Phase I study of anti-epidermal growth factor receptor antibody-drug conjugate serclutamab talirine: Safety, pharmacokinetics, and antitumor activity in advanced glioblastoma

BACKGROUND: Serclutamab talirine (Ser-T, formerly ABBV-321) is an antibody-drug conjugate consisting of an antibody (AM-1-ABT-806) directed against activated epidermal growth factor receptor (EGFR) and a pyrrolobenzodiazepine dimer. We investigated Ser-T monotherapy in a phase I, first-in-human, dose-escalation, and dose-expansion study in patients with advanced solid tumors associated with EGFR overexpression. METHODS: Eligible patients (≥18 years) had advanced, histologically confirmed solid tumors associated with EGFR overexpression (centralized testing). Patients received Ser-T intravenously once every 4 weeks (Q4W; 5-50 μg/kg) in the dose-escalation phase. Herein, preliminary antitumor activity at the recommended phase II dose (RP2D) is reported only for patients with glioblastoma ( RESULTS: Sixty-two patients (median age: 58 years) were enrolled within the dose-escalation ( CONCLUSIONS: Ser-T monotherapy at doses up to 50 μg/kg initial dose, followed by 25 μg/kg Q4W demonstrated a tolerable safety profile with minimal antitumor activity observed in patients with glioblastoma. The glioblastoma dose-expansion cohort was closed due to a lack of efficacy (NCT03234712)

Apple Pomace Consumption Favorably Alters Hepatic Lipid Metabolism in Young Female Sprague-Dawley Rats Fed a Western Diet

Apple pomace, which is a waste byproduct of processing, is rich in several nutrients, particularly dietary fiber, indicating potential benefits for diseases that are attributed to poor diets, such as non-alcoholic fatty liver disease (NAFLD). NAFLD affects over 25% of United States population and is increasing in children. Increasing fruit consumption can influence NAFLD. The study objective was to replace calories in standard or Western diets with apple pomace to determine the effects on genes regulating hepatic lipid metabolism and on risk of NAFLD. Female Sprague-Dawley rats were randomly assigned (n = 8 rats/group) to isocaloric diets of AIN-93G and AIN-93G/10% w/w apple pomace (AIN/AP) or isocaloric diets of Western (45% fat, 33% sucrose) and Western/10% w/w apple pomace (Western/AP) diets for eight weeks. There were no significant effects on hepatic lipid metabolism in rats fed AIN/AP. Western/AP diet containing fiber-rich apple pomace attenuated fat vacuole infiltration, elevated monounsaturated fatty acid content, and triglyceride storage in the liver due to higher circulating bile and upregulated hepatic DGAT2 gene expression induced by feeding a Western diet. The study results showed the replacement of calories in Western diet with apple pomace attenuated NAFLD risk. Therefore, apple pomace has the potential to be developed into a sustainable functional food for human consumption

Different sources of omega-3 polyunsaturated fatty acids affects apparent digestibility, tissue deposition, and tissue oxidative stability in growing female rats

