt mixtures containing M9Cl₂ were impregnated in thimbles of various pore sizes. The accuracy, response time, and service life of the sensors were evaluated. The magnesium contents from the electromotive force (e.m.f.) measurements were comparable with those from the atomic absorption analysis. All sensors responded instantly to the changes of magnesium concentration in aluminium melt. The service life was between 2 to 6 h and the minimum initial equilibration time was 2 min, depending mainly on the pore size of the magnesia thimble and the electrolyte salt mixture in use.     

Co/SiO2 catalysts prepared from Co2(CO)8 for CO hydrogenation into alcohols and hydrocarbons: characterization by magnetic methods and temperature-programmed hydrogenation

The hydrogenation of carbon monoxide over Co/SiO₂ catalysts obtained by reduction of precursors prepared by the reaction of dicobaltoctacarbonyl with silica gives rise to a mixture of alcohols and hydrocarbons. The chain growth probability for hydrocarbon synthesis is similar to that observed over conventional catalysts prepared by the ammonia method (=0.74) with a comparable metal dispersion (metal particle size 4 nm). Alcohol formation yields a smaller chain growth probability (=0.42). Magnetic measurements have shown that in the latter catalyst, small cobalt clusters (1 nm) are likely to be present together with the cobalt particles (4 nm), this observation reconciles apparently conflicting results from the literature. It has been speculated that alcohol formation might be related to the presence of these clusters according to a concerted mechanism. Furthermore, the observation of large amounts of acetates by temperature-programmed hydrogenation, not detected in hydrocarbon selective catalysts, suggests that they may play a role in ethanol synthesis.     

Crystal structures and melting points of unsaturated triacylglycerols in theβ phase

Theβ-phase crystal structures of unsaturated triacyl-glycerols (TAGs) have been analyzed. Long spacings and melting points of monounsaturated TAGs such as16· O· 16 and16· O ·18 indicate aβ-3C packing mode with a methyl terrace that differs from that of the saturatedβ- 3 TAGs. In addition to the hydrocarbon chain subcell packing and the methyl terrace structure, the conformation of the oleoyl chain also has to be considered. This conformation is analyzed in connection with the symmetry relation between the two half-layers on either side of the plane through the double bonds. Geometric analysis shows four possibilities, which have been explored further by means of energy minimization computations. In these calculations the structure of the oleoyl chain, in its crystalline environment, has been optimized while taking all relevant intramolecular and intermolecular forces into account. Though the calculations reveal relatively small energy differences between the four possibilities, the most likely structure can still be identified. On the basis of the results obtained for the monounsaturated TAGs, proposals for the crystal structures of diunsaturated (e.g., O · 18 · O) and triunsaturatede.g., O· O · O TAGs are briefly outlined.