Background Numerous health benefits associated with increased omega-3 polyunsaturated fatty acid (n-3 PUFA) consumption has lead to an increasing variety of available n-3 PUFA sources. However, sources differ in the type, amount, and structural form of the n-3 PUFAs. Therefore, the objective of this study was to determine the effect of different sources of ω-3 PUFAs on digestibility, tissue deposition, eicosanoid metabolism, and oxidative stability. Methods Female Sprague-Dawley rats (age 28 d) were randomly assigned (n = 10/group) to be fed a high fat 12% (wt) diet consisting of either corn oil (CO) or n-3 PUFA rich flaxseed (FO), krill (KO), menhaden (MO), salmon (SO) or tuna (TO) oil for 8 weeks. Rats were individually housed in metabolic cages to determine fatty acid digestibility. Diet and tissue fatty acid composition was analyzed by gas chromatography and lipid classes using thin layer chromatography. Eicosanoid metabolism was determined by measuring urinary metabolites of 2-series prostaglandins (PGs) and thromoboxanes (TXBs) using enzyme immunoassays. Oxidative stability was assessed by measuring thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) using colorimetric assays. Gene expression of antioxidant defense enzymes was determined by real time quantitative polymerase chain reaction (RT-qPCR). Results Rats fed KO had significantly lower DHA digestibility and brain DHA incorporation than SO and TO-fed rats. Of the n-3 PUFA sources, rats fed SO and TO had the highest n-3 PUFAs digestibility and in turn, tissue accretion. Higher tissue n-3 LC-PUFAs had no significant effect on 2-series PG and TXB metabolites. Despite higher tissue n-3 LC-PUFA deposition, there was no increase in oxidation susceptibility indicated by no significant increase in TBARS or decrease in TAC and gene expression of antioxidant defense enzymes, in SO or TO-fed rats. Conclusions On the basis that the optimal n-3 PUFA sources should provide high digestibility and efficient tissue incorporation with the least tissue lipid peroxidation, TO and SO appeared to be the most beneficial of the n-3 PUFAs sources evaluated in this study

Influence of environmental factors on tenuazonic acid production by Epicoccum sorghinum: An integrative approach of field and laboratory conditions

Sorghum is the fifth most cultivated and consumed grain in the world. However, this grain is frequently contaminated with toxins from fungi. The present study evaluated the effects of environmental factors on tenuazonic acid (TeA) production by Epicoccum sorghinum in the field and in controlled laboratory conditions. In this study, 50 sorghum grain samples were collected from summer and autumn growing seasons and analyzed for TeA contamination using LC-MS/MS. To further understand the ecophysiology of this fungus, an isolated strain of E. sorghinum from the field was investigated for its development and TeA production under controlled environmental conditions in the laboratory. In the ecophysiological investigation, the effects of water activity (0.90, 0.95, 0.99) and temperature (18, 22, 26 and 30?°C) were evaluated on the radial growth, enzymatic production and expression of TAS1, which is the gene involved in TeA production. Results showed that in the field, the summer season presented the highest TeA average level in the grains (587.8??g/kg) compared to level found in the autumn (440.5??g/kg). The ecophysiological investigation confirmed that E. sorghinum produces more actively TeA under environmental conditions simulating the summer season. Optimum growth, maximum TAS1 gene expression, and higher extracellular enzymatic production were observed at 26?°C with a water activity of 0.99. Pearson correlation analyses showed that the production of TeA highly correlates with fungal growth. The present study demonstrates that abiotic factors in a combined approach of field and laboratory conditions will assist in predicting the driving environmental factors that could affect growth of E. sorghinum and TeA production in sorghum grains

Herbicide retention by mulching in soybean, under no-tillage system

O objetivo deste trabalho foi avaliar a retenção pela palhada, das misturas imazaquin+pendimethalin e sulfentrazone+metribuzin, aplicadas em pré-emergência, no sistema de plantio direto de soja. Os experimentos foram conduzidos na sede do lAPAR em Londrina-PR, na safra 1998/99, utilizando-se palha de aveia-preta (Avena strigosa) como cobertura morta. O delineamento dos experimentos (em número de dois), foi o de blocos ao acaso com cinco repetições. Os tratamentos foram constituídos pelas doses de herbicidas: zero; 0,5 N; N; 1,5 N e 2 N, sendo N a dose normal recomendada para a cultura (no caso, 150 g/ha de imazaquin + 1200 g/ha de pendimethalin e 350 g/ha de sulfentrazone + 360 g/ha de metribuzin). Utilizou-se a cultivar de soja FT-2000. Os herbicidas foram aplicados com pulverizador de precisão propelido a CO2, munido com barra de seis bicos Teejet Flat Spray em leque, 80.02, distanciados 50 em entre sí, vazão de 200 l/ha. Vinte e quatro horas após a aplicação dos herbicidas, os experimentos receberam 48,3 mm de lâmina de água. No dia seguinte, foram amostrados palha e solo em todas as parcelas para análise cromatográfica de resíduos. ôs resultados mostraram que a lâmina de água promoveu a lixiviação de praticamente todo o imazaquin da palha para o solo, o que não ocorreu com o pendimethalin, que ficou todo retido na palha. O sulfentrazone também foi lixiviado para o solo, sendo que 50% do metribuzin aplicado foi detectado no solo após a chuva. The objective of this trial was to study the mulch retention of the herbicide mixtures imazaquin + pendimethalin and sulfentrazone + metribuzin applied in pre-emergence for soybean under no-tillage system. The experiment was settled in Londrina-PR, Brazil, with black oat (Avena strigosa) mulch. A randomized complete block design was used. The treatrnents comprised the following rates of herbicides: zero, 0.5 N, 1.0 N, 1.5 N and 2.0 N (N=normal rate of the herbicide). ln the present study, N=150 g/ha imazaquin + 1200 g/ha pendimethalin and 350 g/ha sulfentrazone + 360 g/ha metribuzin. After twenty four hours ofherbicide applications, 48.3 mm ofwater was applied in the experiments. ln the next day, samples ofsoil and straw were taken for chromatographic analysis purposes. The results showed that 100% of imazaquin and sulfentrazone leached from the straw to the soil. Approximately 50% of metribuzin and 100% of pendimethalin were retained by the oat straw.

Influence of recirculation rate on the performance of a combined anaerobic-aerobic reactor applied to the removal of carbon and nitrogen from poultry slaughterhouse wastewater

The objective of this study was to evaluate a combined anaerobic-aerobic upflow fixed-bed reactor with liquid phase recirculation for the removal of nitrogen and organic matter from poultry slaughterhouse wastewater. The reactor performance was evaluated with a hydraulic retention time (HRT) of 11 h and three different recirculation rates (R=0.5; 1 and 2). The highest nitrogen removal efficiency value was obtained with an HRT of 11 h (6.8 h in the anaerobic zone and 4.2 h in the aerobic zone) and a recirculation rate of 2. In this condition, the total nitrogen removal efficiency was 69%,  with effluent concentrations of 6 mg NH4+ L-1 and 12 mg NO3- L-1. For all tested conditions, there was good chemical oxygen demand (COD) removal, with efficiency above 95%. The effect of dilution and the favoring of mass transfer caused by the increase in the recirculation rate positively influenced reactor performance.Key words: Anaerobic degradation, nitrification, denitrification, combined reactor

Excited state dynamics and exciton diffusion in triphenylamine/dicyanovinyl push-pull small molecule for organic optoelectronics

Triphenylamine-based small push-pull molecules have recently attracted substantial research attention due to their unique optoelectronic properties. Here, we investigate the excited state de-excitation dynamics and exciton diffusion in TPA-T-DCV-Ph-F small molecule, having simple chemical structure with asymmetrical architecture and end-capped with electron-withdrawing p-fluorodicyanovinyl group. The excited state lifetime in diluted solutions (0.04 ns in toluene and 0.4 ns in chloroform) are found to be surprisingly shorter compared to the solid state (3 ns in PMMA matrix). Time-dependent density functional theory indicates that this behavior originates from non-radiative relaxation of the excited state through a conical intersection between the ground and singlet excited state potential energy surfaces. Exciton diffusion length of similar to 16 nm in solution processed films was retrieved by employing time-resolved photoluminescence volume quenching measurements with Monte Carlo simulations. As means of investigating the device performance of TPA-T-DCV-Ph-F, we manufactured solution and vacuum processed bulk heterojunction solar cells that yielded efficiencies of similar to 1.5% and similar to 3.7%, respectively. Our findings demonstrate that the short lifetime in solutions does not hinder per se long exciton diffusion length in films thereby granting applications of TPA-T-DCV-Ph-F and similar push-pull molecules in vacuum and solution processable devices

Synthesis, antitumor and antimicrobial activity of novel 1-substituted phenyl-3-[3-alkylamino(methyl)-2-thioxo-1,3,4-oxadiazol-5-yl] β-carboline derivatives

With the purpose of activity enhancement of 1-substituted phenyl-3-(2-thioxo-1,3,4-oxadiazol-5-yl) β-carbolines 1a-c, reported as potential antitumor agents in our previous study, herein we report the synthesis and antitumor activity evaluation of several novel Mannich bases 2-7(a-c), by the introduction of different alkylamino(methyl) groups in the 1,3,4-oxadiazole unity of 1a-c. The antimicrobial activities of 1a-c and of 2-7(a-c) were also evaluated. Additionally, an in silico study of the ADME properties of novel synthesized β-carboline derivatives 2-7(a-c) was performed by evaluation of their Lipinski's parameters and topological polar surface area (TPSA) and percentage of absorption (% ABS) data.Com o propósito de aumentar a atividade anticâncer demonstrada anteriormente pelas 1-fenilssubstituído-3-(2-tioxo-1,3,4-oxadiazol-5-il) β-carbolinas 1a-c, neste trabalho foram realizadas a síntese e a avaliação in vitro da atividade antitumoral de novas bases de Mannich 2-7(a-c), derivadas da introdução de diferentes grupos alquilamino(metil) na unidade 1,3,4-oxadiazol de 1a-c. Os derivados 1a-c e 2-7(a-c) foram também avaliados quanto às atividades antibacteriana e antifúngica. Adicionalmente, um estudo in silico das propriedades de ADME dos novos compostos sintetizados 2-7(a-c) foi realizado pela avaliação de seus parâmetros de Lipinski e de dados de área de superfície topológica polar (TPSA) e de porcentagem de absorção (% ABS).288298Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Ultrasonic characterization of pork meat salting

[EN] Salting process plays a key role in the preservation and quality of dry-cured meat products. Therefore, an adequate monitoring of salt content during salting is necessary to reach high quality products. Thus, the main objective of this work was to test the ability of low intensity ultrasound to monitor the salting process of pork meat. Cylindrical samples (diameter 36 mm, height 60±10 mm) of Biceps femoris were salted (brine 20% NaCl, w/w) at 2 ºC for 1, 2, 4 and 7 days. During salting and at each experimental time, three cylinders were taken in order to measure the ultrasonic velocity at 2 ºC. Afterwards, the cylinders were split in three sections (height 20 mm), measuring again the ultrasonic velocity and determining the salt and the moisture content by AOAC standards. In the whole cylinders, moisture content was reduced from 763 (g/kg sample) in fresh samples to 723 (g/kg sample) in samples salted for 7 days, while the maximum salt gain was 37.3 (g/kg sample). Although, moisture and salt contents up to 673 and 118 (g/kg sample) were reached in the sections of meat cylinders, respectively. During salting, the ultrasonic velocity increased due to salt gain and water loss. Thus, significant (p<0.05) linear relationships were found between the ultrasonic velocity and the salt (R2=0.975) and moisture (R2=0.863) contents. In addition, the change of the ultrasonic velocity with the increase of the salt content showed a good agreement with the Kinsler equation. Therefore, low intensity ultrasound emerges as a potential technique to monitor, in a non destructive way, the meat salting processes carried out in the food industry.García Pérez, JV.; Prados Pedraza, MD.; Pérez-Muelas Picón, MN.; Carcel Carrión, JA.; Benedito Fort, JJ. (2012). Ultrasonic characterization of pork meat salting. IOP: Materials Science and Engineering. 42:1-4. doi:10.1088/1757-899X/42/1/012043S144

Universae philosopiae positiones nonnullae, iuxta inconcussa, tutissimaque Divi Thomae Aquinatis Dogmata

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 2016Fecha dada en el tít.: 1788Sign. : A-F